Inhibition of FUSCA3 degradation at high temperature is dependent on ABA signaling and is regulated by the ABA/GA ratio.

PubMed

Chiu, Rex Shun; Saleh, Yazan; Gazzarrini, Sonia

2016-11-01

During seed imbibition at supra-optimal temperature, an increase in the abscisic acid (ABA)/gibberellin (GA) ratio imposes secondary dormancy to prevent germination (thermoinhibition). FUSCA3 (FUS3), a positive regulator of seed dormancy, accumulates in seeds imbibed at high temperature and increases ABA levels to inhibit germination. Recently, we showed that ABA inhibits FUS3 degradation at high temperature, and that ABA and high temperature also inhibit the ubiquitin-proteasome system, by dampening both proteasome activity and protein polyubiquitination. Here, we investigated the role of ABA signaling components and the ABA antagonizing hormone, GA, in the regulation of FUS3 levels. We show that the ABA receptor mutant, pyl1-1, is less sensitive to ABA and thermoinhibition. In this mutant background, FUS3 degradation in vitro is faster. Similarly, GA alleviates thermoinhibition and also increases FUS3 degradation. These results indicate that inhibition of FUS3 degradation at high temperature is dependent on a high ABA/GA ratio and a functional ABA signaling pathway. Thus, FUS3 constitutes an important node in ABA-GA crosstalk during germination at supra-optimal temperature.

Methylene blue protects against TDP-43 and FUS neuronal toxicity in C. elegans and D. rerio.

PubMed

Vaccaro, Alexandra; Patten, Shunmoogum A; Ciura, Sorana; Maios, Claudia; Therrien, Martine; Drapeau, Pierre; Kabashi, Edor; Parker, J Alex

2012-01-01

The DNA/RNA-binding proteins TDP-43 and FUS are found in protein aggregates in a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and related dementia, but little is known about the neurotoxic mechanisms. We have generated Caenorhabditis elegans and zebrafish animal models expressing mutant human TDP-43 (A315T or G348C) or FUS (S57Δ or R521H) that reflect certain aspects of ALS including motor neuron degeneration, axonal deficits, and progressive paralysis. To explore the potential of our humanized transgenic C. elegans and zebrafish in identifying chemical suppressors of mutant TDP-43 and FUS neuronal toxicity, we tested three compounds with potential neuroprotective properties: lithium chloride, methylene blue and riluzole. We identified methylene blue as a potent suppressor of TDP-43 and FUS toxicity in both our models. Our results indicate that methylene blue can rescue toxic phenotypes associated with mutant TDP-43 and FUS including neuronal dysfunction and oxidative stress.

Methylene Blue Protects against TDP-43 and FUS Neuronal Toxicity in C. elegans and D. rerio

PubMed Central

Vaccaro, Alexandra; Patten, Shunmoogum A.; Ciura, Sorana; Maios, Claudia; Therrien, Martine; Drapeau, Pierre; Kabashi, Edor; Parker, J. Alex

2012-01-01

The DNA/RNA-binding proteins TDP-43 and FUS are found in protein aggregates in a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and related dementia, but little is known about the neurotoxic mechanisms. We have generated Caenorhabditis elegans and zebrafish animal models expressing mutant human TDP-43 (A315T or G348C) or FUS (S57Δ or R521H) that reflect certain aspects of ALS including motor neuron degeneration, axonal deficits, and progressive paralysis. To explore the potential of our humanized transgenic C. elegans and zebrafish in identifying chemical suppressors of mutant TDP-43 and FUS neuronal toxicity, we tested three compounds with potential neuroprotective properties: lithium chloride, methylene blue and riluzole. We identified methylene blue as a potent suppressor of TDP-43 and FUS toxicity in both our models. Our results indicate that methylene blue can rescue toxic phenotypes associated with mutant TDP-43 and FUS including neuronal dysfunction and oxidative stress. PMID:22848727

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model

PubMed Central

Baghirov, Habib; Snipstad, Sofie; Sulheim, Einar; Berg, Sigrid; Hansen, Rune; Thorsen, Frits; Mørch, Yrr; Åslund, Andreas K. O.

2018-01-01

The treatment of brain diseases is hindered by the blood-brain barrier (BBB) preventing most drugs from entering the brain. Focused ultrasound (FUS) with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate) nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma. PMID:29338016

FUS immunogold labelling TEM analysis of the neuronal cytoplasmic inclusions of neuronal intermediate filament inclusion disease: a frontotemporal lobar degeneration with FUS proteinopathy

PubMed Central

Page, Tristan; Gitcho, Michael A.; Mosaheb, Sabrina; Carter, Deborah; Chakraverty, Sumi; Perry, Robert H.; Bigio, Eileen H.; Gearing, Marla; Ferrer, Isidre; Goate, Alison M.; Cairns, Nigel J.; Thorpe, Julian R.

2012-01-01

Fused in sarcoma (FUS)-immunoreactive neuronal and glial inclusions define a novel molecular pathology called FUS proteinopathy. FUS has been shown to be a component of inclusions of familial amyotrophic lateral sclerosis with FUS mutation and three FTLD entities, including neuronal intermediate filament inclusion disease (NIFID). The pathogenic role of FUS is unknown. In addition to FUS, many neuronal cytoplasmic inclusions (NCI) of NIFID contain aggregates of α-internexin and neurofilament proteins. Herein, we have: (1) shown that FUS becomes relatively insoluble in NIFID and there are no post-translational modifications; (2) shown there are no pathogenic abnormalities in the FUS gene in NIFID; (3) performed an immunoelectron microscopy analysis of the precise localizations of FUS in NIFID, as this has not previously been described. FUS localized to euchromatin, and strongly with paraspeckles, in nuclei, consistent with its RNA/DNA-binding functions. NCI of varying morphologies were observed. Most frequent were the ‘loosely aggregated cytoplasmic inclusions’ (LACI), 81% of which had moderate or high levels of FUS-immunoreactivity. Much rarer ‘compact cytoplasmic inclusions’ (CCI) and ‘Tangled twine ball inclusions’ (TTBI) were FUS-immunoreactive at their granular peripheries, or heavily FUS-positive throughout, respectively. Thus FUS may aggregate in the cytoplasm and then admix with neuronal intermediate filament accumulations. PMID:21603978

The role of the Arabidopsis FUSCA3 transcription factor during inhibition of seed germination at high temperature.

PubMed

Chiu, Rex S; Nahal, Hardeep; Provart, Nicholas J; Gazzarrini, Sonia

2012-01-27

Imbibed seeds integrate environmental and endogenous signals to break dormancy and initiate growth under optimal conditions. Seed maturation plays an important role in determining the survival of germinating seeds, for example one of the roles of dormancy is to stagger germination to prevent mass growth under suboptimal conditions. The B3-domain transcription factor FUSCA3 (FUS3) is a master regulator of seed development and an important node in hormonal interaction networks in Arabidopsis thaliana. Its function has been mainly characterized during embryonic development, where FUS3 is highly expressed to promote seed maturation and dormancy by regulating ABA/GA levels. In this study, we present evidence for a role of FUS3 in delaying seed germination at supraoptimal temperatures that would be lethal for the developing seedlings. During seed imbibition at supraoptimal temperature, the FUS3 promoter is reactivated and induces de novo synthesis of FUS3 mRNA, followed by FUS3 protein accumulation. Genetic analysis shows that FUS3 contributes to the delay of seed germination at high temperature. Unlike WT, seeds overexpressing FUS3 (ML1:FUS3-GFP) during imbibition are hypersensitive to high temperature and do not germinate, however, they can fully germinate after recovery at control temperature reaching 90% seedling survival. ML1:FUS3-GFP hypersensitivity to high temperature can be partly recovered in the presence of fluridone, an inhibitor of ABA biosynthesis, suggesting this hypersensitivity is due in part to higher ABA level in this mutant. Transcriptomic analysis shows that WT seeds imbibed at supraoptimal temperature activate seed-specific genes and ABA biosynthetic and signaling genes, while inhibiting genes that promote germination and growth, such as GA biosynthetic and signaling genes. In this study, we have uncovered a novel function for the master regulator of seed maturation, FUS3, in delaying germination at supraoptimal temperature. Physiologically, this is important since delaying germination has a protective role at high temperature. Transcriptomic analysis of seeds imbibed at supraoptimal temperature reveal that a complex program is in place, which involves not only the regulation of heat and dehydration response genes to adjust cellular functions, but also the activation of seed-specific programs and the inhibition of germination-promoting programs to delay germination. © 2011 Chiu et al; licensee BioMed Central Ltd.

The role of the Arabidopsis FUSCA3 transcription factor during inhibition of seed germination at high temperature

PubMed Central

2012-01-01

Background Imbibed seeds integrate environmental and endogenous signals to break dormancy and initiate growth under optimal conditions. Seed maturation plays an important role in determining the survival of germinating seeds, for example one of the roles of dormancy is to stagger germination to prevent mass growth under suboptimal conditions. The B3-domain transcription factor FUSCA3 (FUS3) is a master regulator of seed development and an important node in hormonal interaction networks in Arabidopsis thaliana. Its function has been mainly characterized during embryonic development, where FUS3 is highly expressed to promote seed maturation and dormancy by regulating ABA/GA levels. Results In this study, we present evidence for a role of FUS3 in delaying seed germination at supraoptimal temperatures that would be lethal for the developing seedlings. During seed imbibition at supraoptimal temperature, the FUS3 promoter is reactivated and induces de novo synthesis of FUS3 mRNA, followed by FUS3 protein accumulation. Genetic analysis shows that FUS3 contributes to the delay of seed germination at high temperature. Unlike WT, seeds overexpressing FUS3 (ML1:FUS3-GFP) during imbibition are hypersensitive to high temperature and do not germinate, however, they can fully germinate after recovery at control temperature reaching 90% seedling survival. ML1:FUS3-GFP hypersensitivity to high temperature can be partly recovered in the presence of fluridone, an inhibitor of ABA biosynthesis, suggesting this hypersensitivity is due in part to higher ABA level in this mutant. Transcriptomic analysis shows that WT seeds imbibed at supraoptimal temperature activate seed-specific genes and ABA biosynthetic and signaling genes, while inhibiting genes that promote germination and growth, such as GA biosynthetic and signaling genes. Conclusion In this study, we have uncovered a novel function for the master regulator of seed maturation, FUS3, in delaying germination at supraoptimal temperature. Physiologically, this is important since delaying germination has a protective role at high temperature. Transcriptomic analysis of seeds imbibed at supraoptimal temperature reveal that a complex program is in place, which involves not only the regulation of heat and dehydration response genes to adjust cellular functions, but also the activation of seed-specific programs and the inhibition of germination-promoting programs to delay germination. PMID:22279962

The fused in sarcoma protein forms cytoplasmic aggregates in motor neurons derived from integration-free induced pluripotent stem cells generated from a patient with familial amyotrophic lateral sclerosis carrying the FUS-P525L mutation.

PubMed

Liu, Xinxiu; Chen, Jiayu; Liu, Wenchao; Li, Xiaogang; Chen, Qi; Liu, Tao; Gao, Shaorong; Deng, Min

2015-07-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) and has no effective treatment. Mutations in the fused in sarcoma (FUS) gene and abnormal aggregation of FUS protein have been reported in ALS. However, the mechanisms involved in ALS are poorly understood. Clinical drug trails have failed due to a lack of appropriate disease models, including a lack of access to MNs from ALS patients. Induced pluripotent stem (iPS) cells derived from patients with ALS provide an indispensable resource for in vitro mechanistic studies and for future patient-specific cell-based therapies. Previous reports demonstrated that viral-based ALS-iPS cells generated from fibroblasts harvested from Caucasian populations are ideal for basic research; however, ALS-iPS cells are precluded from cell-based therapeutic applications because of the risks associated with the integration of viral sequences into the genome and inconvenience associated with dermal biopsies. To establish a model for use in clinical applications, using episomal vectors, we generated an integration-free iPS cell line from peripheral blood mononuclear cells (PBMCs) harvested from a familial ALS (FALS) patient carrying the FUS-P525L mutation and a healthy control. Furthermore, we successfully differentiated ALS patient-specific iPS cells into MNs and subsequently detected cytoplasmic mislocalization and formation of FUS protein aggregates in MNs due to the FUS-P525L mutation. Our findings offer a cell-based disease model for use in further elucidating ALS pathogenesis and provide a tool for exploring gene repair coupled with cell replacement therapy.

FUS/TLS-immunoreactive neuronal and glial cell inclusions increase with disease duration in familial amyotrophic lateral sclerosis with an R521C FUS/TLS mutation.

PubMed

Suzuki, Naoki; Kato, Shinsuke; Kato, Masako; Warita, Hitoshi; Mizuno, Hideki; Kato, Masaaki; Shimakura, Naoko; Akiyama, Haruhiko; Kobayashi, Zen; Konno, Hidehiko; Aoki, Masashi

2012-09-01

Basophilic inclusions (BIs) are pathological features of a subset of frontotemporal lobar degeneration disorders, including sporadic amyotrophic lateral sclerosis (ALS) and familial ALS (FALS). Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have recently been identified as a cause of FALS. The FUS/TLS-immunoreactive inclusions are consistently found in cases of frontotemporal lobar degeneration with BIs; however, the association between ALS cases with BIs and FUS/TLS accumulation is not well understood. We used immunohistochemistry to analyze 3 autopsy cases of FALS with the FUS/TLS mutation and with BIs using anti-FUS/TLS antibodies. The disease durations were 1, 3, and 9 years. As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions. As early as 1 year after the onset, BIs, neuronal cytoplasmic inclusions and glial cytoplasmic inclusions were found in the substantia nigra in addition to the anterior horn of the spinal cord. Glial cytoplasmic inclusions are found earlier and in a wider distribution than neuronal cytoplasmic inclusions. The distribution of FUS/TLS-immunoreactive inclusions in FUS/TLS-mutated FALS with BIs was broader than that of BIs alone, suggesting that the pathogenetic mechanism may have originated from the FUS/TLS proteinopathy.

Factors associated with successful magnetic resonance-guided focused ultrasound treatment: efficiency of acoustic energy delivery through the skull.

PubMed

Chang, Won Seok; Jung, Hyun Ho; Zadicario, Eyal; Rachmilevitch, Itay; Tlusty, Tal; Vitek, Shuki; Chang, Jin Woo

2016-02-01

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) was recently introduced as treatment for movement disorders such as essential tremor and advanced Parkinson's disease (PD). Although deep brain target lesions are successfully generated in most patients, the target area temperature fails to increase in some cases. The skull is one of the greatest barriers to ultrasonic energy transmission. The authors analyzed the skull-related factors that may have prevented an increase in target area temperatures in patients who underwent MRgFUS. The authors retrospectively reviewed data from clinical trials that involved MRgFUS for essential tremor, idiopathic PD, and obsessive-compulsive disorder. Data from 25 patients were included. The relationships between the maximal temperature during treatment and other factors, including sex, age, skull area of the sonication field, number of elements used, skull volume of the sonication field, and skull density ratio (SDR), were determined. Among the various factors, skull volume and SDR exhibited relationships with the maximum temperature. Skull volume was negatively correlated with maximal temperature (p = 0.023, r(2) = 0.206, y = 64.156 - 0.028x, whereas SDR was positively correlated with maximal temperature (p = 0.009, r(2) = 0.263, y = 49.643 + 11.832x). The other factors correlate with the maximal temperature, although some factors showed a tendency to correlate. Some skull-related factors correlated with the maximal target area temperature. Although the number of patients in the present study was relatively small, the results offer information that could guide the selection of MRgFUS candidates.

A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma Identifies Driver Functions in Addition to NF-κB.

PubMed

Ozawa, Tatsuya; Arora, Sonali; Szulzewsky, Frank; Juric-Sekhar, Gordana; Miyajima, Yoshiteru; Bolouri, Hamid; Yasui, Yoshie; Barber, Jason; Kupp, Robert; Dalton, James; Jones, Terreia S; Nakada, Mitsutoshi; Kumabe, Toshihiro; Ellison, David W; Gilbertson, Richard J; Holland, Eric C

2018-06-26

The majority of supratentorial ependymomas (ST-ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between C11orf95 and RELA (RELA FUS ). Neural stem cells transduced with RELA FUS ex vivo form ependymomas when implanted in the brain. These tumors display enhanced NF-κB signaling, suggesting that this aberrant signal is the principal mechanism of oncogenesis. However, it is not known whether RELA FUS is sufficient to drive de novo ependymoma tumorigenesis in the brain and, if so, whether these tumors also arise from neural stem cells. We show that RELA FUS drives ST-ependymoma formation from periventricular neural stem cells in mice and that RELA FUS -induced tumorigenesis is likely dependent on a series of cell signaling pathways in addition to NF-κB. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Focused ultrasound facilitated thermo-chemotherapy for targeted retinoblastoma treatment: a modeling study.

PubMed

Wang, Shutao; Mahesh, Sankaranarayana P; Liu, Ji; Geist, Craig; Zderic, Vesna

2012-07-01

Retinoblastoma is the most common type of intraocular tumors in children. Currently, with early detection and improved systemic chemo-adjuvant therapies, treatment paradigm has shifted from survival to globe salvation/vision preservation. The objective of our work has been to explore the possible application of focused ultrasound (FUS) for targeted drug delivery in the posterior pole retinoblastoma. Specifically, theoretical models were implemented to evaluate the feasibility of using FUS to generate localized hyperthermia in retinal tumor areas, for potential triggering the chemotherapeutic agent deployment from heat-sensitive drug carriers. In-vitro experiments were conducted in tissue-mimicking phantoms with embedded excised rabbit eyes to validate the reliability of the modeling results. After confirming the reliability of our model, various FUS transducer parameters were investigated to induce maximal hyperthermia coverage in the tumor, while sparing adjacent eye structures (e.g. the lens). The evaluated FUS parameters included operating frequency, total acoustic power, geometric dimensions, transducer f-number, standoff distance, as well as different pulsing scenarios. Our modeling results suggest that the most suitable ultrasound frequency for this type of treatments was in the range of 2-3.5 MHz depending on the size of retinoblastoma. Appropriate transducer f-number (close to 1) and standoff distance could be selected to minimize the risks of over-heating undesired regions. With the total acoustic power of 0.4 W, 56.3% of the tumor was heated to hyperthermic temperature range (39-44 °C) while the temperature in lens was maintained below 41 °C. In conclusion, FUS-induced hyperthermia for targeted drug delivery may be a viable option in treatments of juxta-foveal or posterior pole retinoblastomas. Future in-vivo studies will allow us to determine the effectiveness and safety of the proposed approach. Copyright © 2012 Elsevier Ltd. All rights reserved.

TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update.

PubMed

Lattante, Serena; Rouleau, Guy A; Kabashi, Edor

2013-06-01

Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau-negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS. © 2013 Wiley Periodicals, Inc.

Investigation of temporal vascular effects induced by focused ultrasound treatment with speckle-variance optical coherence tomography

PubMed Central

Tsai, Meng-Tsan; Chang, Feng-Yu; Lee, Cheng-Kuang; Gong, Cihun-Siyong Alex; Lin, Yu-Xiang; Lee, Jiann-Der; Yang, Chih-Hsun; Liu, Hao-Li

2014-01-01

Focused ultrasound (FUS) can be used to locally and temporally enhance vascular permeability, improving the efficiency of drug delivery from the blood vessels into the surrounding tissue. However, it is difficult to evaluate in real time the effect induced by FUS and to noninvasively observe the permeability enhancement. In this study, speckle-variance optical coherence tomography (SVOCT) was implemented for the investigation of temporal effects on vessels induced by FUS treatment. With OCT scanning, the dynamic change in vessels during FUS exposure can be observed and studied. Moreover, the vascular effects induced by FUS treatment with and without the presence of microbubbles were investigated and quantitatively compared. Additionally, 2D and 3D speckle-variance images were used for quantitative observation of blood leakage from vessels due to the permeability enhancement caused by FUS, which could be an indicator that can be used to determine the influence of FUS power exposure. In conclusion, SVOCT can be a useful tool for monitoring FUS treatment in real time, facilitating the dynamic observation of temporal effects and helping to determine the optimal FUS power. PMID:25071945

Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy.

PubMed

Santos, Marc A; Goertz, David E; Hynynen, Kullervo

2017-01-01

The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo . A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.

Position-specific binding of FUS to nascent RNA regulates mRNA length

PubMed Central

Masuda, Akio; Takeda, Jun-ichi; Okuno, Tatsuya; Okamoto, Takaaki; Ohkawara, Bisei; Ito, Mikako; Ishigaki, Shinsuke; Sobue, Gen

2015-01-01

More than half of all human genes produce prematurely terminated polyadenylated short mRNAs. However, the underlying mechanisms remain largely elusive. CLIP-seq (cross-linking immunoprecipitation [CLIP] combined with deep sequencing) of FUS (fused in sarcoma) in neuronal cells showed that FUS is frequently clustered around an alternative polyadenylation (APA) site of nascent RNA. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) of RNA polymerase II (RNAP II) demonstrated that FUS stalls RNAP II and prematurely terminates transcription. When an APA site is located upstream of an FUS cluster, FUS enhances polyadenylation by recruiting CPSF160 and up-regulates the alternative short transcript. In contrast, when an APA site is located downstream from an FUS cluster, polyadenylation is not activated, and the RNAP II-suppressing effect of FUS leads to down-regulation of the alternative short transcript. CAGE-seq (cap analysis of gene expression [CAGE] combined with deep sequencing) and PolyA-seq (a strand-specific and quantitative method for high-throughput sequencing of 3' ends of polyadenylated transcripts) revealed that position-specific regulation of mRNA lengths by FUS is operational in two-thirds of transcripts in neuronal cells, with enrichment in genes involved in synaptic activities. PMID:25995189

Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1.

PubMed

Lin, J; Sun, T; Ji, L; Deng, W; Roth, J; Minna, J; Arlinghaus, R

2007-10-25

In lung cancer, frequent loss of one allele of chromosome 3p is seen in both small cell lung cancer and non-small cell lung cancer (NSCLC), providing evidence of tumor suppressor genes (TSGs) in this chromosomal region. The mechanism of Fus1 tumor suppressor activity is unknown. We have found that a Fus1 peptide inhibits the Abl tyrosine kinase in vitro (IC(50) 35 microM). The inhibitory Fus1 sequence was derived from a region that was deleted in a mutant FUS1 gene (FUS1 (1-80)) detected in some lung cancer cell lines. Importantly, a stearic acid-modified form of this peptide was required for the inhibition, but stearic acid alone was not inhibitory. Two NSCLC cell lines, which lack expression of wild-type Fus1, contain activated c-Abl. Forced expression of an inducible FUS1 cDNA in H1299 NSCLC cells decreased levels of activated c-Abl and inhibited its tyrosine kinase activity. Similarly, treatment of c-Abl immune complexes with the inhibitory Fus1 peptide also reduced the level of c-Abl in these immune complexes. The size and number of colonies of the NSCLC cell line, H1,299, in soft agar was strongly inhibited by the Abl kinase inhibitor imatinib mesylate. Co-expression of FUS1 and c-ABL in COS1 cells blocked activation of c-Abl tyrosine kinase. In contrast, co-expression of mutant FUS1 (1-80) with c-ABL had little inhibitory activity against c-Abl. These findings provide strong evidence that c-Abl is a possible target in NSCLC patients that have reduced expression of Fus1 in their tumor cells.

An in vivo study of the effects on serum glucose, amylase and histopathology of the feline pancreatic tissue treated by focused ultrasound.

PubMed

Mao, Ying; Fang, Liaoqiong; Ai, Liang; Li, Chongyan; Wang, Zhibiao; Wu, Junru; Bai, Jin; Li, Faqi

2014-01-01

Pancreatic cancer is one of the most malignant neoplasms originating in the digestive system. Focused ultrasound (FUS) treatment instead of the surgery operation has been used to treat Pancreatic cancer noninvasively in clinical trials. The endocrine and exocrine glands in pancreas provide the two unique functions for a person to be healthy. It is critically important to find out if the FUS treatment can still keep the normal functions of the two glands. The goal of this study is to examine and analyze changes in histopathology and serum glucose and amylase levels of the targeted in-vivo felines after the FUS treatment. Various percentage volumes of pancreas of felines were insonified. The FUS treatment (7.5 MHz of central frequency; 5 W of acoustical power; transducer f-number = 0.33; 6 s insonification time per point) effectively generated coagulative necrosis at the insonified site while leaving tissue outside the insonified site intact. It was also observed that all felines endured well with the FUS treatment; changes introduced to pancreatic tissue after up to 50% of a pancreas by volume was insonified by the FUS procedure did not affect its normal endocrine and exocrine functions.

Imbalance of mitochondrial dynamics in Drosophila models of amyotrophic lateral sclerosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altanbyek, Volodya; Cha, Sun-Joo; Kang, Ga-Un

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease, characterized by progressive and selective loss of motor neurons in the brain and spinal cord. DNA/RNA-binding proteins such as TDP-43, FUS, and TAF15 have been linked with the sporadic and familial forms of ALS. However, the exact pathogenic mechanism of ALS is still unknown. Recently, we found that ALS-causing genes such as TDP-43, FUS, and TAF15 genetically interact with mitochondrial dynamics regulatory genes. In this study, we show that mitochondrial fission was highly enhanced in muscles and motor neurons of TDP-43, FUS, and TAF15-induced fly models of ALS. Furthermore, themore » mitochondrial fission defects were rescued by co-expression of mitochondrial dynamics regulatory genes such as Marf, Opa1, and the dominant negative mutant form of Drp1. Moreover, we found that the expression level of Marf was decreased in ALS-induced flies. These results indicate that the imbalance of mitochondrial dynamics caused by instability of Marf is linked to the pathogenesis of TDP-43, FUS, and TAF15-associated ALS. - Highlights: • Mitochondrial fission is highly enhanced in TDP-43, FUS, and TAF15-induced fly models of ALS. • Excessive mitochondrial fragmentation in fly models of ALS is restored by mitochondrial dynamics regulatory genes. • Level of Marf protein is decreased in TDP-43, FUS, and TAF15-mediated ALS. • Imbalance of mitochondrial dynamics caused by Marf instability is linked to the pathogenesis of ALS.« less

MR-guided pulsed high intensity focused ultrasound enhancement of docetaxel combined with radiotherapy for prostate cancer treatment

NASA Astrophysics Data System (ADS)

Mu, Zhaomei; Ma, C.-M.; Chen, Xiaoming; Cvetkovic, Dusica; Pollack, Alan; Chen, Lili

2012-01-01

The purpose of this study is to evaluate the efficacy of the enhancement of docetaxel by pulsed focused ultrasound (pFUS) in combination with radiotherapy (RT) for treatment of prostate cancer in vivo. LNCaP cells were grown in the prostates of male nude mice. When the tumors reached a designated volume by MRI, tumor bearing mice were randomly divided into seven groups (n = 5): (1) pFUS alone; (2) RT alone; (3) docetaxel alone; (4) docetaxel + pFUS (5) docetaxel + RT (6) docetaxel + pFUS + RT, and (7) control. MR-guided pFUS treatment was performed using a focused ultrasound treatment system (InSightec ExAblate 2000) with a 1.5T GE MR scanner. Animals were treated once with pFUS, docetaxel, RT or their combinations. Docetaxel was given by i.v. injection at 5 mg kg-1 before pFUS. RT was given 2 Gy after pFUS. Animals were euthanized 4 weeks after treatment. Tumor volumes were measured on MRI at 1 and 4 weeks post-treatment. Results showed that triple combination therapies of docetaxel, pFUS and RT provided the most significant tumor growth inhibition among all groups, which may have potential for the treatment of prostate cancer due to an improved therapeutic ratio.

High Acceleration Cockpit Controller Locations. Volume 3. Onsite Pilot Evaluations

DTIC Science & Technology

1975-05-01

Ratings 31 9 Post Cockpit Questionnaire - Design Feature Ratings 32 VI A/A, A-A AAI A/C ACF ACM AFCS A/G CAP Chan CRT Coram DFC ...Negative Responses TASK RESPONSES NEGATIVE COMMENTS YES MAYBE NO MONITOR FBW STATUS 28 9 3 Obscured by throttles ACTIVATE FBW DFC , MVR, FUS AIM...4J 0 X O 4J O CO o Q UH U-l iH CJ i-H ^ i-1 TD CJ CO 4J CO 01 s c 0 O 4-1 o C 0 C X Si C 0) C -rl C cu C CO c

Mutational analysis of FUS gene and its structural and functional role in amyotrophic lateral sclerosis 6.

PubMed

Kamaraj, Balu; Rajendran, Vidya; Sethumadhavan, Rao; Kumar, Chundi Vinay; Purohit, Rituraj

2015-01-01

Amyotrophic lateral sclerosis 6 (ALS6) is an autosomal recessive disorder caused by heterozygous mutation in the Fused in Sarcoma (FUS) gene. ALS6 is a neurodegenerative disorder, which affects the upper and lower motor neurons in the brain and spinal cord, resulting in fatal paralysis. ALS6 is caused by the genetic mutation in the proline/tyrosine-nuclear localization signals of the Fused in sarcoma Protein (FUS). FUS gene also known as TLS (Translocated in liposarcoma), which encodes a protein called RNA-binding protein-Fus (FUS), has a molecular weight of 75 kDa. In this analysis, we applied computational approach to filter the most deleterious and neurodegenerative disease of ALS6-associated mutation on FUS protein. We found H517Q as most deleterious and disease associated using PolyPhen 2.0, I-Mutant 3.0, SIFT, SNPs&GO, PhD-SNP, Pmut, and Mutpred tools. Molecular dynamics simulation (MDS) approach was conducted to investigate conformational changes in the mutant protein structure with respect to its native conformation. MDS results showed the flexibility loss in mutant (H517Q) FUS protein. Due to mutation, FUS protein became more rigid in nature and might alter the structural and functional behavior of protein and play a major role in inducing ALS6. The results obtained from this investigation would help in the field of pharmacogenomics to develop a potent drug target against FUS-associated neurodegenerative diseases.

WE-AB-BRA-03: Non-Invasive Controlled Release from Implantable Hydrogel Scaffolds Using Ultrasound

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moncion, A; Kripfgans, O.D; Putnam, A.J

Purpose: To control release of a model payload in acoustically responsive scaffolds (ARSs) using focused ultrasound (FUS). Methods: Fluorescently-labeled dextran (10 kDa) was encapsulated in sonosensitive perfluorocarbon (C{sub 6}F{sub 14} or C{sub 5}F{sub 12}) double emulsions (mean diameter: 2.9±0.1 µm). For in vitro release studies, 0.5 mL ARSs (10 mg/mL fibrin, 1% (v/v) emulsion) were polymerized in 24 well plates and covered with 0.5 mL medium. Starting one day after polymerization, ARSs were exposed to FUS (2.5 MHz, Pr = 8 MPa, 13 cycles, 100 Hz PRF) for 2 min daily. The amount of dextran released into the media wasmore » quantified. For in vivo studies, 0.25 mL ARSs were prepared as described previously and injected subcutaneously in the lower back of BALB/c mice. After polymerization, a subset of the implanted ARSs were exposed to FUS (as previously described). Animals were imaged longitudinally using a fluorescence imaging system to quantify the amount of dextran released from the ARSs. Results: In vitro: Over 6 days, +FUS displayed an 8.2-fold increase in dextran release compared to −FUS (−FUS: 2.7±0.6%; +FUS: 22.2±3.0%) for C{sub 6}F{sub 14} ARSs, and a 6.7-fold increase (−FUS: 5.0±0.8%; +FUS: 38.5±1.6%) for C{sub 5}F{sub 12}:C{sub 6}F{sub 14} ARSs. In vivo: +FUS displayed statistically greater dextran release compared to −FUS one day after implantation for C{sub 5}F{sub 12}:C{sub 6}F{sub 14} ARSs (−FUS: 55.1±1.5%; +FUS: 74.1±2.2%) and three days after implantation for C{sub 6}F{sub 14} ARSs (−FUS: 1.4±6.5%; +FUS: 30.4±5.4%). Conclusion: FUS enables non-invasive control of payload release from an ARS, which could benefit growth factor delivery for tissue regeneration. ARS are versatile due to their tunability (i.e. stiffness, emulsion composition, FUS pressure, FUS frequency, etc.) and can be modified to for optimal payload release. Future work will optimize ARS formulations for in vivo use to minimize payload release in the absence of FUS. This work was supported by NIH Grant R21 AR065010 (M.L. Fabiilli) and the Basic Radiologic Sciences Innovative Research Award (M.L. Fabiilli). A. Moncion is supported by the National Science Foundation Graduate Student Research Fellowship (Grant DGE 1256260).« less

Magnetic Resonance-Guided Focused Ultrasound Neurosurgery for Essential Tremor: A Health Technology Assessment

PubMed Central

Schaink, Alexis; Li, Chunmei; Gajic-Veljanoski, Olga; Wells, David; Higgins, Caroline

2018-01-01

Background The standard treatment option for medication-refractory essential tremor is invasive neurosurgery. A new, noninvasive alternative is magnetic resonance-guided focused ultrasound (MRgFUS) neurosurgery. We aimed to determine the effectiveness, safety, and cost-effectiveness of MRgFUS neurosurgery for the treatment of moderate to severe, medication-refractory essential tremor in Ontario. We also spoke with people with essential tremor to gain an understanding of their experiences and thoughts regarding treatment options, including MRgFUS neurosurgery. Methods We performed a systematic review of the clinical literature published up to April 11, 2017, that examined MRgFUS neurosurgery alone or compared with other interventions for the treatment of moderate to severe, medication-refractory essential tremor. We assessed the risk of bias of each study and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic review of the economic literature and created Markov cohort models to assess the cost-effectiveness of MRgFUS neurosurgery compared with other treatment options, including no surgery. We also estimated the budget impact of publicly funding MRgFUS neurosurgery in Ontario for the next 5 years. To contextualize the potential value of MRgFUS neurosurgery as a treatment option for essential tremor, we spoke with people with essential tremor and their families. Results Nine studies met our inclusion criteria for the clinical evidence review. In noncomparative studies, MRgFUS neurosurgery was found to significantly improve tremor severity and quality of life and to significantly reduce functional disability (GRADE: very low). It was also found to be significantly more effective than a sham procedure (GRADE: high). We found no significant difference in improvements in tremor severity, functional disability, or quality of life between MRgFUS neurosurgery and deep brain stimulation (GRADE: very low). We found no significant difference in improvement in tremor severity compared with radiofrequency thalamotomy (GRADE: low). MRgFUS neurosurgery has a favourable safety profile. We estimated that MRgFUS neurosurgery has a mean cost of $23,507 and a mean quality-adjusted survival of 3.69 quality-adjusted life-years (QALYs). We also estimated that the mean costs and QALYs of radiofrequency thalamotomy and deep brain stimulation are $14,978 and 3.61 QALYs, and $57,535 and 3.94 QALYs, respectively. For people ineligible for invasive neurosurgery, we estimated the incremental cost-effectiveness ratio (ICER) of MRgFUS neurosurgery compared with no surgery as $43,075 per QALY gained. In people eligible for invasive neurosurgery, the ICER of MRgFUS neurosurgery compared with radiofrequency thalamotomy is $109,795 per QALY gained; when deep brain stimulation is compared with MRgFUS neurosurgery, the ICER is $134,259 per QALY gained. Of note however, radiofrequency thalamotomy is performed very infrequently in Ontario. We also estimated that the budget impact of publicly funding MRgFUS neurosurgery in Ontario at the current case load (i.e., 48 cases/year) would be about $1 million per year for the next 5 years. People with essential tremor who had undergone MRgFUS neurosurgery reported positive experiences with the procedure. The tremor reduction they experienced improved their ability to perform activities of daily living and improved their quality of life. Conclusions MRgFUS neurosurgery is an effective and generally safe treatment option for moderate to severe, medication-refractory essential tremor. It provides a treatment option for people ineligible for invasive neurosurgery and offers a noninvasive option for all people considering neurosurgery. For people ineligible for invasive neurosurgery, MRgFUS neurosurgery is cost-effective compared with no surgery. In people eligible for invasive neurosurgery, MRgFUS neurosurgery may be one of several reasonable options. Publicly funding MRgFUS neurosurgery for the treatment of moderate to severe, medication-refractory essential tremor in Ontario at the current case load would have a net budget impact of about $1 million per year for the next 5 years. People with essential tremor who had undergone MRgFUS neurosurgery reported positive experiences. They liked that it was a noninvasive procedure and reported a substantial reduction in tremor that resulted in an improvement in their quality of life. PMID:29805721

Fast Lesion Mapping during HIFU Treatment Using Harmonic Motion Imaging guided Focused Ultrasound (HMIgFUS) In Vitro and In Vivo

PubMed Central

Han, Yang; Wang, Shutao; Payen, Thomas; Konofagou, Elisa

2017-01-01

The successful clinical application of High Intensity Focused Ultrasound (HIFU) ablation depends on reliable monitoring of the lesion formation. Harmonic Motion Imaging guided Focused Ultrasound (HMIgFUS) is an ultrasound-based elasticity imaging technique, which monitors HIFU ablation based on the stiffness change of the tissue instead of the echo intensity change in conventional B-mode monitoring, rendering it potentially more sensitive to lesion development. Our group has shown that predicting the lesion location based on the radiation force-excited region is feasible during HMIgFUS. In this study, the feasibility of a fast lesion mapping method is explored to directly monitor the lesion map during HIFU. The HMI lesion map was generated by subtracting the reference HMI image from the present HMI peak-to-peak displacement map to be streamed on the computer display. The dimensions of the HMIgFUS lesions were compared against gross pathology. Excellent agreement was found between the lesion depth (r2 = 0.81, slope = 0.90), width (r2 = 0.85, slope = 1.12) and area (r2 = 0.58, slope = 0.75). In vivo feasibility was assessed in a mouse with a pancreatic tumor. These findings demonstrate that HMIgFUS can successfully map thermal lesion and monitor lesion development in real time in vitro and in vivo. The HMIgFUS technique may therefore constitute a novel clinical tool for HIFU treatment monitoring. PMID:28323638

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.

PubMed

Downs, Matthew E; Buch, Amanda; Sierra, Carlos; Karakatsani, Maria Eleni; Teichert, Tobias; Chen, Shangshang; Konofagou, Elisa E; Ferrera, Vincent P

2015-01-01

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500 kHz, 200-400 kPa, 4-5 μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4-20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of' visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4-5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.

Nonthermal ablation in the rat brain using focused ultrasound and an ultrasound contrast agent: long-term effects

PubMed Central

McDannold, Nathan; Zhang, Yongzhi; Vykhodtseva, Natalia

2016-01-01

OBJECTIVE Thermal ablation with transcranial MRI-guided focused ultrasound (FUS) is currently under investigation as a less invasive alternative to radiosurgery and resection. A major limitation of the method is that its use is currently restricted to centrally located brain targets. The combination of FUS and a microbubble-based ultrasound contrast agent greatly reduces the ultrasound exposure level needed to ablate brain tissue and could be an effective means to increase the “treatment envelope” for FUS in the brain. This method, however, ablates tissue through a different mechanism: destruction of the microvasculature. It is not known whether nonthermal FUS ablation in substantial volumes of tissue can safely be performed without unexpected effects. The authors investigated this question by ablating volumes in the brains of normal rats. METHODS Overlapping sonications were performed in rats (n = 15) to ablate a volume in 1 hemisphere per animal. The sonications (10-msec bursts at 1 Hz for 60 seconds; peak negative pressure 0.8 MPa) were combined with the ultrasound contrast agent Optison (100 μl/kg). The rats were followed with MRI for 4–9 weeks after FUS, and the brains were examined with histological methods. RESULTS Two weeks after sonication and later, the lesions appeared as cyst-like areas in T2-weighted MR images that were stable over time. Histological examination demonstrated well-defined lesions consisting of a cyst-like cavity that remained lined by astrocytic tissue. Some white matter structures within the sonicated area were partially intact. CONCLUSIONS The results of this study indicate that nonthermal FUS ablation can be used to safely ablate tissue volumes in the brain without unexpected delayed effects. The findings are encouraging for the use of this ablation method in the brain. PMID:26848919

Trans-cranial opening of the blood-brain barrier in targeted regions using a stereotaxic brain atlas and focused ultrasound energy.

PubMed

Bing, Chenchen; Ladouceur-Wodzak, Michelle; Wanner, Clinton R; Shelton, John M; Richardson, James A; Chopra, Rajiv

2014-01-01

The blood-brain barrier (BBB) protects the brain by preventing the entry of large molecules; this poses a major obstacle for the delivery of drugs to the brain. A novel technique using focused ultrasound (FUS) energy combined with microbubble contrast agents has been widely used for non-invasive trans-cranial BBB opening. Traditionally, FUS research is conducted with magnetic resonance imaging (MRI) guidance, which is expensive and poses physical limitations due to the magnetic field. A system that could allow researchers to test brain therapies without MR intervention could facilitate and accelerate translational research. In this study, we present a novel FUS system that uses a custom-built FUS generator mounted on a motorized stereotaxic apparatus with embedded brain atlas to locally open the BBB in rodents. The system was initially characterized using a tissue-mimicking phantom. Rodent studies were also performed to evaluate whether non-invasive, localized BBB opening could be achieved using brain atlas-based targeting. Brains were exposed to pulsed focused ultrasound energy at 1.06 MHz in rats and 3.23 MHz in mice, with the focal pressure estimated to be 0.5-0.6 MPa through the skull. BBB opening was confirmed in gross tissue sections by the presence of Evans blue leakage in the exposed region of the brain and by histological assessment. The targeting accuracy of the stereotaxic system was better than 0.5 mm in the tissue-mimicking phantom. Reproducible localized BBB opening was verified with Evans blue dye leakage in 32/33 rats and had a targeting accuracy of ±0.3 mm. The use of higher frequency exposures in mice enabled a similar precision of localized BBB opening as was observed with the low frequency in the rat model. With this dedicated small-animal motorized stereotaxic-FUS system, we achieved accurate targeting of focused ultrasound exposures in the brain for non-invasive opening of the BBB. This system can be used as an alternative to MR-guided FUS and offers researchers the ability to perform efficient studies (30 min per experiment including preparation) at a reduced cost in a conventional laboratory environment.

FUS GENE MUTATIONS IN FAMILIAL AND SPORADIC AMYOTROPHIC LATERAL SCLEROSIS

PubMed Central

Rademakers, Rosa; Stewart, Heather; DeJesus-Hernandez, Mariely; Krieger, Charles; Graff-Radford, Neill; Fabros, Marife; Briemberg, Hannah; Cashman, Neil; Eisen, Andrew; Mackenzie, Ian R. A.

2010-01-01

Introduction Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). Methods We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. Results In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. Discussion This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS. It suggests there are specific clinicogenetic correlations and provides the first detailed neuropathological description. PMID:20544928

A long arm for ultrasound: a combined robotic focused ultrasound setup for magnetic resonance-guided focused ultrasound surgery.

PubMed

Krafft, Axel J; Jenne, Jürgen W; Maier, Florian; Stafford, R Jason; Huber, Peter E; Semmler, Wolfhard; Bock, Michael

2010-05-01

Focused ultrasound surgery (FUS) is a highly precise noninvasive procedure to ablate pathogenic tissue. FUS therapy is often combined with magnetic resonance (MR) imaging as MR imaging offers excellent target identification and allows for continuous monitoring of FUS induced temperature changes. As the dimensions of the ultrasound (US) focus are typically much smaller than the targeted volume, multiple sonications and focus repositioning are interleaved to scan the focus over the target volume. Focal scanning can be achieved electronically by using phased-array US transducers or mechanically by using dedicated mechanical actuators. In this study, the authors propose and evaluate the precision of a combined robotic FUS setup to overcome some of the limitations of the existing MRgFUS systems. Such systems are typically integrated into the patient table of the MR scanner and thus only provide an application of the US wave within a limited spatial range from below the patient. The fully MR-compatible robotic assistance system InnoMotion (InnoMedic GmbH, Herxheim, Germany) was originally designed for MR-guided interventions with needles. It offers five pneumatically driven degrees of freedom and can be moved over a wide range within the bore of the magnet. In this work, the robotic system was combined with a fixed-focus US transducer (frequency: 1.7 MHz; focal length: 68 mm, and numerical aperture: 0.44) that was integrated into a dedicated, in-house developed treatment unit for FUS application. A series of MR-guided focal scanning procedures was performed in a polyacrylamide-egg white gel phantom to assess the positioning accuracy of the combined FUS setup. In animal experiments with a 3-month-old domestic pig, the system's potential and suitability for MRgFUS was tested. In phantom experiments, a total targeting precision of about 3 mm was found, which is comparable to that of the existing MRgFUS systems. Focus positioning could be performed within a few seconds. During in vivo experiments, a defined pattern of single thermal lesions and a therapeutically relevant confluent thermal lesion could be created. The creation of local tissue necrosis by coagulation was confirmed by post-FUS MR imaging and histological examinations on the treated tissue sample. During all sonications in phantom and in vivo, reliable MR imaging and online MR thermometry could be performed without compromises due to operation of the combined robotic FUS setup. Compared to the existing MRgFUS systems, the combined robotic FUS approach offers a wide range of spatial flexibility so that highly flexible application of the US wave would be possible, for example, to avoid risk structures within the US field. The setup might help to realize new ways of patient access in MRgFUS therapy. The setup is compatible with any closed-bore MR system and does not require an especially designed patient table.

MRI-guided Focused Ultrasound Ablation of Lumbar Medial Branch Nerve: Feasibility and Safety Study in a Swine Model

PubMed Central

Kaye, Elena A; Monette, Sebastien; Srimathveeravalli, Govindarajan; Maybody, Majid; Solomon, Stephen B; Gulati, Amitabh

2016-01-01

Purpose About 10–40% of chronic low back pain cases involve facet joints, which are commonly treated with lumbar medial branch (MB) radiofrequency neurotomy. Magnetic Resonance Imaging-guided Focused Ultrasound (MRgFUS), a non-invasive, non-ionizing ablation modality used to treat tumors, neuropathic pain and painful bone metastasis, can also be used to disrupt nerve conduction. This work’s purpose was to study the feasibility and safety of direct MRgFUS ablation of the lumbar MB nerve in acute and subacute swine models. Materials and Methods In vivo MRgFUS ablation was performed in six swine (3 acute and 3 subacute) using a clinical MRgFUS system (ExAblate 2000®; InSightec Ltd., Haifa, Israel) and 3 T MRI scanner (SIGNA; GE Healthcare, Waukesha, WI, USA) combination. Behavioral assessment was performed, and imaging and histology were used to assess the treatment. Results and Conclusions Histological analysis of the in vivo studies confirmed thermal necrosis of the MB nerve could be achieved without damaging the spinal cord or adjacent nerve roots. MRgFUS did not cause changes in the animals’ behavior and ambulation. PMID:27443328

Assessment of FUS-Tissue Interactions In Vivo

NASA Astrophysics Data System (ADS)

Haritonova, Alyona V.

Focused ultrasound (FUS) has been proposed for a variety of minimally invasive therapeutic applications, including tumor ablation, neuromodulation, targeted drug delivery and blood brain barrier opening. To date, FUS beams have been primarily monitored through MR and ultrasound diagnostic imaging modalities. The recent introduction of real-time dual-mode ultrasound array (DMUA) systems offers a new paradigm for the guidance of therapeutic focused ultrasound. The DMUA approach allows for inherent registration between the therapeutic and imaging coordinate systems. In this thesis we investigated the use of ultrasound-based thermography to assess FUS-tissue interactions. Specifically, we focused on two aspects of image-guided therapy: 1) monitoring and localization of FUS-tissue interactions, and 2) tissue damage assessment. Towards this end, we presented first experimental results of ultrasound-guided transcranial FUS in a rat brain, both ex vivo and in vivo. DMUA imaging was used to monitor and localize FUS-tissue thermal interactions in real-time. The transcranial echo data allowed for a reliable estimation of temperature change in brain tissue, which had never been done before using ultrasound image guidance. Despite some measurable distortion and loss in focusing gain, transcranial FUS beams at 3.2 MHz were localized axially and laterally. This confirms the results obtained using DMUA-based transcranial ultrasound thermography. A high degree of focusing with the DMUA was then successfully leveraged to perform localized tissue damage assessment in both ex vivo and in vivo. The experimental results presented in this thesis demonstrate some of the unique aspects of image guidance using DMUAs, especially when FUS is subject to significant distortions as in transcranial applications.

Controlled Drug Release and Chemotherapy Response in a Novel Acoustofluidic 3D Tumor Platform.

PubMed

Zervantonakis, Ioannis K; Arvanitis, Costas D

2016-05-01

Overcoming transport barriers to delivery of therapeutic agents in tumors remains a major challenge. Focused ultrasound (FUS), in combination with modern nanomedicine drug formulations, offers the ability to maximize drug transport to tumor tissue while minimizing toxicity to normal tissue. This potential remains unfulfilled due to the limitations of current approaches in accurately assessing and quantifying how FUS modulates drug transport in solid tumors. A novel acoustofluidic platform is developed by integrating a physiologically relevant 3D microfluidic device and a FUS system with a closed-loop controller to study drug transport and assess the response of cancer cells to chemotherapy in real time using live cell microscopy. FUS-induced heating triggers local release of the chemotherapeutic agent doxorubicin from a liposomal carrier and results in higher cellular drug uptake in the FUS focal region. This differential drug uptake induces locally confined DNA damage and glioblastoma cell death in the 3D environment. The capabilities of acoustofluidics for accurate control of drug release and monitoring of localized cell response are demonstrated in a 3D in vitro tumor mode. This has important implications for developing novel strategies to deliver therapeutic agents directly to the tumor tissue while sparing healthy tissue. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of the pain and local tenderness in bone metastasis treated with magnetic resonance-guided focused ultrasound surgery (MRgFUS)

NASA Astrophysics Data System (ADS)

Namba, Hirofumi; Kawasaki, Motohiro; Kato, Tomonari; Tani, Toshikazu; Ushida, Takahiro; Koizumi, Norihiro

2017-03-01

It has been reported that MRgFUS has pain palliative effects on the local pain in patients with bone metastasis. In general, a severity of pain has been evaluated using only subjective method with numerical rating scale (NRS) or visual analogue scale (VAS). It is important to evaluate local pain-palliative effects of MRgFUS treatment with objective and quantitative method. The aim of this study is to investigate changes in the severity of local pain of bone metastasis before and after MRgFUS treatments, measuring pressure pain threshold (PPT) using pressure algometer, and pain intensity using electrical stimulation device (the Pain Vision system) at most painful site of bone metastasis. We have conducted MRgFUS for pain palliation of bone metastasis for 8 patients, and evaluated the local tenderness quantitatively for 8 patients, and evaluated local pain intensity for 7 patients. Before the treatments, PPTs were 106.3kPa [40.0-431.5] at metastatic site and 344.8 kPa [206.0-667.0] at normal control site, which showed a significant difference. The PPTs at metastatic site shows a significant increase from 106.3 kPa [40.0-431.5] at the baseline to 270.5 kPa [93.5-533.5] at 3 months after the treatment. The NRS score shows a significant decrease from 6.0 [4-8] at baseline to 1 [0-3] at 3 months after the treatment. Similarly, the pain intensity shows a significant decrease 245 [96.3-888.7] at baseline to 55.9 [2.8-292] at 3 months after the treatment. The results of our study illustrate the pain-relieving effects of MRgFUS for the treatment of painful bone metastasis. PPT might be a useful parameter not only for assessing a treatment's effect, but also for the decision of the painful area to treat with MRgFUS. Pain Vision seems to be useful for quantitative and objective evaluation of local pain of painful bone metastasis.

Genetic link between Cabeza, a Drosophila homologue of Fused in Sarcoma (FUS), and the EGFR signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shimamura, Mai; Kyotani, Akane; Insect Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585

2014-08-01

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular weakness. Fused in Sarcoma (FUS) that has been identified in familial ALS is an RNA binding protein that is normally localized in the nucleus. However, its function in vivo is not fully understood. Drosophila has Cabeza (Caz) as a FUS homologue and specific knockdown of Caz in the eye imaginal disc and pupal retina using a GMR-GAL4 driver was here found to induce an abnormal morphology of the adult compound eyes, a rough eye phenotype. This was partially suppressed by expression of the apoptosis inhibitor P35. Knockdownmore » of Caz exerted no apparent effect on differentiation of photoreceptor cells. However, immunostaining with an antibody to Cut that marks cone cells revealed fusion of these and ommatidia of pupal retinae. These results indicate that Caz knockdown induces apoptosis and also inhibits differentiation of cone cells, resulting in abnormal eye morphology in adults. Mutation in EGFR pathway-related genes, such as rhomboid-1, rhomboid-3 and mirror suppressed the rough eye phenotype induced by Caz knockdown. Moreover, the rhomboid-1 mutation rescued the fusion of cone cells and ommatidia observed in Caz knockdown flies. The results suggest that Caz negatively regulates the EGFR signaling pathway required for determination of cone cell fate in Drosophila. - Highlights: • Knockdown of Cabeza induced rough eye phenotype. • Knockdown of Cabeza induced fusion of cone cells in pupal retinae. • Knockdown of Cabeza induced apoptosis in pupal retinae. • Mutation in EGFR pathway-related genes suppressed the rough eye phenotype. • Cabeza may negatively regulate the EGFR pathway.« less

Fast lesion mapping during HIFU treatment using harmonic motion imaging guided focused ultrasound (HMIgFUS) in vitro and in vivo

NASA Astrophysics Data System (ADS)

Han, Yang; Wang, Shutao; Payen, Thomas; Konofagou, Elisa

2017-04-01

The successful clinical application of high intensity focused ultrasound (HIFU) ablation depends on reliable monitoring of the lesion formation. Harmonic motion imaging guided focused ultrasound (HMIgFUS) is an ultrasound-based elasticity imaging technique, which monitors HIFU ablation based on the stiffness change of the tissue instead of the echo intensity change in conventional B-mode monitoring, rendering it potentially more sensitive to lesion development. Our group has shown that predicting the lesion location based on the radiation force-excited region is feasible during HMIgFUS. In this study, the feasibility of a fast lesion mapping method is explored to directly monitor the lesion map during HIFU. The harmonic motion imaging (HMI) lesion map was generated by subtracting the reference HMI image from the present HMI peak-to-peak displacement map, as streamed on the computer display. The dimensions of the HMIgFUS lesions were compared against gross pathology. Excellent agreement was found between the lesion depth (r 2  =  0.81, slope  =  0.90), width (r 2  =  0.85, slope  =  1.12) and area (r 2  =  0.58, slope  =  0.75). In vivo feasibility was assessed in a mouse with a pancreatic tumor. These findings demonstrate that HMIgFUS can successfully map thermal lesions and monitor lesion development in real time in vitro and in vivo. The HMIgFUS technique may therefore constitute a novel clinical tool for HIFU treatment monitoring.

Fast lesion mapping during HIFU treatment using harmonic motion imaging guided focused ultrasound (HMIgFUS) in vitro and in vivo.

PubMed

Han, Yang; Wang, Shutao; Payen, Thomas; Konofagou, Elisa

2017-04-21

The successful clinical application of high intensity focused ultrasound (HIFU) ablation depends on reliable monitoring of the lesion formation. Harmonic motion imaging guided focused ultrasound (HMIgFUS) is an ultrasound-based elasticity imaging technique, which monitors HIFU ablation based on the stiffness change of the tissue instead of the echo intensity change in conventional B-mode monitoring, rendering it potentially more sensitive to lesion development. Our group has shown that predicting the lesion location based on the radiation force-excited region is feasible during HMIgFUS. In this study, the feasibility of a fast lesion mapping method is explored to directly monitor the lesion map during HIFU. The harmonic motion imaging (HMI) lesion map was generated by subtracting the reference HMI image from the present HMI peak-to-peak displacement map, as streamed on the computer display. The dimensions of the HMIgFUS lesions were compared against gross pathology. Excellent agreement was found between the lesion depth (r 2   =  0.81, slope  =  0.90), width (r 2   =  0.85, slope  =  1.12) and area (r 2   =  0.58, slope  =  0.75). In vivo feasibility was assessed in a mouse with a pancreatic tumor. These findings demonstrate that HMIgFUS can successfully map thermal lesions and monitor lesion development in real time in vitro and in vivo. The HMIgFUS technique may therefore constitute a novel clinical tool for HIFU treatment monitoring.

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function

PubMed Central

Sharma, Aarti; Lyashchenko, Alexander K.; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z.; Shneider, Neil A.

2016-01-01

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations. PMID:26842965

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.

PubMed

Sharma, Aarti; Lyashchenko, Alexander K; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z; Shneider, Neil A

2016-02-04

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.

Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia/reperfusion-induced neuronal injury: a long-term and short-term study.

PubMed

Wu, Sheng-Kai; Yang, Ming-Tao; Kang, Kai-Hsiang; Liou, Houng-Chi; Lu, Dai-Hua; Fu, Wen-Mei; Lin, Win-Li

2014-01-01

Erythropoietin (EPO) is a neuroprotective agent against cerebral ischemia/reperfusion (I/R)-induced brain injury. However, its crossing of blood-brain barrier is limited. Focused ultrasound (FUS) sonication with microbubbles (MBs) can effectively open blood-brain barrier to boost the vascular permeability. In this study, we investigated the effects of MBs/FUS on extending the therapeutic time window of EPO and its neuroprotective effects in both acute and chronic phases. Male Wistar rats were firstly subjected to two common carotid arteries and right middle cerebral artery occlusion (three vessels occlusion, 3VO) for 50 min, and then the rats were treated with hEPO (human recombinant EPO, 5000 IU/kg) with or without MBs/FUS at 5 h after occlusion/reperfusion. Acute phase investigation (I/R, I/R+MBs/FUS, I/R+hEPO, and I/R+hEPO+MBs/FUS) was performed 24 h after I/R; chronic tests including cylinder test and gait analysis were performed one month after I/R. The experimental results showed that MBs/FUS significantly increased the cerebral content of EPO by bettering vascular permeability. In acute phase, both significant improvement of neurological score and reduction of infarct volume were found in the I/R+hEPO+MBs/FUS group, as compared with I/R and I/R+hEPO groups. In chronic phase, long-term behavioral recovery and neuronal loss in brain cortex after I/R injury was significantly improved in the I/R+hEPO+MBs/FUS group. This study indicates that hEPO administration with MBs/FUS sonication even at 5 h after occlusion/reperfusion can produce a significant neuroprotection.

Open-source, small-animal magnetic resonance-guided focused ultrasound system.

PubMed

Poorman, Megan E; Chaplin, Vandiver L; Wilkens, Ken; Dockery, Mary D; Giorgio, Todd D; Grissom, William A; Caskey, Charles F

2016-01-01

MR-guided focused ultrasound or high-intensity focused ultrasound (MRgFUS/MRgHIFU) is a non-invasive therapeutic modality with many potential applications in areas such as cancer therapy, drug delivery, and blood-brain barrier opening. However, the large financial costs involved in developing preclinical MRgFUS systems represent a barrier to research groups interested in developing new techniques and applications. We aim to mitigate these challenges by detailing a validated, open-source preclinical MRgFUS system capable of delivering thermal and mechanical FUS in a quantifiable and repeatable manner under real-time MRI guidance. A hardware and software package was developed that includes closed-loop feedback controlled thermometry code and CAD drawings for a therapy table designed for a preclinical MRI scanner. For thermal treatments, the modular software uses a proportional integral derivative controller to maintain a precise focal temperature rise in the target given input from MR phase images obtained concurrently. The software computes the required voltage output and transmits it to a FUS transducer that is embedded in the delivery table within the magnet bore. The delivery table holds the FUS transducer, a small animal and its monitoring equipment, and a transmit/receive RF coil. The transducer is coupled to the animal via a water bath and is translatable in two dimensions from outside the magnet. The transducer is driven by a waveform generator and amplifier controlled by real-time software in Matlab. MR acoustic radiation force imaging is also implemented to confirm the position of the focus for mechanical and thermal treatments. The system was validated in tissue-mimicking phantoms and in vivo during murine tumor hyperthermia treatments. Sonications were successfully controlled over a range of temperatures and thermal doses for up to 20 min with minimal temperature overshoot. MR thermometry was validated with an optical temperature probe, and focus visualization was achieved with acoustic radiation force imaging. We developed an MRgFUS platform for small-animal treatments that robustly delivers accurate, precise, and controllable sonications over extended time periods. This system is an open source and could increase the availability of low-cost small-animal systems to interdisciplinary researchers seeking to develop new MRgFUS applications and technology.

FUS and TARDBP but Not SOD1 Interact in Genetic Models of Amyotrophic Lateral Sclerosis

PubMed Central

Kabashi, Edor; Bercier, Valérie; Lissouba, Alexandra; Liao, Meijiang; Brustein, Edna; Rouleau, Guy A.; Drapeau, Pierre

2011-01-01

Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS–related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS–related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1. PMID:21829392

FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis.

PubMed

Kabashi, Edor; Bercier, Valérie; Lissouba, Alexandra; Liao, Meijiang; Brustein, Edna; Rouleau, Guy A; Drapeau, Pierre

2011-08-01

Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS-related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS-related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1.

Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery.

PubMed

Alli, Saira; Figueiredo, Carlyn A; Golbourn, Brian; Sabha, Nesrin; Wu, Megan Yijun; Bondoc, Andrew; Luck, Amanda; Coluccia, Daniel; Maslink, Colin; Smith, Christian; Wurdak, Heiko; Hynynen, Kullervo; O'Reilly, Meaghan; Rutka, James T

2018-05-15

Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H&E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions. Copyright © 2018 Elsevier B.V. All rights reserved.

Neuronavigation-guided focused ultrasound-induced blood-brain barrier opening: A preliminary study in swine

NASA Astrophysics Data System (ADS)

Liu, Hao-Li; Tsai, Hong-Chieh; Lu, Yu-Jen; Wei, Kuo-Chen

2012-11-01

FUS-induced BBB opening is a promising technique for noninvasive and local delivery of drugs into the brain. Here we propose the novel use of a neuronavigation system to guide the FUS-induced BBB opening procedure, and investigate its feasibility in vivo in large animals. We developed an interface between the neuronavigator and FUS to allow guidance of the focal energy produced by the FUS transducer. The system was tested in 29 pigs by more than 40 sonication procedures and evaluated by MRI. Gd-DTPA concentration was quantitated in vivo by MRI R1 relaxometry and compared by ICP-OES assay. Brain histology after FUS exposure was investigated by HE and TUNEL staining. Neuronavigation could successfully guide the focal beam with comparable precision to neurosurgical stereotactic procedures (2.3 ± 0.9 mm). FUS pressure of 0.43 MPa resulted in consistent BBB-opening. Neuronavigation-guided BBB-opening increased Gd-DTPA deposition by up to 1.83 mM (140% increase). MR relaxometry demonstrated high correlation to ICP-OES measurements (r2 = 0.822), suggesting that Gd-DTPA deposition can be directly measured by imaging. Neuronavigation could provide sufficient precision for guiding FUS to temporally and locally open the BBB. Gd-DTPA deposition in the brain could be quantified by MR relaxometry, providing a potential tool for the in vivo quantification of therapeutic agents in CNS disease treatment.

FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice.

PubMed

Kino, Yoshihiro; Washizu, Chika; Kurosawa, Masaru; Yamada, Mizuki; Doi, Hiroshi; Takumi, Toru; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Hicks, Geoffrey G; Hattori, Nobutaka; Shimogori, Tomomi; Nukina, Nobuyuki

2016-10-14

FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington's disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS. Co-aggregation between FUS/TLS and mutant huntingtin resulted in the depletion of free FUS/TLS protein in HD mice that was detected as a monomer in SDS-PAGE analysis. Recently, we found that FUS/TLS paralogs, TAF15 and EWS, were up-regulated in homozygous FUS/TLS knockout mice. These two proteins were up-regulated in both HD and FUS/TLS heterozygote mice, and were further elevated in HD-TLS +/- double mutant mice, consistent with the functional impairment of FUS/TLS. These results suggest that FUS/TLS sequestration by co-aggregation is a rate-limiting factor of disease phenotypes of HD and that inclusions may have an adverse aspect, rather than being simply benign or protective. In addition, our results highlight inclusions as repositories of potential modifiers of neurodegeneration.

FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress.

PubMed

Sama, Reddy Ranjith K; Ward, Catherine L; Kaushansky, Laura J; Lemay, Nathan; Ishigaki, Shinsuke; Urano, Fumihiko; Bosco, Daryl A

2013-11-01

FUsed in Sarcoma/Translocated in LipoSarcoma (FUS/TLS or FUS) has been linked to several biological processes involving DNA and RNA processing, and has been associated with multiple diseases, including myxoid liposarcoma and amyotrophic lateral sclerosis (ALS). ALS-associated mutations cause FUS to associate with stalled translational complexes called stress granules under conditions of stress. However, little is known regarding the normal role of endogenous (non-disease linked) FUS in cellular stress response. Here, we demonstrate that endogenous FUS exerts a robust response to hyperosmolar stress induced by sorbitol. Hyperosmolar stress causes an immediate re-distribution of nuclear FUS to the cytoplasm, where it incorporates into stress granules. The redistribution of FUS to the cytoplasm is modulated by methyltransferase activity, whereas the inhibition of methyltransferase activity does not affect the incorporation of FUS into stress granules. The response to hyperosmolar stress is specific, since endogenous FUS does not redistribute to the cytoplasm in response to sodium arsenite, hydrogen peroxide, thapsigargin, or heat shock, all of which induce stress granule assembly. Intriguingly, cells with reduced expression of FUS exhibit a loss of cell viability in response to sorbitol, indicating a prosurvival role for endogenous FUS in the cellular response to hyperosmolar stress. Copyright © 2013 Wiley Periodicals, Inc.

Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

NASA Astrophysics Data System (ADS)

Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

2016-06-01

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress

PubMed Central

Sama, Reddy Ranjith K; Ward, Catherine L.; Kaushansky, Laura J.; Lemay, Nathan; Ishigaki, Shinsuke; Urano, Fumihiko; Bosco, Daryl A.

2014-01-01

FUsed in Sarcoma/Translocated in LipoSarcoma (FUS/TLS or FUS) has been linked to several biological processes involving DNA and RNA processing, and has been associated with multiple diseases, including myxoid liposarcoma and amyotrophic lateral sclerosis (ALS). ALS-associated mutations cause FUS to associate with stalled translational complexes called stress granules under conditions of stress. However, little is known regarding the normal role of endogenous (non-disease linked) FUS in cellular stress response. Here, we demonstrate that endogenous FUS exerts a robust response to hyperosmolar stress induced by sorbitol. Hyperosmolar stress causes an immediate re-distribution of nuclear FUS to the cytoplasm, where it incorporates into stress granules. The redistribution of FUS to the cytoplasm is modulated by methyltransferase activity, whereas the inhibition of methyltransferase activity does not affect the incorporation of FUS into stress granules. The response to hyperosmolar stress is specific, since endogenous FUS does not redistribute to the cytoplasm in response to sodium arsenite, hydrogen peroxide, thapsigargin, or heat shock, all of which induce stress granule assembly. Intriguingly, cells with reduced expression of FUS exhibit a loss of cell viability in response to sorbitol, indicating a prosurvival role for endogenous FUS in the cellular response to hyperosmolar stress. PMID:23625794

Symptomatic improvement in uterine myomas after MRgFUS: 4 year follow up

NASA Astrophysics Data System (ADS)

Funaki, Kaoru; Fukunishi, Hidenobu

2011-09-01

Objective: To assess the long-term improvement in symptoms after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for uterine myomas. Methods: Japanese women with symptomatic myomas underwent MRgFUS using the ExAblate 2000 system. The symptom severity score (SSS) was examined before and after the treatment at 3, 6, 12, 24, and 48 months. Simultaneously, we asked the patients' satisfaction level regarding the overall change of subjective symptoms: symptom free, improved a great deal, improved to some extent, no change, or worsened. The myoma volumes were measured at 6, 12, 24, 36 and 48 months after MRgFUS. Results: No severe adverse event occurred with any of the patients. The mean SSS value before treatment was 38.3±21.5 (n = 106), which diminished significantly during follow-up for 3-48 months after treatment. Patients' satisfaction level was favorable, although the response rate was low. Over 80% of the patients replied that their symptoms were improved to at least some extent, and over 50% of the patients replied that their symptoms were improved a great deal. This trend continued throughout this follow up period. The mean myoma volume was also decreased from the pretreatment volume in this follow up period. Conclusion: MRgFUS is an effective and safe method for treating symptomatic uterine myomas. Long-term symptomatic improvement is promising.

Aggregation of ALS-linked FUS mutant sequesters RNA binding proteins and impairs RNA granules formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takanashi, Keisuke; Yamaguchi, Atsushi, E-mail: atsyama@restaff.chiba-u.jp

Highlights: • Aggregation of ALS-linked FUS mutant sequesters ALS-associated RNA-binding proteins (FUS wt, hnRNP A1, and hnRNP A2). • Aggregation of ALS-linked FUS mutant sequesters SMN1 in the detergent-insoluble fraction. • Aggregation of ALS-linked FUS mutant reduced the number of speckles in the nucleus. • Overproduced ALS-linked FUS mutant reduced the number of processing-bodies (PBs). - Abstract: Protein aggregate/inclusion is one of hallmarks for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). FUS/TLS, one of causative genes for familial ALS, encodes a multifunctional DNA/RNA binding protein predominantly localized in the nucleus. C-terminal mutations in FUS/TLS cause the retention and the inclusionmore » of FUS/TLS mutants in the cytoplasm. In the present study, we examined the effects of ALS-linked FUS mutants on ALS-associated RNA binding proteins and RNA granules. FUS C-terminal mutants were diffusely mislocalized in the cytoplasm as small granules in transiently transfected SH-SY5Y cells, whereas large aggregates were spontaneously formed in ∼10% of those cells. hnRNP A1, hnRNP A2, and SMN1 as well as FUS wild type were assembled into stress granules under stress conditions, and these were also recruited to FUS mutant-derived spontaneous aggregates in the cytoplasm. These aggregates stalled poly(A) mRNAs and sequestered SMN1 in the detergent insoluble fraction, which also reduced the number of nuclear oligo(dT)-positive foci (speckles) in FISH (fluorescence in situ hybridization) assay. In addition, the number of P-bodies was decreased in cells harboring cytoplasmic granules of FUS P525L. These findings raise the possibility that ALS-linked C-terminal FUS mutants could sequester a variety of RNA binding proteins and mRNAs in the cytoplasmic aggregates, which could disrupt various aspects of RNA equilibrium and biogenesis.« less

Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

PubMed Central

Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

2013-01-01

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment. PMID:23527068

Magnetic resonance-guided focused ultrasound surgery for treatment of painful osseous metastases

NASA Astrophysics Data System (ADS)

Hurwitz, Mark; Machtinger, Ronit; Fennessy, Fiona

2011-03-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is an emerging technology that can non-invasively heat and ablate targeted tissue utilizing ultrasound energy. Use of MR imaging for treatment guidance provides several key advantages over more widely used ultrasound guidance for focused ultrasound ablation. MR allows for precise targeting, detailed beam path visualization, real time non-invasive temperature measurement, and treatment feedback to ensure therapeutic goals are achieved. In the realm of oncology, management of painful bone metastases is a common and daunting clinical problem. The Insightec ExAblate System has been shown in phase I/II trials for treatment of bone metastases to have an excellent safety profile and high rates of pain response. An international multi-center phase III trial for patients with painful bone metastases or multiple myeloma who are not candidates for radiation therapy is currently open. Patients are randomized 3:1 to MRgFUS or sham treatment with crossover to study treatment allowed for sham failures. The primary study endpoint is assessment of pain control over 3 months following treatment. In addition safety, quality of life, cost effectiveness analysis, and patient perceived clinical benefit are also being assessed. Details of the MRgFUS system, technical and clinical therapeutic parameters, use of real time non-invasive MR thermometry, and examples of patient treatments with use of MRgFUS to treat bone metastases will be discussed. New directions in use of MRgFUS including an update on development of a new mobile applicator and integration of MRgFUS in multimodality oncologic care will also be presented.

R521C and R521H mutations in FUS result in weak binding with Karyopherinβ2 leading to Amyotrophic lateral sclerosis: a molecular docking and dynamics study.

PubMed

Swetha, Rayapadi G; Ramaiah, Sudha; Anbarasu, Anand

2017-08-01

Fused in sarcoma (FUS) gene encodes the RNA binding protein FUS. This gene is mapped to chromosome 16p11.2. The FUS protein binds with karyopherineβ2 (Kapβ2) through its proline/tyrosine nuclear localization signal (PY-NLS) that helps in the localization of FUS protein within the nucleus. Arginine residue in 521 position (R521) of PY-NLS plays a vital role in the binding of FUS protein with Kapβ2. Mutations in this position (R521C and R521H) are the most predominant mutations associated with amyotrophic lateral sclerosis (ALS). However, the mechanism by which these mutations lead to ALS is poorly understood. We examined the binding behaviour of the mutants FUS (R521C) and FUS (R521H) with Kapβ2 through protein-protein docking and molecular dynamics simulation. The binding patterns of mutants were compared with the binding behaviour of wild FUS-Kapβ2. Our results suggest that these mutants have relatively weak binding affinity with Kapβ2 when compared with wild FUS-Kapβ2 as indicated by the lesser number of interactions found between the mutant FUS and Kapβ2. Hence, these mutations weakens the binding and this results in the cytoplasmic mislocalization of mutant FUS; and thereby it increases the severity of ALS.

A study of novel bilateral thermal capsulotomy with focused ultrasound for treatment-refractory obsessive-compulsive disorder: 2-year follow-up.

PubMed

Kim, Se Joo; Roh, Daeyoung; Jung, Hyun Ho; Chang, Won Seok; Kim, Chan-Hyung; Chang, Jin Woo

2018-05-02

Recently, a new thermal lesioning approach using magnetic-resonance-guided focused ultrasound (MRgFUS) was introduced for the treatment of neurologic disorders. However, only 2 studies have used this approach for treatment-refractory obsessive-compulsive disorder (OCD), and follow-up was short-term. We investigated the efficacy and safety of bilateral thermal lesioning of the anterior limb of the internal capsule using MRgFUS in patients with treatment-refractory OCD and followed them for 2 years. Eleven patients with treatment-refractory OCD were included in the study. Clinical outcomes were evaluated using the Yale-Brown Obsessive Compulsive Scale, the Clinical Global Impression scale (including improvement and severity), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A) at 1 week and 1, 3, 6, 12 and 24 months following MRgFUS. Neuropsychological functioning, Global Assessment of Functioning and adverse events were also assessed. After MRgFUS, Yale-Brown Obsessive Compulsive Scale scores decreased significantly across the 24-month follow-up period (mean ± standard deviation, 34.4 ± 2.3 at baseline v. 21.3 ± 6.2 at 24 months, p < 0.001). Scores on the Hamilton rating scales for depression and anxiety also significantly decreased from baseline to 24 months (HAM-D, 19.0 ± 5.3 v. 7.6 ± 5.3, p < 0.001; HAM-A, 22.4 ± 5.9 v. 7.9 ± 3.9, p < 0.001). Global Assessment of Functioning scores improved significantly (35.8 ± 4.9 at baseline v. 56.0 ± 10.3 at 24 months, p < 0.001) and Memory Quotient significantly improved, but other neuropsychological functions were unchanged. The side effects of MRgFUS included headache and vestibular symptoms, but these were mild and transient. The main limitations of this study were the small sample size and the open-label design. Bilateral thermal lesioning of the anterior limb of the internal capsule using MRgFUS may improve obsessive-compulsive, depressive and anxiety symptoms in patients with treatment-refractory OCD, without serious adverse effects.

The ALS gene FUS regulates synaptic transmission at the Drosophila neuromuscular junction

PubMed Central

Machamer, James B.; Collins, Sarah E.; Lloyd, Thomas E.

2014-01-01

Mutations in the RNA binding protein Fused in sarcoma (FUS) are estimated to account for 5–10% of all inherited cases of amyotrophic lateral sclerosis (ALS), but the function of FUS in motor neurons is poorly understood. Here, we investigate the early functional consequences of overexpressing wild-type or ALS-associated mutant FUS proteins in Drosophila motor neurons, and compare them to phenotypes arising from loss of the Drosophila homolog of FUS, Cabeza (Caz). We find that lethality and locomotor phenotypes correlate with levels of FUS transgene expression, indicating that toxicity in developing motor neurons is largely independent of ALS-linked mutations. At the neuromuscular junction (NMJ), overexpression of either wild-type or mutant FUS results in decreased number of presynaptic active zones and altered postsynaptic glutamate receptor subunit composition, coinciding with a reduction in synaptic transmission as a result of both reduced quantal size and quantal content. Interestingly, expression of human FUS downregulates endogenous Caz levels, demonstrating that FUS autoregulation occurs in motor neurons in vivo. However, loss of Caz from motor neurons increases synaptic transmission as a result of increased quantal size, suggesting that the loss of Caz in animals expressing FUS does not contribute to motor deficits. These data demonstrate that FUS/Caz regulates NMJ development and plays an evolutionarily conserved role in modulating the strength of synaptic transmission in motor neurons. PMID:24569165

Comparison of the clinical and cognitive features of genetically positive ALS patients from the largest tertiary center in Serbia.

PubMed

Marjanović, Ivan V; Selak-Djokić, Biljana; Perić, Stojan; Janković, Milena; Arsenijević, Vladimir; Basta, Ivana; Lavrnić, Dragana; Stefanova, Elka; Stević, Zorica

2017-06-01

Discovering novel mutations in C9orf72, FUS, ANG, and TDP-43 genes in ALS patients arises necessities for better clinical characterizations of these subjects. The aim is to determine clinical and cognitive profile of genetically positive Serbian ALS patients. 241 ALS patients were included in the study (17 familiar and 224 apparently sporadic). The following genes were analyzed: SOD1, C9orf72, ANG, FUS, and TDP-43. An extensive battery of classic neuropsychological tests was used in 27 ALS patients (22 SOD1 positive and 5 SOD1 negative) and 82 healthy controls (HCs). Overall 37 (15.4%) of 241 ALS patients carried mutations in tested genes-among 17 familiar ALS patients 16 (94.1%) were positive and among 224 apparently sporadic 21 (9.4%) had causative mutation. Mutations in SOD1 gene were the most common, representing 27 (73.0%) of all genetically positive ALS patients. The main clinical characteristics of SOD1 positive patients were: spinal onset in lower extremities, common sphincter and sensitive disturbances, and dysexecutive syndrome. Within SOD1 positive patients, we noticed somewhat earlier onset in patients with A145G, sensory and sphincter disturbances were dominant in patients with L144F, while D90A patients had significant sensory involvement. SOD1 negative group consisted of ten (27.0%) patients (six C9orf72, two ANG, one TDP-43, and one patient baring triple FUS, C9orf72 expansion, and ANG variants). Bulbar involvement and more extensive neuropsychological impairment (including executive, visuospatial, and memory difficulties) were the main features of SOD1 negative cohort. Our results suggest that meaningful clinical suspicion of certain ALS genotype might be made based on thorough clinical evaluation of patients.

Expulsion of Fibroids to the Endometrial Cavity after Magnetic Resonance Imaging-guided High Intensity Focused Ultrasound Surgery (MRgFUS) Treatment of Intramural Uterine Fibroids

PubMed Central

Jeong, Jae-Hyeok; Hong, Gil Pyo; Kim, Yu-Ri; Hong, Da Gyo; Ha, Jae-Eun; Yeom, Jung In; Kim, Eun-Jeong; Kim, Hyung-Il

2016-01-01

Objectives This report seeks to introduce some cases of the patients who received magnetic resonance imaging (MRI)-guided high intensity focused ultrasound (HIFU) surgery (MRgFUS)-based intramural uterine fibroids treatment where the post-MRgFUS intramural uterine fibroids decreased in its volume and protruded towards the endometrial cavity to be expelled by hysteroscopy. Methods Of the 157 patients who had received MRgFUS treatment in the Obstetrics and Gynecology of the Hospital from March, 2015 to February, 2016; this study examined 6 of the cases where, after high intensity focused ultrasound treatment, intramural uterine fibroids protruded towards the endometrial cavity to be removed by hysteroscopic myomectomy. The high intensity focused ultrasound utilized in the cases were Philips Achieva 1.5 Tesla MR (Philips Healthcare, Best, The Netherlands) and Sonalleve HIFU system. Results The volume of fibroids ranged from 26.0 cm3 to 199.5 cm3, averaging 95.6 cm3. The major axis length ranged from 4.0 cm to 8.2 cm, averaging 6.3 cm. Fibroid location in all of the patients was in intramural uterine before treatment but after the high intensity focused ultrasound treatment, the fibroids were observed to protrude towards the endometrial cavity in at least Day 5 or up to Day 73 to allow hysteroscopic myomectomy. Conclusions In some cases, after an intramural uterine fibroid is treated with MRgFUS, fibroid volume is decreased and the fibroid protrudes towards the endometrial cavity. In this case, hysteroscopic myomectomy can be a useful solution. PMID:28119893

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity

PubMed Central

Daigle, J Gavin; Krishnamurthy, Karthik; Ramesh, Nandini; Casci, Ian; Monaghan, John; McAvoy, Kevin; Godfrey, Earl W; Daniel, Dianne C.; Johnson, Edward M.; Monahan, Zach; Shewmaker, Frank; Pasinelli, Piera; Pandey, Udai Bhan

2016-01-01

Amyotrophic lateral Sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA binding proteins, have been linked to ALS pathology. Recently, Pur-alpha a DNA/RNA binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models. However, the function of Pur-alpha in regulating ALS pathogenesis has not been fully understood. We identified Pur-alpha as a novel component of cytoplasmic stress granules (SGs) in ALS patient cells carrying disease-causing mutations in FUS. When cells were challenged with stress, we observed that Pur-alpha co-localized with mutant FUS in ALS patient cells and became trapped in constitutive SGs. We also found that FUS physically interacted with Pur-alpha in mammalian neuronal cells. Interestingly, shRNA mediated knock down of endogenous Pur-alpha significantly reduced formation of cytoplasmic stress granules in mammalian cells suggesting that Pur-alpha is essential for the formation of SGs. Furthermore, ectopic expression of Pur-alpha blocked cytoplasmic mislocalization of mutant FUS and strongly suppressed toxicity associated with mutant FUS expression in primary motor neurons. Our data emphasizes the importance of stress granules in ALS pathogenesis and identifies Pur-alpha as a novel regulator of SG dynamics. PMID:26728149

The investigation of genetic and clinical features in Chinese patients with juvenile amyotrophic lateral sclerosis.

PubMed

Liu, Z-J; Lin, H-X; Liu, G-L; Tao, Q-Q; Ni, W; Xiao, B-G; Wu, Z-Y

2017-09-01

Juvenile amyotrophic lateral sclerosis (JALS) occurs at an age of onset below 25 years with a heterogeneous disease onset location, variable progression and survival time. To investigate whether an ALS gene profile could resolve any aspects of clinical symptom heterogeneity, we have used targeted sequencing technology in a cohort of 12 JALS patients of Chinese descent. We detected 5 likely pathogenic mutations, 2 in familial probands and 3 in sporadic patients. One was a known TARDBP mutation (p.G348V) and 4 were FUS frameshift mutations including a known p.Gln519Ilefs*9 mutation and 3 novel mutations, p.Gly515Valfs*14, p.Gly486Profs*30, and p.Arg498Alafs*32. Of the 4 FUS mutations, 2 were able to be confirmed as de novo mutations. The TARDBP mutation carrier showed a classic ALS phenotype. All patients with FUS mutations experienced limb weakness at an early age and developed bulbar symptoms during the disease course. FUS mutations have previously been associated with increased JALS disease progression, however, we found a large range 12 to 84 months in disease survival (mean 58.2 months). Our results justify future screening for variants in FUS as it remains the most frequent genetic determinant of early onset, JALS (found in 30% of our patients). © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A new polymorph of 4'-hydroxyvalerophenone revealed by thermoanalytical and X-ray diffraction studies

NASA Astrophysics Data System (ADS)

Lopes, Cátia S. D.; Bernardes, Carlos E. S.; Piedade, M. Fátima M.; Diogo, Hermínio P.; da Piedade, Manuel E. Minas

2017-04-01

A new polymorph of 1-(4-hydroxyphenyl)pentan-1-one (4'-hydroxyvalerophenone, HVP) was identified by using differential scanning calorimetry, hot stage microscopy, and X-ray powder diffraction. This novel crystal form (form II) was obtained by crystallization from melt. It has a fusion temperature of T fus = 324.3 ± 0.2 K and an enthalpy of fusion Δfus H m o = 18.14±0.18 kJ·mol-1. These values are significantly lower than those observed for the previously known phase (form I, monoclinic, space group P21/ c, T fus = 335.6 ± 0.7 K; Δfus H m o = 26.67±0.04 kJ·mol-1), which can be prepared by crystallization from ethanol. The results here obtained, therefore, suggest that form I is thermodynamically more stable than the newly identified form II and, furthermore, that the two polymorphs are monotropically related.

FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis

PubMed Central

Deng, Han-Xiang; Zhai, Hong; Bigio, Eileen H.; Yan, Jianhua; Fecto, Faisal; Ajroud, Kaouther; Mishra, Manjari; Ajroud-Driss, Senda; Heller, Scott; Sufit, Robert; Siddique, Nailah; Mugnaini, Enrico; Siddique, Teepu

2014-01-01

Objective Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration. Most cases of ALS are sporadic (SALS), but about 5-10% of ALS cases are familial (FALS). Recent studies have shown that mutations in FUS are causal in approximately 4-5% of FALS and some apparent SALS cases. The pathogenic mechanism of the mutant FUS-mediated ALS and potential roles of FUS in non-FUS ALS remain to be investigated. Methods Immunostaining was performed on postmortem spinal cords from 78 ALS cases, including SALS (n=52), ALS with dementia (ALS/dementia, n=10) and FALS (n=16). In addition, postmortem brains or spinal cords from 22 cases with or without frontotemporal lobar degeneration (FTLD) were also studied. In total, 100 cases were studied. Results FUS-immunoreactive inclusions were observed in spinal anterior horn neurons in all sporadic and familial ALS cases, except for those with SOD1 mutations. The FUS-containing inclusions were also immunoreactive with antibodies to TDP43, p62 and ubiquitin. A fraction of tested FUS antibodies recognized FUS inclusions and an unusual antigen retrieval appeared to be important for detection of the skein-like FUS inclusions. Interpretation Although mutations in FUS account for only a small fraction of FALS and SALS, our data suggest that FUS protein may be a common component of the cellular inclusions in non-SOD1 ALS and some other neurodegenerative conditions, implying a shared pathogenic pathway underlying SALS, non-SOD1 FALS, ALS/dementia and related disorders. Our data also indicate that SOD1-linked ALS may have a distinct pathogenic pathway from SALS and other types of FALS. PMID:20517935

CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs.

PubMed

Wang, Lixia; Yi, Fei; Fu, Lina; Yang, Jiping; Wang, Si; Wang, Zhaoxia; Suzuki, Keiichiro; Sun, Liang; Xu, Xiuling; Yu, Yang; Qiao, Jie; Belmonte, Juan Carlos Izpisua; Yang, Ze; Yuan, Yun; Qu, Jing; Liu, Guang-Hui

2017-05-01

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts of familial ALS patients bearing SOD1 +/A272C and FUS +/G1566A mutations, respectively. We further generated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing (RNA-seq) analysis of motor neurons derived from SOD1 +/A272C and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

LEC1 (NF-YB9) directly interacts with LEC2 to control gene expression in seed.

PubMed

Boulard, C; Thévenin, J; Tranquet, O; Laporte, V; Lepiniec, L; Dubreucq, B

2018-05-01

The LAFL transcription factors LEC2, ABI3, FUS3 and LEC1 are master regulators of seed development. LEC2, ABI3 and FUS3 are closely related proteins that contain a B3-type DNA binding domain. We have previously shown that LEC1 (a NF-YB type protein) can increase LEC2 and ABI3 but not FUS3 activity. Interestingly, FUS3, LEC2 and ABI3 contain a B2 domain, the function of which remains elusive. We showed that LEC1 and LEC2 partially co-localised in the nucleus of developing embryos. By comparing protein sequences from various species, we identified within the B2 domains a set of highly conserved residues (i.e. TKxxARxxRxxAxxR). This domain directly interacts with LEC1 in yeast. Mutations of the conserved amino acids of the motif in the B2 domain abolished this interaction both in yeast and in moss protoplasts and did not alter the nuclear localisation of LEC2 in planta. Conversely, the mutations of key amino acids for the function of LEC1 in planta (D86K) prevented the interaction with LEC2. These results provide molecular evidences for the binding of LEC1 to B2-domain containing transcription factors, to form heteromers, involved in the control of gene expression. Copyright © 2018 Elsevier B.V. All rights reserved.

Low-intensity focused ultrasound alters the latency and spatial patterns of sensory-evoked cortical responses in vivo

NASA Astrophysics Data System (ADS)

Fisher, Jonathan A. N.; Gumenchuk, Iryna

2018-06-01

Objective. The use of transcranial, low intensity focused ultrasound (FUS) is an emerging neuromodulation technology that shows promise for both therapeutic and research applications. Among many, one of the most exciting applications is the use of FUS to rehabilitate or augment human sensory capabilities. While there is compelling empirical evidence demonstrating this capability, basic questions regarding the spatiotemporal extent of the modulatory effects remain. Our objective was to assess the basic, yet often overlooked hypothesis that FUS in fact alters sensory-evoked neural activity within the region of the cerebral cortex at the beam’s focus. Approach. To address this knowledge gap, we developed an approach to optically interrogate patterns of neural activity in the cortex directly at the acoustic focus, in vivo. Implementing simultaneous wide-field optical imaging and FUS stimulation in mice, our experiments probed somatosensory-evoked electrical activity through the use of voltage sensitive dyes (VSDs) and, in transgenic mice expressing GCaMP6f, monitored associated Ca2+ responses. Main results. Our results demonstrate that low-intensity FUS alters both the kinetics and spatial patterns of neural activity in primary somatosensory cortex at the acoustic focus. When preceded by 1 s of pulsed ultrasound at intensities below 1 W cm‑2 (I sppa), the onset of sensory-evoked cortical responses occurred 3.0  ±  0.7 ms earlier and altered the surface spatial morphology of Ca2+ responses. Significance. These findings support the heretofore unconfirmed assumption that FUS-induced sensory modulation reflects, at least in part, altered reactivity in primary sensory cortex at the site of sonication. The findings are significant given the interest in using FUS to target and alter spatial aspects of sensory receptive fields on the cerebral cortex.

Low-intensity focused ultrasound alters the latency and spatial patterns of sensory-evoked cortical responses in vivo.

PubMed

Fisher, Jonathan A N; Gumenchuk, Iryna

2018-06-01

The use of transcranial, low intensity focused ultrasound (FUS) is an emerging neuromodulation technology that shows promise for both therapeutic and research applications. Among many, one of the most exciting applications is the use of FUS to rehabilitate or augment human sensory capabilities. While there is compelling empirical evidence demonstrating this capability, basic questions regarding the spatiotemporal extent of the modulatory effects remain. Our objective was to assess the basic, yet often overlooked hypothesis that FUS in fact alters sensory-evoked neural activity within the region of the cerebral cortex at the beam's focus. To address this knowledge gap, we developed an approach to optically interrogate patterns of neural activity in the cortex directly at the acoustic focus, in vivo. Implementing simultaneous wide-field optical imaging and FUS stimulation in mice, our experiments probed somatosensory-evoked electrical activity through the use of voltage sensitive dyes (VSDs) and, in transgenic mice expressing GCaMP6f, monitored associated Ca 2+ responses. Our results demonstrate that low-intensity FUS alters both the kinetics and spatial patterns of neural activity in primary somatosensory cortex at the acoustic focus. When preceded by 1 s of pulsed ultrasound at intensities below 1 W cm -2 (I sppa ), the onset of sensory-evoked cortical responses occurred 3.0  ±  0.7 ms earlier and altered the surface spatial morphology of Ca 2+ responses. These findings support the heretofore unconfirmed assumption that FUS-induced sensory modulation reflects, at least in part, altered reactivity in primary sensory cortex at the site of sonication. The findings are significant given the interest in using FUS to target and alter spatial aspects of sensory receptive fields on the cerebral cortex.

Arabidopsis cop8 and fus4 mutations define the same gene that encodes subunit 4 of the COP9 signalosome.

PubMed Central

Serino, G; Tsuge, T; Kwok, S; Matsui, M; Wei, N; Deng, X W

1999-01-01

The pleiotropic constitutive photomorphogenic/deetiolated/fusca (cop/det/fus) mutants of Arabidopsis exhibit features of light-grown seedlings when grown in the dark. Cloning and biochemical analysis of COP9 have revealed that it is a component of a multiprotein complex, the COP9 signalosome (previously known as the COP9 complex). Here, we compare the immunoaffinity and the biochemical purification of the COP9 signalosome from cauliflower and confirm its eight-subunit composition. Molecular cloning of subunit 4 of the complex revealed that it is a proteasome-COP9 complex-eIF3 domain protein encoded by a gene that maps to chromosome 5, near the chromosomal location of the cop8 and fus4 mutations. Genetic complementation tests showed that the cop8 and fus4 mutations define the same locus, now designated as COP8. Molecular analysis of the subunit 4-encoding gene in both cop8 and fus4 mutants identified specific molecular lesions, and overexpression of the subunit 4 cDNA in a cop8 mutant background resulted in complete rescue of the mutant phenotype. Thus, we conclude that COP8 encodes subunit 4 of the COP9 signalosome. Examination of possible molecular interactions by using the yeast two-hybrid assay indicated that COP8 is capable of strong self-association as well as interaction with COP9, FUS6/COP11, FUS5, and Arabidopsis JAB1 homolog 1, the latter four proteins being previously defined subunits of the Arabidopsis COP9 signalosome. A comparative sequence analysis indicated that COP8 is highly conserved among multicellular eukaryotes and is also similar to a subunit of the 19S regulatory particle of the 26S proteasome. PMID:10521526

FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.

PubMed

Qamar, Seema; Wang, GuoZhen; Randle, Suzanne J; Ruggeri, Francesco Simone; Varela, Juan A; Lin, Julie Qiaojin; Phillips, Emma C; Miyashita, Akinori; Williams, Declan; Ströhl, Florian; Meadows, William; Ferry, Rodylyn; Dardov, Victoria J; Tartaglia, Gian G; Farrer, Lindsay A; Kaminski Schierle, Gabriele S; Kaminski, Clemens F; Holt, Christine E; Fraser, Paul E; Schmitt-Ulms, Gerold; Klenerman, David; Knowles, Tuomas; Vendruscolo, Michele; St George-Hyslop, Peter

2018-04-19

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Detection of FUS induced lesions by MR-elastography

NASA Astrophysics Data System (ADS)

Jenne, Jürgen W.; Divkovic, Gabriela; Siegler, Peter

2005-03-01

MRI (Magnetic Resonance Imaging) has proven to be an exact and safe method to guide FUS (Focused ultrasound surgery) therapy. Besides its excellent soft tissue contrast, important for a precise treatment planning, MRI allows fast and reliable measurement of temperature changes caused by FUS application. In this study we compare standard MR-imaging parameters (relaxation times, spin density) with MR measured tissue elasticity in order to differentiate between FUS induced thermal lesions and normal tissue in vitro. In addition we tried to observe FUS induced shear waves by dynamic MRE. FUS was performed with an MRI compatible 1.7 MHz fixed focus transducer (NA 0.44; f'= 68 mm). With increasing acoustic power (30-70 W) the difference in relaxation times T1, T2 and spin density between normal and lesioned tissue also increased. We measured values in the range 5% to 24%. The difference in tissue strain had a value of 23% at 30 W and was nearly constant (52-61%) at higher FUS power. Compared with standard MRI parameters MRE showed a clearly higher sensitivity to detect FUS induced lesions. With our experimental setup it was possible to image FUS induced shear waves. The measured wave length at 400Hz repetition rate was 7 mm. However, further experiments are necessary to utilize the potential of MRE in practice.

The prion-like domain of FUS is multiphosphorylated following DNA damage without altering nuclear localization.

PubMed

Rhoads, Shannon N; Monahan, Zachary T; Yee, Debra S; Leung, Andrew Y; Newcombe, Cameron G; O'Meally, Robert N; Cole, Robert N; Shewmaker, Frank P

2018-06-13

FUS is an abundant, predominantly nuclear protein involved in RNA processing. Under various conditions, FUS functionally associates with RNA and other macromolecules to form distinct, reversible phase-separated liquid structures. Persistence of the phase-separated state and increased cytoplasmic localization are both hypothesized to predispose FUS to irreversible aggregation, which is a pathological hallmark of subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. We previously showed that phosphorylation of FUS's prion-like domain suppressed phase separation and toxic aggregation, proportionally to the number of added phosphates. However, phosphorylation of FUS's prion-like domain was previously reported to promote its cytoplasmic localization, potentially favoring pathological behavior. Here, we used mass spectrometry and human cell models to further identify phosphorylation sites within FUS's prion-like domain, specifically following DNA-damaging stress. In total, 28 putative sites have been identified, about half of which are DNA-dependent protein kinase (DNA-PK) consensus sites. Custom antibodies were developed to confirm the phosphorylation of two of these sites (Ser26 and Ser30). Both sites were usually phosphorylated in a sub-population of cellular FUS following a variety of DNA-damaging stresses, but not necessarily equally or simultaneously. Importantly, we found DNA-PK-dependent multi-phosphorylation of FUS's prion-like domain does not cause cytoplasmic localization.

A Yeast Model of FUS/TLS-Dependent Cytotoxicity

PubMed Central

Ju, Shulin; Tardiff, Daniel F.; Han, Haesun; Divya, Kanneganti; Zhong, Quan; Maquat, Lynne E.; Bosco, Daryl A.; Hayward, Lawrence J.; Brown, Robert H.; Lindquist, Susan; Ringe, Dagmar; Petsko, Gregory A.

2011-01-01

FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression. PMID:21541368

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) of uterine fibroids in Singapore.

PubMed

Han, Nian-Lin R; Ong, Chiou Li

2014-11-01

Uterine fibroids are the most common type of gynaecologic benign tumours, occurring in 25% to 50% of women during their reproductive lives. About half of the affected women have clinically significant symptoms, including abnormal bleeding, menstrual pain, frequent urination, constipation and abdominal distension. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) has been used to treat patients with benign lesions and a variety of malignancies. The objective of this study is to evaluate symptom relief before and after MR-guided ultrasound ablation of fibroids. A total of 37 patients with symptomatic uterine fibroids were treated in this study. MRgFUS treatment led to a significant, time-dependent decrease in not only Symptom Severity Scores (SSS), but also the mean fibroid volume. The average reductions in volume were 41.6% and 52.6% at 6 months and 12 months respectively (P <0.05). The mean SSS of the 37 patients was 41.7 ± 2.8 before treatment whereas the average SSS was 26.9 ± 3.6, 20.7 ± 3.4, 18.5 ± 3.6, 16.5 ± 7.1, 9.8 ± 3.6 at 3 months, 6 months, 1 year, 2 years, and 3 to 4 years respectively. The decrease in scores was significant at all time points up to 3 to 4 years (P <0.05 and P <0.001). MRgFUS is a safe and effective non-invasive treatment for patients with symptomatic fibroids.

TDP-43/FUS in Motor Neuron Disease: Complexity and Challenges

PubMed Central

Mitra, Joy; Hegde, Pavana M.; Stowell, Sara E.; Liachko, Nicole F; Kraemer, Brian C.; Garruto, Ralph M.; Rao, K. S.; Hegde, Muralidhar L.

2016-01-01

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases. PMID:27693252

PET/CT imaging evidence of FUS-mediated (18)F-FDG uptake changes in rat brain

PubMed Central

Kim, Hyungmin; Park, Mi-Ae; Wang, Shuyan; Chiu, Alan; Fischer, Krisztina; Yoo, Seung-Schik

2013-01-01

Purpose: Transcranial focused ultrasound (FUS) delivers highly focused acoustic energy to a small region of the brain in a noninvasive manner. Recent studies have revealed that FUS, which is administered either in pulsed or continuous waves, can elicit or suppress neural tissue excitability. This neuromodulatory property of FUS has been demonstrated via direct motion detection, electrophysiological recordings, functional magnetic resonance imaging (fMRI), confocal imaging, and microdialysis sampling of neurotransmitters. This study presents new evidence of local increase in glucose metabolism induced by FUS to the rat brain using FDG (18-fludeoxyglucose) positron emission tomography (PET). Methods: Sprague–Dawley rats underwent sonication to a unilateral hemispheric area of the brain prior to PET scan. The pulsed sonication (350 kHz, tone burst duration of 0.5 ms, pulse repetition frequency of 1 kHz, and duration of 300 ms) was applied in 2 s intervals for 40 min immediately after the FDG injection via tail vein. Subsequently, the PET was acquired in dynamic list-mode to image FDG activity for an hour, and reconstructed into a single volume representing standardized uptake value (SUV). The raw SUV as well as its asymmetry index (AI) were measured from five different volume-of-interests (VOIs) of the brain for both hemispheres, and compared between sonicated and unsonicated groups. Results: Statistically significant hemispheric changes in SUV were observed only at the center of sonication focus within the FUS group [paired t-test; t(7) = 3.57, p < 0.05]. There were no significant hemispheric differences in SUV within the control group in any of the VOIs. A statistically significant elevation in AI (t-test; t(7) = 3.40, p < 0.05) was observed at the center of sonication focus (7.9 ± 2.5%, the deviations are in standard error) among the FUS group when compared to the control group (−0.8 ± 1.2%). Conclusions: Spatially distinct increases in the glucose metabolic activity in the rat brain is present only at the center of sonication focus, suggesting localized functional neuromodulation mediated by the sonication. PMID:23464343

Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Zi Chao; Chook, Yuh Min

Mutations in the proline/tyrosine–nuclear localization signal (PY-NLS) of the Fused in Sarcoma protein (FUS) cause amyotrophic lateral sclerosis (ALS). Here we report the crystal structure of the FUS PY-NLS bound to its nuclear import receptor Karyopherinβ2 (Kapβ2; also known as Transportin). The FUS PY-NLS occupies the structurally invariant C-terminal arch of Kapβ2, tracing a path similar to that of other characterized PY-NLSs. Unlike other PY-NLSs, which generally bind Kapβ2 in fully extended conformations, the FUS peptide is atypical as its central portion forms a 2.5-turn α-helix. The Kapβ2-binding epitopes of the FUS PY-NLS consist of an N-terminal PGKM hydrophobic motif,more » a central arginine-rich α-helix, and a C-terminal PY motif. ALS mutations are found almost exclusively within these epitopes. Each ALS mutation site makes multiple contacts with Kapβ2 and mutations of these residues decrease binding affinities for Kapβ2 (K D for wild-type FUS PY-NLS is 9.5 nM) up to ninefold. Thermodynamic analyses of ALS mutations in the FUS PY-NLS show that the weakening of FUS-Kapβ2 binding affinity, the degree of cytoplasmic mislocalization, and ALS disease severity are correlated.« less

PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage

PubMed Central

Rulten, Stuart L.; Rotheray, Amy; Green, Ryan L.; Grundy, Gabrielle J.; Moore, Duncan A. Q.; Gómez-Herreros, Fernando; Hafezparast, Majid; Caldecott, Keith W

2014-01-01

Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUSR521G, harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS. PMID:24049082

Cost-effectiveness of uterine-preserving procedures for the treatment of uterine fibroid symptoms in the USA.

PubMed

Cain-Nielsen, Anne H; Moriarty, James P; Stewart, Elizabeth A; Borah, Bijan J

2014-09-01

To evaluate the cost-effectiveness of the following three treatments of uterine fibroids in a population of premenopausal women who wish to preserve their uteri: myomectomy, magnetic resonance-guided focused ultrasound (MRgFUS) and uterine artery embolization (UAE). A decision analytic Markov model was constructed. Cost-effectiveness was calculated in terms of US$ per quality-adjusted life year (QALY) over 5 years. Two types of costs were calculated: direct costs only, and the sum of direct and indirect (productivity) costs. Women in the hypothetical cohort were assessed for treatment type eligibility, were treated based on eligibility, and experienced adequate or inadequate symptom relief. Additional treatment (myomectomy) occurred for inadequate symptom relief or recurrence. Sensitivity analysis was conducted to evaluate uncertainty in the model parameters.  In the base case, myomectomy, MRgFUS and UAE had the following combinations of mean cost and mean QALYs, respectively: US$15,459, 3.957; US$15,274, 3.953; and US$18,653, 3.943. When incorporating productivity costs, MRgFUS incurred a mean cost of US$21,232; myomectomy US$22,599; and UAE US$22,819. Using probabilistic sensitivity analysis (PSA) and excluding productivity costs, myomectomy was cost effective at almost every decision threshold. Using PSA and incorporating productivity costs, myomectomy was cost effective at decision thresholds above US$105,000/QALY; MRgFUS was cost effective between US$30,000 and US$105,000/QALY; and UAE was cost effective below US$30,000/QALY. Myomectomy, MRgFUS, and UAE were similarly effective in terms of QALYs gained. Depending on assumptions about costs and willingness to pay for additional QALYs, all three treatments can be deemed cost effective in a 5-year time frame.

Autophagy meets fused in sarcoma-positive stress granules.

PubMed

Matus, Soledad; Bosco, Daryl A; Hetz, Claudio

2014-12-01

Mutations in fused in sarcoma and/or translocated in liposarcoma (FUS, TLS or FUS) are linked to familial cases of amyotrophic lateral sclerosis (ALS). Mutant FUS selectively accumulates into discrete cytosolic structures known as stress granules under various stress conditions. In addition, mutant FUS expression can alter the dynamics and morphology of stress granules. Although the link between mutant FUS and stress granules is well established, the mechanisms modulating stress granule formation and disassembly in the context of ALS are poorly understood. In this issue of Neurobiology of Aging, Ryu et al. uncover the impact of autophagy on the potential toxicity of mutant FUS-positive stress granules. The authors provide evidence indicating that enhanced autophagy activity reduces the number of stress granules, which in the case of cells containing mutant FUS-positive stress granules, is neuroprotective. Overall, this study identifies an intersection between the proteostasis network and alterations in RNA metabolism in ALS through the dynamic assembly and disassembly of stress granules. Copyright © 2014 Elsevier Inc. All rights reserved.

Full-wave acoustic and thermal modeling of transcranial ultrasound propagation and investigation of skull-induced aberration correction techniques: a feasibility study.

PubMed

Kyriakou, Adamos; Neufeld, Esra; Werner, Beat; Székely, Gábor; Kuster, Niels

2015-01-01

Transcranial focused ultrasound (tcFUS) is an attractive noninvasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of tcFUS therapy, as its heterogeneous nature and acoustic characteristics induce significant distortion of the acoustic energy deposition, focal shifts, and thermal gain decrease. Phased-array transducers allow for partial compensation of skull-induced aberrations by application of precalculated phase and amplitude corrections. An integrated numerical framework allowing for 3D full-wave, nonlinear acoustic and thermal simulations has been developed and applied to tcFUS. Simulations were performed to investigate the impact of skull aberrations, the possibility of extending the treatment envelope, and adverse secondary effects. The simulated setup comprised an idealized model of the ExAblate Neuro and a detailed MR-based anatomical head model. Four different approaches were employed to calculate aberration corrections (analytical calculation of the aberration corrections disregarding tissue heterogeneities; a semi-analytical ray-tracing approach compensating for the presence of the skull; two simulation-based time-reversal approaches with and without pressure amplitude corrections which account for the entire anatomy). These impact of these approaches on the pressure and temperature distributions were evaluated for 22 brain-targets. While (semi-)analytical approaches failed to induced high pressure or ablative temperatures in any but the targets in the close vicinity of the geometric focus, simulation-based approaches indicate the possibility of considerably extending the treatment envelope (including targets below the transducer level and locations several centimeters off the geometric focus), generation of sharper foci, and increased targeting accuracy. While the prediction of achievable aberration correction appears to be unaffected by the detailed bone-structure, proper consideration of inhomogeneity is required to predict the pressure distribution for given steering parameters. Simulation-based approaches to calculate aberration corrections may aid in the extension of the tcFUS treatment envelope as well as predict and avoid secondary effects (standing waves, skull heating). Due to their superior performance, simulationbased techniques may prove invaluable in the amelioration of skull-induced aberration effects in tcFUS therapy. The next steps are to investigate shear-wave-induced effects in order to reliably exclude secondary hot-spots, and to develop comprehensive uncertainty assessment and validation procedures.

FET Proteins TAF15 and EWS Are Selective Markers that Distinguish FTLD with FUS Pathology from Amyotrophic Lateral Sclerosis with "FUS" Mutations

ERIC Educational Resources Information Center

Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; DeJesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A.; Munoz, David G.; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee-Cyn; Bilbao, Juan; Rademakers, Rosa; Haass, Christian; Mackenzie, Ian R. A.

2011-01-01

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in "FUS" as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with "FUS" mutations. The mechanisms…

Enhanced homing permeability and retention of bone marrow stromal cells (BMSC) by non-invasive pulsed focused ultrasound

PubMed Central

Ziadloo, Ali; Burks, Scott R.; Gold, Eric M.; Lewis, Bobbi K.; Chaudhry, Aneeka; Merino, Maria J.; Frenkel, Victor; Frank, Joseph A.

2012-01-01

Bone marrow stromal cells (BMSC) have shown significant promise in the treatment of disease, but their therapeutic efficacy is often limited by inefficient homing of systemically-administered cells, which results in low numbers of cells accumulating at sites of pathology. BMSC home to areas of inflammation where local expression of integrins and chemokine gradients are present. We demonstrated that non-destructive pulsed focused ultrasound (pFUS) exposures that emphasize the mechanical effects of ultrasound-tissue interactions induced local and transient elevations of chemoattractants (i.e., cytokines, integrins, and growth factors) in the murine kidney. pFUS-induced upregulation of cytokines occurred through approximately 1 day post-treatment and returned to contralateral kidney levels by day 3. This window of significant increases in cytokine expression was accompanied by local increases of other trophic factors and integrins that have been shown to promote BMSC homing. When BMSC were administered intravenously following pFUS treatment to a single kidney, enhanced homing, permeability, and retention of BMSC was observed in the treated kidney versus the contralateral kidney. Histological analysis revealed up to 8 times more BMSC in the peritubular regions of the treated kidneys on days 1 and 3 post-treatment. Furthermore, cytokine levels in pFUS-treated kidneys following BMSC administration were found to be similar to controls, suggesting modulation of cytokine levels by BMSC. pFUS could potentially improve cell-based therapies as a noninvasive modality to target BMSC homing by establishing local chemoattractant gradients and increasing expression of integrins to enhance tropism of BMSC toward treated tissues. PMID:22593018

Deficient RNA-editing enzyme ADAR2 in an amyotrophic lateral sclerosis patient with a FUS(P525L) mutation.

PubMed

Aizawa, Hitoshi; Hideyama, Takuto; Yamashita, Takenari; Kimura, Takashi; Suzuki, Naoki; Aoki, Masashi; Kwak, Shin

2016-10-01

Mutations in the fused in sarcoma (FUS) gene can cause amyotrophic lateral sclerosis (ALS), and FUS gene mutations have been reported in sporadic ALS patients with basophilic cytoplasmic inclusions. Deficiency of adenosine deaminase acting on RNA 2 (ADAR2), an enzyme that specifically catalyzes GluA2 Q/R site-editing, has been reported in considerable proportions of spinal motor neurons of the majority of sporadic ALS patients. We describe the relationship between GluA2 Q/R site-editing efficiency and FUS-positive inclusions in a patient with FUS(P525L). A 24-year-old woman with ALS presented with basophilic cytoplasmic inclusions, significantly reduced GluA2 Q/R site-editing efficiency in the spinal motor neurons, and markedly decreased ADAR2 mRNA levels. Neuropathologic examination showed that not all spinal motor neurons expressed ADAR2 and revealed FUS-positive cytoplasmic inclusions in motor neurons irrespective of ADAR2 immunoreactivity. There were no phosphorylated transactive response (TAR) DNA-binding protein 43 kDa (TDP-43)-positive inclusions, indicating that there was no tight correlation between ADAR2 deficiency and TDP-43 deposition. ADAR2 deficiency can occur in ALS patients with a FUS(P525L) mutation and is unrelated to the presence of FUS-positive inclusions. FUS-associated ALS may share neurodegenerative characteristics with classical sporadic ALS. Copyright © 2016 Elsevier Ltd. All rights reserved.

A follow-up urine sample has limited value after treatment for urinary tract infection in children.

PubMed

Lytzen, Rebekka; Kaalund-Jørgensen, Kristine; Ahmed, Akhlaq; Abd-El-Redda, Haidar Karim; Thorup, Jørgen; Knudsen, Jenny Dahl; Cortes, Dina

2015-01-01

A routine follow-up urine sample (FUS) in the form of a midstream urine sample (MSU) is recommended after treatment for urinary tract infection (UTI) according to the Danish Paediatric Society (DPS) and "Lægehåndbogen" published by Danish Regions. We studied the effect of FUS with a focus on patients without symptoms at the time of FUS. Consecutive patients below 16.0 years treated for upper or lower UTI from 1 January 2009 to 31 December 2009 at Hvidovre Hospital in accordance with the guidelines of the department and the DPS. All patients were asked to provide a FUS within 21 days. A total of 87 patients were treated for upper UTI: 59 girls and 28 boys, the median age was 1.1 year (range: 0.1-15.6 years); and 42 girls were treated for lower UTI, their median age was 8.2 years (range: 2.5-15.3 years). After treatment, the risk of a UTI was 0% (0/87) after upper UTI versus 19% (8/42) after lower UTI (Fisher's exact test (FE), p < 0.0001). Among those without symptoms at FUS, the risk of a UTI was 0% (0/75) (95% confidence interval (CI): 0-4.9%) after upper UTI versus 4% (1/26) (95% CI: 0.1-19.6%) after lower UTI (FE, p = 0.2754). The cost of requesting a FUS in patients without symptoms was 166 euro after treatment for upper UTI and 66 euro after treatment of lower UTI. We do not recommend a FUS after treatment for UTI as the 95% CI of risk of missing UTI after treatment for upper UTI was below 5%. This strategy will save the patients/families and the health-care system. However, if a child has symptoms after treatment for UTI, it must be examined. not relevant. The study was approved by the Danish Data Protection Agency (J. no. 2007-58-0015).

Neurosurgical Applications of High-Intensity Focused Ultrasound with Magnetic Resonance Thermometry.

PubMed

Colen, Rivka R; Sahnoune, Iman; Weinberg, Jeffrey S

2017-10-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) has potential noninvasive effects on targeted tissue. MRgFUS integrates MRI and focused ultrasound surgery (FUS) into a single platform. MRI enables visualization of the target tissue and monitors ultrasound-induced effects in near real-time during FUS treatment. MRgFUS may serve as an adjunct or replace invasive surgery and radiotherapy for specific conditions. Its thermal effects ablate tumors in locations involved in movement disorders and essential tremors. Its nonthermal effects increase blood-brain barrier permeability to enhance delivery of therapeutics and other molecules. Copyright © 2017 Elsevier Inc. All rights reserved.

Mutations in FUS cause FALS and SALS in French and French Canadian populations

PubMed Central

Belzil, V. V.; Valdmanis, P. N.; Dion, P. A.; Daoud, H.; Kabashi, E.; Noreau, A.; Gauthier, J.; Hince, P.; Desjarlais, A.; Bouchard, J. -P.; Lacomblez, L.; Salachas, F.; Pradat, P. -F.; Camu, W.; Meininger, V.; Dupré, N.; Rouleau, G. A.

2009-01-01

Background: The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. Methods: To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. Results: In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Conclusions: Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis. PMID:19741216

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

PubMed

Belzil, V V; Valdmanis, P N; Dion, P A; Daoud, H; Kabashi, E; Noreau, A; Gauthier, J; Hince, P; Desjarlais, A; Bouchard, J-P; Lacomblez, L; Salachas, F; Pradat, P-F; Camu, W; Meininger, V; Dupré, N; Rouleau, G A

2009-10-13

The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

Identification and regulation of fusA, the polyketide synthase gene responsible for fusarin production in Fusarium fujikuroi.

PubMed

Díaz-Sánchez, Violeta; Avalos, Javier; Limón, M Carmen

2012-10-01

Fusarins are a class of mycotoxins of the polyketide family produced by different Fusarium species, including the gibberellin-producing fungus Fusarium fujikuroi. Based on sequence comparisons between polyketide synthase (PKS) enzymes for fusarin production in other Fusarium strains, we have identified the F. fujikuroi orthologue, called fusA. The participation of fusA in fusarin biosynthesis was demonstrated by targeted mutagenesis. Fusarin production is transiently stimulated by nitrogen availability in this fungus, a regulation paralleled by the fusA mRNA levels in the cell. Illumination of the cultures results in a reduction of the fusarin content, an effect partially explained by a high sensitivity of these compounds to light. Mutants of the fusA gene exhibit no external phenotypic alterations, including morphology and conidiation, except for a lack of the characteristic yellow and/or orange pigmentation of fusarins. Moreover, the fusA mutants are less efficient than the wild type at degrading cellophane on agar cultures, a trait associated with pathogenesis functions in Fusarium oxysporum. The fusA mutants, however, are not affected in their capacities to grow on plant tissues.

MR guided FUS therapy with a Robotic Assistance System

NASA Astrophysics Data System (ADS)

Jenne, Jürgen W.; Krafft, Axel J.; Maier, Florian; Rauschenberg, Jaane; Semmler, Wolfhard; Huber, Peter E.; Bock, Michael

2009-04-01

Magnetic Resonance imaging guided Focus Ultrasound Surgery (MRgFUS) is a highly precise method to ablate tissue non-invasively. To date, there is only one commercial MRgFUS system available and only a few are in a prototype stage. The objective of this ongoing project is to establish an MRgFUS therapy unit as add-on for a commercially available robotic assistance system originally designed for percutaneous needle interventions in whole-body MR scanners.

Evaluation of mineral oil as an acoustic coupling medium in clinical MRgFUS.

PubMed

Gorny, K R; Hangiandreou, N J; Hesley, G K; Felmlee, J P

2007-01-07

We empirically evaluate mineral oil as an alternative to the mixture of de-gassed water and ultrasound gel, which is currently used as an acoustic coupling medium in clinical magnetic resonance guided focused ultrasound (MRgFUS) treatments. The tests were performed on an ExAblate 2000 MRgFUS system (InSightec Inc., Haifa, Israel) using a clinical patient set-up. Acoustic reflections, treatment temperatures, sonication spot dimensions and position with respect to target location were measured, using both coupling media, in repeated sonications in a tissue mimicking gel phantom. In comparison with the water-gel mix, strengths of acoustic reflections from coupling layers prepared with mineral oil were on average 39% lower and the difference was found to be statistically significant (p = 3.3 x 10(-8)). The treatment temperatures were found to be statistically equivalent for both coupling media, although temperatures corresponding to mineral oil tended to be somewhat higher (on average 1.9 degrees C) and their standard deviations were reduced by about 1 degrees C. Measurements of sonication spot dimensions and positions with respect to target location did not reveal systematic differences. We conclude that mineral oil may be used as an effective non-evaporating acoustic coupling medium for clinical MRgFUS treatments.

The Dependence of the Ultrasound-Induced Blood-Brain Barrier Opening Characteristics on Microbubble Size In Vivo

NASA Astrophysics Data System (ADS)

Choi, James J.; Feshitan, Jameel A.; Wang, Shougang; Tung, Yao-Sheng; Baseri, Babak; Borden, Mark A.; Konofagou, Elisa E.

2009-04-01

Recent neuropharmaceutical developments have led to potent disease-modifying drugs. In spite of these advancements, most agents cannot traverse the blood-brain barrier (BBB) and deposit in the brain. Focused ultrasound (FUS) with microbubbles has been shown to induce noninvasive, localized, and transient BBB opening. Although promising, safety and efficacy concerns still remain. Previously reported experiments used conventional imaging contrast agents that have a wide size distribution. In this study, we hypothesize that BBB opening characteristics are dependent on bubble diameter. A 25 μl bolus of in-house manufactured, lipid-shelled bubbles with either 1-2 or 4-5 μm diameter ranges was injected intravenously. Pulsed FUS (frequency: 1.5 MHz, peak-negative pressure: 146-607 kPa, duty cycle: 20%, duration: 1-min) was then applied to the left hippocampus of mice (n = 16) in vivo through the intact skin and skull. MRI or fluorescence microscopy was used to determine BBB opening. Contrast-enhanced (Omniscan™; 0.75 mL; molecular weight: 574 Da) MRI (9.4-T) was acquired on multiple days after sonication to determine BBB opening and closing. Fluorescence microscopy was also used to determine the feasibility of delivering large, 3 kDa dextran compounds through the BBB. The BBB opening acoustic pressure threshold for the 4-5μm bubbles was in the 146-304 kPa range while the threshold for the 1-2μm bubbles was higher. In conclusion, FUS-induced BBB opening and closing was shown to be dependent on the bubble diameter indicating the possibility of specifically designing bubbles to enhance this therapeutic application.

In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice.

PubMed

Tung, Yao-Sheng; Vlachos, Fotios; Choi, James J; Deffieux, Thomas; Selert, Kirsten; Konofagou, Elisa E

2010-10-21

The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity® microbubbles (mean diameter range: 1.1-3.3 µm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 µm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity® microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without craniotomy in mice and IC may not be required for BBB opening at relatively low pressures.

Transcranial cavitation-mediated ultrasound therapy at sub-MHz frequency via temporal interference modulation

NASA Astrophysics Data System (ADS)

Sun, Tao; Sutton, Jonathan T.; Power, Chanikarn; Zhang, Yongzhi; Miller, Eric L.; McDannold, Nathan J.

2017-10-01

Sub-megahertz transmission is not usually adopted in pre-clinical small animal experiments for focused ultrasound (FUS) brain therapy due to the large focal size. However, low frequency FUS is vital for preclinical evaluations due to the frequency-dependence of cavitation behavior. To maximize clinical relevance, a dual-aperture FUS system was designed for low-frequency (274.3 kHz) cavitation-mediated FUS therapy. Combining two spherically curved transducers provides significantly improved focusing in the axial direction while yielding an interference pattern with strong side lobes, leading to inhomogeneously distributed cavitation activities. By operating the two transducers at slightly offset frequencies to modulate this interference pattern over the period of sonication, the acoustic energy was redistributed and resulted in a spatially homogenous treatment profile. Simulation and pressure field measurements in water were performed to assess the beam profiles. In addition, the system performance was demonstrated in vivo in rats via drug delivery through microbubble-mediated blood-brain barrier disruption. This design resulted in a homogenous treatment profile that was fully contained within the rat brain at a clinically relevant acoustic frequency.

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts.

PubMed

Shen, Yuanyuan; Pi, Zhaoke; Yan, Fei; Yeh, Chih-Kuang; Zeng, Xiaojun; Diao, Xianfen; Hu, Yaxin; Chen, Siping; Chen, Xin; Zheng, Hairong

2017-01-01

Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood-brain barrier (BBB) or blood-tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma.

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.

PubMed

Uzhachenko, Roman; Boyd, Kelli; Olivares-Villagomez, Danyvid; Zhu, Yueming; Goodwin, J Shawn; Rana, Tanu; Shanker, Anil; Tan, Winston J T; Bondar, Tanya; Medzhitov, Ruslan; Ivanova, Alla V

2017-03-26

Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.

FUS and TDP43 genetic variability in FTD and CBS

PubMed Central

Huey, Edward D.; Ferrari, Raffaele; Moreno, Jorge H.; Jensen, Christopher; Morris, Christopher M.; Potocnik, Felix; Kalaria, Rajesh N.; Tierney, Michael; Wassermann, Eric M.; Hardy, John; Grafman, Jordan; Momeni, Parastoo

2015-01-01

This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180–4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185–4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls. PMID:21943958

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis

PubMed Central

Uzhachenko, Roman; Boyd, Kelli; Olivares-Villagomez, Danyvid; Zhu, Yueming; Goodwin, J. Shawn; Rana, Tanu; Shanker, Anil; Tan, Winston J.T.; Bondar, Tanya; Medzhitov, Ruslan; Ivanova, Alla V.

2017-01-01

Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response. Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies. PMID:28351997

Robotically assisted MRgFUS system

NASA Astrophysics Data System (ADS)

Jenne, Jürgen W.; Krafft, Axel J.; Maier, Florian; Rauschenberg, Jaane; Semmler, Wolfhard; Huber, Peter E.; Bock, Michael

2010-03-01

Magnetic resonance imaging guided focus ultrasound surgery (MRgFUS) is a highly precise method to ablate tissue non-invasively. The objective of this ongoing work is to establish an MRgFUS therapy unit consisting of a specially designed FUS applicator as an add-on to a commercial robotic assistance system originally designed for percutaneous needle interventions in whole-body MRI systems. The fully MR compatible robotic assistance system InnoMotion™ (Synthes Inc., West Chester, USA; formerly InnoMedic GmbH, Herxheim, Germany) offers six degrees of freedom. The developed add-on FUS treatment applicator features a fixed focus ultrasound transducer (f = 1.7 MHz; f' = 68 mm, NA = 0.44, elliptical shaped -6-dB-focus: 8.1 mm length; O/ = 1.1 mm) embedded in a water-filled flexible bellow. A Mylar® foil is used as acoustic window encompassed by a dedicated MRI loop coil. For FUS application, the therapy unit is directly connected to the head of the robotic system, and the treatment region is targeted from above. A newly in-house developed software tool allowed for complete remote control of the MRgFUS-robot system and online analysis of MRI thermometry data. The system's ability for therapeutic relevant focal spot scanning was tested in a closed-bore clinical 1.5 T MR scanner (Magnetom Symphony, Siemens AG, Erlangen, Germany) in animal experiments with pigs. The FUS therapy procedure was performed entirely under MRI guidance including initial therapy planning, online MR-thermometry, and final contrast enhanced imaging for lesion detection. In vivo trials proved the MRgFUS-robot system as highly MR compatible. MR-guided focal spot scanning experiments were performed and a well-defined pattern of thermal tissue lesions was created. A total in vivo positioning accuracy of the US focus better than 2 mm was estimated which is comparable to existing MRgFUS systems. The newly developed FUS-robotic system offers an accurate, highly flexible focus positioning. With its access to the patient from above, it provides a wide range of flexibility for acoustic target access. In the next step, motion correction unit should be integrated.

MRI-guided focused ultrasound surgery in musculoskeletal diseases: the hot topics

PubMed Central

Napoli, Alessandro; Sacconi, Beatrice; Battista, Giuseppe; Guglielmi, Giuseppe; Catalano, Carlo; Albisinni, Ugo

2016-01-01

MRI-guided focused ultrasound surgery (MRgFUS) is a minimally invasive treatment guided by the most sophisticated imaging tool available in today's clinical practice. Both the imaging and therapeutic sides of the equipment are based on non-ionizing energy. This technique is a very promising option as potential treatment for several pathologies, including musculoskeletal (MSK) disorders. Apart from clinical applications, MRgFUS technology is the result of long, heavy and cumulative efforts exploring the effects of ultrasound on biological tissues and function, the generation of focused ultrasound and treatment monitoring by MRI. The aim of this article is to give an updated overview on a “new” interventional technique and on its applications for MSK and allied sciences. PMID:26607640

The dynamic of FUS-induced BBB Opening in Mouse Brain assessed by contrast enhanced MRI

NASA Astrophysics Data System (ADS)

Jenne, Jürgen W.; Krafft, Axel J.; Maier, Florian; Krause, Marie N.; Kleber, Susanne; Huber, Peter E.; Martin-Villalba, Ana; Bock, Michael

2010-03-01

Focused ultrasound (FUS) in combination with the administration of gas-filled microbubbles, can induce a localized and reversible opening of the blood brain barrier (BBB). Contrast enhanced magnetic resonance imaging (MRI) has been demonstrated as a precise tool to monitor such a local BBB disruption. However, the opening/closing mechanisms of the BBB with FUS are still largely unknown. In this ongoing project, we study the BBB opening dynamics in mouse brain comparing an interstitial and an intravascular MR contrast agent (CA). FUS in mouse brain was performed with an MRI compatible treatment setup (1.7 MHz fix-focus US transducer, f' = 68 mm, NA = 0.44; focus: 8.1 mm length; O/ = 1.1 mm) in a 1.5 T whole body MRI system. For BBB opening, forty 10 ms-long FUS-pulses were applied at a repetition rate of 1 Hz at 1 MPa. The i.v. administration of the micro bubbles (50 μl SonoVue®) was started simultaneously with FUS exposure. To analyze the BBB opening process, short-term and long-term MRI signal dynamics of the interstitial MR contrast agent Magnevist® and the intravascular CA Vasovist® (Bayer-Schering) were studied. To assess short-term signal dynamics, T1-weighted inversion recovery turbo FLASH images (1s) were repeatedly acquired. Repeated 3D FLASH acquisitions (90 s) were used to assess long-term MRI signal dynamics. The short-term MRI signal enhancements showed comparable time constants for both types of MR contrast agents: 1.1 s (interstitial) vs. 0.8 s (intravascular). This time constant may serve as a time constant of the BBB opening process with the given FUS exposure parameters. For the long-term signal dynamics the intravascular CA (62±10 min) showed a fife times greater time constant as the interstitial contrast agent (12±10 min). This might be explained by the high molecular weight (˜60 kDa) of the intravascular Vasovist due to its reversible binding to blood serum albumin resulting in a prolonged half-life in the blood stream compared to the interstitial CA. As the intravascular CA offers a much longer time window for therapy assessment, FUS-BBB therapy control with an intravascular CA might be favorable.

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

PubMed Central

Coronas-Samano, Guillermo; Baker, Keeley L.; Tan, Winston J. T.; Ivanova, Alla V.; Verhagen, Justus V.

2016-01-01

Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology. Here we characterize and propose the Fus1 KO mice that lack a mitochondrial protein Fus1/Tusc2 as a new sAD model. To establish sAD relevance, we assessed sAD related deficits in Fus1 KO and WT adult mice of 4–5 months old, the equivalent human age when the earliest cognitive and olfactory sAD symptoms arise. Fus1 KO mice showed oxidative stress (increased levels of ROS, decreased levels of PRDX1), disruption of metabolic homeostasis (decreased levels of ACC2, increased phosphorylation of AMPK), autophagy (decreased levels of LC3-II), PKC (decreased levels of RACK1) and calcium signaling (decreased levels of Calb2) in the olfactory bulb and/or hippocampus. Mice were behaviorally tested using objective and accurate video tracking (Noldus), in which Fus1 KO mice showed clear deficits in olfactory memory (decreased habituation/cross-habituation in the short and long term), olfactory guided navigation memory (inability to reduce their latency to find the hidden cookie), spatial memory (learning impairments on finding the platform in the Morris water maze) and showed more sleep time during the diurnal cycle. Fus1 KO mice did not show clear deficits in olfactory perception (cross-habituation), association memory (passive avoidance) or in species-typical behavior (nest building) and no increased anxiety (open field, light-dark box) or depression/anhedonia (sucrose preference) at this relatively young age. These neurobehavioral deficits of the Fus1 KO mice at this relatively young age are highly relevant to sAD, making them suitable for effective research on pharmacological targets in the context of early intervention of sAD. PMID:27895577

Quantification of transient increase of the blood–brain barrier permeability to macromolecules by optimized focused ultrasound combined with microbubbles

PubMed Central

Shi, Lingyan; Palacio-Mancheno, Paolo; Badami, Joseph; Shin, Da Wi; Zeng, Min; Cardoso, Luis; Tu, Raymond; Fu, Bingmei M

2014-01-01

Radioimmunotherapy using a radiolabeled monoclonal antibody that targets tumor cells has been shown to be efficient for the treatment of many malignant cancers, with reduced side effects. However, the blood–brain barrier (BBB) inhibits the transport of intravenous antibodies to tumors in the brain. Recent studies have demonstrated that focused ultrasound (FUS) combined with microbubbles (MBs) is a promising method to transiently disrupt the BBB for the drug delivery to the central nervous system. To find the optimal FUS and MBs that can induce reversible increase in the BBB permeability, we employed minimally invasive multiphoton microscopy to quantify the BBB permeability to dextran-155 kDa with similar molecular weight to an antibody by applying different doses of FUS in the presence of MBs with an optimal size and concentration. The cerebral microcirculation was observed through a section of frontoparietal bone thinned with a micro-grinder. About 5 minutes after applying the FUS on the thinned skull in the presence of MBs for 1 minute, TRITC (tetramethylrhodamine isothiocyanate)-dextran-155 kDa in 1% bovine serum albumin in mammalian Ringer’s solution was injected into the cerebral circulation via the ipsilateral carotid artery by a syringe pump. Simultaneously, the temporal images were collected from the brain parenchyma ~100–200 μm below the pia mater. Permeability was determined from the rate of tissue solute accumulation around individual microvessels. After several trials, we found the optimal dose of FUS. At the optimal dose, permeability increased by ~14-fold after 5 minutes post-FUS, and permeability returned to the control level after 25 minutes. FUS without MBs or MBs injected without FUS did not change the permeability. Our method provides an accurate in vivo assessment for the transient BBB permeability change under the treatment of FUS. The optimal FUS dose found for the reversible BBB permeability increase without BBB disruption is reliable and can be applied to future clinical trials. PMID:25258533

MRI-Guided Focused Ultrasound as a New Method of Drug Delivery

PubMed Central

Thanou, M.; Gedroyc, W.

2013-01-01

Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to “activate” nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery. PMID:23738076

MRI predictors of clinical success in MR-guided focused ultrasound (MRgFUS) treatments of uterine fibroids: results from a single centre.

PubMed

Mindjuk, Irene; Trumm, Christoph G; Herzog, Peter; Stahl, Robert; Matzko, Matthias

2015-05-01

To assess the technical and clinical results of MRgFUS treatment and factors affecting clinical treatment success. A total of 252 women (mean age, 42.1 ± 6.9 years) with uterine fibroids underwent MRgFUS. All patients underwent MRI before treatment. Results were evaluated with respect to post-treatment nonperfused volume (NPV), symptom severity score (SSS), reintervention rate, pregnancy and safety data. NPV ratio was significantly higher in fibroids characterized by low signal intensity in contrast-enhanced T1-weighted fat saturated MR images and in fibroids distant from the spine (>3 cm). NPV ratio was lower in fibroids with septations, with subserosal component and in skin-distant fibroids (p < 0.001). NPV ratio was highly correlated with clinical success: NPV of more than 80 % resulted in clinical success in more than 80 % of patients. Reintervention rate was 12.7 % (mean follow-up time, 19.4 ± 8 months; range, 3-38). Expulsion of fibroids (21 %) was significantly correlated with a high clinical success rate. No severe adverse events were reported. Adequate patient selection and correct treatment techniques, based on the learning curve of this technology, combined with technical advances of the system, lead to higher clinical success rates with low complications rate, comparable to other uterine-sparing treatment options. • MRgFUS appears to be a valid alternative to other uterus-preserving therapies • Patient selection is a significant factor in achieving high NPV ratios • MRI screening parameters correlate with the amount of fibroid ablation in MRgFUS • NPV results of more than 80 % correlate with higher clinical success rates.

MRI-Guided Focused Ultrasound Surgery

PubMed Central

Jolesz, Ferenc A.

2014-01-01

MRI-guided focused ultrasound (MRgFUS) surgery is a noninvasive thermal ablation method that uses magnetic resonance imaging (MRI) for target definition, treatment planning, and closed-loop control of energy deposition. Integrating FUS and MRI as a therapy delivery system allows us to localize, target, and monitor in real time, and thus to ablate targeted tissue without damaging normal structures. This precision makes MRgFUS an attractive alternative to surgical resection or radiation therapy of benign and malignant tumors. Already approved for the treatment of uterine fibroids, MRgFUS is in ongoing clinical trials for the treatment of breast, liver, prostate, and brain cancer and for the palliation of pain in bone metastasis. In addition to thermal ablation, FUS, with or without the use of microbubbles, can temporarily change vascular or cell membrane permeability and release or activate various compounds for targeted drug delivery or gene therapy. A disruptive technology, MRgFUS provides new therapeutic approaches and may cause major changes in patient management and several medical disciplines. PMID:19630579

Efficacy of Magnetic Resonance-guided Focused Ultrasound Surgery for Bone Metastases Pain Palliation

NASA Astrophysics Data System (ADS)

Kawasaki, Motohiro; Nanba, Hirofumi; Kato, Tomonari; Tani, Toshikazu; Ushida, Takahiro

2011-09-01

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a novel treatment method that achieves non-invasive thermal ablation by focusing many ultrasound waves on a target tissue with real-time monitoring of the location and temperature of the target during the procedure. We investigated the palliative effect on pain and safety of MRgFUS in painful bone metastases. Six patients (mean age, 65.8 years) who met eligibility criteria for the clinical study approved by our Institutional Ethics Committee based on the cooperative protocol were treated with MRgFUS. Targeted sites included the sacrum (n = 1), ilium (n = 2), scapula (n = 2), and femur (n = 1). The mean follow-up period was 9.2 months. All procedures were performed as a single-session treatment using the treatment system that is integrated into the patient table of a magnetic resonance image (MRI) scanner. Endpoints were change in the intensity of pain due to bone metastases from before to after the treatment, as measured on a numerical rating scale, pain interference with daily activities as determined by the Brief pain inventory (BPI), change in images, and safety. Pain relief was obtained in all patients early after treatment, with a reduction in the mean pain score from 6.0±1.3 at baseline to 1.2±1.0 at the end of follow-up as well as in pain interference with daily activities. The mean time required for a single-session treatment was 83.7±37.0 min, with a mean number of sonications required of 13.3±3.7 and mean energy applied of 846.4±273.5 J. No significant growth of tumors was observed, nor were there treatment-related adverse events. These results suggest that MRgFUS has a non-invasive palliative effect on the localized pain in patients with bone metastasis. MRgFUS could become an option in treatment strategies for painful bone metastases in the future.

Delineation of Chondroid Lipoma: An Immunohistochemical and Molecular Biological Analysis

PubMed Central

de Vreeze, Ronald S. A.; van Coevorden, Frits; Boerrigter, Lucie; Nederlof, Petra M.; Haas, Rick L.; Bras, Johannes; Rosenwald, Andreas; Mentzel, Thomas; de Jong, Daphne

2011-01-01

Aims. Chondroid lipoma (CL) is a benign tumor that mimics a variety of soft tissue tumors and is characterized by translocation t(11;16). Here, we analyze CL and its histological mimics. Methods. CL (n = 4) was compared to a variety of histological mimics (n = 83) for morphological aspects and immunohistochemical features including cyclinD1(CCND1). Using FISH analysis, CCND1 and FUS were investigated as potential translocation partners. Results. All CLs were strongly positive for CCND1. One of 4 myoepitheliomas, CCND1, was positive. In well-differentiated lipomatous tumors and in chondrosarcomas, CCND1 was frequently expressed, but all myxoid liposarcomas were negative. FISH analysis did not give support for direct involvement of CCND1 and FUS as translocation partners. Conclusions. Chondroid lipoma is extremely rare and has several and more prevalent histological mimics. The differential diagnosis of chondroid lipomas can be unraveled using immunohistochemical and molecular support. PMID:21559269

Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation.

PubMed

Kovacs, Zsofia I; Kim, Saejeong; Jikaria, Neekita; Qureshi, Farhan; Milo, Blerta; Lewis, Bobbi K; Bresler, Michele; Burks, Scott R; Frank, Joseph A

2017-01-03

MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China.

PubMed

Hou, Lihua; Jiao, Bin; Xiao, Tingting; Zhou, Lu; Zhou, Zhifan; Du, Juan; Yan, Xinxiang; Wang, Junling; Tang, Beisha; Shen, Lu

2016-09-08

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons of the brain, brainstem and spinal cord. To date, mutations in more than 30 genes have been linked to the pathogenesis of ALS. Among them, SOD1, FUS and TARDBP are ranked as the three most common genes associated with ALS. However, no mutation analysis has been reported in central-southern China. In this study, we sequenced SOD1, FUS and TARDBP in a central-southern Chinese cohort of 173 patients with ALS (15 familial ALS and 158 sporadic ALS) to detect mutations. As a result, five missense mutations in SOD1, namely, p.D101N, p.D101G, p.C111Y, p.N86S and p.V87A, were identified in three unrelated familial probands and three sporadic cases; two mutations in FUS were found in two unrelated familial probands, including an insertion mutation (p.P525_Y526insY) and a missense mutation (p.R521H); no variants of TARDBP were observed in patients. Therefore, SOD1 mutations were present in 20.0% of familial ALS patients and 1.9% of sporadic ALS patients, while FUS mutations were responsible for 13.3% of familial ALS cases, and TARDBP mutations were rare in either familial or sporadic ALS cases. This study broadens the known mutational spectrum in patients with ALS and further demonstrates the necessity for genetic screening in ALS patients from central-southern China.

Low-Pressure Burst-Mode Focused Ultrasound Wave Reconstruction and Mapping for Blood-Brain Barrier Opening: A Preclinical Examination

PubMed Central

Xia, Jingjing; Tsui, Po-Hsiang; Liu, Hao-Li

2016-01-01

Burst-mode focused ultrasound (FUS) exposure has been shown to induce transient blood-brain barrier (BBB) opening for potential CNS drug delivery. FUS-BBB opening requires imaging guidance during the intervention, yet current imaging technology only enables postoperative outcome confirmation. In this study, we propose an approach to visualize short-burst low-pressure focal beam distribution that allows to be applied in FUS-BBB opening intervention on small animals. A backscattered acoustic-wave reconstruction method based on synchronization among focused ultrasound emission, diagnostic ultrasound receiving and passively beamformed processing were developed. We observed that focal beam could be successfully visualized for in vitro FUS exposure with 0.5–2 MHz without involvement of microbubbles. The detectable level of FUS exposure was 0.467 MPa in pressure and 0.05 ms in burst length. The signal intensity (SI) of the reconstructions was linearly correlated with the FUS exposure level both in-vitro (r2 = 0.9878) and in-vivo (r2 = 0.9943), and SI level of the reconstructed focal beam also correlated with the success and level of BBB-opening. The proposed approach provides a feasible way to perform real-time and closed-loop control of FUS-based brain drug delivery. PMID:27295608

Low-Pressure Burst-Mode Focused Ultrasound Wave Reconstruction and Mapping for Blood-Brain Barrier Opening: A Preclinical Examination

NASA Astrophysics Data System (ADS)

Xia, Jingjing; Tsui, Po-Hsiang; Liu, Hao-Li

2016-06-01

Burst-mode focused ultrasound (FUS) exposure has been shown to induce transient blood-brain barrier (BBB) opening for potential CNS drug delivery. FUS-BBB opening requires imaging guidance during the intervention, yet current imaging technology only enables postoperative outcome confirmation. In this study, we propose an approach to visualize short-burst low-pressure focal beam distribution that allows to be applied in FUS-BBB opening intervention on small animals. A backscattered acoustic-wave reconstruction method based on synchronization among focused ultrasound emission, diagnostic ultrasound receiving and passively beamformed processing were developed. We observed that focal beam could be successfully visualized for in vitro FUS exposure with 0.5-2 MHz without involvement of microbubbles. The detectable level of FUS exposure was 0.467 MPa in pressure and 0.05 ms in burst length. The signal intensity (SI) of the reconstructions was linearly correlated with the FUS exposure level both in-vitro (r2 = 0.9878) and in-vivo (r2 = 0.9943), and SI level of the reconstructed focal beam also correlated with the success and level of BBB-opening. The proposed approach provides a feasible way to perform real-time and closed-loop control of FUS-based brain drug delivery.

Treatment envelope evaluation in transcranial magnetic resonance-guided focused ultrasound utilizing 3D MR thermometry

PubMed Central

2014-01-01

Background Current clinical targets for transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) are all located close to the geometric center of the skull convexity, which minimizes challenges related to focusing the ultrasound through the skull bone. Non-central targets will have to be reached to treat a wider variety of neurological disorders and solid tumors. Treatment envelope studies utilizing two-dimensional (2D) magnetic resonance (MR) thermometry have previously been performed to determine the regions in which therapeutic levels of FUS can currently be delivered. Since 2D MR thermometry was used, very limited information about unintended heating in near-field tissue/bone interfaces could be deduced. Methods In this paper, we present a proof-of-concept treatment envelope study with three-dimensional (3D) MR thermometry monitoring of FUS heatings performed in a phantom and a lamb model. While the moderate-sized transducer used was not designed for transcranial geometries, the 3D temperature maps enable monitoring of the entire sonication field of view, including both the focal spot and near-field tissue/bone interfaces, for full characterization of all heating that may occur. 3D MR thermometry is achieved by a combination of k-space subsampling and a previously described temporally constrained reconstruction method. Results We present two different types of treatment envelopes. The first is based only on the focal spot heating—the type that can be derived from 2D MR thermometry. The second type is based on the relative near-field heating and is calculated as the ratio between the focal spot heating and the near-field heating. This utilizes the full 3D MR thermometry data achieved in this study. Conclusions It is shown that 3D MR thermometry can be used to improve the safety assessment in treatment envelope evaluations. Using a non-optimal transducer, it is shown that some regions where therapeutic levels of FUS can be delivered, as suggested by the first type of envelope, are not necessarily safely treated due to the amount of unintended near-field heating occurring. The results presented in this study highlight the need for 3D MR thermometry in tcMRgFUS. PMID:25343028

MR-guided focused ultrasound surgery, present and future

PubMed Central

Schlesinger, David; Benedict, Stanley; Diederich, Chris; Gedroyc, Wladyslaw; Klibanov, Alexander; Larner, James

2013-01-01

MR-guided focused ultrasound surgery (MRgFUS) is a quickly developing technology with potential applications across a spectrum of indications traditionally within the domain of radiation oncology. Especially for applications where focal treatment is the preferred technique (for example, radiosurgery), MRgFUS has the potential to be a disruptive technology that could shift traditional patterns of care. While currently cleared in the United States for the noninvasive treatment of uterine fibroids and bone metastases, a wide range of clinical trials are currently underway, and the number of publications describing advances in MRgFUS is increasing. However, for MRgFUS to make the transition from a research curiosity to a clinical standard of care, a variety of challenges, technical, financial, clinical, and practical, must be overcome. This installment of the Vision 20/20 series examines the current status of MRgFUS, focusing on the hurdles the technology faces before it can cross over from a research technique to a standard fixture in the clinic. It then reviews current and near-term technical developments which may overcome these hurdles and allow MRgFUS to break through into clinical practice. PMID:23927296

Clinical characterization of bvFTD due to FUS neuropathology

PubMed Central

Lee, Suzee E.; Seeley, William W.; Poorzand, Pardis; Rademakers, Rosa; Karydas, Anna; Stanley, Christine M.; Miller, Bruce L.; Rankin, Katherine P.

2011-01-01

In 2009, inclusions containing the fused in sarcoma (FUS) protein were identified as a third major molecular class of pathology underlying the behavioral variant frontotemporal dementia (bvFTD) syndrome. Due to the low prevalence of FUS pathology, few clinical descriptions have been published and none provides information about specific social-emotional deficits despite evidence for severe behavioral manifestations in this disorder. We evaluated a patient with bvFTD due to FUS pathology using a comprehensive battery of cognitive and social-emotional tests. A structural MRI scan and genetic tests for tau, progranulin, and FUS mutations were also performed. The patient showed preserved general cognitive functioning and superior working memory, but severe deficits in emotion attribution, sensitivity to punishment, and the capacity for interpersonal warmth and empathy. The gray matter atrophy pattern corresponded to this focal deficit profile, with preservation of dorsolateral fronto-parietal regions associated with executive functioning but severe damage to right worse than left frontoinsula, temporal pole, subgenual anterior cingulate, medial orbitofrontal cortex, amygdala, and caudate. This patient demonstrates the striking focality associated with FUS neuropathology in patients with bvFTD. PMID:22060063

Evaluation of Mechanical Properties and Marginal Fit of Crowns Fabricated Using Commercially Pure Titanium and FUS-Invest

PubMed Central

Wu, Jinshuang; Wang, Xianli; Xing, Helin; Guo, Tianwen; Dong, Chaofang

2017-01-01

This study investigated the mechanical properties and single crown accuracy of the tailor-made Fourth University Stomatology investment (FUS-invest) for casting titanium. Background. Current investment for casting titanium is not optimal for obtaining high-quality castings, and the commercially available titanium investment is costly. Methods. Titanium specimens were cast using the tailor-made FUS-invest. The mechanical properties were tested using a universal testing machine. Fractured castings were characterized by energy-dispersive spectroscopy. 19 titanium crowns were produced using FUS-invest and another 19 by Symbion. The accuracy of crowns was evaluated. Results. The mechanical properties of the titanium cast by FUS-invest were elastic modulus 125.6 ± 8.8 GPa, yield strength 567.5 ± 11.1 MPa, tensile strength 671.2 ± 15.6 MPa, and elongation 4.6 ± 0.2%. For marginal fit, no significant difference (P > 0.05) was found at four marker points of each group. For internal fit, no significant difference (P > 0.05) was found between two groups, whereas significant difference (P < 0.01) was found at different mark point of each group. Conclusions. The mechanical properties of titanium casted using FUS-invest fulfilled the ISO 9693 criteria. The marginal and internal fit of the titanium crowns using either the FUS-invest or Symbion were similar. PMID:28913355

Update on Clinical MR-guided Focused Ultrasound Applications

PubMed Central

McDannold, Nathan

2015-01-01

SYNOPSIS Focused ultrasound (FUS) can be used to thermally ablate tissue. The performance of FUS under magnetic resonance (MR) guidance enables aiming the focus at the target, accurate treatment planning, real-time temperature mapping, and evaluation of the treatment. This review updates several clinical applications of MR-guided FUS. MR-guided FUS has a CE mark and FDA approval for thermal ablation for uterine fibroids and bone metastases related pain management. Thousands of uterine fibroid patients have successfully been treated with minor side effects. Technical improvements, increased experience, and the use of a screening MRI examination should further improve treatment outcome. When used for bone metastases and other bone diseases, thermal ablation leads to pain relief due to denervation, and debulking of the tumor. The use of a hemi-spherical multi-element transducer and phase corrections have enabled application of FUS through the skull. Transcranial MR-guided FUS has received CE certification for ablation of deep, central locations in the brain such as the thalamus. Thermal ablation of specific parts of the thalamus can result in relief of the symptoms in neurological disorders such as essential tremor, Parkinson’s, and neuropathic pain. No CE mark or FDA approval has been obtained as yet for treatment of prostate cancer or breast cancer, but several approaches have been proposed and clinical trials should show the potential of MR-guided FUS for these and other applications. PMID:26499282

Mechanisms of FUS mutations in familial amyotrophic lateral sclerosis.

PubMed

Shang, Yulei; Huang, Eric J

2016-09-15

Recent advances in the genetics of amyotrophic lateral sclerosis (ALS) have provided key mechanistic insights to the pathogenesis of this devastating neurodegenerative disease. Among many etiologies for ALS, the identification of mutations and proteinopathies in two RNA binding proteins, TDP-43 (TARDBP or TAR DNA binding protein 43) and its closely related RNA/DNA binding protein FUS (fused in sarcoma), raises the intriguing possibility that perturbations to the RNA homeostasis and metabolism in neurons may contribute to the pathogenesis of these diseases. Although the similarities between TDP-43 and FUS suggest that mutations and proteinopathy involving these two proteins may converge on the same mechanisms leading to neurodegeneration, there is increasing evidence that FUS mutations target distinct mechanisms to cause early disease onset and aggressive progression of disease. This review focuses on the recent advances on the molecular, cellular and genetic approaches to uncover the mechanisms of wild type and mutant FUS proteins during development and in neurodegeneration. These findings provide important insights to understand how FUS mutations may perturb the maintenance of dendrites through fundamental processes in RNA splicing, RNA transport and DNA damage response/repair. These results contribute to the understanding of phenotypic manifestations in neurodegeneration related to FUS mutations, and to identify important directions for future investigations. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts

PubMed Central

Shen, Yuanyuan; Pi, Zhaoke; Yan, Fei; Yeh, Chih-Kuang; Zeng, Xiaojun; Diao, Xianfen; Hu, Yaxin; Chen, Siping; Chen, Xin; Zheng, Hairong

2017-01-01

Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood–brain barrier (BBB) or blood–tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma. PMID:28848341

Primary Renal Hybrid Low-grade Fibromyxoid Sarcoma-Sclerosing Epithelioid Fibrosarcoma: An Unusual Pediatric Case With EWSR1-CREB3L1 Fusion.

PubMed

Mok, Yingting; Pang, Yin Huei; Sanjeev, Jain Sudhanshi; Kuick, Chik Hong; Chang, Kenneth Tou-En

2018-01-01

Low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF) are rare tumors with distinct sets of morphological features, both characterized by MUC4 immunoreactivity. Tumors exhibiting features of both entities are considered hybrid LGFMS-SEF lesions. While the majority of LGFMS cases are characterized by FUS-CREB3L2 gene fusions, most cases of pure SEF show EWSR1 gene rearrangements. In the largest study of hybrid LGFMS-SEF tumors to date, all cases exhibited FUS rearrangements, a similar genetic profile to LGFMS. We herein describe the clinicopathological features and genetic findings of a case of primary renal hybrid LGFMS-SEF occurring in a 10-year-old child, with disseminated metastases. Fusion gene detection using a next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) was performed on both the primary renal tumor that showed the morphology of a LGFMS, and a cervical metastasis that showed the morphology of SEF. An EWSR1-CREB3L1 gene fusion occurring between exon 11 of EWSR1 and exon 6 of CREB3L1 was present in both the LGFMS and SEF components. This unusual case provides evidence that a subset of hybrid LGFMS-SEF harbor EWSR1-CREB3L1 gene fusions. In this case, these features were associated with an aggressive clinical course, with disease-associated mortality occurring within 12 months of diagnosis.

[Magnetic resonance guided focused ultrasound surgery for pain palliation of bone metastases: early experience of clinical application in China].

PubMed

Gu, Jianjun; Wang, Han; Tang, Na; Hua, Yingqi; Yang, Haiyan; Qiu, Yimin; Ge, Renbin; Zhou, Ying; Wang, Wenwen; Zhang, Guixiang

2015-11-03

To evaluate the safety and efficacy of magnetic resonance guided focused ultrasound surgery (MRgFUS) in treatment for pain palliation of bone metastases. Eighty-one patients of painful bone metastases were volunteered to screen for this study in Shanghai General Hospital from June 2014 to February 2015. Twenty-three patients among them were treated by MRgFUS, who was more than 18-years old, having the ability to fully understand the informed consent of the research, suffering with pain of numeric rating scale (NRS) ≥ 4, non-received radiotherapy or chemotherapy for pain palliation of bone metastases in the past two weeks. The NRS, the standard question of Brief Pain Inventory (BPI-QoL), and the standard question of Europe Organization for Research and Treatment of Cancer Quality of Life Questionnaire- Bone Metastases 22 (EORTC QLQ-BM22) were respectively recorded before and 1-week, 1-month, 3-month after the treatment. The related adverse events of MRgFUS were observed and recorded in 3 months after the treatment as well. (1)Twenty-three metastatic bone tumor lesions of 23 patients were treated by MRgFUS, the treatment data was as follows: the mean treatment time was (88 ± 33) minutes, the mean sonication number was 13 ± 8. (2) Adverse events included: pain in therapy area 3/23, which spontaneous relieving within one week; numbness in lower limb (1/23), which relieved after physiotherapy. (3) The NRS of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 6.0 ± 1.5, 3.7 ± 1.7,3.1 ± 2.0, and 2.2 ± 1.0,which significantly decreased after the treatment (P<0.01). (4) The BPI-QoL score of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 39 ± 16, 27 ± 18, 26 ± 18, and 21 ± 18, which significantly decreased after the treatment (P<0.01). (5) The EORTC QLQ-BM22 score of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 52 ± 13, 44 ± 12, 42 ± 12, and 39 ± 12, which also significantly decreased after the treatment (P<0.01). MRgFUS can be used as a non-invasive, safe, and effective method for treating painful bone metastases. Its clinical benefits of pain palliation and patient's quality of life improving are sustained after the treatment at least to 3 months.

Focused ultrasound-mediated drug delivery through the blood-brain barrier

PubMed Central

Burgess, Alison; Shah, Kairavi; Hough, Olivia; Hynynen, Kullervo

2015-01-01

Despite recent advances in blood-brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods which can be used to circumvent the BBB to promote drug delivery is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents. PMID:25936845

ExAblate magnetic resonance-guided focused ultrasound system in multiple body applications.

PubMed

Dick, E A; Gedroyc, W M W

2010-09-01

Focused ultrasound surgery (FUS) is a completely noninvasive method of thermally destroying a target tissue while sparing adjacent tissues and organs. Treatment is relatively painless and can be carried out under conscious sedation on an out-patient basis. The combination of magnetic resonance guidance with FUS (MRgFUS) provides the ability to plan and monitor treatments in near real-time, further increasing the safety profile of MRgFUS. This technology provides a very personalized treatment, adjusted to the individual patient anatomy, pathology and treatment response, hence it meets the needs of patients, as well as of physicians. MRgFUS has been used extensively in the successful treatment of uterine fibroids, and has been shown to be an effective treatment in the breast and in bone metastases in smaller scale studies. It shows great potential in the treatment of prostate and liver tumors, as well as in the brain and facet joints.

Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin.

PubMed

Zou, Zhang-Yu; Liu, Ming-Sheng; Li, Xiao-Guang; Cui, Li-Ying

2016-01-01

Juvenile onset ALS is a very rare form of motor neuron disease, with the first symptoms of motor neuron degeneration manifested before 25 years of age. Mutations in the alsin (ALS2), senataxin (SETX), and spatacsin (SPG11) genes have been associated with familial ALS with juvenile onset and slow progression, whereas the genetic architecture of sporadic juvenile ALS remains unclear. We screened mutations in C9orf72, SOD1, FUS, TARDBP, ANG, VCP and PFN1 in 16 juvenile sporadic ALS patients. Four cases (25%) carrying FUS mutations and one individual (6%) harbouring a SOD1 mutation were identified. All cases had an aggressive disease course. Our results suggest that FUS mutations are the most frequent genetic cause in early-onset sporadic ALS patients of Chinese origin. Genetic testing of FUS should be performed in early-onset ALS patients especially those with an aggressive disease course.

Identifying the Inertial Cavitation Pressure Threshold and Skull Effects in a Vessel Phantom Using Focused Ultrasound and Microbubbles

NASA Astrophysics Data System (ADS)

Tung, Yao-Sheng; Choi, James J.; Konofagou, Elisa E.

2010-03-01

Using Focused Ultrasound (FUS) and microbubbles to open the blood-brain barrier (BBB) has been shown promising for brain drug delivery. However, the exact mechanism behind the opening remains unknown. Here, the effects of the murine skull on the threshold of inertial cavitation were investigated. In order to investigate the pressure threshold for inertial cavitation of preformed microbubbles during sonication, passive cavitation detection in conjunction with B-mode imaging was used. A cylindrical vessel with a 610-μm diameter inside a polyacrylamide gel was generated within a polyacrylamide gel to simulate large blood vessels. Definity® (Lantheus Medical Imaging, MA, USA) microbubbles with a 1.1-3.3 μm in diameter at 2.5×107 bubbles/mL were injected into the channel before sonication (frequency: 1.525 MHz; pulse length: 100 cycles; PRF: 10 Hz; sonication duration: 2 s) through an excised mouse skull. A cylindrically focused hydrophone, confocal with the FUS transducer, acted as a passive cavitation detector (PCD) to identify the threshold. A 7.5 MHz linear array with the field-of-view perpendicular to the axial length of the FUS beam was also used to image the occurrence of bubble fragmentation. The broadband spectral response acquired at the passive cavitation detector (PCD) and the B-mode images identified the occurrence and location of the inertial cavitation, respectively. Findings indicated that the peak-rarefactional pressure threshold was approximately equal to 0.45 MPa at the presence or the absence of the skull. However, the skull induced 10-50% lower inertial cavitation dose. Mouse skulls did not affect the pressure threshold of inertial cavitation but resulted in a lower inertial cavitation dose. The broadband response could be captured through the murine skull, so the same PCD setup can be used in future in vivo applications.

Combined passive acoustic mapping and magnetic resonance thermometry for monitoring phase-shift nanoemulsion enhanced focused ultrasound therapy

NASA Astrophysics Data System (ADS)

Crake, Calum; Meral, F. Can; Burgess, Mark T.; Papademetriou, Iason T.; McDannold, Nathan J.; Porter, Tyrone M.

2017-08-01

Focused ultrasound (FUS) has the potential to enable precise, image-guided noninvasive surgery for the treatment of cancer in which tumors are identified and destroyed in a single integrated procedure. However, success of the method in highly vascular organs has been limited due to heat losses to perfusion, requiring development of techniques to locally enhance energy absorption and heating. In addition, FUS procedures are conventionally monitored using MRI, which provides excellent anatomical images and can map temperature, but is not capable of capturing the full gamut of available data such as the acoustic emissions generated during this inherently acoustically-driven procedure. Here, we employed phase-shift nanoemulsions (PSNE) embedded in tissue phantoms to promote cavitation and hence temperature rise induced by FUS. In addition, we incorporated passive acoustic mapping (PAM) alongside simultaneous MR thermometry in order to visualize both acoustic emissions and temperature rise, within the bore of a full scale clinical MRI scanner. Focal cavitation of PSNE could be resolved using PAM and resulted in accelerated heating and increased the maximum elevated temperature measured via MR thermometry compared to experiments without nanoemulsions. Over time, the simultaneously acquired acoustic and temperature maps show translation of the focus of activity towards the FUS transducer, and the magnitude of the increase in cavitation and focal shift both increased with nanoemulsion concentration. PAM results were well correlated with MRI thermometry and demonstrated greater sensitivity, with the ability to detect cavitation before enhanced heating was observed. The results suggest that PSNE could be beneficial for enhancement of thermal focused ultrasound therapies and that PAM could be a critical tool for monitoring this process.

In vivo feasibility of real-time monitoring of focused ultrasound surgery (FUS) using harmonic motion imaging (HMI).

PubMed

Maleke, Caroline; Konofagou, Elisa E

2010-01-01

In this study, the Harmonic Motion Imaging for Focused Ultrasound (HMIFU) technique is applied to monitor changes in mechanical properties of tissues during thermal therapy in a transgenic breast cancer mouse model in vivo. An HMIFU system, composed of a 4.5-MHz focused ultrasound (FUS) and a 3.3-MHz phased-array imaging transducer, was mechanically moved to image and ablate the entire tumor. The FUS transducer was driven by an amplitude-modulated (AM) signal at 15 Hz. The acoustic intensity ( I(spta)) was equal to 1050 W/cm(2) at the focus. A digital low-pass filter was used to filter out the spectrum of the FUS beam and its harmonics prior to displacement estimation. The resulting axial displacement was estimated using 1-D cross-correlation on the acquired RF signals. Results from two mice with eight lesions formed in each mouse (16 lesions total) showed that the average peak-to-peak displacement amplitude before and after lesion formation was respectively equal to 17.34 +/- 1.34 microm and 10.98 +/- 1.82 microm ( p < 0.001). Cell death was also confirmed by hematoxylin and eosin histology. HMI displacement can be used to monitor the relative tissue stiffness changes in real time during heating so that the treatment procedure can be performed in a time-efficient manner. The HMIFU system may, therefore, constitute a cost-efficient and reliable alternative for real-time monitoring of thermal ablation.

An integrated model-based software for FUS in moving abdominal organs.

PubMed

Schwenke, Michael; Strehlow, Jan; Haase, Sabrina; Jenne, Juergen; Tanner, Christine; Langø, Thomas; Loeve, Arjo J; Karakitsios, Ioannis; Xiao, Xu; Levy, Yoav; Sat, Giora; Bezzi, Mario; Braunewell, Stefan; Guenther, Matthias; Melzer, Andreas; Preusser, Tobias

2015-05-01

Focused ultrasound surgery (FUS) is a non-invasive method for tissue ablation that has the potential for complete and controlled local tumour destruction with minimal side effects. The treatment of abdominal organs such as the liver, however, requires particular technological support in order to enable a safe, efficient and effective treatment. As FUS is applied from outside the patient's body, suitable imaging methods, such as magnetic resonance imaging or diagnostic ultrasound, are needed to guide and track the procedure. To facilitate an efficient FUS procedure in the liver, the organ motion during breathing and the partial occlusion by the rib cage need to be taken into account in real time, demanding a continuous patient-specific adaptation of the treatment configuration. Modelling the patient's respiratory motion and combining this with tracking data improves the accuracy of motion predictions. Modelling and simulation of the FUS effects within the body allows the use of treatment planning and has the potential to be used within therapy to increase knowledge about the patient status. This article describes integrated model-based software for patient-specific modelling and prediction for FUS treatments of moving abdominal organs.

Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles

NASA Astrophysics Data System (ADS)

Burgess, M. T.; Apostolakis, I.; Konofagou, E. E.

2018-03-01

Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.

Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles.

PubMed

Burgess, M T; Apostolakis, I; Konofagou, E E

2018-03-15

Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.

Detoxification of Fusarium-contaminated maize with sodium sulphite - in vivo efficacy with special emphasis on mycotoxin residues and piglet health.

PubMed

Tran, Anh Tuan; Kluess, Jeannette; Berk, Andreas; Paulick, Marleen; Frahm, Jana; Schatzmayr, Dian; Winkler, Janine; Kersten, Susanne; Dänicke, Sven

2018-02-01

A feeding experiment with piglets was performed to examine the efficacy of a wet preservation of Fusarium (FUS)-contaminated maize with sodium sulphite (SoS) based on deoxynivalenol (DON) and zearalenone (ZEN) residue levels in urine, bile and liquor and health traits of piglets. For this purpose, 80 castrated male piglets (7.57 ± 0.92 kg BW) were assigned to four treatment groups: CON- (control diet, with 0.09 mg DON and <0.01 mg ZEN/kg diet), CON+ (diet CON-, wet-preserved with 5 g SoS/kg maize; containing 0.05 mg DON and <0.01 mg ZEN/kg diet), FUS- (diet with mycotoxin-contaminated maize; containing 5.36 mg DON and 0.29 mg ZEN/kg diet), and FUS+ (diet FUS-, wet-preserved with 5 g SoS/kg maize; resulting in 0.83 mg DON and 0.27 mg ZEN/kg diet). After 42 d, 40 piglets (n = 10 per group) were sampled. A clear reduction of DON levels by approximately 75% was detected in all specimens of pigs fed diet FUS+. ZEN was detected in all urine, bile and liquor samples, while their metabolites were only detectable in urine and bile. Additionally, their concentrations were not influenced by SoS treatment. Among the health-related traits, feeding of FUS diets increased the total counts of leukocytes and segmented neutrophil granulocytes irrespective of SoS treatment. SoS treatment increased the total blood protein content slightly with a similar numerical trend in albumin concentration. These effects occurred at an obviously lower level in FUS-fed groups. Moreover, SoS treatment recovered the reduction of NO production induced by feeding diet FUS- indicating an effect on the redox level. As this effect only occurred in group FUS+, it is obviously related to the adverse effects of the Fusarium toxins. In conclusion, treatment of FUS-contaminated maize with SoS decreased the inner exposure with DON as indicated by the lower DON levels in various piglet specimens. However, health-related traits did not consistently reflect this decreased exposure.

The BABY BOOM Transcription Factor Activates the LEC1-ABI3-FUS3-LEC2 Network to Induce Somatic Embryogenesis1[OPEN

PubMed Central

Weemen, Mieke

2017-01-01

Somatic embryogenesis is an example of induced cellular totipotency, where embryos develop from vegetative cells rather than from gamete fusion. Somatic embryogenesis can be induced in vitro by exposing explants to growth regulators and/or stress treatments. The BABY BOOM (BBM) and LEAFY COTYLEDON1 (LEC1) and LEC2 transcription factors are key regulators of plant cell totipotency, as ectopic overexpression of either transcription factor induces somatic embryo formation from Arabidopsis (Arabidopsis thaliana) seedlings without exogenous growth regulators or stress treatments. Although LEC and BBM proteins regulate the same developmental process, it is not known whether they function in the same molecular pathway. We show that BBM transcriptionally regulates LEC1 and LEC2, as well as the two other LAFL genes, FUSCA3 (FUS3) and ABSCISIC ACID INSENSITIVE3 (ABI3). LEC2 and ABI3 quantitatively regulate BBM-mediated somatic embryogenesis, while FUS3 and LEC1 are essential for this process. BBM-mediated somatic embryogenesis is dose and context dependent, and the context-dependent phenotypes are associated with differential LAFL expression. We also uncover functional redundancy for somatic embryogenesis among other Arabidopsis BBM-like proteins and show that one of these proteins, PLETHORA2, also regulates LAFL gene expression. Our data place BBM upstream of other major regulators of plant embryo identity and totipotency. PMID:28830937

Determination of the Fusarium mycotoxins, fusaproliferin and beauvericin by high-performance liquid chromatography-electrospray ionization mass spectrometry.

PubMed

Sewram, V; Nieuwoudt, T W; Marasas, W F; Shephard, G S; Ritieni, A

1999-10-15

A method is described using LC-MS for the detection of the mycotoxins fusaproliferin (FUS) and beauvericin (BEA) in cultures of Fusarium subglutinans and in naturally contaminated maize. Protonated molecular ion signals for FUS and BEA were observed at m/z 445 and m/z 784, respectively. Collision induced dissociation of the readily dehydrated protonated molecular ion of the sesterterpene FUS (m/z 427) led to the loss of another water molecule (m/z 409) and acetic acid (m/z 385), while the cyclic lactone trimer BEA fragmented to yield the protonated dimer (m/z 523) and monomer (m/z 262), respectively. Detection of FUS was best performed in the MS-MS mode while BEA displayed a stronger signal in the MS mode. The on-column instrumental detection limits for pure FUS and BEA were found to be 2 ng and 20 pg (S/N=2) while those in naturally contaminated maize were 1 microg/kg and 0.5 microg/kg, respectively. Five South African strains of F. subglutinans were analyzed following methanol extraction of which four produced FUS at levels between 330 mg/kg and 2630 mg/kg while only three produced BEA at levels between 140 mg/kg and 700 mg/kg. Application of this method to naturally contaminated maize samples from the Transkei region of South Africa showed FUS at levels of 8.8-39.6 microg/kg and BEA at 7.6-238.8 microg/kg.

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

PubMed Central

Kia, Azadeh; McAvoy, Kevin; Krishnamurthy, Karthik; Trotti, Davide

2018-01-01

Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS. PMID:29380416

Workflow and intervention times of MR-guided focused ultrasound - Predicting the impact of new techniques.

PubMed

Loeve, Arjo J; Al-Issawi, Jumana; Fernandez-Gutiérrez, Fabiola; Langø, Thomas; Strehlow, Jan; Haase, Sabrina; Matzko, Matthias; Napoli, Alessandro; Melzer, Andreas; Dankelman, Jenny

2016-04-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) has become an attractive, non-invasive treatment for benign and malignant tumours, and offers specific benefits for poorly accessible locations in the liver. However, the presence of the ribcage and the occurrence of liver motion due to respiration limit the applicability MRgFUS. Several techniques are being developed to address these issues or to decrease treatment times in other ways. However, the potential benefit of such improvements has not been quantified. In this research, the detailed workflow of current MRgFUS procedures was determined qualitatively and quantitatively by using observation studies on uterine MRgFUS interventions, and the bottlenecks in MRgFUS were identified. A validated simulation model based on discrete events simulation was developed to quantitatively predict the effect of new technological developments on the intervention duration of MRgFUS on the liver. During the observation studies, the duration and occurrence frequencies of all actions and decisions in the MRgFUS workflow were registered, as were the occurrence frequencies of motion detections and intervention halts. The observation results show that current MRgFUS uterine interventions take on average 213min. Organ motion was detected on average 2.9 times per intervention, of which on average 1.0 actually caused a need for rework. Nevertheless, these motion occurrences and the actions required to continue after their detection consumed on average 11% and up to 29% of the total intervention duration. The simulation results suggest that, depending on the motion occurrence frequency, the addition of new technology to automate currently manual MRgFUS tasks and motion compensation could potentially reduce the intervention durations by 98.4% (from 256h 5min to 4h 4min) in the case of 90% motion occurrence, and with 24% (from 5h 19min to 4h 2min) in the case of no motion. In conclusion, new tools were developed to predict how intervention durations will be affected by future workflow changes and by the introduction of new technology. Copyright © 2016 Elsevier Inc. All rights reserved.

A focused ultrasound treatment system for moving targets (part I): generic system design and in-silico first-stage evaluation.

PubMed

Schwenke, Michael; Strehlow, Jan; Demedts, Daniel; Haase, Sabrina; Barrios Romero, Diego; Rothlübbers, Sven; von Dresky, Caroline; Zidowitz, Stephan; Georgii, Joachim; Mihcin, Senay; Bezzi, Mario; Tanner, Christine; Sat, Giora; Levy, Yoav; Jenne, Jürgen; Günther, Matthias; Melzer, Andreas; Preusser, Tobias

2017-01-01

Focused ultrasound (FUS) is entering clinical routine as a treatment option. Currently, no clinically available FUS treatment system features automated respiratory motion compensation. The required quality standards make developing such a system challenging. A novel FUS treatment system with motion compensation is described, developed with the goal of clinical use. The system comprises a clinically available MR device and FUS transducer system. The controller is very generic and could use any suitable MR or FUS device. MR image sequences (echo planar imaging) are acquired for both motion observation and thermometry. Based on anatomical feature tracking, motion predictions are estimated to compensate for processing delays. FUS control parameters are computed repeatedly and sent to the hardware to steer the focus to the (estimated) target position. All involved calculations produce individually known errors, yet their impact on therapy outcome is unclear. This is solved by defining an intuitive quality measure that compares the achieved temperature to the static scenario, resulting in an overall efficiency with respect to temperature rise. To allow for extensive testing of the system over wide ranges of parameters and algorithmic choices, we replace the actual MR and FUS devices by a virtual system. It emulates the hardware and, using numerical simulations of FUS during motion, predicts the local temperature rise in the tissue resulting from the controls it receives. With a clinically available monitoring image rate of 6.67 Hz and 20 FUS control updates per second, normal respiratory motion is estimated to be compensable with an estimated efficiency of 80%. This reduces to about 70% for motion scaled by 1.5. Extensive testing (6347 simulated sonications) over wide ranges of parameters shows that the main source of error is the temporal motion prediction. A history-based motion prediction method performs better than a simple linear extrapolator. The estimated efficiency of the new treatment system is already suited for clinical applications. The simulation-based in-silico testing as a first-stage validation reduces the efforts of real-world testing. Due to the extensible modular design, the described approach might lead to faster translations from research to clinical practice.

Initial evaluation of acoustic reflectors for the preservation of sensitive abdominal skin areas during MRgFUS treatment.

PubMed

Gorny, Krzysztof R; Chen, Shigao; Hangiandreou, Nicholas J; Hesley, Gina K; Woodrum, David A; Brown, Douglas L; Felmlee, Joel P

2009-04-21

During MR-guided focused ultrasound (MRgFUS) treatments of uterine fibroids using ExAblate(R)2000 (InSightec, Haifa, Israel), individual tissue ablations are performed extracorporeally through the patient's abdomen using an annular array FUS transducer embedded within the MR table. Ultrasound intensities in the near field are below therapeutic levels and, under normal conditions, heating of the patient skin is minimal. However, increased absorption of ultrasound energy within sensitive skin areas or areas with differing acoustic properties, such as scars, may lead to skin burns and therefore these areas must be kept outside the near field of the FUS beam. Depending on their location and size the sensitive areas may either obstruct parts of the fibroid from being treated or prevent the entire MRgFUS treatment altogether. The purpose of this work is to evaluate acoustic reflector materials that can be applied to protect skin and the underlying sensitive areas. Reflection coefficients of cork (0.88) and foam (0.91) based materials were evaluated with a hydrophone. An ExAblate 2000 MRgFUS system was used to simulate clinical treatment with discs of reflector materials placed in a near field underneath a gel phantom. MR thermometry was used to monitor temperature elevations as well as the integrity of the focal spot. The phantom measurements showed acoustic shadow zones behind the reflectors with zone depths changing between 7 and 27 mm, for reflector disc diameters increasing from 10 to 30 mm (40 mm diameter discs completely blocked the FUS beam at the depth evaluated). The effects on thermal lesions due to the presence of the reflectors in the FUS beam were found to diminish with decreasing disc diameter and increasing sonication depth. For a 20 mm diameter disc and beyond 50 mm sonication depth, thermal lesions were minimally affected by the presence of the disc. No heating was observed on the skin side of the foam reflectors, as confirmed by measurements performed with adhesive temperature labels. We present these data and discuss possible applications to clinical MRgFUS treatments.

Neurotrophic effects of progranulin in vivo in reversing motor neuron defects caused by over or under expression of TDP-43 or FUS

PubMed Central

Chitramuthu, Babykumari P.; Kay, Denis G.; Bateman, Andrew; Bennett, Hugh P. J.

2017-01-01

Progranulin (PGRN) is a glycoprotein with multiple roles in normal and disease states. Mutations within the GRN gene cause frontotemporal lobar degeneration (FTLD). The affected neurons display distinctive TAR DNA binding protein 43 (TDP-43) inclusions. How partial loss of PGRN causes TDP-43 neuropathology is poorly understood. TDP-43 inclusions are also found in affected neurons of patients with other neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, TDP-43 inclusions are typically also immunoreactive for fused in sarcoma (FUS). Mutations within TDP-43 or FUS are themselves neuropathogenic in ALS and some cases of FTLD. We used the outgrowth of caudal primary motor neurons (MNs) in zebrafish embryos to investigate the interaction of PGRN with TDP-43 and FUS in vivo. As reported previously, depletion of zebrafish PGRN-A (zfPGRN-A) is associated with truncated primary MNs and impaired motor function. Here we found that depletion of zfPGRN-A results in primary MNs outgrowth stalling at the horizontal myoseptum, a line of demarcation separating the myotome into dorsal and ventral compartments that is where the final destination of primary motor is assigned. Successful axonal outgrowth beyond the horizontal myoseptum depends in part upon formation of acetylcholine receptor clusters and this was found to be disorganized upon depletion of zfPGRN-A. PGRN reversed the effects of zfPGRN-A knockdown, but a related gene, zfPGRN-1, was without effect. Both knockdown of TDP-43 or FUS, as well as expression of humanTDP-43 and FUS mutants results in MN abnormalities that are reversed by co-expression of hPGRN mRNA. Neither TDP-43 nor FUS reversed MN phenotypes caused by the depletion of PGRN. Thus TDP-43 and FUS lie upstream of PGRN in a gene complementation pathway. The ability of PGRN to override TDP-43 and FUS neurotoxicity due to partial loss of function or mutation in the corresponding genes may have therapeutic relevance. PMID:28358904

Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo

PubMed Central

Choi, James J.; Wang, Shougang; Tung, Yao-Sheng; Morrison, Barclay; Konofagou, Elisa E.

2009-01-01

Focused ultrasound (FUS) is hereby shown to noninvasively and selectively deliver compounds at pharmacologically relevant molecular weights through the opened blood-brain barrier (BBB). A complete examination on the size of the FUS-induced BBB opening, the spatial distribution of the delivered agents and its dependence on the agent's molecular weight were imaged and quantified using fluorescence microscopy. BBB opening in mice (n=13) was achieved in vivo after systemic administration of microbubbles and subsequent application of pulsed FUS (frequency: 1.525 MHz, peak-rarefactional pressure in situ: 569 kPa) to the left murine hippocampus through the intact skin and skull. BBB-impermeant, fluorescent-tagged dextrans at three distinct molecular weights spanning over several orders of magnitude were systemically administered and acted as model therapeutic compounds. First, dextrans of 3 and 70 kDa were delivered trans-BBB while 2000 kDa dextran was not. Second, compared to 70 kDa dextran, a higher concentration of 3 kDa dextran was delivered through the opened BBB. Third, the 3 and 70 kDa dextrans were both diffusely distributed throughout the targeted brain region. However, high concentrations of 70 kDa dextran appeared more punctated throughout the targeted region. In conclusion, FUS combined with microbubbles opened the BBB sufficiently to allow passage of compounds of at least 70 kDa, but not greater than 2000 kDa, into the brain parenchyma. This noninvasive and localized BBB opening technique could thus provide a unique means for the delivery of compounds of several magnitudes of kDa that include agents with shown therapeutic promise in vitro, but whose in vivo translation has been hampered by their associated BBB impermeability. PMID:19900750

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

PubMed Central

2013-01-01

Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer’s disease. The requirements for clinical translation of FUS will be discussed. PMID:23379618

RNA Seeds Higher Order Assembly of FUS Protein

PubMed Central

Schwartz, Jacob C.; Wang, Xueyin; Podell, Elaine R.; Cech, Thomas R.

2014-01-01

SUMMARY The abundant nuclear RNA-binding protein FUS binds the CTD of RNA polymerase II in an RNA-dependent manner, affecting Ser2 phosphorylation and transcription. Here we examine the mechanism of this process and find that RNA binding nucleates the formation of higher order FUS RNP assemblies that bind the CTD. Both the low-complexity domain and the RGG domain of FUS contribute to assembly. The assemblies appear fibrous by electron microscopy and have characteristics of beta-zipper structures. These results support the emerging view that the pathologic protein aggregation seen in neurodegenerative diseases such as ALS may occur by exaggeration of functionally important assemblies of RNA-binding proteins. PMID:24268778

Focused Ultrasound Steering for Harmonic Motion Imaging.

PubMed

Han, Yang; Payen, Thomas; Wang, Shutao; Konofagou, Elisa

2018-02-01

Harmonic motion imaging (HMI) is a radiation-force-based ultrasound elasticity imaging technique, which is designed for both tissue relative stiffness imaging and reliable high-intensity focused ultrasound treatment monitoring. The objective of this letter is to develop and demonstrate the feasibility of 2-D focused ultrasound (FUS) beam steering for HMI using a 93-element, FUS phased array. HMI with steered FUS beam was acquired in tissue-mimicking phantoms. The HMI displacement was imaged within the steering range of ±1.7 mm laterally and ±2 mm axially. Using the steered FUS beam, HMI can be used to image a larger tissue volume with higher efficiency and without requiring mechanical movement of the transducer.

Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles

NASA Astrophysics Data System (ADS)

Downs, Matthew E.; Buch, Amanda; Karakatsani, Maria Eleni; Konofagou, Elisa E.; Ferrera, Vincent P.

2015-10-01

Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.

Systematic review of frequent users of emergency departments in non-US hospitals: state of the art.

PubMed

van Tiel, Sofie; Rood, Pleunie P M; Bertoli-Avella, Aida M; Erasmus, Vicky; Haagsma, Juanita; van Beeck, Ed; Patka, Peter; Polinder, Suzanne

2015-10-01

This review focuses on frequent users (FUs) of the emergency department (ED). Elucidation of the characteristics of frequent ED users will help to improve healthcare services. A systematic review of the literature (from 1999 onwards) on frequent ED users in non-US hospitals was performed. Twenty-two studies were included. FUs are responsible for a wide variety of 1-31% of ED visits depending on the FU definition used. They have a mean age between 40 and 50 years and are older than nonfrequent users. Chronic physical and mental diseases seem to be the main reasons for frequent ED visits. In terms of social characteristics, lacking a partner is more frequently reported among FUs in some studies. The absence of a universal definition for FUs complicates the determination of the burden on emergency healthcare services. FUs are a heterogeneous group of patients with genuine medical needs and high consumption of other healthcare services.

Focused ultrasound-mediated sonochemical internalization: an alternative to light-based therapies

NASA Astrophysics Data System (ADS)

Gonzales, Jonathan; Nair, Rohit Kumar; Madsen, Steen J.; Krasieva, Tatiana; Hirschberg, Henry

2016-07-01

Activation of sonosensitizers via focused ultrasound (FUS), i.e., sonodynamic therapy has been proposed as an extension to light-activated photodynamic therapy for the treatment of brain as well as other tumors. The use of FUS, as opposed to light, allows treatment to tumor sites buried deep within tissues as well as through the intact skull. We have examined ultrasonic activation of sonosensitizers together with the anticancer agent bleomycin (BLM), i.e., sonochemical internalization (SCI). SCI is a technique that utilizes FUS for the enhanced delivery of endo-lysosomal trapped macromolecules into the cell cytoplasm in a similar manner to light-based photochemical internalization. The released agent can, therefore, exert its full biological activity, in contrast to being degraded by lysosomal hydrolases. Our results indicate that, compared to drug or FUS treatment alone, FUS activation of the sonosensitizer AlPcS2a together with BLM significantly inhibits the ability of treated glioma cells to grow as three-dimensional tumor spheroids in vitro.

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

PubMed Central

Murakami, Tetsuro; Qamar, Seema; Lin, Julie Qiaojin; Schierle, Gabriele S. Kaminski; Rees, Eric; Miyashita, Akinori; Costa, Ana R.; Dodd, Roger B.; Chan, Fiona T.S.; Michel, Claire H.; Kronenberg-Versteeg, Deborah; Li, Yi; Yang, Seung-Pil; Wakutani, Yosuke; Meadows, William; Ferry, Rodylyn Rose; Dong, Liang; Tartaglia, Gian Gaetano; Favrin, Giorgio; Lin, Wen-Lang; Dickson, Dennis W.; Zhen, Mei; Ron, David; Schmitt-Ulms, Gerold; Fraser, Paul E.; Shneider, Neil A.; Holt, Christine; Vendruscolo, Michele; Kaminski, Clemens F.; St George-Hyslop, Peter

2015-01-01

Summary The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins. PMID:26526393

Magnetic resonance guided focused ultrasound surgery (MRgFUS) of bone metastases: From primary pain palliation to local tumor control

NASA Astrophysics Data System (ADS)

Napoli, A.; Leonardi, A.; Andrani, F.; Boni, F.; Anzidei, M.; Catalano, C.

2017-03-01

Purpose: To evaluate the clinical performance of MRgFUS in primary pain palliation of painful bone metastases and in local tumor control. Materials and Methods: We enrolled 26 consecutive patients (female/male 12/14; age: 64.7±7.5yrs) with painful bone metastases. Before and 3 months after MRgFUS treatment pain severity and pain interference scores were assessed according to Brief Pain Inventory-Quality of Life (BPI-QoL) criteria and patients underwent both CT and MRI. Local tumor control was evaluated according to lesion size, density and perfusion at CT, dynamic contrast enhancement at MRI (Discovery 750HD, GE; Gd-Bopta, Bracco) and metabolic activity at PET or scintigraphy. Patients were classified as responders or non-responders. Results: No treatment-related adverse events were recorded during the study. As statistically significant difference between baseline and follow-up values for both pain severity and pain interference scores was observed (p<0.05). Increased bone density was observed in 9/26 (34.6%) patients. Non-Perfused Volume values ranged between 20% and 92%. There was no difference in NPV values between responders and non-responders (46.7±24.2% [25 - 90 %] vs. 45±24.9% [20 - 93 %]; p=0.7). In 6 patients (5 prostate and 1 breast primary cancer) there was nearly absence of metabolic activity after treatment (mean SUV=1.2). Conclusion: MRgFUS can be safely and effectively used as the primary treatment for pain palliation in patients with painful bone metastases; moreover our experience demonstrated also a potential role for the MRgFUS in local tumor control.

Effects of feeding a Fusarium toxin-contaminated diet to infectious bursal disease virus-infected broilers on the protein turnover of the bursa of Fabricius and spleen.

PubMed

Dänicke, Sven; Pappritz, Julia; Goyarts, Tanja; Xu, Bu; Rautenschlein, Silke

2011-02-01

Two experiments were carried out to examine the effects of feeding an uncontaminated control diet (CON) or a Fusarium toxin-contaminated diet (FUS; 10.7 mg deoxynivalenol [DON]/kg diet) to growing broilers, which were either uninfected or infected with infectious bursal disease virus (IBDV) beginning at 1 day post hatch. Broilers had been infected at three weeks post hatch with either a classical virulent infectious bursal disease virus (IBDV-IM, Exp. 1) or a very virulent IBDV (vvIBDV, Exp. 2) strain. The effects of the DON-contaminated diet in combination with the virus-infection on the bursa of Fabricius and spleen were determined at 3 and 6-7 days post infection. The transient development of the bursa oedema and the bursa atrophy was not significantly affected by the diet after infection with the different IBDV-strains. The histopathological lesions were more severe in IBDV-IM-infected birds at 6 days post infection when additionally exposed to the FUS diet as compared to the FUS-free feed. Most parameters of the bursa of Fabricius and spleen protein turnover (e.g. fractional protein synthesis rate, protein, DNA and RNA content and derived indices) were significantly and interactively influenced by infection and stage of infection. The vvIBDV-infected birds responded with a more pronounced depressing effect on the fractional protein synthesis rate after feeding the DON-containing FUS diet when compared to their IBDV-IM-infected counterparts, where the opposite effect was observed. It can be concluded that feeding a FUS diet to IBDV-infected broilers might modulate the virulence-dependent pathogenesis of an IBDV infection.

Active MRI tracking for robotic assisted FUS

NASA Astrophysics Data System (ADS)

Xiao, Xu; Huang, Zhihong; Melzer, Andreas

2017-03-01

MR guided FUS is a noninvasive method producing thermal necrosis at the position of tumors with high accuracy and temperature control. Because the typical size of the ultrasound focus is smaller than the area of interested treatment tissues, focus repositioning become necessary to achieve multiple sonications to cover the whole targeted area. Using MR compatible mechanical actuators could help the ultrasound beam to reach a wider treatment range than using electrical beam steering technique and more flexibility in position the transducer. An active MR tracking technique was combined into the MRgFUS system to help locating the position of the mechanical actuator and the FUS transducer. For this study, a precise agar reference model was designed and fabricated to test the performance of the active tracking technique when it was used on the MR-compatible robotics InnoMotion™ (IBSMM, Engineering spol. s r.o. / Ltd, Czech Republic). The precision, tracking range and positioning speed of the combined robotic FUS system were evaluated in this study. Compared to the existing MR guided HIFU systems, the combined robotic system with active tracking techniques provides a potential that allows the FUS treatment to operate in a larger spatial range and with a faster speed, which is one of the main challenges for organ motion tracking.

Non-invasive peripheral nerve stimulation via focused ultrasound in vivo

NASA Astrophysics Data System (ADS)

Downs, Matthew E.; Lee, Stephen A.; Yang, Georgiana; Kim, Seaok; Wang, Qi; Konofagou, Elisa E.

2018-02-01

Focused ultrasound (FUS) has been employed on a wide range of clinical applications to safely and non-invasively achieve desired effects that have previously required invasive and lengthy procedures with conventional methods. Conventional electrical neuromodulation therapies that are applied to the peripheral nervous system (PNS) are invasive and/or non-specific. Recently, focused ultrasound has demonstrated the ability to modulate the central nervous system and ex vivo peripheral neurons. Here, for the first time, noninvasive stimulation of the sciatic nerve eliciting a physiological response in vivo is demonstrated with FUS. FUS was applied on the sciatic nerve in mice with simultaneous electromyography (EMG) on the tibialis anterior muscle. EMG signals were detected during or directly after ultrasound stimulation along with observable muscle contraction of the hind limb. Transecting the sciatic nerve downstream of FUS stimulation eliminated EMG activity during FUS stimulation. Peak-to-peak EMG response amplitudes and latency were found to be comparable to conventional electrical stimulation methods. Histology along with behavioral and thermal testing did not indicate damage to the nerve or surrounding regions. The findings presented herein demonstrate that FUS can serve as a targeted, safe and non-invasive alternative to conventional peripheral nervous system stimulation to treat peripheral neuropathic diseases in the clinic.

Focused ultrasound thermal therapy system with ultrasound image guidance and temperature measurement feedback.

PubMed

Lin, Kao-Han; Young, Sun-Yi; Hsu, Ming-Chuan; Chan, Hsu; Chen, Yung-Yaw; Lin, Win-Li

2008-01-01

In this study, we developed a focused ultrasound (FUS) thermal therapy system with ultrasound image guidance and thermocouple temperature measurement feedback. Hydraulic position devices and computer-controlled servo motors were used to move the FUS transducer to the desired location with the measurement of actual movement by linear scale. The entire system integrated automatic position devices, FUS transducer, power amplifier, ultrasound image system, and thermocouple temperature measurement into a graphical user interface. For the treatment procedure, a thermocouple was implanted into a targeted treatment region in a tissue-mimicking phantom under ultrasound image guidance, and then the acoustic interference pattern formed by image ultrasound beam and low-power FUS beam was employed as image guidance to move the FUS transducer to have its focal zone coincident with the thermocouple tip. The thermocouple temperature rise was used to determine the sonication duration for a suitable thermal lesion as a high power was turned on and ultrasound image was used to capture the thermal lesion formation. For a multiple lesion formation, the FUS transducer was moved under the acoustic interference guidance to a new location and then it sonicated with the same power level and duration. This system was evaluated and the results showed that it could perform two-dimensional motion control to do a two-dimensional thermal therapy with a small localization error 0.5 mm. Through the user interface, the FUS transducer could be moved to heat the target region with the guidance of ultrasound image and acoustic interference pattern. The preliminary phantom experimental results demonstrated that the system could achieve the desired treatment plan satisfactorily.

Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities

PubMed Central

Curley, Colleen T.; Sheybani, Natasha D.; Bullock, Timothy N.; Price, Richard J.

2017-01-01

Immunotherapy is rapidly emerging as the cornerstone for the treatment of several forms of metastatic cancer, as well as for a host of other pathologies. Meanwhile, several new high-profile studies have uncovered remarkable linkages between the central nervous and immune systems. With these recent developments, harnessing the immune system for the treatment of brain pathologies is a promising strategy. Here, we contend that MR image-guided focused ultrasound (FUS) represents a noninvasive approach that will allow for favorable therapeutic immunomodulation in the setting of the central nervous system. One obstacle to effective immunotherapeutic drug delivery to the brain is the blood brain barrier (BBB), which refers to the specialized structure of brain capillaries that prevents transport of most therapeutics from the blood into brain tissue. When applied in the presence of circulating microbubbles, FUS can safely and transiently open the BBB to facilitate the delivery of immunotherapeutic agents into the brain parenchyma. Furthermore, it has been demonstrated that physical perturbations of the tissue microenvironment via FUS can modulate immune response in both normal and diseased tissue. In this review article, we provide an overview of FUS energy regimens and corresponding tissue bioeffects, followed by a review of the literature pertaining to FUS for therapeutic antibody delivery in normal brain and preclinical models of brain disease. We provide an overview of studies that demonstrate FUS-mediated immune modulation in both the brain and peripheral settings. Finally, we provide remarks on challenges facing FUS immunotherapy and opportunities for future expansion in this area. PMID:29109764

A software tool for advanced MRgFUS prostate therapy planning and follow up

NASA Astrophysics Data System (ADS)

van Straaten, Dörte; Hoogenboom, Martijn; van Amerongen, Martinus J.; Weiler, Florian; Issawi, Jumana Al; Günther, Matthias; Fütterer, Jurgen; Jenne, Jürgen W.

2017-03-01

US guided HIFU/FUS ablation for the therapy of prostate cancer is a clinical established method, while MR guided HIFU/FUS applications for prostate recently started clinical evaluation. Even if MRI examination is an excellent diagnostic tool for prostate cancer, it is a time consuming procedure and not practicable within an MRgFUS therapy session. The aim of our ongoing work is to develop software to support therapy planning and post-therapy follow-up for MRgFUS on localized prostate cancer, based on multi-parametric MR protocols. The clinical workflow of diagnosis, therapy and follow-up of MR guided FUS on prostate cancer was deeply analyzed. Based on this, the image processing workflow was designed and all necessary components, e.g. GUI, viewer, registration tools etc. were defined and implemented. The software bases on MeVisLab with several implemented C++ modules for the image processing tasks. The developed software, called LTC (Local Therapy Control) will register and visualize automatically all images (T1w, T2w, DWI etc.) and ADC or perfusion maps gained from the diagnostic MRI session. This maximum of diagnostic information helps to segment all necessary ROIs, e.g. the tumor, for therapy planning. Final therapy planning will be performed based on these segmentation data in the following MRgFUS therapy session. In addition, the developed software should help to evaluate the therapy success, by synchronization and display of pre-therapeutic, therapy and follow-up image data including the therapy plan and thermal dose information. In this ongoing project, the first stand-alone prototype was completed and will be clinically evaluated.

Juvenile-onset Sporadic Amyotrophic Lateral Sclerosis with a Frameshift FUS Gene Mutation Presenting Unique Neuroradiological Findings and Cognitive Impairment.

PubMed

Hirayanagi, Kimitoshi; Sato, Masayuki; Furuta, Natsumi; Makioka, Kouki; Ikeda, Yoshio

2016-01-01

A 24-year-old Japanese woman developed anterocollis, weakness of the proximal arms, and subsequent cognitive impairment. A neurological examination revealed amyotrophic lateral sclerosis (ALS) without a family history. Systemic muscle atrophy progressed rapidly. Cerebral MRI clearly exhibited high signal intensities along the bilateral pyramidal tracts. An analysis of the FUS gene revealed a heterozygous two-base pair deletion, c.1507-1508delAG (p.G504WfsX515). A subset of juvenile-onset familial/sporadic ALS cases with FUS gene mutations reportedly demonstrates mental retardation or learning difficulty. Our study emphasizes the importance of conducting a FUS gene analysis in juvenile-onset ALS cases, even when no family occurrence is confirmed.

Robotically assisted velocity-sensitive triggered focused ultrasound surgery

NASA Astrophysics Data System (ADS)

Maier, Florian; Brunner, Alexander; Jenne, Jürgen W.; Krafft, Axel J.; Semmler, Wolfhard; Bock, Michael

2012-11-01

Magnetic Resonance (MR) guided Focused Ultrasound Surgery (FUS) of abdominal organs is challenging due to breathing motion and limited patient access in the MR environment. In this work, an experimental robotically assisted FUS setup was combined with a MR-based navigator technique to realize motion-compensated sonications and online temperature imaging. Experiments were carried out in a static phantom, during periodic manual motion of the phantom without triggering, and with triggering to evaluate the triggering method. In contrast to the non-triggered sonication, the results of the triggered sonication show a confined symmetric temperature distribution. In conclusion, the velocity sensitive navigator can be employed for triggered FUS to compensate for periodic motion. Combined with the robotic FUS setup, flexible treatment of abdominal targets might be realized.

TRANSPARENT TESTA GLABRA1 Regulates the Accumulation of Seed Storage Reserves in Arabidopsis1[OPEN

PubMed Central

Chen, Mingxun; Zhang, Bin; Li, Chengxiang; Kulaveerasingam, Harikrishna; Chew, Fook Tim; Yu, Hao

2015-01-01

Seed storage reserves mainly consist of starch, triacylglycerols, and storage proteins. They not only provide energy for seed germination and seedling establishment, but also supply essential dietary nutrients for human beings and animals. So far, the regulatory networks that govern the accumulation of seed storage reserves in plants are still largely unknown. Here, we show that TRANSPARENT TESTA GLABRA1 (TTG1), which encodes a WD40 repeat transcription factor involved in many aspects of plant development, plays an important role in mediating the accumulation of seed storage reserves in Arabidopsis (Arabidopsis thaliana). The dry weight of ttg1-1 embryos significantly increases compared with that of wild-type embryos, which is accompanied by an increase in the contents of starch, total protein, and fatty acids in ttg1-1 seeds. FUSCA3 (FUS3), a master regulator of seed maturation, binds directly to the TTG1 genomic region and suppresses TTG1 expression in developing seeds. TTG1 negatively regulates the accumulation of seed storage proteins partially through transcriptional repression of 2S3, a gene encoding a 2S albumin precursor. TTG1 also indirectly suppresses the expression of genes involved in either seed development or synthesis/modification of fatty acids in developing seeds. In addition, we demonstrate that the maternal allele of the TTG1 gene suppresses the accumulation of storage proteins and fatty acids in seeds. Our results suggest that TTG1 is a direct target of FUS3 in the framework of the regulatory hierarchy controlling seed filling and regulates the accumulation of seed storage proteins and fatty acids during the seed maturation process. PMID:26152712

TRANSPARENT TESTA GLABRA1 Regulates the Accumulation of Seed Storage Reserves in Arabidopsis.

PubMed

Chen, Mingxun; Zhang, Bin; Li, Chengxiang; Kulaveerasingam, Harikrishna; Chew, Fook Tim; Yu, Hao

2015-09-01

Seed storage reserves mainly consist of starch, triacylglycerols, and storage proteins. They not only provide energy for seed germination and seedling establishment, but also supply essential dietary nutrients for human beings and animals. So far, the regulatory networks that govern the accumulation of seed storage reserves in plants are still largely unknown. Here, we show that TRANSPARENT TESTA GLABRA1 (TTG1), which encodes a WD40 repeat transcription factor involved in many aspects of plant development, plays an important role in mediating the accumulation of seed storage reserves in Arabidopsis (Arabidopsis thaliana). The dry weight of ttg1-1 embryos significantly increases compared with that of wild-type embryos, which is accompanied by an increase in the contents of starch, total protein, and fatty acids in ttg1-1 seeds. FUSCA3 (FUS3), a master regulator of seed maturation, binds directly to the TTG1 genomic region and suppresses TTG1 expression in developing seeds. TTG1 negatively regulates the accumulation of seed storage proteins partially through transcriptional repression of 2S3, a gene encoding a 2S albumin precursor. TTG1 also indirectly suppresses the expression of genes involved in either seed development or synthesis/modification of fatty acids in developing seeds. In addition, we demonstrate that the maternal allele of the TTG1 gene suppresses the accumulation of storage proteins and fatty acids in seeds. Our results suggest that TTG1 is a direct target of FUS3 in the framework of the regulatory hierarchy controlling seed filling and regulates the accumulation of seed storage proteins and fatty acids during the seed maturation process. © 2015 American Society of Plant Biologists. All Rights Reserved.

MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes.

PubMed

Fasano, Alfonso; Llinas, Maheleth; Munhoz, Renato P; Hlasny, Eugen; Kucharczyk, Walter; Lozano, Andres M

2017-08-22

To report the 6-month single-blinded results of unilateral thalamotomy with MRI-guided focused ultrasound (MRgFUS) in patients with tremors other than essential tremor. Three patients with tremor due to Parkinson disease, 2 with dystonic tremor in the context of cervicobrachial dystonia and writer's cramp, and 1 with dystonia gene-associated tremor underwent MRgFUS targeting the ventro-intermedius nucleus (Vim) of the dominant hemisphere. The primary endpoint was the reduction of lateralized items of the Tremor Rating Scale of contralateral hemibody assessed by a blinded rater. All patients achieved a statistically significant, immediate, and sustained improvement of the contralateral tremor score by 42.2%, 52.0%, 55.9%, and 52.9% at 1 week and 1, 3, and 6 months after the procedure, respectively. All patients experienced transient side effects and 2 patients experienced persistent side effects at the time of last evaluation: hemitongue numbness and hemiparesis with hemihypoesthesia. Vim MRgFUS is a promising, incision-free, but nevertheless invasive technique to effectively treat tremors other than essential tremor. Future studies on larger samples and longer follow-up will further define its effectiveness and safety. NCT02252380. This study provides Class IV evidence that for patients with tremor not caused by essential tremor, MRgFUS of the Vim improves the tremor of the contralateral hemibody at 6 months. © 2017 American Academy of Neurology.

Real-time imaging and kinetics measurements of focused ultrasound-induced extravasation in skeletal muscle using SPECT/CT.

PubMed

Sanches, Pedro Gomes; Rossin, Raffaella; Böhmer, Marcel; Tiemann, Klaus; Grüll, Holger

2013-06-28

Drugs need to overcome several biological barriers such as the endothelium and cellular membranes in order to reach their target. Promising new therapeutics, many of which are charged and macromolecular, are not able to passively extravasate, let alone cross cell membranes, and stay mainly in the blood pool upon intravenous injection until clearance. Using focused ultrasound (fUS) in combination with circulating microbubbles (MBs) leads to temporary localized tissue permeabilization allowing extravasation of (macro) molecules from the vascular system. Thus, fUS is a promising approach for localized drug delivery. However, little is known about the permeabilization kinetics in skeletal muscle. In this study, we used single photon emission computed tomography (SPECT) to characterize the kinetics of extravasation of ¹¹¹In-labeled bovine serum albumin (BSA), a model macromolecular drug, in muscle treated with fUS and MBs. The same fUS protocol was applied to 6 groups of mice with different times, ∆t, between fUS application and BSA injection (∆t=-10, 2.5, 10, 30, 60, 90 min) followed by SPECT imaging. For ∆t ≤30min we observed an exponential accumulation of activity in an area of the treated muscle which extended to a volume larger than the fUS pattern with highest accumulation for short waiting times ∆t. The extent of extravasation decreased exponentially with increasing ∆t, with a calculated half-life of ca. 21 min, defining the time window of extravasation. The same treatment without MBs did not induce extravasation of BSA thus supporting MBs and drug co-injection strategies. These results provide essential information for the development of fUS based strategies for localized drug delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

MRI-Guided Focused Ultrasound Surgery for Uterine Fibroid Treatment: A Cost-Effectiveness Analysis

PubMed Central

Kong, Chung Y.; Omer, Zehra B.; Pandharipande, Pari V.; Swan, J. Shannon; Srouji, Serene; Gazelle, G. Scott; Fennessy, Fiona M.

2015-01-01

Objective To evaluate the cost-effectiveness of a treatment strategy for symptomatic uterine fibroids that employs Magnetic Resonance guided Focused Ultrasound (MRgFUS) as a first-line therapy relative to uterine artery embolization (UAE) or abdominal hysterectomy (HYST). Materials and Methods We developed a decision-analytic model to compare the cost-effectiveness of three treatment strategies: MRgFUS, UAE and HYST. Short and long-term utilities specific to each treatment were incorporated, allowing us to account for differences in quality of life across the strategies considered. Lifetime costs and quality-adjusted life-years (QALYs) were calculated for each strategy. An incremental cost-effectiveness analysis was performed, using a societal willingness-to-pay (WTP) threshold of $50,000 per QALY to designate a strategy as cost-effective. Sensitivity analysis was performed on all key model parameters. Results In the base-case analysis, in which treatment for symptomatic fibroids started at age 40, UAE was the most effective and expensive strategy (22.81 QALYs, $22,164), followed by MRgFUS (22.80 QALYs, $19,796) and HYST (22.60 QALYs, $13,291). MRgFUS was cost-effective relative to HYST, with an associated incremental cost-effectiveness ratio (ICER) of $33,110/QALY. MRgFUS was also cost-effective relative to UAE – the ICER of UAE relative to MRgFUS ($270,057) far exceeded the WTP threshold of $50,000/QALY. In sensitivity analysis, results were robust to changes in most parameters, but were sensitive to changes in probabilities of recurrence and symptom relief following certain procedures, and quality of life associated with symptomatic fibroids. Conclusions MRgFUS is cost-effective relative to both UAE and hysterectomy for the treatment of women with symptomatic fibroids. PMID:25055272

Noninvasive pulsed focused ultrasound allows spatiotemporal control of targeted homing for multiple stem cell types in murine skeletal muscle and the magnitude of cell homing can be increased through repeated applications.

PubMed

Burks, Scott R; Ziadloo, Ali; Kim, Saejeong J; Nguyen, Ben A; Frank, Joseph A

2013-11-01

Stem cells are promising therapeutics for cardiovascular diseases, and i.v. injection is the most desirable route of administration clinically. Subsequent homing of exogenous stem cells to pathological loci is frequently required for therapeutic efficacy and is mediated by chemoattractants (cell adhesion molecules, cytokines, and growth factors). Homing processes are inefficient and depend on short-lived pathological inflammation that limits the window of opportunity for cell injections. Noninvasive pulsed focused ultrasound (pFUS), which emphasizes mechanical ultrasound-tissue interactions, can be precisely targeted in the body and is a promising approach to target and maximize stem cell delivery by stimulating chemoattractant expression in pFUS-treated tissue prior to cell infusions. We demonstrate that pFUS is nondestructive to murine skeletal muscle tissue (no necrosis, hemorrhage, or muscle stem cell activation) and initiates a largely M2-type macrophage response. We also demonstrate that local upregulation of chemoattractants in pFUS-treated skeletal muscle leads to enhance homing, permeability, and retention of human mesenchymal stem cells (MSC) and human endothelial precursor cells (EPC). Furthermore, the magnitude of MSC or EPC homing was increased when pFUS treatments and cell infusions were repeated daily. This study demonstrates that pFUS defines transient "molecular zip codes" of elevated chemoattractants in targeted muscle tissue, which effectively provides spatiotemporal control and tunability of the homing process for multiple stem cell types. pFUS is a clinically translatable modality that may ultimately improve homing efficiency and flexibility of cell therapies for cardiovascular diseases. © AlphaMed Press.

Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers

NASA Astrophysics Data System (ADS)

Tsai, Chih-Hung; Zhang, Jia-Wei; Liao, Yi-Yi; Liu, Hao-Li

2016-04-01

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a surrogate to on/off control the FUS exposure in stage-2 experiments, we demonstrated both excellent sensitivity (92%) and specificity (92.3%) in discriminating BBB-opening occurrence can be obtained in animal treatments, while concurrently achieving a high positive predicted value (95.8%). Wideband ESD was also highly correlated with the occurrence and level of erythrocyte extravasations (r 2  =  0.81). The proposed system configuration and corresponding analysis based on subharmonic acoustic emissions has the potential to be implemented as a real-time feedback control structure for reliable indication of intact FUS-BBB opening for CNS brain drug delivery.

Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers.

PubMed

Tsai, Chih-Hung; Zhang, Jia-Wei; Liao, Yi-Yi; Liu, Hao-Li

2016-04-07

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a surrogate to on/off control the FUS exposure in stage-2 experiments, we demonstrated both excellent sensitivity (92%) and specificity (92.3%) in discriminating BBB-opening occurrence can be obtained in animal treatments, while concurrently achieving a high positive predicted value (95.8%). Wideband ESD was also highly correlated with the occurrence and level of erythrocyte extravasations (r (2)  =  0.81). The proposed system configuration and corresponding analysis based on subharmonic acoustic emissions has the potential to be implemented as a real-time feedback control structure for reliable indication of intact FUS-BBB opening for CNS brain drug delivery.

Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1.

PubMed

Ederle, Helena; Funk, Christina; Abou-Ajram, Claudia; Hutten, Saskia; Funk, Eva B E; Kehlenbach, Ralph H; Bailer, Susanne M; Dormann, Dorothee

2018-05-04

TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in nucleocytoplasmic transport contribute to this pathology, hence nuclear import of both proteins has been studied in detail. However, their nuclear export routes remain poorly characterized and it is unclear whether aberrant nuclear export contributes to TDP-43 or FUS pathology. Here we show that predicted nuclear export signals in TDP-43 and FUS are non-functional and that both proteins are exported independently of the export receptor CRM1/Exportin-1. Silencing of Exportin-5 or the mRNA export factor Aly/REF, as well as mutations that abrogate RNA-binding do not impair export of TDP-43 and FUS. However, artificially enlarging TDP-43 or FUS impairs their nuclear egress, suggesting that they could leave the nucleus by passive diffusion. Finally, we found that inhibition of transcription causes accelerated nuclear egress of TDP-43, suggesting that newly synthesized RNA retains TDP-43 in the nucleus, limiting its egress into the cytoplasm. Our findings implicate reduced nuclear retention as a possible factor contributing to mislocalization of TDP-43 in ALS/FTD.

Enhanced cavitation and heating of flowing polymer- and lipid-shelled microbubbles and phase-shift nanodroplets during focused ultrasound exposures

NASA Astrophysics Data System (ADS)

Zhang, Siyuan; Cui, Zhiwei; Li, Chong; Zhou, Fanyu; Zong, Yujin; Wang, Supin; Wan, Mingxi

2017-03-01

Cavitation and heating are the primary mechanisms of numerous therapeutic applications of ultrasound. Various encapsulated microbubbles (MBs) and phase-shift nanodroplets (NDs) have been used to enhance local cavitation and heating, creating interests in developing ultrasound therapy using these encapsulated MBs and NDs. This work compared the efficiency of flowing polymer- and lipid-shelled MBs and phase-shift NDs in cavitation and heating during focused ultrasound (FUS) exposures. Cavitation activity and temperature were investigated when the solution of polymer- and lipid-shelled MBs and NDs flowed through the vessel in a tissue-mimicking phantom with varying flow velocities when exposed to FUS at various acoustic power levels. The inertial cavitation dose (ICD) for the encapsulated MBs and NDs were higher than those for the saline. Temperature initially increased with increasing flow velocities of the encapsulated MBs, followed by a decrease of the temperature with increasing flow velocities when the velocity was much higher. Meanwhile, ICD showed a trend of increases with increasing flow velocity. For the phase-shift NDs, ICD after the first FUS exposure was lower than those after the second FUS exposure. For the encapsulated MBs, ICD after the first FUS exposure was higher than those after the second FUS exposure. Further studies are necessary to investigate the treatment efficiency of different encapsulated MBs and phase-shift NDs in cavitation and heating.

Magnetic Resonance Guided Focused Ultrasound Surgery: Part 2 – A Review of Current and Future Applications

PubMed Central

Medel, Ricky; Monteith, Stephen J.; Elias, W. Jeffrey; Eames, Matthew; Snell, John; Sheehan, Jason P.; Wintermark, Max; Jolesz, Ferenc A.; Kassell, Neal F.

2014-01-01

Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) represents a novel combination of technologies that is actively being realized as a non-invasive therapeutic tool for a myriad of conditions. These applications are reviewed with a focus on neurological utilization. A combined search of Pubmed and Medline was performed to identify the key events and current status of MRgFUS, with a focus on neurological applications. MRgFUS signifies a potentially ideal device for the treatment of neurological diseases. As it is nearly real-time, it allows monitored provision of treatment location and energy deposition, is noninvasive, thereby limiting or eliminating disruption of normal tissue, provides focal delivery of therapeutic agents, enhances radiation delivery, and permits modulation of neural function. Multiple clinical applications are currently in clinical use and many more are under active preclinical investigation. The therapeutic potential of MRgFUS is expanding rapidly. Although clinically in its infancy, preclinical and early phase I clinical trials in neurosurgery suggest a promising future for MRgFUS. Further investigation is necessary to define its true potential and impact. PMID:22791029

[MR-guided focused ultrasound. Current and future applications].

PubMed

Trumm, C G; Napoli, A; Peller, M; Clevert, D-A; Stahl, R; Reiser, M; Matzko, M

2013-03-01

High-intensity focused ultrasound (synonyms FUS and HIFU) under magnetic resonance imaging (MRI) guidance (synonyms MRgFUS and MR-HIFU) is a completely non-invasive technology for accurate thermal ablation of a target tissue while neighboring tissues and organs are preserved. The combination of FUS with MRI for planning, (near) real-time monitoring and outcome assessment of treatment markedly enhances the safety of the procedure. The MRgFUS procedure is clinically established in particular for the treatment of symptomatic uterine fibroids, followed by palliative ablation of painful bone metastases. Furthermore, promising results have been shown for the treatment of adenomyosis, malignant tumors of the prostate, breast and liver and for various intracranial applications, such as thermal ablation of brain tumors, functional neurosurgery and transient disruption of the blood-brain barrier.

Intrinsically disordered RGG/RG domains mediate degenerate specificity in RNA binding

PubMed Central

Ozdilek, Bagdeser A.; Thompson, Valery F.; Ahmed, Nasiha S.; White, Connor I.

2017-01-01

Abstract RGG/RG domains are the second most common RNA binding domain in the human genome, yet their RNA-binding properties remain poorly understood. Here, we report a detailed analysis of the RNA binding characteristics of intrinsically disordered RGG/RG domains from Fused in Sarcoma (FUS), FMRP and hnRNPU. For FUS, previous studies defined RNA binding as mediated by its well-folded domains; however, we show that RGG/RG domains are the primary mediators of binding. RGG/RG domains coupled to adjacent folded domains can achieve affinities approaching that of full-length FUS. Analysis of RGG/RG domains from FUS, FMRP and hnRNPU against a spectrum of contrasting RNAs reveals that each display degenerate binding specificity, while still displaying different degrees of preference for RNA. PMID:28575444

Simulating thermal effects of MR-guided focused ultrasound in cortical bone and its surrounding tissue.

PubMed

Hudson, Thomas J; Looi, Thomas; Pichardo, Samuel; Amaral, Joao; Temple, Michael; Drake, James M; Waspe, Adam C

2018-02-01

Magnetic resonance-guided focused ultrasound (MRgFUS) is emerging as a treatment alternative for osteoid osteoma and painful bone metastases. This study describes a new simulation platform that predicts the distribution of heat generated by MRgFUS when applied to bone tissue. Calculation of the temperature distribution was performed using two mathematical models. The first determined the propagation and absorption of acoustic energy through each medium, and this was performed using a multilayered approximation of the Rayleigh integral method. The ultrasound energy distribution derived from these equations could then be converted to heat energy, and the second mathematical model would then use the heat generated to determine the final temperature distribution using a finite-difference time-domain application of Pennes' bio-heat transfer equation. Anatomical surface geometry was generated using a modified version of a mesh-based semiautomatic segmentation algorithm, and both the acoustic and thermodynamic models were calculated using a parallelized algorithm running on a graphics processing unit (GPU) to greatly accelerate computation time. A series of seven porcine experiments were performed to validate the model, comparing simulated temperatures to MR thermometry and assessing spatial, temporal, and maximum temperature accuracy in the soft tissue. The parallelized algorithm performed acoustic and thermodynamic calculations on grids of over 10 8 voxels in under 30 s for a simulated 20 s of heating and 40 s of cooling, with a maximum time per calculated voxel of less than 0.3 μs. Accuracy was assessed by comparing the soft tissue thermometry to the simulation in the soft tissue adjacent to bone using four metrics. The maximum temperature difference between the simulation and thermometry in a region of interest around the bone was measured to be 5.43 ± 3.51°C average absolute difference and a percentage difference of 16.7%. The difference in heating location resulted in a total root-mean-square error of 4.21 ± 1.43 mm. The total size of the ablated tissue calculated from the thermal dose approximation in the simulation was, on average, 67.6% smaller than measured from the thermometry. The cooldown was much faster in the simulation, where it decreased by 14.22 ± 4.10°C more than the thermometry in 40 s after sonication ended. The use of a Rayleigh-based acoustic model combined with a discretized bio-heat transfer model provided a rapid three-dimensional calculation of the temperature distribution through bone and soft tissue during MRgFUS application, and the parallelized GPU algorithm provided the computational speed that would be necessary for an intraoperative treatment planning software platform. © 2017 American Association of Physicists in Medicine.

Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.

PubMed

Luty, Agnes A; Kwok, John B J; Dobson-Stone, Carol; Loy, Clement T; Coupland, Kirsten G; Karlström, Helena; Sobow, Tomasz; Tchorzewska, Joanna; Maruszak, Aleksandra; Barcikowska, Maria; Panegyres, Peter K; Zekanowski, Cezary; Brooks, William S; Williams, Kelly L; Blair, Ian P; Mather, Karen A; Sachdev, Perminder S; Halliday, Glenda M; Schofield, Peter R

2010-11-01

Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold. SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.

Semiclassical treatment of fusion and breakup processes of ^{6,8}He halo nuclei

NASA Astrophysics Data System (ADS)

Majeed, Fouad A.; Abdul-Hussien, Yousif A.

2016-06-01

A semiclassical approach has been used to study the effect of channel coupling on the calculations of the total fusion reaction cross section σ _{fus}, and the fusion barrier distribution D_{fus} for the systems 6He +^{238}U and 8He +^{197}Au. Since these systems invloves light exotic nuclei, breakup states channel play an important role that should be considered in the calculations. In semiclassical treatment, the relative motion between the projectile and target nuclei is approximated by a classical trajectory while the intrinsic dynamics is handled by time-dependent quantum mechanics. The calculations of the total fusion cross section σ _{fus}, and the fusion barrier distribution D_{fus} are compared with the full quantum mechanical calculations using the coupled-channels calculations with all order coupling using the computer code and with the available experimental data.

Transient disruption of vascular barriers using focused ultrasound and microbubbles for targeted drug delivery in the brain

NASA Astrophysics Data System (ADS)

Aryal, Muna

The physiology of the vasculature in the central nervous system (CNS) which includes the blood-brain-barrier (BBB) and other factors, prevents the transport of most anticancer agents to the brain and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels (blood-tumor barrier; BTB), along with several other factors, creates additional hurdles for drug treatment of brain tumors. Different methods have been used to bypass the BBB/BTB, but they have their own limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Magnetic Resonance Imaging guided Focused Ultrasound (MRIgFUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and BTB. The purpose of this thesis was to use this alternative approach to deliver chemotherapeutic agents through the BBB/BTB for brain tumor treatment in a rodent model to overcome the hinderances encountered in prior approaches tested for drug delivery in the CNS. The results presented in thesis demonstrate that MRIgFUS can be used to achieve consistent and reproducible BBB/BTB disruption in rats. It enabled us to achieve clinically-relevant concentrations of doxorubicin (~ 4.8+/-0.5 microg/g) delivered to the brain with the sonication parameters (0.69 MHz; 0.55 MPa; 10 ms bursts; 1 Hz PRF; 60 s duration), microbubble concentration (Definity, 10 microl/kg), and liposomoal doxorubicin (Lipo-DOX) dose (5.67 mg/kg) used. The resulting doxorubicin concentration was reduced by 32% when the agent was injected 10 minute after the last sonication. Three weekly sessions of FUS and Lipo-DOX appeared to be safe in the rat brain, despite some minor tissue damage. Importantly, the severe neurotoxicity seen in earlier works using other approaches does not appear to occur with delivery via FUS-BBB disruption. The resuls from three weekly treatments of FUS and Lipo-DOX in a rat glioma model are highly promising since they demonstrated that the method significantly inhibits tumor growth and improves survival. Animals that received three weekly sessions of FUS + Lipo-DOX (N = 8) had a median survival time that was increased significantly (P<0.001) compared to animals who received Lipo-DOX only (N = 6), FUS only (N = 8), or no treatment (N = 7). Median survival for animals that received FUS + Lipo-DOX was increased by 100% relative to untreated controls, whereas animals who received Lipo-DOX alone had only a 16% improvement. Animals who received only FUS showed no improvement. No tumor cells were found in histology in 4/8 animals in the FUS + Lipo-DOX group, and only a few tumor cells were detected in two animals. Tumor doxorubicin concentrations increased monotonically (823+/-600, 1817+/-732 and 2432+/-448 ng/g) in the control tumors at 9, 14 and 17 days respectively after administration of Lipo-DOX. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P<0.05, P<0.01, and P<0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222+/-784, 3687+/-796 and 5658+/-821 ng/g) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (p<0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery for Lipo-DOX are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da). Overall, this thesis research provides pre-clinical data toward the development of MRIgFUS as a noninvasive method for the delivery of agents such as Lipo-DOX across the BBB/BTB to treat patients with diseases of the central nervous system.

Pharmacokinetic analysis and drug delivery efficiency of the focused ultrasound-induced blood-brain barrier opening in non-human primates

PubMed Central

Samiotaki, Gesthimani; Karakatsani, Maria Eleni; Buch, Amanda; Papadopoulos, Stephanos; Wu, Shih Ying; Jambawalikar, Sachin; Konofagou, Elisa E.

2016-01-01

Purpose Focused Ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the Blood-Brain Barrier (BBB) locally, non-invasively and reversibly in rodents and non-human primates (NHP), suggesting the immense potential of this technique. The objective of this study entailed the investigation of the physiologic changes in the brain following the FUS-induced BBB opening and their relationship with the underlying anatomy. Materials and Methods Pharmacokinetic analysis was implemented in NHP’s that received FUS at various acoustic pressures. Relaxivity mapping enabled the robust quantitative detection of the BBB opening as well as gray and white matter segmentation. Drug delivery efficiency was measured for pre-clinical validation of the technique. Results Based on our results, the opening volume and the amount of the gadolinium delivered were found mostly contained in the grey matter, while FUS-induced permeability and drug concentration varied depending upon the underlying brain inhomogeneity, and increased with the acoustic pressure. Conclusions Overall, apart from the in vivo protocols for BBB analysis developed here, this study also suggests the important role that FUS can have in efficient drug delivery via localized and transient BBB opening. PMID:27916657

Drug delivery across the blood-brain barrier using focused ultrasound

PubMed Central

Burgess, Alison; Hynynen, Kullervo H.

2015-01-01

Introduction The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a non-invasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. Areas Covered The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. Expert Opinion The introduction of MRI guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient, and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development. PMID:24650132

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage.

PubMed

Hill, Sarah J; Mordes, Daniel A; Cameron, Lisa A; Neuberg, Donna S; Landini, Serena; Eggan, Kevin; Livingston, David M

2016-11-29

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.

Drug delivery across the blood-brain barrier using focused ultrasound.

PubMed

Burgess, Alison; Hynynen, Kullervo

2014-05-01

The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a noninvasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. The introduction of magnetic resonance imaging guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development.

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

PubMed Central

Hill, Sarah J.; Mordes, Daniel A.; Cameron, Lisa A.; Neuberg, Donna S.; Landini, Serena; Eggan, Kevin; Livingston, David M.

2016-01-01

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis. PMID:27849576

Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

PubMed

Zou, Zhang-Yu; Zhou, Zhi-Rui; Che, Chun-Hui; Liu, Chang-Yun; He, Rao-Li; Huang, Hua-Pin

2017-07-01

Genetic studies have shown that C9orf72 , SOD1 , TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS. We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72 , SOD1 , TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined. Possible sources of heterogeneity across studies were determined by meta-regression, sensitivity analysis and subgroup analysis. 111 studies were included in the meta-analysis. The overall pooled mutation frequencies of these major ALS-related genes were 47.7% in familial amyotrophic lateral sclerosis (FALS) and 5.2% in sporadic ALS (SALS). A significant difference was identified regarding the frequencies of mutations in major ALS genes between European and Asian patients. In European populations, the most common mutations were the C9orf72 repeat expansions (FALS 33.7%, SALS 5.1%), followed by SOD1 (FALS 14.8%, SALS 1.2%), TARDBP (FALS 4.2%, SALS 0.8%) and FUS mutations (FALS 2.8%, SALS 0.3%), while in Asian populations the most common mutations were SOD1 mutations (FALS 30.0%, SALS 1.5%), followed by FUS (FALS 6.4%, SALS 0.9%), C9orf72 (FALS 2.3%, SALS 0.3%) and TARDBP (FALS 1.5%, SALS 0.2%) mutations. These findings demonstrated that the genetic architecture of ALS in Asian populations is distinct from that in European populations, which need to be given appropriate consideration when performing genetic testing of patients with ALS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

HSI2/VAL1 Silences AGL15 to Regulate the Developmental Transition from Seed Maturation to Vegetative Growth in Arabidopsis[OPEN

PubMed Central

Abdelmageed, Haggag; Kang, Miyoung

2018-01-01

Gene expression during seed development in Arabidopsis thaliana is controlled by transcription factors including LEAFY COTYLEDON1 (LEC1) and LEC2, ABA INSENSITIVE3 (ABI3), FUSCA3 (FUS3), known as LAFL proteins, and AGAMOUS-LIKE15 (AGL15). The transition from seed maturation to germination and seedling growth requires the transcriptional silencing of these seed maturation-specific factors leading to downregulation of structural genes including those that encode seed storage proteins, oleosins, and dehydrins. During seed germination and vegetative growth, B3-domain protein HSI2/VAL1 is required for the transcriptional silencing of LAFL genes. Here, we report chromatin immunoprecipitation analysis indicating that HSI2/VAL1 binds to the upstream sequences of the AGL15 gene but not at LEC1, ABI3, FUS3, or LEC2 loci. Functional analysis indicates that the HSI2/VAL1 B3 domain interacts with two RY elements upstream of the AGL15 coding region and at least one of them is required for HSI2/VAL1-dependent AGL15 repression. Expression analysis of the major seed maturation regulatory genes LEC1, ABI3, FUS3, and LEC2 in different genetic backgrounds demonstrates that HSI2/VAL1 is epistatic to AGL15 and represses the seed maturation regulatory program through downregulation of AGL15 by deposition of H3K27me3 at this locus. This hypothesis is further supported by results that show that HSI2/VAL1 physically interacts with the Polycomb Repressive Complex 2 component protein MSI1, which is also enriched at the AGL15 locus. PMID:29475938

Ver-i-Fus: an integrated access control and information monitoring and management system

NASA Astrophysics Data System (ADS)

Thomopoulos, Stelios C.; Reisman, James G.; Papelis, Yiannis E.

1997-01-01

This paper describes the Ver-i-Fus Integrated Access Control and Information Monitoring and Management (IAC-I2M) system that INTELNET Inc. has developed. The Ver-i-Fus IAC-I2M system has been designed to meet the most stringent security and information monitoring requirements while allowing two- way communication between the user and the system. The systems offers a flexible interface that permits to integrate practically any sensing device, or combination of sensing devices, including a live-scan fingerprint reader, thus providing biometrics verification for enhanced security. Different configurations of the system provide solutions to different sets of access control problems. The re-configurable hardware interface, tied together with biometrics verification and a flexible interface that allows to integrate Ver-i-Fus with an MIS, provide an integrated solution to security, time and attendance, labor monitoring, production monitoring, and payroll applications.

Optimizing MR imaging-guided navigation for focused ultrasound interventions in the brain

NASA Astrophysics Data System (ADS)

Werner, B.; Martin, E.; Bauer, R.; O'Gorman, R.

2017-03-01

MR imaging during transcranial MR imaging-guided Focused Ultrasound surgery (tcMRIgFUS) is challenging due to the complex ultrasound transducer setup and the water bolus used for acoustic coupling. Achievable image quality in the tcMRIgFUS setup using the standard body coil is significantly inferior to current neuroradiologic standards. As a consequence, MR image guidance for precise navigation in functional neurosurgical interventions using tcMRIgFUS is basically limited to the acquisition of MR coordinates of salient landmarks such as the anterior and posterior commissure for aligning a stereotactic atlas. Here, we show how improved MR image quality provided by a custom built MR coil and optimized MR imaging sequences can support imaging-guided navigation for functional tcMRIgFUS neurosurgery by visualizing anatomical landmarks that can be integrated into the navigation process to accommodate for patient specific anatomy.

In-vivo imaging of blood-brain barrier permeability using positron emission tomography with 2-amino-[3-11C]isobutyric acid.

PubMed

Okada, Maki; Kikuchi, Tatsuya; Okamura, Toshimitsu; Ikoma, Yoko; Tsuji, Atsushi B; Wakizaka, Hidekatsu; Kamakura, Tomoo; Aoki, Ichio; Zhang, Ming-Rong; Kato, Koichi

2015-12-01

The blood-brain barrier (BBB) limits the entry of some therapeutics into the brain, resulting in reduced efficacy. BBB-opening techniques have been developed to enhance the entry into the brain. However, a noninvasive, highly sensitive and quantitative method for evaluating the changes in BBB permeability induced by such techniques is needed to optimize treatment protocols. We evaluated 2-amino-[3-C]isobutyric acid ([3-C]AIB) as a PET probe to quantify BBB permeability in model rats. BBB opening was induced by a lipopolysaccharide injection or focused ultrasound (FUS) sonication. [3-C]AIB distribution in the brain was evaluated by autoradiography and PET and compared with that of Evans blue, a traditional BBB permeability marker. Kinetics of [3-C]AIB was compared with that of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced MRI. The unidirectional blood-brain transfer constant (Ki) of [3-C]AIB was estimated using the Patlak plot. [3-C]AIB uptake in the lesion area was significantly higher than that in the control area and radioactivity colocalized with Evans blue in both models. [3-C]AIB uptake in the FUS-sonicated region decreased over time after sonication. The ratio of [3-C]AIB accumulation in the FUS-treated to the contralateral side increased during the experimental period, whereas that of the Gd-DTPA intensity reached a maximum at 10 min after injection and decreased thereafter. The [3-C]AIB Ki values were significantly higher in the lesion area than the control area. [3-C]AIB PET is a promising, highly sensitive and quantitative imaging method for assessment of BBB permeability.

Microtubules as platforms for probing liquid-liquid phase separation in cells: application to RNA-binding proteins.

PubMed

Maucuer, Alexandre; Desforges, Bénédicte; Joshi, Vandana; Boca, Mirela; Kretov, Dmitry; Hamon, Loic; Bouhss, Ahmed; Curmi, Patrick A; Pastré, David

2018-05-04

Liquid-liquid phase separation enables compartmentalization of biomolecules in cells, notably RNA and associated proteins in the nucleus. Besides critical functions in RNA processing, there is a major interest in deciphering the molecular mechanisms of compartmentalization orchestrated by RNA-binding proteins such as TDP-43 and FUS due to their link to neuron diseases. However, tools for probing compartmentalization in cells are lacking. Here we developed a method to analyze the mixing:demixing of two different phases in a cellular context. The principle is the following: mRNA-binding proteins are confined on microtubules and quantitative parameters defining their spatial segregation are measured along the microtubule network. Through this approach, we found that four mRNA binding proteins, HuR, G3BP1, TDP-43 and FUS form mRNA-rich liquid-like compartments on microtubules. TDP-43 is partly miscible with FUS but immiscible with either HuR or G3BP1. We also demonstrate that mRNA is essential to capture the mixing:demixing behavior of RNA-binding proteins in cells. Altogether we show that microtubules can be used as platforms to understand the mechanisms underlying liquid-liquid phase separation and their deregulation in human diseases. © 2018. Published by The Company of Biologists Ltd.

Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center.

PubMed

Chadi, Gerson; Maximino, Jessica Ruivo; Jorge, Frederico Mennucci de Haidar; Borba, Fabrício Castro de; Gilio, Joyce Meire; Callegaro, Dagoberto; Lopes, Camila Galvão; Santos, Samantha Nakamura Dos; Rebelo, Gabriela Natania Sales

2017-05-01

To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

PubMed

Shin, Jaewoo; Kong, Chanho; Cho, Jae Sung; Lee, Jihyeon; Koh, Chin Su; Yoon, Min-Sik; Na, Young Cheol; Chang, Won Seok; Chang, Jin Woo

2018-02-01

OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

Targeted Gene Transfer to the Brain via the Delivery of Brain-Penetrating DNA Nanoparticles with Focused Ultrasound

PubMed Central

Mead, Brian P.; Mastorakos, Panagiotis; Suk, Jung Soo; Klibanov, Alexander L.; Hanes, Justin; Price, Richard J.

2016-01-01

Gene therapy holds promise for the treatment of many pathologies of the central nervous system (CNS), including brain tumors and neurodegenerative diseases. However, the delivery of systemically administered gene carriers to the CNS is hindered by both the blood-brain barrier (BBB) and the nanoporous and electrostatically charged brain extracelluar matrix (ECM), which acts as a steric and adhesive barrier. We have previously shown that these physiological barriers may be overcome by, respectively, opening the BBB with MR image-guided focused ultrasound (FUS) and microbubbles and using highly compact “brain penetrating” nanoparticles (BPN) coated with a dense polyethylene glycol corona that prevents adhesion to ECM components. Here, we tested whether this combined approach could be utilized to deliver systemically administered DNA-bearing BPN (DNA-BPN) across the BBB and mediate localized, robust, and sustained transgene expression in the rat brain. Systemically administered DNA-BPN delivered through the BBB with FUS led to dose-dependent transgene expression only in the FUS-treated region that was evident as early as 24 h post administration and lasted for at least 28 days. In the FUS-treated region ~42% of all cells, including neurons and astrocytes, were transfected, while less than 6% were transfected in the contralateral non-FUS treated hemisphere. Importantly, this was achieved without any sign of toxicity or astrocyte activation. We conclude that the image-guided delivery of DNA-BPN with FUS and microbubbles constitutes a safe and non-invasive strategy for targeted gene therapy to the brain. PMID:26732553

FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations.

PubMed

Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; DeJesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A; Munoz, David G; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee-Cyn; Bilbao, Juan; Rademakers, Rosa; Haass, Christian; Mackenzie, Ian R A

2011-09-01

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.

Molecular determinants of Cytochrome C oxidase IV mRNA axonal trafficking

PubMed Central

Kar, Amar N.; Vargas, Jose Norberto S.; Chen, Cai-Yun; Kowalak, Jeffrey A; Gioio, Anthony E.; Kaplan, Barry B.

2017-01-01

In previous studies, we identified a putative 38-nucleotide stem-loop structure (zipcode) in the 3′ untranslated region of the cytochrome c oxidase subunit IV (COXIV) mRNA that was necessary and sufficient for the axonal localization of the message in primary superior cervical ganglion (SCG) neurons. However, little is known about the proteins that interact with the COXIV-zipcode and regulate the axonal trafficking and local translation of the COXIV message. To identify proteins involved in the axonal transport of the COXIV mRNA, we used the biotinylated 38-nucleotide COXIV RNA zipcode as bait in the affinity purification of COXIV zipcode binding proteins. Gel-shift assays of the biotinylated COXIV zipcode indicated that the putative stem-loop structure functions as a nucleation site for the formation of ribonucleoprotein complexes. Mass spectrometric analysis of the COXIV zipcode ribonucleoprotein complex led to the identification of a large number RNA binding proteins, including fused in sarcoma/translated in liposarcoma (FUS/TLS), and Y-box protein 1 (YB-1). Validation experiments, using western analyses, confirmed the presence of the candidate proteins in the COXIV zipcode affinity purified complexes obtained from SCG axons. Immunohistochemical studies show that FUS, and YB-1 are present in SCG axons. Importantly, RNA immunoprecipitation studies show that FUS, and YB-1 interact with endogenous axonal COXIV transcripts. siRNA-mediated downregulation of the candidate proteins FUS and YB-1 expression in the cell-bodies diminishes the levels of COXIV mRNA in the axon, suggesting functional roles for these proteins in the axonal trafficking of COXIV mRNA. PMID:28161363

Restoring Neurological Physiology: The Innovative Role of High-Energy MR-Guided Focused Ultrasound (HIMRgFUS). Preliminary Data from a New Method of Lesioning Surgery.

PubMed

Giugno, Antonella; Maugeri, Rosario; Graziano, Francesca; Gagliardo, Cesare; Franzini, Angelo; Catalano, Carlo; Midiri, Massimo; Iacopino, Domenico Gerardo

2017-01-01

Tremor is a disabling condition, common to several neurodegenerative diseases. Lesioning procedures and deep brain stimulation, respectively, of the ventralis intermedius nucleus for intentional tremor, and of the subthalamic nucleus for parkinsonian resting tremor, have been introduced in clinical practice for patients refractory to medical treatment. The combination of high-energy focused ultrasound (HIFUS) with sophisticated magnetic resonance (MR) instrumentation, together with accurate knowledge of the stereotactic brain coordinates, represents a revolution in neuromodulation. At the Neurosurgical Clinic and the Radiology Department of the University of Palermo,, two patients affected by severe and refractory forms of intentional tremor were treated by MRI-guided FUS (MRgFUS) with a unique 1.5 T MR scanner prototype that uses FUS. This apparatus is the only one of its type in the world." This is the first Italian experience, and the second in Europe, of treatment with MRI-gFUS for intentional tremor. But this is the very first experience in which a 1.5 T MRI apparatus was used. In both patients, the treatment completely abolished the tremor on the treated side, with results being excellent and stable after 7 and 5 months, respectively; no side effects were encountered. MRgFUS, recently introduced in clinical practice, and widely used at several clinical centers, has been shown to be a valid therapeutic alternative in the treatment of tremor in several neurodegenerative diseases. It is virtually safe, noninvasive, and very efficacious. We report this technique in which a 1.5 T MR scanner was used. Further investigations with long-term follow up and larger clinical series are needed.

Transcranial functional ultrasound imaging of the brain using microbubble-enhanced ultrasensitive Doppler

PubMed Central

Errico, Claudia; Osmanski, Bruno-Félix; Pezet, Sophie; Couture, Olivier; Lenkei, Zsolt; Tanter, Mickael

2016-01-01

Functional ultrasound (fUS) is a novel neuroimaging technique, based on high-sensitivity ultrafast Doppler imaging of cerebral blood volume, capable of measuring brain activation and connectivity in rodents with high spatiotemporal resolution (100 μm, 1 ms). However, the skull attenuates acoustic waves, so fUS in rats currently requires craniotomy or a thinned-skull window. Here we propose a non-invasive approach by enhancing the fUS signal with a contrast agent, inert gas microbubbles. Plane-wave illumination of the brain at high frame rate (500 Hz compounded sequence with three tilted plane waves, PRF = 1500Hz with a 128 element 15 MHz linear transducer), yields highly-resolved neurovascular maps. We compared fUS imaging performance through the intact skull bone (transcranial fUS) versus a thinned-skull window in the same animal. First, we show that the vascular network of the adult rat brain can be imaged transcranially only after a bolus intravenous injection of microbubbles, which leads to a 9 dB gain in the contrast-to-tissue ratio. Next, we demonstrate that functional increase in the blood volume of the primary sensory cortex after targeted electrical-evoked stimulations of the sciatic nerve is observable transcranially in presence of contrast agents, with high reproducibility (Pearson's coefficient ρ = 0.7 ± 0.1, p = 0.85). Our work demonstrates that the combination of ultrafast Doppler imaging and injection of contrast agent allows non-invasive functional brain imaging through the intact skull bone in rats. These results should ease non-invasive longitudinal studies in rodents and open a promising perspective for the adoption of highly resolved fUS approaches for the adult human brain. PMID:26416649

Spindle Cell Rhabdomyosarcoma of Bone with FUS-TFCP2 Fusion: Confirmation of a Very Recently Described Rhabdomyosarcoma Subtype.

PubMed

Dashti, Nooshin K; Wehrs, Rebecca N; Thomas, Brittany C; Nair, Asha; Davila, Jaime; Buckner, Jan C; Martinez, Anthony P; Sukov, William R; Halling, Kevin C; Howe, Benjamin M; Folpe, Andrew L

2018-05-14

Rhabdomyosarcomas of bone are extremely rare, with fewer than 10 reported cases. A very rare subtype of spindle cell/sclerosing rhabdomyosarcoma harboring a FUS-TFCP2 fusion and involving both soft tissue and bone locations has very recently been reported. We report only the fourth case of this unusual, clinically aggressive rhabdomyosarcoma. A previously-well 72-year old male presented with a destructive lesion of the mandible. Morphological and immunohistochemical study of a needle biopsy and the subsequent resection showed a spindle cell rhabdomyosarcoma. RNA-seq, RT-PCR and FISH confirmed the presence of the FUS-TFCP2 fusion. Spindle cell rhabdomyosarcomas carrying the FUS-TFCP2 fusion are very rare rhabdomyosarcoma variants with osseous predilection. The classification and differential diagnosis of this unusual molecular variant of spindle cell/ sclerosing rhabdomyosarcoma are discussed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential into the Brain using MRI-Guided Focused Ultrasound

PubMed Central

Etame, Arnold B.; Diaz, Roberto J.; O’Reilly, Meaghan A.; Smith, Christian A.; Mainprize, Todd G.; Hynynen, Kullervo; Rutka, James T.

2014-01-01

The blood brain barrier (BBB) is a major impediment to the delivery of therapeutics into the central nervous system (CNS). Gold nanoparticles (AuNPs) have been successfully employed in multiple potential therapeutic and diagnostic applications outside the CNS. However, AuNPs have very limited biodistribution within the CNS following intravenous administration. Magnetic resonance imaging guided focused ultrasound (MRgFUS) is a novel technique that can transiently increase BBB permeability allowing delivery of therapeutics into the CNS. MRgFUS has not been previously employed for delivery of AuNPs into the CNS. This work represents the first demonstration of focal enhanced delivery of AuNPs into the CNS using MRgFUS in a rat model both safely and effectively. Histologic visualization and analytical quantification of AuNPs within the brain parenchyma suggest BBB transgression. These results suggest a role for MRgFUS in the delivery of AuNPs with therapeutic potential into the CNS for targeting neurological diseases. PMID:22349099

Intraoperative Functional Ultrasound Imaging of Human Brain Activity.

PubMed

Imbault, Marion; Chauvet, Dorian; Gennisson, Jean-Luc; Capelle, Laurent; Tanter, Mickael

2017-08-04

The functional mapping of brain activity is essential to perform optimal glioma surgery and to minimize the risk of postoperative deficits. We introduce a new, portable neuroimaging modality of the human brain based on functional ultrasound (fUS) for deep functional cortical mapping. Using plane-wave transmissions at an ultrafast frame rate (1 kHz), fUS is performed during surgery to measure transient changes in cerebral blood volume with a high spatiotemporal resolution (250 µm, 1 ms). fUS identifies, maps and differentiates regions of brain activation during task-evoked cortical responses within the depth of a sulcus in both awake and anaesthetized patients.

High-intensity focused ultrasound: advances in technology and experimental trials support enhanced utility of focused ultrasound surgery in oncology

PubMed Central

Malietzis, G; Monzon, L; Hand, J; Wasan, H; Leen, E; Abel, M; Muhammad, A; Abel, P

2013-01-01

High-intensity focused ultrasound (HIFU) is a rapidly maturing technology with diverse clinical applications. In the field of oncology, the use of HIFU to non-invasively cause tissue necrosis in a defined target, a technique known as focused ultrasound surgery (FUS), has considerable potential for tumour ablation. In this article, we outline the development and underlying principles of HIFU, overview the limitations and commercially available equipment for FUS, then summarise some of the recent technological advances and experimental clinical trials that we predict will have a positive impact on extending the role of FUS in cancer therapy. PMID:23403455

Development, Characterization, and Implementation of a System for Focused Ultrasound-Mediated Blood-Brain Barrier Opening in Mice

NASA Astrophysics Data System (ADS)

Valdez, Michael Aaron

The blood-brain barrier BBB refers to the set of specialized endothelial cells that line the vasculature in the brain and effectively control movement of molecules into and out of the brain. While necessary for proper brain function, the BBB blocks 98% of drugs from entering the brain and is the most significant barrier to developing therapies for neurodegenerative diseases. Active transport allows some specific molecules to cross the BBB, but therapeutic development using this route has had limited success. A number of techniques have been used to bypass the BBB, but are often highly invasive and ineffective. Over the last two decades, a minimally invasive technique to transiently open the BBB has been under development that utilizes transcranial focused ultrasound (FUS) in combination with intravascular microbubble contrast agents. This method is often carried out in conjunction with magnetic resonance imaging (MRI) to guide and assess BBB opening and has been referred to as MRI guided FUS (MRgFUS). Because of the utility of mouse models of neurological disease and the exploratory nature of MRgFUS, systems that allow BBB opening in mice are a useful and necessary tool to develop and evaluate this method for clinical application. In this dissertation project, a custom built, cost-effective FUS system for opening the BBB in mice was developed, with the objective of using this device to deliver therapeutics to the brain. Being a custom device, it was necessary to evaluate the ultrasound output, verify in vivo safety, and anticipate the therapeutic effect. The scope of the work herein consists of the design, construction, and evaluation of system that fulfills these requirements. The final constructed system cost was an order of magnitude less than any commercially available MRgFUS system. At this low price point, the hardware could allow the implementation of the methodology in many more research areas than previously possible. Additionally, to anticipate the therapeutic effect, molecules of pharmacologically-relevant sizes were delivered to brain with a novel, multispectral approach. Results demonstrated that the device was able to safely open the BBB, and macromolecule delivery showed that both molecule size and FUS pressure both influence the amount and distribution of molecules in the brain. Using different ultrasound pressures, the threshold for BBB opening was found to be ≥ 180 kPa (0.13 MI). The threshold for damage was found to be ≥ 420 kPa (0.30 MI), and was minor at this pressure, but extensive for higher pressure (870 kPa, 0.62 MI), in which minor damage was caused by this pressure. Performing a novel implementation of a diffusion model on the fluorescence images of 500, 70, and 3 kDa dextran resulted in calculated diffusion coefficients of 0.032 +/- 0.015, 12 +/- 6.0, and 0.13 +/- 0.094 square microns per second, respectively.

Real-time Focused Ultrasound Surgery (FUS) Monitoring Using Harmonic Motion Imaging (HMI)

NASA Astrophysics Data System (ADS)

Maleke, Caroline; Konofagou, Elisa E.

2009-04-01

Monitoring changes in tissue mechanical properties to optimally control thermal exposure is important in thermal therapies. The amplitude-modulated (AM) harmonic motion imaging (HMI) for focused ultrasound (HMIFU) technique is a radiation force technique, which has the capability of tracking tissue stiffness during application of an oscillatory force. The feasibility of HMIFU for assessing mechanical tissue properties has been previously demonstrated. In this paper, a confocal transducer, combining a 4.5 MHz FUS transducer and a 3.3 MHz phased array imaging transducer, was used. The FUS transducer was driven by AM wave at 15 Hz with an acoustic intensity (Ispta) was equal to 1050 W/cm2. A lowpass digital filter was used to remove the spectrum of the higher power beam prior to displacement estimation. The resulting axial tissue displacement was estimated using 1D cross-correlation with a correlation window of 2 mm and a 92.5% overlap. A thermocouple was also used to measure the temperature near the ablated region. 2D HMI-images from six-bovine-liver specimens indicated the onset of coagulation necrosis through changes in amplitude displacement after coagulation due to its simultaneous probing and heating capability. The HMI technique can thus be used to monitor temperature-related stiffness changes of tissues during thermal therapies in real-time, i.e., without interrupting or modifying the treatment protocol.

Real-time Focused Ultrasound Surgery (FUS) Monitoring Using Harmonic Motion Imaging (HMI)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maleke, Caroline; Konofagou, Elisa E.; Department of Radiology, Columbia University, New York, NY

2009-04-14

Monitoring changes in tissue mechanical properties to optimally control thermal exposure is important in thermal therapies. The amplitude-modulated (AM) harmonic motion imaging (HMI) for focused ultrasound (HMIFU) technique is a radiation force technique, which has the capability of tracking tissue stiffness during application of an oscillatory force. The feasibility of HMIFU for assessing mechanical tissue properties has been previously demonstrated. In this paper, a confocal transducer, combining a 4.5 MHz FUS transducer and a 3.3 MHz phased array imaging transducer, was used. The FUS transducer was driven by AM wave at 15 Hz with an acoustic intensity (I{sub spta}) wasmore » equal to 1050 W/cm{sup 2}. A lowpass digital filter was used to remove the spectrum of the higher power beam prior to displacement estimation. The resulting axial tissue displacement was estimated using 1D cross-correlation with a correlation window of 2 mm and a 92.5% overlap. A thermocouple was also used to measure the temperature near the ablated region. 2D HMI-images from six-bovine-liver specimens indicated the onset of coagulation necrosis through changes in amplitude displacement after coagulation due to its simultaneous probing and heating capability. The HMI technique can thus be used to monitor temperature-related stiffness changes of tissues during thermal therapies in real-time, i.e., without interrupting or modifying the treatment protocol.« less

Occurrence and Characterization of Cronobacter spp. in Dehydrated Rice Powder from Chinese Supermarket

PubMed Central

Huang, Yan; Pang, Yiheng; Wang, Hong; Tang, Zhengzhu; Zhou, Yan; Zhang, Weiyu; Li, Xiugui; Tan, Dongmei; Li, Jian; Lin, Ying; Liu, Xiaoling; Huang, Weiyi; Shi, Yunliang

2015-01-01

Cronobacter spp. are emerging food-borne pathogens and have been identified as causative agents of meningitis and necrotizing enterocolitis in infants. Dehydrated rice is popular with a wide range of people and it is frequently used as a substitute for infant milk powder to baby older than four months. The occurrence of Cronobacter spp. was investigated in 1,012 samples of dehydrated rice powder collected from 14 manufacturers in China during 2010 to 2012. The isolates were identified using fusA allele sequencing and subtyped using pulsed-field gel electrophoresis. Seventy-six samples (7.5%) contained Cronobacter spp. The prevalence among manufacturers ranged from 0-28.8%. The 76 isolates included 4 species [Cronobacter sakazakii (52 isolates) Cronobacter malonaticus (14 isolates), Cronobacter dublinensis (7 isolates), and Cronobacter muytjensii (3 isolates)]. Twenty-three unique fusA alleles and sixty-six PFGE-patterns were detected. All isolated strains were observed to be sensitive or to show intermediate susceptibility to eight tested antimicrobial agents. The study revealed serious contamination of dehydrated rice powder by Cronobacter spp., with prevalence varying among manufacturers in China. Identified Cronobacter species, fusA alleles, and subtypes were diverse. PMID:26132635

Safety and Efficacy of Focused Ultrasound Thalamotomy for Patients With Medication-Refractory, Tremor-Dominant Parkinson Disease: A Randomized Clinical Trial.

PubMed

Bond, Aaron E; Shah, Binit B; Huss, Diane S; Dallapiazza, Robert F; Warren, Amy; Harrison, Madaline B; Sperling, Scott A; Wang, Xin-Qun; Gwinn, Ryder; Witt, Jennie; Ro, Susie; Elias, W Jeffrey

2017-12-01

Clinical trials have confirmed the efficacy of focused ultrasound (FUS) thalamotomy in essential tremor, but its effectiveness and safety for managing tremor-dominant Parkinson disease (TDPD) is unknown. To assess safety and efficacy at 12-month follow-up, accounting for placebo response, of unilateral FUS thalamotomy for patients with TDPD. Of the 326 patients identified from an in-house database, 53 patients consented to be screened. Twenty-six were ineligible, and 27 were randomized (2:1) to FUS thalamotomy or a sham procedure at 2 centers from October18, 2012, to January 8, 2015. The most common reasons for disqualification were withdrawal (8 persons [31%]), and not being medication refractory (8 persons [31%]). Data were analyzed using intention-to-treat analysis, and assessments were double-blinded through the primary outcome. Twenty patients were randomized to unilateral FUS thalamotomy, and 7 to sham procedure. The sham group was offered open-label treatment after unblinding. The predefined primary outcomes were safety and difference in improvement between groups at 3 months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor (CRST). Secondary outcomes included descriptive results of Unified Parkinson's Disease Rating Scale (UPDRS) scores and quality of life measures. Of the 27 patients, 26 (96%) were male and the median age was 67.8 years (interquartile range [IQR], 62.1-73.8 years). On-medication median tremor scores improved 62% (IQR, 22%-79%) from a baseline of 17 points (IQR, 10.5-27.5) following FUS thalamotomy and 22% (IQR, -11% to 29%) from a baseline of 23 points (IQR, 14.0-27.0) after sham procedures; the between-group difference was significant (Wilcoxon P = .04). On-medication median UPDRS motor scores improved 8 points (IQR, 0.5-11.0) from a baseline of 23 points (IQR, 15.5-34.0) following FUS thalamotomy and 1 point (IQR, -5.0 to 9.0) from a baseline of 25 points (IQR, 15.0-33.0) after sham procedures. Early in the study, heating of the internal capsule resulted in 2 cases (8%) of mild hemiparesis, which improved and prompted monitoring of an additional axis during magnetic resonance thermometry. Other persistent adverse events were orofacial paresthesia (4 events [20%]), finger paresthesia (1 event [5%]), and ataxia (1 event [5%]). Focused ultrasound thalamotomy for patients with TDPD demonstrated improvements in medication-refractory tremor by CRST assessments, even in the setting of a placebo response. ClinicalTrials.gov identifier NCT01772693.

Focused Ultrasound-Induced Blood-Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed by Dynamic Contrast-Enhanced Magnetic-Resonance Imaging

NASA Astrophysics Data System (ADS)

Chu, Po-Chun; Chai, Wen-Yen; Tsai, Chih-Hung; Kang, Shih-Tsung; Yeh, Chih-Kuang; Liu, Hao-Li

2016-09-01

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

Focused Ultrasound-Induced Blood-Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed by Dynamic Contrast-Enhanced Magnetic-Resonance Imaging.

PubMed

Chu, Po-Chun; Chai, Wen-Yen; Tsai, Chih-Hung; Kang, Shih-Tsung; Yeh, Chih-Kuang; Liu, Hao-Li

2016-09-15

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

A cytoplasmic long noncoding RNA LINC00470 as a new AKT activator to mediate glioblastoma cell autophagy.

PubMed

Liu, Changhong; Zhang, Yan; She, Xiaoling; Fan, Li; Li, Peiyao; Feng, Jianbo; Fu, Haijuan; Liu, Qing; Liu, Qiang; Zhao, Chunhua; Sun, Yingnan; Wu, Minghua

2018-06-04

Despite the overwhelming number of investigations on AKT, little is known about lncRNA on AKT regulation, especially in GBM cells. RNA-binding protein immunoprecipitation assay (RIP) and RNA pulldown were used to confirm the binding of LINC00470 and fused in sarcoma (FUS). Confocal imaging, co-immunoprecipitation (Co-IP) and GST pulldown assays were used to detect the interaction between FUS and AKT. EdU assay, CCK-8 assay, and intracranial xenograft assays were performed to demonstrate the effect of LINC00470 on the malignant phenotype of GBM cells. RT-qPCR and Western blotting were performed to test the effect of LINC00470 on AKT and pAKT. In this study, we demonstrated that LINC00470 was a positive regulator for AKT activation in GBM. LINC00470 bound to FUS and AKT to form a ternary complex, anchoring FUS in the cytoplasm to increase AKT activity. Higher pAKT activated by LINC00470 inhibited ubiquitination of HK1, which affected glycolysis, and inhibited cell autophagy. Furthermore, higher LINC00470 expression was associated with GBM tumorigenesis and poor patient prognosis. Our findings revealed a noncanonical AKT activation signaling pathway, i.e., LINC00470 directly interacts with FUS, serving as an AKT activator to promote GBM progression. LINC00470 has an important referential significance to evaluate the prognosis of patients.

Genomic characterization of a persistent rubella virus from a case of Fuch' uveitis syndrome in a 73 year old man.

PubMed

Abernathy, Emily; Peairs, Randall R; Chen, Min-hsin; Icenogle, Joseph; Namdari, Hassan

2015-08-01

Many cases of Fuchs' uveitis have been associated with persistent rubella virus infection. A 73-year-old male patient with typical Fuchs' Uveitis Syndrome (FUS) first experienced heterochromia of the left eye at the age fourteen, when rubella was endemic in the US. The purposes of this report are to describe the patient's FUS clinical presentations and to characterize the virus detected in the vitreous fluid. The patient underwent a therapeutic pars plana vitrectomy in May 2013. A real-time RT-PCR assay for rubella virus was performed on the vitreous fluid by Focus Diagnostics. Additional real-time RT-PCR assays for rubella virus detection and RT-PCR assays for generation of templates for sequencing were performed at the Centers for Disease Control and Prevention (CDC). The results from Focus Diagnostics were positive for rubella virus RNA. Real-time RT-PCR assays at CDC were also positive for rubella virus. A rubella virus sequence of 739 nucleotides was determined and phylogenetic analysis showed that the virus was the sole member of a new phylogenetic group when compared to reference virus sequences. While FUS remains a clinical diagnosis, findings in this case support the association between rubella virus and the disease. Phylogenetic analysis provided evidence that this rubella virus was likely a previously undetected genotype which is no longer circulating. Since the patient had rubella prior to 1955, this sequence is from the earliest rubella virus yet characterized. Copyright © 2015 Elsevier B.V. All rights reserved.

Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: a safety study.

PubMed

Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-04-28

Transcranial MRI-guided focused ultrasound is a rapidly advancing method for delivering therapeutic and imaging agents to the brain. It has the ability to facilitate the passage of therapeutics from the vasculature to the brain parenchyma, which is normally protected by the blood-brain barrier (BBB). The method's main advantages are that it is both targeted and noninvasive, and that it can be easily repeated. Studies have shown that liposomal doxorubicin (Lipo-DOX), a chemotherapy agent with promise for tumors in the central nervous system, can be delivered into the brain across BBB. However, prior studies have suggested that doxorubicin can be significantly neurotoxic, even at small concentrations. Here, we studied whether multiple sessions of Lipo-DOX administered after FUS-induced BBB disruption (FUS-BBBD) induces severe adverse events in the normal brain tissues. First, we used fluorometry to measure the doxorubicin concentrations in the brain after FUS-BBBD to ensure that a clinically relevant doxorubicin concentration was achieved in the brain. Next, we performed three weekly sessions with FUS-BBBD±Lipo-DOX administration. Five to twelve targets were sonicated each week, following a schedule described previously in a survival study in glioma-bearing rats (Aryal et al., 2013). Five rats received three weekly sessions where i.v. injected Lipo-DOX was combined with FUS-BBBD; an additional four rats received FUS-BBBD only. Animals were euthanized 70days from the first session and brains were examined in histology. We found that clinically-relevant concentrations of doxorubicin (4.8±0.5μg/g) were delivered to the brain with the sonication parameters (0.69MHz; 0.55-0.81MPa; 10ms bursts; 1Hz PRF; 60s duration), microbubble concentration (Definity, 10μl/kg), and the administered Lipo-DOX dose (5.67mg/kg) used. The resulting concentration of Lipo-DOX was reduced by 32% when it was injected 10min after the last sonication compared to cases where the agent was delivered before sonication. In histology, the severe neurotoxicity observed in some previous studies with doxorubicin by other investigators was not observed here. However, four of the five rats who received FUS-BBBD and Lipo-DOX had regions (dimensions: 0.5-2mm) at the focal targets with evidence of minor prior damage, either a small scar (n=4) or a small cyst (n=1). The focal targets were unaffected in rats who received FUS-BBBD alone. The result indicates that while delivery of Lipo-DOX to the rat brain might result in minor damage, the severe neurotoxicity seen in earlier works does not appear to occur with delivery via FUS-BBB disruption. The damage may be related to capillary damage produced by inertial cavitation, which might have resulted in excessive doxorubicin concentrations in some areas. Copyright © 2015 Elsevier B.V. All rights reserved.

Treatment with Saccharomyces boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in 5-fluorouracil-induced intestinal mucositis in mice.

PubMed

Justino, Priscilla F C; Melo, Luis F M; Nogueira, Andre F; Costa, Jose V G; Silva, Luara M N; Santos, Cecila M; Mendes, Walber O; Costa, Marina R; Franco, Alvaro X; Lima, Aldo A; Ribeiro, Ronaldo A; Souza, Marcellus H L P; Soares, Pedro M G

2014-05-01

Intestinal mucositis is an important toxic side effect of 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii is known to protect from intestinal injury via an effect on the gastrointestinal microbiota. The objective of the present study was to evaluate the effect of S. boulardii on intestinal mucositis induced by 5-FU in a murine model. Mice were divided into saline, saline (control)+5-FU or 5-FU+S. boulardii (16 × 10⁹ colony-forming units/kg) treatment groups, and the jejunum and ileum were removed after killing of mice for the evaluation of histopathology, myeloperoxidase (MPO) activity, and non-protein sulfhydryl group (mainly reduced glutathione; GSH), nitrite and cytokine concentrations. To determine gastric emptying, phenol red was administered orally, mice were killed 20 min after administration, and the absorbance of samples collected from the mice was measured by spectrophotometry. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following oral administration. S. boulardii significantly reversed the histopathological changes in intestinal mucositis induced by 5-FU and reduced the inflammatory parameters: neutrophil infiltration (control 1·73 (SEM 0·37) ultrastructural MPO (UMPO)/mg, 5-FU 7·37 (SEM 1·77) UMPO/mg and 5-FU+S. boulardii 4·15 (SEM 0·73) UMPO/mg); nitrite concentration (control 37·00 (SEM 2·39) μm, 5-FU 59·04 (SEM 11·41) μm and 5-FU+S. boulardii 37·90 (SEM 5·78) μm); GSH concentration (control 477·60 (SEM 25·25) μg/mg, 5-FU 270·90 (SEM 38·50) μg/mg and 5-FU+S. boulardii 514·00 (SEM 38·64) μg/mg). Treatment with S. Boulardii significantly reduced the concentrations of TNF-α and IL-1β by 48·92 and 32·21 % in the jejunum and 38·92 and 61·79 % in the ileum. In addition, S. boulardii decreased the concentrations of chemokine (C-X-C motif) ligand 1 by 5-fold in the jejunum and 3-fold in the ileum. Interestingly, S. boulardii reduced the delay in gastric emptying (control 25·21 (SEM 2·55) %, 5-FU 54·91 (SEM 3·43) % and 5-FU+S. boulardii 31·38 (SEM 2·80) %) and induced the recovery of intestinal permeability (lactulose:mannitol ratio: control 0·52 (SEM 0·03), 5-FU 1·38 (SEM 0·24) and 5-FU+S. boulardii 0·62 (SEM 0·03)). In conclusion, S. boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in intestinal mucositis induced by 5-FU.

Driving Circuitry for Focused Ultrasound Noninvasive Surgery and Drug Delivery Applications

PubMed Central

El-Desouki, Munir M.; Hynynen, Kullervo

2011-01-01

Recent works on focused ultrasound (FUS) have shown great promise for cancer therapy. Researchers are continuously trying to improve system performance, which is resulting in an increased complexity that is more apparent when using multi-element phased array systems. This has led to significant efforts to reduce system size and cost by relying on system integration. Although ideas from other fields such as microwave antenna phased arrays can be adopted in FUS, the application requirements differ significantly since the frequency range used in FUS is much lower. In this paper, we review recent efforts to design efficient power monitoring, phase shifting and output driving techniques used specifically for high intensity focused ultrasound (HIFU). PMID:22346589

Driving circuitry for focused ultrasound noninvasive surgery and drug delivery applications.

PubMed

El-Desouki, Munir M; Hynynen, Kullervo

2011-01-01

Recent works on focused ultrasound (FUS) have shown great promise for cancer therapy. Researchers are continuously trying to improve system performance, which is resulting in an increased complexity that is more apparent when using multi-element phased array systems. This has led to significant efforts to reduce system size and cost by relying on system integration. Although ideas from other fields such as microwave antenna phased arrays can be adopted in FUS, the application requirements differ significantly since the frequency range used in FUS is much lower. In this paper, we review recent efforts to design efficient power monitoring, phase shifting and output driving techniques used specifically for high intensity focused ultrasound (HIFU).

Transcranial focused ultrasound stimulation of human primary visual cortex

NASA Astrophysics Data System (ADS)

Lee, Wonhye; Kim, Hyun-Chul; Jung, Yujin; Chung, Yong An; Song, In-Uk; Lee, Jong-Hwan; Yoo, Seung-Schik

2016-09-01

Transcranial focused ultrasound (FUS) is making progress as a new non-invasive mode of regional brain stimulation. Current evidence of FUS-mediated neurostimulation for humans has been limited to the observation of subjective sensory manifestations and electrophysiological responses, thus warranting the identification of stimulated brain regions. Here, we report FUS sonication of the primary visual cortex (V1) in humans, resulting in elicited activation not only from the sonicated brain area, but also from the network of regions involved in visual and higher-order cognitive processes (as revealed by simultaneous acquisition of blood-oxygenation-level-dependent functional magnetic resonance imaging). Accompanying phosphene perception was also reported. The electroencephalo graphic (EEG) responses showed distinct peaks associated with the stimulation. None of the participants showed any adverse effects from the sonication based on neuroimaging and neurological examinations. Retrospective numerical simulation of the acoustic profile showed the presence of individual variability in terms of the location and intensity of the acoustic focus. With exquisite spatial selectivity and capability for depth penetration, FUS may confer a unique utility in providing non-invasive stimulation of region-specific brain circuits for neuroscientific and therapeutic applications.

WE-G-12A-01: High Intensity Focused Ultrasound Surgery and Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farahani, K; O'Neill, B

More and more emphasis is being made on alternatives to invasive surgery and the use of ionizing radiation to treat various diseases including cancer. Novel screening, diagnosis, treatment and monitoring of response to treatment are also hot areas of research and new clinical technologies. Ultrasound(US) has gained traction in all of the aforementioned areas of focus. Especially with recent advances in the use of ultrasound to noninvasively treat various diseases/organ systems. This session will focus on covering MR-guided focused ultrasound and the state of the art clinical applications, and the second speaker will survey the more cutting edge technologies e.g.more » Focused Ultrasound (FUS) mediated drug delivery, principles of cavitation and US guided FUS. Learning Objectives: Fundamental physics and physical limitations of US interaction with tissue and nanoparticles The alteration of tissue transport using focused ultrasound US control of nanoparticle drug carriers for targeted release The basic principles of MRI-guided focused ultrasound (MRgFUS) surgery and therapy the current state of the art clinical applications of MRgFUS requirements for quality assurance and treatment planning.« less

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

PubMed Central

Goedert, Michel; Ghetti, Bernardino; Spillantini, Maria Grazia

2012-01-01

Frontotemporal dementia (FTD) comprises a group of behavioral, language, and movement disorders. On the basis of the nature of the characteristic protein inclusions, frontotemporal lobar degeneration (FTLD) can be subdivided into the common FTLD-tau and FTLD-TDP as well as the less common FTLD-FUS and FTLD-UPS. Approximately 10% of cases of FTD are inherited in an autosomal-dominant manner. Mutations in seven genes cause FTD, with those in tau (MAPT), chromosome 9 open reading frame 72 (C9ORF72), and progranulin (GRN) being the most common. Mutations in MAPT give rise to FTLD-tau and mutations in C9ORF72 and GRN to FTLD-TDP. The other four genes are transactive response–DNA binding protein-43 (TARDBP), fused in sarcoma (FUS), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). Mutations in TARDBP and VCP give rise to FTLD-TDP, mutations in FUS to FTLD-FUS, and mutations in CHMP2B to FTLD-UPS. The discovery that mutations in MAPT cause neurodegeneration and dementia has important implications for understanding Alzheimer disease. PMID:22355793

Life-cycle and growth-phase-dependent regulation of the ubiquitin genes of Trypanosoma cruzi.

PubMed

Manning-Cela, Rebeca; Jaishankar, Sobha; Swindle, John

2006-07-01

Trypanosoma cruzi, the causative agent of Chagas disease, exhibits a complex life cycle that is accompanied by the stage-specific gene expression. At the molecular level, very little is known about gene regulation in trypanosomes. Complex gene organizations coupled with polycistronic transcription units make the analysis of regulated gene expression difficult in trypanosomes. The ubiquitin genes of T. cruzi are a good example of this complexity. They are organized as a single cluster containing five ubiquitin fusion (FUS) and five polyubiquitin (PUB) genes that are polycistronically transcribed but expressed differently in response to developmental and environmental changes. Gene replacements were used to study FUS and PUB gene expression at different stages of growth and at different points in the life cycle of T. cruzi. Based on the levels of reporter gene expression, it was determined that FUS1 expression was downregulated as the parasites approached stationary phase, whereas PUB12.5 polyubiquitin gene expression increased. Conversely, FUS1 expression increases when epimastigotes and amastigotes differentiate into trypomastigotes, whereas the expression of PUB12.5 decreases when epimastigotes differentiate into amastigotes and trypomastigotes. Although the level of CAT activity in logarithmic growing epimastigotes is six- to seven-fold higher when the gene was expressed from the FUS1 locus than when expressed from the PUB12.5 locus, the rate of transcription from the two loci was the same implying that post-transcriptional mechanisms play a dominant role in the regulation of gene expression.

Magnetic resonance-guided focused ultrasound treatment of facet joint pain: summary of preclinical phase

PubMed Central

2014-01-01

Study design A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted to test the feasibility, safety, and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) for treating facet joint pain. Objective The goal of the current study was to develop a novel method for accurate and safe noninvasive facet joint ablation using MRgFUS. Summary of background data Facet joints are a common source of chronic back pain. Direct facet joint interventions include medial branch nerve ablation and intra-articular injections, which are widely used, but limited in the short and long term. MRgFUS is a breakthrough technology that enables accurate delivery of high-intensity focused ultrasound energy to create a localized temperature rise for tissue ablation, using MR guidance for treatment planning and real-time feedback. Methods We validated the feasibility, safety, and efficacy of MRgFUS for facet joint ablation using the ExAblate 2000® System (InSightec Ltd., Tirat Carmel, Israel) and confirmed the system's ability to ablate the edge of the facet joint and all terminal nerves innervating the joint. A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted. Results The experiments showed that targeting the facet joint with energies of 150–450 J provides controlled and accurate heating at the facet joint edge without penetration to the vertebral body, spinal canal, or root foramina. Treating with reduced diameter of the acoustic beam is recommended since a narrower beam improves access to the targeted areas. Conclusions MRgFUS can safely and effectively target and ablate the facet joint. These results are highly significant, given that this is the first study to demonstrate the potential of MRgFUS to treat facet joint pain. PMID:24921048

Bibliography of Documents Related to the Theory, Operation, Performance and Applications of Coaxial Plasma Guns. Revision

DTIC Science & Technology

1990-11-01

V., Grunberger, L. and Prior, W., "Observation of Solar Flare Type Processes in the Laboratory," in Solar Magnetic Fields, Symposium No. 43 of the...RF/FUS/84/6, Associazione EURATOM--Comitato Nazionale Energia Nucleare sulla Fusione, Centro di Frascati, Rome, Italy, September 1984. Brzosko, J. S...Energy Deuteron Beam Generation in Plasma Focus," Report No. 80.5, Associazione EURATOM--Comitato Nazionale Energia Nucleare sulla Fusione, Centro di

Crystal Structure of the 3.8-MDa Respiratory Supermolecule Hemocyanin at 3.0 Å Resolution.

PubMed

Gai, Zuoqi; Matsuno, Asuka; Kato, Koji; Kato, Sanae; Khan, Md Rafiqul Islam; Shimizu, Takeshi; Yoshioka, Takeya; Kato, Yuki; Kishimura, Hideki; Kanno, Gaku; Miyabe, Yoshikatsu; Terada, Tohru; Tanaka, Yoshikazu; Yao, Min

2015-12-01

Molluscan hemocyanin, a copper-containing oxygen transporter, is one of the largest known proteins. Although molluscan hemocyanins are currently applied as immunotherapeutic agents, their precise structure has not been determined because of their enormous size. Here, we have determined the first X-ray crystal structure of intact molluscan hemocyanin. The structure unveiled the architecture of the 3.8-MDa supermolecule composed of homologous functional units (FUs), wherein the dimers of FUs hierarchically associated to form the entire cylindrical decamer. Most of the specific inter-FU interactions were localized at narrow regions in the FU dimers, suggesting that rigid FU dimers formed by specific interactions assemble with flexibility. Furthermore, the roles of carbohydrates in assembly and allosteric effect, and conserved sulfur-containing residues in copper incorporation, were revealed. The precise structural information obtained in this study will accelerate our understanding of the molecular basis of hemocyanin and its future applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma.

PubMed

Doyle, Leona A; Möller, Emely; Dal Cin, Paola; Fletcher, Christopher D M; Mertens, Fredrik; Hornick, Jason L

2011-05-01

Low-grade fibromyxoid sarcoma (LGFMS) is a distinctive fibroblastic neoplasm that is characterized by alternating collagenous and myxoid areas, deceptively bland spindle cell morphology, a whorling architecture, and a t(7;16) translocation involving FUS and CREB3L2. Owing to variable morphology and a lack of discriminatory markers, LGFMS can be difficult to distinguish from benign mesenchymal tumors and other low-grade sarcomas. Gene expression profiling has identified differential upregulation of the mucin 4 (MUC4) gene in LGFMS compared with histologically similar tumors. MUC4 is a transmembrane glycoprotein that functions in cell growth signaling pathways; aberrant MUC4 expression has been reported in various carcinomas. We investigated MUC4 protein expression by immunohistochemistry in LGFMS and in other soft tissue tumors to determine the potential diagnostic use of this novel marker. Whole-tissue sections of 309 tumors were evaluated: 49 LGFMSs (all with FUS gene rearrangement confirmed by fluorescence in situ hybridization), 40 soft tissue perineuriomas, 40 myxofibrosarcomas, 20 cellular myxomas, 20 solitary fibrous tumors, 20 low-grade malignant peripheral nerve sheath tumors, 20 cases of desmoid fibromatosis, 20 neurofibromas, 20 schwannomas, 20 monophasic synovial sarcomas, 20 cases of dermatofibrosarcoma protuberans, 10 myxoid liposarcomas, and 10 extraskeletal myxoid chondrosarcomas. The LGFMS cases included 7 with marked hypercellularity, 4 with prominent hemangiopericytoma-like vessels, 3 with giant collagen rosettes, 3 with epithelioid morphology, 2 with focal nuclear pleomorphism, and 2 with areas of sclerosing epithelioid fibrosarcoma. All 49 LGFMS cases (100%) showed cytoplasmic staining for MUC4, which was usually diffuse and intense. All the other tumor types were negative for MUC4, apart from 6 (30%) monophasic synovial sarcomas. In conclusion, MUC4 is a highly sensitive and quite specific immunohistochemical marker for LGFMS, and can be helpful to distinguish this tumor type from histologic mimics.

Amyotrophic Lateral Sclerosis after Receiving the Human Papilloma Virus Vaccine: A Case Report of a 15-year-old Girl.

PubMed

Hikiami, Ryota; Yamakado, Hodaka; Tatsumi, Shinsui; Ayaki, Takashi; Hashi, Yuichiro; Yamashita, Hirofumi; Sawamoto, Nobukatsu; Tsuji, Teruyuki; Urushitani, Makoto; Takahashi, Ryosuke

2018-02-09

We herein report a 15-year-old girl who developed rapid progressive muscle weakness soon after the third injection of a bivalent human papilloma virus (HPV) vaccine. Although immunotherapies were performed for possible vaccine-related disorders, she died of respiratory failure 14 months after the onset of the disease. A genetic analysis identified a heterozygous p.P525L mutation of the fused in sarcoma (FUS) gene, and a histopathological analysis was also consistent with FUS-associated amyotrophic lateral sclerosis (ALS) without any evidence of neuroinflammation. We concluded the diagnosis to be FUS-ALS, although we cannot completely rule out the possibility that the vaccination worked as a trigger.

Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain

NASA Astrophysics Data System (ADS)

Arvanitis, Costas D.; Livingstone, Margaret S.; McDannold, Nathan

2013-07-01

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation—the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies.

Pharmacodynamic and Therapeutic Investigation of Focused Ultrasound-Induced Blood-Brain Barrier Opening for Enhanced Temozolomide Delivery in Glioma Treatment

PubMed Central

Liu, Hao-Li; Huang, Chiung-Yin; Chen, Ju-Yu; Wang, Hay-Yan Jack; Chen, Pin-Yuan; Wei, Kuo-Chen

2014-01-01

Focused ultrasound (FUS) exposure with the presence of microbubbles has been shown to transiently open the blood-brain barrier (BBB), and thus has potential to enhance the delivery of various kinds of therapeutic agents into brain tumors. The purpose of this study was to assess the preclinical therapeutic efficacy of FUS-BBB opening for enhanced temozolomide (TMZ) delivery in glioma treatment. FUS exposure with microbubbles was delivered to open the BBB of nude mice that were either normal or implanted with U87 human glioma cells. Different TMZ dose regimens were tested, ranging from 2.5 to 25 mg/kg. Plasma and brain samples were obtained at different time-points ranging from 0.5 to 4 hours, and the TMZ concentration within samples was quantitated via a developed LC-MS/MS procedure. Tumor progression was followed with T2-MRI, and animal survival and brain tissue histology were conducted. Results demonstrated that FUS-BBB opening caused the local TMZ accumulation in the brain to increase from 6.98 to 19 ng/mg. TMZ degradation time in the tumor core was found to increase from 1.02 to 1.56 hours. Improved tumor progression and animal survival were found at different TMZ doses (up to 15% and 30%, respectively). In conclusion, this study provides preclinical evidence that FUS-BBB opening increases the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting the potential for clinical application to improve current brain tumor treatment. PMID:25490097

Focused Ultrasound Surgery in Oncology: Overview and Principles

PubMed Central

McDannold, Nathan J.; Hynynen, Kullervo; Jolesz, Ferenc A.

2011-01-01

Focused ultrasound surgery (FUS) is a noninvasive image-guided therapy and an alternative to surgical interventions. It presents an opportunity to revolutionize cancer therapy and to affect or change drug delivery of therapeutic agents in new focally targeted ways. In this article the background, principles, technical devices, and clinical cancer applications of image-guided FUS are reviewed. © RSNA, 2011 PMID:21436096

Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response.

PubMed

Liu, Hao-Li; Hsieh, Han-Yi; Lu, Li-An; Kang, Chiao-Wen; Wu, Ming-Fang; Lin, Chun-Yen

2012-11-11

High-intensity focused-ultrasound (HIFU) has been successfully employed for thermal ablation of tumors in clinical settings. Continuous- or pulsed-mode HIFU may also induce a host antitumor immune response, mainly through expansion of antigen-presenting cells in response to increased cellular debris and through increased macrophage activation/infiltration. Here we demonstrated that another form of focused ultrasound delivery, using low-pressure, pulsed-mode exposure in the presence of microbubbles (MBs), may also trigger an antitumor immunological response and inhibit tumor growth. A total of 280 tumor-bearing animals were subjected to sonographically-guided FUS. Implanted tumors were exposed to low-pressure FUS (0.6 to 1.4 MPa) with MBs to increase the permeability of tumor microvasculature. Tumor progression was suppressed by both 0.6 and 1.4-MPa MB-enhanced FUS exposures. We observed a transient increase in infiltration of non-T regulatory (non-Treg) tumor infiltrating lymphocytes (TILs) and continual infiltration of CD8+ cytotoxic T-lymphocytes (CTL). The ratio of CD8+/Treg increased significantly and tumor growth was inhibited. Our findings suggest that low-pressure FUS exposure with MBs may constitute a useful tool for triggering an anticancer immune response, for potential cancer immunotherapy.

Two-photon microscopy for real-time monitoring of focused ultrasound-mediated drug delivery to the brain in a mouse model of Alzheimer's disease

NASA Astrophysics Data System (ADS)

Burgess, Alison; Eterman, Naomi; Aubert, Isabelle; Hynynen, Kullervo

2013-02-01

There is substantial evidence that focused ultrasound (FUS) in combination with microbubble contrast agent can cause disruption of the blood-brain barrier (BBB) to aid in drug delivery to the brain. We have previously demonstrated that FUS efficiently delivers antibodies against amyloid-β peptides (Aβ) through the BBB, leading to a reduction in amyloid pathology at 4 days in a mouse model of Alzheimer's disease. In the current study, we used two-photon microscopy to characterize the effect of FUS in real time on amyloid pathology in the mouse brain. Mice were anesthetized and a cranial window was made in the skull. A custom-built ultrasound transducer was fixed to a coverslip and attached to the skull, covering the cranial window. Methoxy-X04 [2-5mg/kg] delivered intravenously 1 hr prior to the experiment clearly labelled the Aβ surrounding the vessels and the amyloid plaques in the cortex. Dextran conjugated Texas Red (70kDa) administered intravenously, confirmed BBB disruption. BBB disruption occurred in transgenic and non-transgenic animals at similar ultrasound pressures tested. However, the time required for BBB closure following FUS was longer in the Tg mice. We have conjugated Aβ antibodies to the fluorescent molecule FITC for real time monitoring of the antibody distribution in the brain. Our current experiments are aimed at optimizing the parameters to achieve maximal fluorescent intensity of the BAM10 antibody at the plaque surface. Two-photon microscopy has proven to be a valuable tool for evaluating the efficacy of FUS mediated drug delivery, including antibodies, to the Alzheimer brain.

Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets.

PubMed

Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying; Olumolade, Oluyemi O; Dayton, Paul A; Konofagou, Elisa E

2013-12-28

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature. © 2013.

Micro-SPECT/CT-based pharmacokinetic analysis of 99mTc-diethylenetriaminepentaacetic acid in rats with blood-brain barrier disruption induced by focused ultrasound.

PubMed

Yang, Feng-Yi; Wang, Hsin-Ell; Lin, Guan-Liang; Teng, Ming-Che; Lin, Hui-Hsien; Wong, Tai-Tong; Liu, Ren-Shyan

2011-03-01

This study evaluated the pharmacokinetics of (99m)Tc-diethylenetriamine pentaacetate acid ((99m)Tc-DTPA) after intravenous administration in healthy and F98 glioma-bearing F344 rats in the presence of blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). The pharmacokinetics of the healthy and tumor-containing brains after BBB-D were compared to identify the optimal time period for combined treatment. Healthy and F98 glioma-bearing rats were injected intravenously with Evans blue (EB) and (99m)Tc-DTPA; these treatments took place with or without BBB-D induced by transcranial FUS of 1 hemisphere of the brain. The permeability of the BBB was quantified by EB extravasation. Twelve rats were scanned for 2 h to estimate uptake of (99m)Tc radioactivity with respect to time for the pharmacokinetic analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed to examine tissue damage. The accumulations of EB and (99m)Tc-DTPA in normal brains or brains with a tumor were significantly elevated after the intravenous injection when BBB-D was induced. The disruption-to-nondisruption ratio of the brains and the tumor-to-ipsilateral brain ratio of the tumors in terms of radioactivity reached a peak at 45 and 60 min, respectively. EB injection followed by sonication showed that there was an increase of about 2-fold in the tumor-to-ipsilateral brain EB ratio of the target tumors (7.36), compared with the control tumors (3.73). TUNEL staining showed no significant differences between the sonicated tumors and control tumors. This study demonstrates that (99m)Tc-DTPA micro-SPECT/CT can be used for the pharmacokinetic analysis of BBB-D induced by FUS. This method should be able to provide important information that will help with establishing an optimal treatment protocol for drug administration after FUS-induced BBB-D in clinical brain disease therapy.

Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis.

PubMed

Tibshirani, Michael; Zhao, Beibei; Gentil, Benoit J; Minotti, Sandra; Marques, Christine; Keith, Julia; Rogaeva, Ekaterina; Zinman, Lorne; Rouaux, Caroline; Robertson, Janice; Durham, Heather D

2017-11-01

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Clinical Application of High-intensity Focused Ultrasound in Cancer Therapy

PubMed Central

Hsiao, Yi-Hsuan; Kuo, Shou-Jen; Tsai, Horng-Der; Chou, Ming-Chih; Yeh, Guang-Perng

2016-01-01

The treatment of cancer is an important issue in both developing and developed countries. Clinical use of ultrasound in cancer is not only for the diagnosis but also for the treatment. Focused ultrasound surgery (FUS) is a noninvasive technique. By using the combination of high-intensity focused ultrasound (HIFU) and imaging method, FUS has the potential to ablate tumor lesions precisely. The main mechanisms of HIFU ablation involve mechanical and thermal effects. Recent advances in HIFU have increased its popularity. Some promising results were achieved in managing various malignancies, including pancreas, prostate, liver, kidney, breast and bone. Other applications include brain tumor ablation and disruption of the blood-brain barrier. We aim at briefly outlining the clinical utility of FUS as a noninvasive technique for a variety of types of cancer treatment. PMID:26918034

Numerical study on microbubble-enhanced heating for various parameters in EUS-FUS

NASA Astrophysics Data System (ADS)

Okita, Kohei; Maezawa, Miyuki; Takagi, Shu; Matsumoto, Yoichiro

2012-11-01

Endoscopic ultrasonography guided focused ultrasound surgery (EUS-FUS) have been developed as a less-invasive treatment for pancreatic cancer. In the present study, microbubble-enhanced heating for various parameters in EUS-FUS is investigated numerically. Mass and momentum equations for bubbly mixture are solved to reproduce the propagation of ultrasound of 4.8MHz through the gel containing microbubbles as Sonazoid®. The dynamics of bubble is governed by the equation which considers the elasticity of both shell and surrounding media. Additionally, the heat equation with the time averaged heat source is solved to obtain a temperature distribution. The basic equations are discretized by the 6th-order finite difference method and developed based on FDTD method. The mixture and bubbles are coupled by Euler-Lagrange method. As the results, the temperature around the target increased due to the microbubble oscillation with increasing the initial void fraction fG0 from 10-5 to 10-4%. However, at fG0=10-3%, ultrasounds were too attenuated to heat the target. The heating region moved from the target to the transducer side. By comparing the results with and without shell, the shell of bubble induced the heating around focus. This is because the decrease of the attenuation due to the elasticity of the shell and the increase of the viscous dissipation rate due to the viscosity of the shell.

Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity

PubMed Central

Uzhachenko, Roman; Shanker, Anil; Yarbrough, Wendell G.; Ivanova, Alla V.

2015-01-01

Mitochondria present a unique set of key intracellular functions such as ATP synthesis, production of reactive oxygen species (ROS) and Ca2+ buffering. Mitochondria both encode and decode Ca2+ signals and these interrelated functions have a direct impact on cell signaling and metabolism. High proliferative potential is a key energy-demanding feature shared by cancer cells and activated T lymphocytes. Switch of a metabolic state mediated by alterations in mitochondrial homeostasis plays a fundamental role in maintenance of the proliferative state. Recent studies show that tumor suppressors have the ability to affect mitochondrial homeostasis controlling both cancer and autoimmunity. Herein, we discuss established and putative mechanisms of calcium–dependent regulation of both T cell and tumor cell activities. We use the mitochondrial protein Fus1 as a case of tumor suppressor that controls immune response and tumor growth via maintenance of mitochondrial homeostasis. We focus on the regulation of mitochondrial Ca2+ handling as a key function of Fus1 and highlight the mechanisms of a crosstalk between Ca2+ accumulation and mitochondrial homeostasis. Given the important role of Ca2+ signaling, mitochondrial Ca2+ transport and ROS production in the activation of NFAT and NF-κB transcription factors, we outline the importance of Fus1 activities in this context. PMID:26246474

High intensity focused ultrasound surgery (HIFU) of the brain: A historical perspective, with modern applications

PubMed Central

Jagannathan, Jay; Sanghvi, Narendra K; Crum, Lawrence A; Yen, Chun-Po; Medel, Ricky; Dumont, Aaron S; Sheehan, Jason P; Steiner, Ladislau; Jolesz, Ferenc; Kassell, Neal F

2014-01-01

The field of MRI-guided high intensity focused ultrasound surgery (MRgFUS) is a rapidly evolving one with many potential applications in neurosurgery. This is the first of three articles on MRgFUS, this paper focuses on the historical development of the technology and it's potential applications to modern neurosurgery. The evolution of MRgFUS has occurred in parallel with modern neurological surgery and the two seemingly distinct disciplines share many of the same pioneering figures. Early studies on focused ultrasound treatment in the 1940's and 1950's demonstrated the ability to perform precise lesioning in the human brain, with a favorable risk-benefit profile. However, the need for a craniotomy, as well as lack of sophisticated imaging technology resulted in limited growth of HIFU for neurosurgery. More recently, technological advances, have permitted the combination of HIFU along with MRI guidance to provide an opportunity to effectively treat a variety of CNS disorders. Although challenges remain, HIFU-mediated neurosurgery may offer the ability to target and treat CNS conditions that were previously extremely difficult to perform. The remaining two articles in this series will focus on the physical principles of modern MRgFUS as well as current and future avenues for investigation. PMID:19190451

Transcranial MRI-guided FUS-induced BBB opening in the rat brain

NASA Astrophysics Data System (ADS)

Treat, Lisa H.; McDannold, Nathan J.; Hynynen, Kullervo

2004-05-01

The blood-brain barrier (BBB) has been a major limitation in treating diseases of the brain because therapeutic agents are either unable to penetrate or have dose-limiting side effects in diffuse opening of the BBB. A previous study demonstrated that focused ultrasound (FUS) can locally open the BBB in a rabbit model when a piece of skull is removed and that magnetic resonance imaging (MRI) can be used to guide and monitor the procedure. This study examined whether the same desired effect of local BBB disruption can be achieved by applying FUS through an intact skull in a rat model. Twenty-eight Sprague-Dawley rats were anesthetized, shaved, and sonicated at four focal locations in the brain, using a 1.5-MHz focused transducer. Contrast-enhanced MR images were obtained before and after sonication. The images indicated contrast agent penetration at the focal coordinates following Optison-enhanced sonication. This study demonstrated that the distortion of the ultrasound beam by the rat skull was not significant enough to inhibit focal BBB opening. Subsequent experiments using MRI-guided FUS to aid in targeted drug delivery to brain tumors in a rodent model could thus be performed more efficiently without cranial surgery. [Research funded by NIH Grant No. CA76550.

Characterization of Different Microbubbles in Assisting Focused Ultrasound-Induced Blood-Brain Barrier Opening

NASA Astrophysics Data System (ADS)

Wu, Sheng-Kai; Chu, Po-Chun; Chai, Wen-Yen; Kang, Shih-Tsung; Tsai, Chih-Hung; Fan, Ching-Hsiang; Yeh, Chih-Kuang; Liu, Hao-Li

2017-04-01

Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62-1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.

Prospective randomized trial comparing magnetic resonance imaging (MRI)-guided in-bore biopsy to MRI-ultrasound fusion and transrectal ultrasound-guided prostate biopsy in patients with prior negative biopsies.

PubMed

Arsov, Christian; Rabenalt, Robert; Blondin, Dirk; Quentin, Michael; Hiester, Andreas; Godehardt, Erhard; Gabbert, Helmut E; Becker, Nikolaus; Antoch, Gerald; Albers, Peter; Schimmöller, Lars

2015-10-01

A significant proportion of prostate cancers (PCas) are missed by conventional transrectal ultrasound-guided biopsy (TRUS-GB). It remains unclear whether the combined approach using targeted magnetic resonance imaging (MRI)-ultrasound fusion-guided biopsy (FUS-GB) and systematic TRUS-GB is superior to targeted MRI-guided in-bore biopsy (IB-GB) for PCa detection. To compare PCa detection between IB-GB alone and FUS-GB + TRUS-GB in patients with at least one negative TRUS-GB and prostate-specific antigen ≥4 ng/ml. Patients were prospectively randomized after multiparametric prostate MRI to IB-GB (arm A) or FUS-GB + TRUS-GB (arm B) from November 2011 to July 2014. The study was powered at 80% to demonstrate an overall PCa detection rate of ≥60% in arm B compared to 40% in arm A. Secondary endpoints were the distribution of highest Gleason scores, the rate of detection of significant PCa (Gleason ≥7), the number of biopsy cores to detect one (significant) PCa, the positivity rate for biopsy cores, and tumor involvement per biopsy core. The study was halted after interim analysis because the primary endpoint was not met. The trial enrolled 267 patients, of whom 210 were analyzed (106 randomized to arm A and 104 to arm B). PCa detection was 37% in arm A and 39% in arm B (95% confidence interval for difference, -16% to 11%; p=0.7). Detection rates for significant PCa (29% vs 32%; p=0.7) and the highest percentage tumor involvement per biopsy core (48% vs 42%; p=0.4) were similar between the arms. The mean number of cores was 5.6 versus 17 (p<0.001). A limitation is the limited number of patients because of early cessation of accrual. This trial failed to identify an important improvement in detection rate for the combined biopsy approach over MRI-targeted biopsy alone. A prospective comparison between MRI-targeted biopsy alone and systematic TRUS-GB is justified. Our randomized study showed similar prostate cancer detection rates between targeted prostate biopsy guided by magnetic resonance imaging and the combination of targeted biopsy and systematic transrectal ultrasound-guided prostate biopsy. An important improvement in detection rates using the combined biopsy approach can be excluded. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Optimized Hyperthermia Treatment of Prostate Cancer Using a Novel Intracavitary Ultrasound Array

DTIC Science & Technology

2005-01-01

many problems Introduction involved with transducer fabrication. Focused ultrasound surgery ( FUS ) has been shown to give promising results in treating...low frequencies are used) (Hutchinson 1997). With focused ultrasound ( FUS ), tissue is noninvasively necrosed by elevating the temperature at the focal...curved 1.5 dimensional (1.5-D) array that could, but had of a 1.75 dimensional (1.75-D) tapered ultrasound phased array restrictions to the focusing

Acoustic characterization of Thiel liver for magnetic resonance-guided focused ultrasound treatment.

PubMed

Karakitsios, Ioannis; Joy, Joyce; Mihcin, Senay; Melzer, Andreas

2017-04-01

The purpose of this work was to measure the essential acoustic parameters, i.e., acoustic impedance, reflection coefficient, attenuation coefficient, of Thiel embalmed human and animal liver. The Thiel embalmed tissue can be a promising, pre-clinical model to study liver treatment with Magnetic Resonance-guided Focused Ultrasound (MRgFUS). Using a single-element transducer and the contact pulse-echo method, the acoustic parameters, i.e., acoustic impedance, reflection coefficient and attenuation coefficient of Thiel embalmed human and animal liver were measured. The Thiel embalmed livers had higher impedance, similar reflection and lower attenuation compared to the fresh tissue. Embalming liver with Thiel fluid affects its acoustic properties. During MRgFUS sonication of a Thiel organ, more focused ultrasound (FUS) will be backscattered by the organ, and higher acoustic powers are required to reach coagulation levels (temperatures >56 °C).

A random phased-array for MR-guided transcranial ultrasound neuromodulation in non-human primates

NASA Astrophysics Data System (ADS)

Chaplin, Vandiver; Phipps, Marshal A.; Caskey, Charles F.

2018-05-01

Transcranial focused ultrasound (FUS) is a non-invasive technique for therapy and study of brain neural activation. Here we report on the design and characterization of a new MR-guided FUS transducer for neuromodulation in non-human primates at 650 kHz. The array is randomized with 128 elements 6.6 mm in diameter, radius of curvature 7.2 cm, opening diameter 10.3 cm (focal ratio 0.7), and 46% coverage. Simulations were used to optimize transducer geometry with respect to focus size, grating lobes, and directivity. Focus size and grating lobes during electronic steering were quantified using hydrophone measurements in water and a three-axis stage. A novel combination of optical tracking and acoustic mapping enabled measurement of the 3D pressure distribution in the cortical region of an ex vivo skull to within ~3.5 mm of the surface, and allowed accurate modelling of the experiment via non-homogeneous 3D acoustic simulations. The data demonstrates acoustic focusing beyond the skull bone, with the focus slightly broadened and shifted proximal to the skull. The fabricated design is capable of targeting regions within the S1 sensorimotor cortex of macaques.

A random phased-array for MR-guided transcranial ultrasound neuromodulation in non-human primates.

PubMed

Chaplin, Vandiver; Phipps, Marshal A; Caskey, Charles F

2018-05-17

Transcranial focused ultrasound (FUS) is a non-invasive technique for therapy and study of brain neural activation. Here we report on the design and characterization of a new MR-guided FUS transducer for neuromodulation in non-human primates at 650 kHz. The array is randomized with 128 elements 6.6 mm in diameter, radius of curvature 7.2 cm, opening diameter 10.3 cm (focal ratio 0.7), and 46% coverage. Simulations were used to optimize transducer geometry with respect to focus size, grating lobes, and directivity. Focus size and grating lobes during electronic steering were quantified using hydrophone measurements in water and a three-axis stage. A novel combination of optical tracking and acoustic mapping enabled measurement of the 3D pressure distribution in the cortical region of an ex vivo skull to within ~3.5 mm of the surface, and allowed accurate modelling of the experiment via non-homogeneous 3D acoustic simulations. The data demonstrates acoustic focusing beyond the skull bone, with the focus slightly broadened and shifted proximal to the skull. The fabricated design is capable of targeting regions within the S1 sensorimotor cortex of macaques.

Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model.

PubMed

Arvanitis, Costas D; Vykhodtseva, Natalia; Jolesz, Ferenc; Livingstone, Margaret; McDannold, Nathan

2016-05-01

OBJECT Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an emerging noninvasive alternative to surgery and radiosurgery that is undergoing testing for tumor ablation and functional neurosurgery. The method is currently limited to central brain targets due to skull heating and other factors. An alternative ablative approach combines very low intensity ultrasound bursts and an intravenously administered microbubble agent to locally destroy the vasculature. The objective of this work was to investigate whether it is feasible to use this approach at deep brain targets near the skull base in nonhuman primates. METHODS In 4 rhesus macaques, targets near the skull base were ablated using a clinical TcMRgFUS system operating at 220 kHz. Low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes in conjunction with the ultrasound contrast agent Definity, which was administered as a bolus injection or continuous infusion. The acoustic power level was set to be near the inertial cavitation threshold, which was measured using passive monitoring of the acoustic emissions. The resulting tissue effects were investigated with MRI and with histological analysis performed 3 hours to 1 week after sonication. RESULTS Thirteen targets were sonicated in regions next to the optic tract in the 4 animals. Inertial cavitation, indicated by broadband acoustic emissions, occurred at acoustic pressure amplitudes ranging from 340 to 540 kPa. MRI analysis suggested that the lesions had a central region containing red blood cell extravasations that was surrounded by edema. Blood-brain barrier disruption was observed on contrast-enhanced MRI in the lesions and in a surrounding region corresponding to the prefocal area of the FUS system. In histology, lesions consisting of tissue undergoing ischemic necrosis were found in all regions that were sonicated above the inertial cavitation threshold. Tissue damage in prefocal areas was found in several cases, suggesting that in those cases the sonication exceeded the inertial cavitation threshold in the beam path. CONCLUSIONS It is feasible to use a clinical TcMRgFUS system to ablate skull base targets in nonhuman primates at time-averaged acoustic power levels at least 2 orders of magnitude below what is needed for thermal ablation with this device. The results point to the risks associated with the method if the exposure levels are not carefully controlled to avoid inertial cavitation in the acoustic beam path. If methods can be developed to provide this control, this nonthermal approach could greatly expand the use of TcMRgFUS for precisely targeted ablation to locations across the entire brain.

Ultrashort echo-time MRI versus CT for skull aberration correction in MR-guided transcranial focused ultrasound: In vitro comparison on human calvaria.

PubMed

Miller, G Wilson; Eames, Matthew; Snell, John; Aubry, Jean-François

2015-05-01

Transcranial magnetic resonance-guided focused ultrasound (TcMRgFUS) brain treatment systems compensate for skull-induced beam aberrations by adjusting the phase and amplitude of individual ultrasound transducer elements. These corrections are currently calculated based on a preacquired computed tomography (CT) scan of the patient's head. The purpose of the work presented here is to demonstrate the feasibility of using ultrashort echo-time magnetic resonance imaging (UTE MRI) instead of CT to calculate and apply aberration corrections on a clinical TcMRgFUS system. Phantom experiments were performed in three ex-vivo human skulls filled with tissue-mimicking hydrogel. Each skull phantom was imaged with both CT and UTE MRI. The MR images were then segmented into "skull" and "not-skull" pixels using a computationally efficient, threshold-based algorithm, and the resulting 3D binary skull map was converted into a series of 2D virtual CT images. Each skull was mounted in the head transducer of a clinical TcMRgFUS system (ExAblate Neuro, Insightec, Israel), and transcranial sonications were performed using a power setting of approximately 750 acoustic watts at several different target locations within the electronic steering range of the transducer. Each target location was sonicated three times: once using aberration corrections calculated from the actual CT scan, once using corrections calculated from the MRI-derived virtual CT scan, and once without applying any aberration correction. MR thermometry was performed in conjunction with each 10-s sonication, and the highest single-pixel temperature rise and surrounding-pixel mean were recorded for each sonication. The measured temperature rises were ∼ 45% larger for aberration-corrected sonications than for noncorrected sonications. This improvement was highly significant (p < 10(-4)). The difference between the single-pixel peak temperature rise and the surrounding-pixel mean, which reflects the sharpness of the thermal focus, was also significantly larger for aberration-corrected sonications. There was no significant difference between the sonication results achieved using CT-based and MR-based aberration correction. The authors have demonstrated that transcranial focal heating can be significantly improved in vitro by using UTE MRI to compute skull-induced ultrasound aberration corrections. Their results suggest that UTE MRI could be used instead of CT to implement such corrections on current 0.7 MHz clinical TcMRgFUS devices. The MR image acquisition and segmentation procedure demonstrated here would add less than 15 min to a clinical MRgFUS treatment session.

Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound.

PubMed

Stavarache, Mihaela A; Petersen, Nicholas; Jurgens, Eric M; Milstein, Elizabeth R; Rosenfeld, Zachary B; Ballon, Douglas J; Kaplitt, Michael G

2018-04-27

OBJECTIVE Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain. METHODS Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses. RESULTS Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%-75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons. CONCLUSIONS This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders.

Isolation, molecular and phenotypic characterization of Cronobacter spp. in ready-to-eat salads and foods from Japanese cuisine commercialized in Brazil.

PubMed

Vasconcellos, Luiza; Carvalho, Carla Trece; Tavares, Rodrigo Overas; de Mello Medeiros, Valéria; de Oliveira Rosas, Carla; Silva, Júlia Nunes; Dos Reis Lopes, Silvia Maria; Forsythe, Stephen James; Brandão, Marcelo Luiz Lima

2018-05-01

The aim of this study was to detect Cronobacter from 30 samples of ready-to-eat (RTE) salads and 30 foods from Japanese cuisine as commercially available in Brazil. The detection of Cronobacter was as according to the ISO standard 22964:2017. The isolates were phenotypically characterized by Vitek 2.0 and the antibiotic susceptibility profile was determined using the standardized agar disc diffusion method. Molecular characterization was accomplished by real-time PCR targeting dnaG gene, multiplex-PCR targeting cgcA gene, and fusA allele sequencing. Twenty-seven samples (45.0%) contained Cronobacter, 14 (23.3%) samples of foods from Japanese cuisine and 13 (21.7%) samples of RTE salads. Twenty-nine unique Cronobacter isolates were selected from the 27 positive samples and were identified as C. sakazakii (n = 18), C. malonaticus (n = 8), and C. dublinensis (n = 3). A high genetic diversity was observed, with 29 Cronobacter strains being assigned to 11 different fusA alleles, a ratio of 2.6 strains by fusA allele was found. The cgcA multiplex-PCR failed to identify many of the Cronobacter isolates at the species level. Four (13.8%) Cronobacter isolates were resistant to one or more antibiotics tested (n = 12). The presence of Cronobacter in RTE foods could be a potential threat to human health and highlights the need for high levels of hygiene, particularly when preparing food for elderly, immunosuppressed persons or adults with prior underlying pathology. Epidemiological surveillance agencies should be aware of the risk that these RTE foods may represent, for these groups. Copyright © 2018 Elsevier Ltd. All rights reserved.

Dynamical Cluster-decay Model (DCM) applied to 9Li+208Pb reaction

NASA Astrophysics Data System (ADS)

Kaur, Arshdeep; Hemdeep; Kaushal, Pooja; Behera, Bivash R.; Gupta, Raj K.

2017-10-01

The decay mechanism of 217At* formed in 9Li+208Pb reaction is studied within the dynamical cluster-decay model (DCM) at various center-of-mass energies. The aim is to see the behavior of a light neutron-rich radioactive beam on a doubly-magic target nucleus for the (total) fusion cross section σfus and the individual decay channel cross sections. Experimentally, only the isotopic yield of heavy mass residues * 211- 214At [equivalently, the light-particles (LPs) evaporation residue cross sections σxn for x = 3- 6 neutrons emission] are measured, with the fusion-fission (ff) component σff taken zero. For a fixed neck-length parameter ΔR, the only parameter in the DCM, we are able to fit σfus =∑x=16σxn almost exactly for 9Li on 208Pb at all E c . m .'s. However, the observed individual decay channels (3n-6n) are very poorly fitted, with unobserved channels (1n, 2n) and σff strongly over-estimated. Different ΔR values, meaning thereby different reaction time scales, are required to fit individually both the observed and unobserved evaporation residue channels (1n-6n) and σff, but then the compound nucleus (CN) contribution σCN is very small (< 1%), and the non-compound nucleus (nCN) decay cross section σnCN contributes the most towards total σfus (=σCN +σnCN). Thus, the 9Li induced reaction on doubly-magic 208Pb is more of a quasi-fission-like nCN decay, which is further analyzed in terms of the statistical CN formation probability PCN and CN survival probability Psurv. For the reaction under study, PCN < < 1 and Psurv → 1, in particular at above barrier energies.

The hemocyanin from a living fossil, the cephalopod Nautilus pompilius: protein structure, gene organization, and evolution.

PubMed

Bergmann, Sandra; Lieb, Bernhard; Ruth, Peter; Markl, Jürgen

2006-03-01

By electron microscopic and immunobiochemical analyses we have confirmed earlier evidence that Nautilus pompilius hemocyanin (NpH) is a ring-like decamer (M(r) = approximately 3.5 million), assembled from 10 identical copies of an approximately 350-kDa polypeptide. This subunit in turn is substructured into seven sequential covalently linked functional units of approximately 50 kDa each (FUs a-g). We have cloned and sequenced the cDNA encoding the complete polypeptide; it comprises 9198 bp and is subdivided into a 5' UTR of 58 bp, a 3' UTR of 365 bp, and an open reading frame for a signal peptide of 21 amino acids plus a polypeptide of 2903 amino acids (M(r) = 335,881). According to sequence alignments, the seven FUs of Nautilus hemocyanin directly correspond to the seven FU types of the previously sequenced hemocyanin "OdH" from the cephalopod Octopus dofleini. Thirteen potential N-glycosylation sites are distributed among the seven Nautilus hemocyanin FUs; the structural consequences of putatively attached glycans are discussed on the basis of the published X-ray structure for an Octopus dofleini and a Rapana thomasiana FU. Moreover, the complete gene structure of Nautilus hemocyanin was analyzed; it resembles that of Octopus hemocyanin with respect to linker introns but shows two internal introns that differ in position from the three internal introns of the Octopus hemocyanin gene. Multiple sequence alignments allowed calculation of a rather robust phylogenetic tree and a statistically firm molecular clock. This reveals that the last common ancestor of Nautilus and Octopus lived 415 +/- 24 million years ago, in close agreement with fossil records from the early Devonian.

A yeast functional screen predicts new candidate ALS disease genes

PubMed Central

Couthouis, Julien; Hart, Michael P.; Shorter, James; DeJesus-Hernandez, Mariely; Erion, Renske; Oristano, Rachel; Liu, Annie X.; Ramos, Daniel; Jethava, Niti; Hosangadi, Divya; Epstein, James; Chiang, Ashley; Diaz, Zamia; Nakaya, Tadashi; Ibrahim, Fadia; Kim, Hyung-Jun; Solski, Jennifer A.; Williams, Kelly L.; Mojsilovic-Petrovic, Jelena; Ingre, Caroline; Boylan, Kevin; Graff-Radford, Neill R.; Dickson, Dennis W.; Clay-Falcone, Dana; Elman, Lauren; McCluskey, Leo; Greene, Robert; Kalb, Robert G.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Ludolph, Albert; Robberecht, Wim; Andersen, Peter M.; Nicholson, Garth A.; Blair, Ian P.; King, Oliver D.; Bonini, Nancy M.; Van Deerlin, Vivianna; Rademakers, Rosa; Mourelatos, Zissimos; Gitler, Aaron D.

2011-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery. PMID:22065782

Combined Ultrasound and MR Imaging to Guide Focused Ultrasound Therapies in the Brain

PubMed Central

Arvanitis, Costas D.; Livingstone, Margaret S.; McDannold, Nathan

2013-01-01

Purpose Several emerging therapies with potential for use in the brain harness effects produced by acoustic cavitation – the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength, and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. Materials and Methods We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. Results The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. Conclusion While preliminary, these data clearly demonstrate, for the first time, that is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies. PMID:23788054

Colorimetric TMPRSS2-ERG Gene Fusion Detection in Prostate Cancer Urinary Samples via Recombinase Polymerase Amplification.

PubMed

Koo, Kevin M; Wee, Eugene J H; Trau, Matt

2016-01-01

TMPRSS2 (Exon 1)-ERG (Exon 4) is the most frequent gene fusion event in prostate cancer (PC), and is highly PC-specific unlike the current serum prostate specific antigen (PSA) biomarker. However, TMPRSS2-ERG levels are currently measured with quantitative reverse-transcription PCR (RT-qPCR) which is time-consuming and requires costly equipment, thus limiting its use in clinical diagnostics. Herein, we report a novel rapid, cost-efficient and minimal-equipment assay named "FusBLU" for detecting TMPRSS2-ERG gene fusions from urine. TMPRSS2-ERG mRNA was amplified by isothermal reverse transcription-recombinase polymerase amplification (RT-RPA), magnetically-isolated, and detected through horseradish peroxidase (HRP)-catalyzed colorimetric reaction. FusBLU was specific for TMPRSS2-ERG mRNA with a low visual detection limit of 10(5) copies. We also demonstrated assay readout versatility on 3 potentially useful platforms. The colorimetric readout was detectable by naked eye for a quick yes/no evaluation of gene fusion presence. On the other hand, a more quantitative TMPRSS2-ERG detection was achievable by absorbance/electrochemical measurements. FusBLU was successfully applied to 12 urinary samples and results were validated by gold-standard RT-qPCR. We also showed that sediment RNA was likely the main source of TMPRSS2-ERG mRNA in urinary samples. We believe that our assay is a potential clinical screening tool for PC and could also have wide applications for other disease-related fusion genes.

Liposarcoma: multimodality management and future targeted therapies

PubMed Central

Crago, Aimee M.; Dickson, Mark A.

2016-01-01

SYNOPSIS There are three biologic groups of liposarcoma: well- and dedifferentiated liposarcoma (WD/DDLS), myxoid/round cell liposarcoma (M/RCLS) and pleomorphic liposarcoma. WD/DDLS is characterized by amplification of 12q13-15 (including the oncogenes MDM2 and CDK4), M/RCLS by FUS-DDIT3 translocations, and pleomorphic liposarcoma by loss of p53 and Rb. In all three groups, complete surgical resection is central in treatment aimed at cure and is based on grade. Radiation can reduce risk of local recurrence in high-grade lesions or minimize surgical morbidity in the highly radiosensitive M/RCLS group. The biologic groups differ greatly in their chemosensitivity, so adjuvant chemotherapy is selectively utilized in chemosensitive histologies with metastatic potential (i.e. round cell and pleomorphic liposarcomas) but not in the relatively resistant subtype DDLS. An improved understanding of the genetic aberrations that lead to liposarcoma initiation is also allowing for the rapid development of targeted therapies for liposarcoma. Among such therapies are CDK4 inhibitors in WD/DDLS and trabectedin, which prevents FUS-DDIT3 binding to DNA, in M/RCLS. PMID:27591497

An examination of the thermodynamics of fusion, vaporization, and sublimation of several parabens by correlation gas chromatography.

PubMed

Umnahanant, Patamaporn; Chickos, James

2011-05-01

The vaporization, fusion, and sublimation enthalpies of methyl, ethyl, propyl, and butyl paraben are reported and compared with literature values. The vaporization enthalpies were measured by correlation gas chromatography and the fusion enthalpies by differential scanning calorimetry. Adjusted to T = 298.15 K, these enthalpies were combined to yield the sublimation enthalpy. The results compare favorably to some of the literature values but do not support the reversal in magnitude of both the vaporization and sublimation enthalpy previously reported for propyl and butyl paraben. The following fusion and vaporization enthalpies were measured for methyl through to butyl paraben, respectively: ΔH(fus) (T(fus) ) 26.3 ± 0.1 (398.6 K), 26.5 ± 0.1 (388.5 K), 27.3 ± 0.1 (368.8), and 25.9 ± 0.3 (340.7 K) kJ·mol(-1); ΔH(vap) (298.15 K) 79.5 ± 0.5, 84.0 ± 0.5, 89.7 ± 0.6, and 95.8 ± 0.6 kJ·mol(-1). The results are believed to be accurate to ± 4 kJ·mol(-1). Copyright © 2011 Wiley-Liss, Inc.

Multi-modality safety assessment of blood-brain barrier opening using focused ultrasound and definity microbubbles: a short-term study.

PubMed

Baseri, Babak; Choi, James J; Tung, Yao-Sheng; Konofagou, Elisa E

2010-09-01

As a potentially viable method of brain drug delivery, the safety profile of blood-brain barrier (BBB) opening using focused ultrasound (FUS) and ultrasound contrast agents (UCA) needs to be established. In this study, we provide a short-term (30-min or 5-h survival) histological assessment of murine brains undergoing FUS-induced BBB opening. Forty-nine mice were intravenously injected with Definity microbubbles (0.05 microL/kg) and sonicated under the following parameters: frequency of 1.525 MHz, pulse length of 20 ms, pulse repetition frequency of 10 Hz, peak rarefactional acoustic pressures of 0.15-0.98 MPa and two 30-s sonication intervals with an intermittent 30-s delay. The BBB opening threshold was found to be 0.15-0.3 MPa based on fluorescence and magnetic resonance imaging of systemically injected tracers. Analysis of three histological measures in hematoxylin and eosin-stained sections revealed the safest acoustic pressure to be within the range of 0.3-0.46 MPa in all examined time periods post sonication. Across different pressure amplitudes, only the samples 30 min post opening showed significant difference (p < 0.05) in the average number of distinct damaged sites, microvacuolated sites, dark neurons and sites with extravasated erythrocytes. Enhanced fluorescence around severed microvessels was also noted and found to be associated with the largest tissue effects, whereas mildly diffuse BBB opening with uniform fluorescence in the parenchyma was associated with no or mild tissue injury. Region-specific areas of the sonicated brain (thalamus, hippocampal fissure, dentate gyrus and CA3 area of hippocampus) exhibited variation in fluorescence intensity based on the position, orientation and size of affected vessels. The results of this short-term histological analysis demonstrated the feasibility of a safe FUS-UCA-induced BBB opening under a specific set of sonication parameters and provided new insights on the mechanism of BBB opening.

Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

NASA Astrophysics Data System (ADS)

Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-03-01

Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P < 0.05, P < 0.01, and P < 0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222  ±  784, 3687  ±  796 and 5658  ±  821 ng g-1) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P < 0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used.

Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood-brain barrier opening in Parkinson's disease mouse model.

PubMed

Lin, Chung-Yin; Hsieh, Han-Yi; Chen, Chiung-Mei; Wu, Shang-Rung; Tsai, Chih-Hung; Huang, Chiung-Yin; Hua, Mu-Yi; Wei, Kuo-Chen; Yeh, Chih-Kuang; Liu, Hao-Li

2016-08-10

Focused ultrasound (FUS)-induced with microbubbles (MBs) is a promising technique for noninvasive opening of the blood-brain barrier (BBB) to allow targeted delivery of therapeutic substances into the brain and thus the noninvasive delivery of gene vectors for CNS treatment. We have previously demonstrated that a separated gene-carrying liposome and MBs administration plus FUS exposure can deliver genes into the brain, with the successful expression of the reporter gene and glial cell line-derived neurotrophic factor (GDNF) gene. In this study, we further modify the delivery system by conjugating gene-carrying liposomes with MBs to improve the GDNF gene-delivery efficiency, and to verify the possibility of using this system to perform treatment in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal disease model. FUS-BBB opening was verified by contrast-enhanced MRI, and GFP gene expression was verified via in vivo imaging system (IVIS). Western blots as well as enzyme-linked immunosorbent assay (ELISA) were conducted to measure protein expression, and immunohistochemistry (IHC) was conducted to test the Tyrosine hydroxylase (TH)-neuron distribution. Dopamine (DA) and its metabolites as well as dopamine active transporter (DAT) were quantitatively analyzed to show dopaminergic neuronal dopamine secretion/activity/metabolism. Motor performance was evaluated by rotarod test weekly. Results demonstrated that the LpDNA-MBs (gene-liposome-MBs) complexes successfully serve as gene carrier and BBB-opening catalyst, and outperformed the separated LpDNA/MBs administration both in terms of gene delivery and expression. TH-positive IHC and measurement of DA and its metabolites DOPAC and HVA confirmed improved neuronal function, and the proposed system also provided the best neuroprotective effect to retard the progression of motor-related behavioral abnormalities. Immunoblotting and histological staining further confirmed the expression of reporter genes in neuronal cells. This study suggests that FUS exposures with the administration of LpDNA-MBs complexes synergistically can serve as an effective gene therapy strategy for MPTP-animal treatment, and may have potential for further application to perform gene therapy for neurodegenerative disease. Copyright © 2016 Elsevier B.V. All rights reserved.

MR-guided focused ultrasound: a potentially disruptive technology.

PubMed

Bradley, William G

2009-07-01

A disruptive technology is a technological innovation that overturns the existing dominant technologies in a market. Magnetic resonance (MR)-guided focused ultrasound (MRgFUS) is a noninvasive procedure based on the combination of real-time MR anatomic guidance, MR thermometry, and high-intensity focused ultrasound. Several hundred transducer elements become convergent at a point under MR guidance, leading to heating and coagulation necrosis. Outside the focal point, there is no significant heating. There is no need to break the skin for procedures in the body or to perform a craniotomy for procedures in the brain. This lack of invasiveness is what makes MRgFUS so disruptive compared with surgery. At present, MRgFUS has been used for the ablation of uterine fibroids, breast tumors, painful bony metastases, and liver tumors. In the brain, it has been used for the ablation of glioblastomas and for functional neurosurgery. Phantom and animal studies suggest future applications for prostate cancer and acute stroke treatment.

First noninvasive thermal ablation of a brain tumor with MR-guided focused ultrasound

PubMed Central

2014-01-01

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) allows for precise thermal ablation of target tissues. While this emerging modality is increasingly used for the treatment of various types of extracranial soft tissue tumors, it has only recently been acknowledged as a modality for noninvasive neurosurgery. MRgFUS has been particularly successful for functional neurosurgery, whereas its clinical application for tumor neurosurgery has been delayed for various technical and procedural reasons. Here, we report the case of a 63-year-old patient presenting with a centrally located recurrent glioblastoma who was included in our ongoing clinical phase I study aimed at evaluating the feasibility and safety of transcranial MRgFUS for brain tumor ablation. Applying 25 high-power sonications under MR imaging guidance, partial tumor ablation could be achieved without provoking neurological deficits or other adverse effects in the patient. This proves, for the first time, the feasibility of using transcranial MR-guided focused ultrasound to safely ablate substantial volumes of brain tumor tissue. PMID:25671132

Usage of Magnetic Resonance Guided Focused Ultrasound Surgery (mrgfus) in Oncology

NASA Astrophysics Data System (ADS)

Bauer, Yair

2011-09-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is a non-invasive incision-less surgical approach which limits the tissue destruction to the targeted tumor. Acoustic energy penetrates through intact skin and through the tissues surrounding the tumor without causing any significant bio-effects. Energy deposition takes place mainly at the focal spot where heat induced thermal coagulation of the targeted tissue is accomplished. Real time targeting and image guidance is provided by MRI tumor margin definition and real time thermometry provides closed loop feedback control of energy deposition. The patient lies in the MRI scanner throughout the treatment planning and treatment, and the physician conducts the treatment from the MRgFUS workstation in the adjacent MR control room. The ExAblate system for MRgFUS is commercially available in many countries for treatment of uterine fibroids. The system has also received CE and KFDA approval for pain palliation of bone metastases, and research of other oncologic applications is underway.

Review of MRI positioning devices for guiding focused ultrasound systems.

PubMed

Yiallouras, C; Damianou, C

2015-06-01

This article contains a review of positioning devices that are currently used in the area of magnetic resonance imaging (MRI) guided focused ultrasound surgery (MRgFUS). The paper includes an extensive review of literature published since the first prototype system was invented in 1991. The technology has grown into a fast developing area with application to any organ accessible to ultrasound. The initial design operated using hydraulic principles, while the latest technology incorporates piezoelectric motors. Although, in the beginning there were fears regarding MRI safety, during recent years, the deployment of MR-safe positioning devices in FUS has become routine. Many of these positioning devices are now undergoing testing in clinical trials. Existing MRgFUS systems have been utilized mostly in oncology (fibroids, brain, liver, kidney, bone, pancreas, eye, thyroid, and prostate). It is anticipated that, in the near future, there will be a positioning device for every organ that is accessible by focused ultrasound. Copyright © 2014 John Wiley & Sons, Ltd.

Fast Numerical Simulation of Focused Ultrasound Treatments During Respiratory Motion With Discontinuous Motion Boundaries.

PubMed

Schwenke, Michael; Georgii, Joachim; Preusser, Tobias

2017-07-01

Focused ultrasound (FUS) is rapidly gaining clinical acceptance for several target tissues in the human body. Yet, treating liver targets is not clinically applied due to a high complexity of the procedure (noninvasiveness, target motion, complex anatomy, blood cooling effects, shielding by ribs, and limited image-based monitoring). To reduce the complexity, numerical FUS simulations can be utilized for both treatment planning and execution. These use-cases demand highly accurate and computationally efficient simulations. We propose a numerical method for the simulation of abdominal FUS treatments during respiratory motion of the organs and target. Especially, a novel approach is proposed to simulate the heating during motion by solving Pennes' bioheat equation in a computational reference space, i.e., the equation is mathematically transformed to the reference. The approach allows for motion discontinuities, e.g., the sliding of the liver along the abdominal wall. Implementing the solver completely on the graphics processing unit and combining it with an atlas-based ultrasound simulation approach yields a simulation performance faster than real time (less than 50-s computing time for 100 s of treatment time) on a modern off-the-shelf laptop. The simulation method is incorporated into a treatment planning demonstration application that allows to simulate real patient cases including respiratory motion. The high performance of the presented simulation method opens the door to clinical applications. The methods bear the potential to enable the application of FUS for moving organs.

Apatite and Chitin Amendments Promote Microbial Activity and Augment Metal Removal in Marine Sediments

DTIC Science & Technology

2013-07-01

abundance of Deltaproteobacteria and decrease of Actinobacteria , Alphaproteobacteria, and Nitrospirae. Many of these groups of bacteria have been shown to...shifts were observed from clone library analyses (Table 2 and Fig- ure 4). Actinobacteria , Alphaproteobacteria, Gam- maproteobacteria...abundance (%) Phylum FUS FCS FACS Impact Acidobacteria - - 1.9 Induced Actinobacteria 20.8 8.6 3.8 Decreased Alphaproteobacteria 22.9 14.3 13.2 Decreased

[AML(M7) associated with t(16;21)(p11;q22) showing relapse after unrelated bone marrow transplantation and disappearance of TLS/FUS-ERG mRNA].

PubMed

Fukushima, Y; Fujii, N; Tabata, Y; Nishimura, Y; Fusaoka, T; Yoshihara, T; Tsunamoto, K; Kasubuchi, Y; Morimoto, A; Hibi, S; Taketani, K; Hayashi, Y; Imashuku, S

2001-06-01

A 3-year-old boy with poorly prognostic acute megakaryoblastic leukemia (AML M7) showing t(16;21)(p11;q22) karyotype underwent unrelated bone marrow transplantation (U-BMT) during his first hematological remission. The conditioning regimen consisted of BU, VP-16 and L-PAM. Engraftment was smooth, but the patient developed grade I acute GVHD. During hematological remission before U-BMT, the TLS/FUS-ERG chimeric transcript of t(16;21)(p11;q22) was consistently detectable as minimal residual disease (MRD) by RT-PCR. However, after U-BMT it soon became undetectable. There was no detectable MRD until 7 months after U-BMT, but bone marrow relapse occurred 10 months after U-BMT. We consider that U-BMT is a promising treatment for t(16;21)(p11;q22) AML. However, an intensified conditioning regimen or modification of GVHD prophylaxis is needed.

Localised drug release using MRI-controlled focused ultrasound hyperthermia.

PubMed

Staruch, Robert; Chopra, Rajiv; Hynynen, Kullervo

2011-01-01

Thermosensitive liposomes provide a mechanism for triggering the local release of anticancer drugs, but this technology requires precise temperature control in targeted regions with minimal heating of surrounding tissue. The objective of this study was to evaluate the feasibility of using MRI-controlled focused ultrasound (FUS) and thermosensitive liposomes to achieve thermally mediated localised drug delivery in vivo. Results are reported from ten rabbits, where a FUS beam was scanned in a circular trajectory to heat 10-15 mm diameter regions in normal thigh to 43°C for 20-30 min. MRI thermometry was used for closed-loop feedback control to achieve temporally and spatially uniform heating. Lyso-thermosensitive liposomal doxorubicin was infused intravenously during hyperthermia. Unabsorbed liposomes were flushed from the vasculature by saline perfusion 2 h later, and tissue samples were harvested from heated and unheated thigh regions. The fluorescence intensity of the homogenised samples was used to calculate the concentration of doxorubicin in tissue. Closed-loop control of FUS heating using MRI thermometry achieved temperature distributions with mean, T90 and T10 of 42.9°C, 41.0°C and 44.8°C, respectively, over a period of 20 min. Doxorubicin concentrations were significantly higher in tissues sampled from heated than unheated regions of normal thigh muscle (8.3 versus 0.5 ng/mg, mean per-animal difference = 7.8 ng/mg, P < 0.05, Wilcoxon matched pairs signed rank test). The results show the potential of MRI-controlled focused ultrasound hyperthermia for enhanced local drug delivery with temperature-sensitive drug carriers.

Clinical Consideration of Treatment to Ablate Uterine Fibroids with Magnetic Resonance Imaging-guided High Intensity Focused Ultrasound (MRgFUS): Sonalleve

PubMed Central

Jeong, Jae-Hyeok; Hong, Gil Pyo; Kim, Yu-Ri; Ha, Jae-Eun

2016-01-01

Objectives Magnetic resonance imaging (MRI)-guided high intensity focused ultrasound surgery (MRgFUS) is a newly emerging non-invasive technique for the treatment of uterine fibroids. The purpose of this study is to review the clinical impact of MRgFUS. Methods This study examined 157 patients. The high intensity focused ultrasound (HIFU) utilized in this study was Philips Achieva 1.5 Tesla MR (Philips Healthcare, Best, the Netherlands) and Sonalleve HIFU system. The patients were followed in post-operative Month 1, Month 3, and Month 6 to investigate any change. Then, these were further classified according to the use of uterine stimulant (oxytocin) in parallel, Funaki Type of uterine fibroid, HIFU intensity, and non-perfused volume (NPV) ratio. Results When the uterine stimulant was utilized, the HIFU intensity was measured at significantly lower levels, compared with the group not using uterine stimulant, and treatment duration was significantly. The NPV ratio was found significantly higher in the group using uterine stimulant. Concerning the correlation between Funaki Type of uterine fibroid and average sonication power, it was found that the closer to Type I, the lower the sonication power, the shorter the treatment duration, and the higher the NPV ratio significantly. Conclusions In this study, it was found that the lower the Funaki Types of uterine fibroids, and the higher the NPV ratio immediately after the operation, the larger the uterine fibroid volume decrease and SSS change were. Also, if uterine stimulant was used in parallel in treatment, treatment duration and HIFU intensity could become shorter and lower. PMID:27617244

Sulcus reproduction with elastomeric impression materials: a new in vitro testing method.

PubMed

Finger, Werner J; Kurokawa, Rie; Takahashi, Hidekazu; Komatsu, Masashi

2008-12-01

Aim of this study was to investigate the depth reproduction of differently wide sulci with elastomeric impression materials by single- and double-mix techniques using a tooth and sulcus model, simulating clinical conditions. Impressions with one vinyl polysiloxane (VPS; FLE), two polyethers (PE; IMP and P2), and one hybrid VPS/PE elastomer (FUS) were taken from a truncated steel cone with a circumferential 2 mm deep sulcus, 50, 100 or 200 microm wide. The "root surface" was in steel and the "periodontal tissue" in reversible hydrocolloid. Single-mix impressions were taken with light-body (L) or monophase (M) pastes, double-mix impressions with L as syringe and M or heavy-body (H) as tray materials (n=8). Sulcus reproduction was determined by 3D laser topography of impressions at eight locations, 45 degrees apart. Statistical data analysis by ANOVA and multiple comparison tests (p<0.05). For 200 microm wide sulci, significant differences were found between impression materials only: FLE=IMP>FUS=P2. At 50 and 100 microm width, significant differences were found between materials (IMP>FUS=FLE>P2) and techniques (L+H=L+M>M>L). The sulcus model is considered useful for screening evaluation of elastomeric impression materials ability to reproduce narrow sulci. All tested materials and techniques reproduced 200 microm wide sulci to almost nominal depth. Irrespective of the impression technique used, IMP showed the best penetration ability in 50 and 100 microm sulci. Double-mix techniques are more suitable to reproduce narrow sulci than single-mix techniques.

Development of an Atmospheric Dispersion Model for Heavier-Than-Air Gas Mixtures. Volume 1.

DTIC Science & Technology

1985-05-01

aspirated concentration sensor used a balanced Wheatstone bridge to measure the heat loss from a sensing element placed in the sample stream. Shaded...a semipermeable membrane and electrochemical cell. A fast response sensor (10 Hz) basically aspirated a sample past the cell membrane. Reported...ramp function around the freezing point of water by X11., X= vap for T 273.15 K vap fus 263.15 for 263.15 <T < 273.15 Xvap +x fus for T < 263.15 (A-4

SU-E-J-03: Characterization of the Precision and Accuracy of a New, Preclinical, MRI-Guided Focused Ultrasound System for Image-Guided Interventions in Small-Bore, High-Field Magnets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellens, N; Farahani, K

2015-06-15

Purpose: MRI-guided focused ultrasound (MRgFUS) has many potential and realized applications including controlled heating and localized drug delivery. The development of many of these applications requires extensive preclinical work, much of it in small animal models. The goal of this study is to characterize the spatial targeting accuracy and reproducibility of a preclinical high field MRgFUS system for thermal ablation and drug delivery applications. Methods: The RK300 (FUS Instruments, Toronto, Canada) is a motorized, 2-axis FUS positioning system suitable for small bore (72 mm), high-field MRI systems. The accuracy of the system was assessed in three ways. First, the precisionmore » of the system was assessed by sonicating regular grids of 5 mm squares on polystyrene plates and comparing the resulting focal dimples to the intended pattern, thereby assessing the reproducibility and precision of the motion control alone. Second, the targeting accuracy was assessed by imaging a polystyrene plate with randomly drilled holes and replicating the hole pattern by sonicating the observed hole locations on intact polystyrene plates and comparing the results. Third, the practicallyrealizable accuracy and precision were assessed by comparing the locations of transcranial, FUS-induced blood-brain-barrier disruption (BBBD) (observed through Gadolinium enhancement) to the intended targets in a retrospective analysis of animals sonicated for other experiments. Results: The evenly-spaced grids indicated that the precision was 0.11 +/− 0.05 mm. When image-guidance was included by targeting random locations, the accuracy was 0.5 +/− 0.2 mm. The effective accuracy in the four rodent brains assessed was 0.8 +/− 0.6 mm. In all cases, the error appeared normally distributed (p<0.05) in both orthogonal axes, though the left/right error was systematically greater than the superior/inferior error. Conclusions: The targeting accuracy of this device is sub-millimeter, suitable for many preclinical applications including focused drug delivery and thermal therapy. Funding support provided by Philips Healthcare.« less

Image-guided Navigation of Single-element Focused Ultrasound Transducer

PubMed Central

Kim, Hyungmin; Chiu, Alan; Park, Shinsuk; Yoo, Seung-Schik

2014-01-01

The spatial specificity and controllability of focused ultrasound (FUS), in addition to its ability to modify the excitability of neural tissue, allows for the selective and reversible neuromodulation of the brain function, with great potential in neurotherapeutics. Intra-operative magnetic resonance imaging (MRI) guidance (in short, MRg) has limitations due to its complicated examination logistics, such as fixation through skull screws to mount the stereotactic frame, simultaneous sonication in the MRI environment, and restrictions in choosing MR-compatible materials. In order to overcome these limitations, an image-guidance system based on optical tracking and pre-operative imaging data is developed, separating the imaging acquisition for guidance and sonication procedure for treatment. Techniques to define the local coordinates of the focal point of sonication are presented. First, mechanical calibration detects the concentric rotational motion of a rigid-body optical tracker, attached to a straight rod mimicking the sonication path, pivoted at the virtual FUS focus. The spatial error presented in the mechanical calibration was compensated further by MRI-based calibration, which estimates the spatial offset between the navigated focal point and the ground-truth location of the sonication focus obtained from a temperature-sensitive MR sequence. MRI-based calibration offered a significant decrease in spatial errors (1.9±0.8 mm; 57% reduction) compared to the mechanical calibration method alone (4.4±0.9 mm). Using the presented method, pulse-mode FUS was applied to the motor area of the rat brain, and successfully stimulated the motor cortex. The presented techniques can be readily adapted for the transcranial application of FUS to intact human brain. PMID:25232203

Scaled signal intensity of uterine fibroids based on T2-weighted MR images: a potential objective method to determine the suitability for magnetic resonance-guided focused ultrasound surgery of uterine fibroids.

PubMed

Park, Hyun; Yoon, Sang-Wook; Sokolov, Amit

2015-12-01

Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) is a non-invasive method to treat uterine fibroids. To help determine the patient suitability for MRgFUS, we propose a new objective measure: the scaled signal intensity (SSI) of uterine fibroids in T2 weighted MR images (T2WI). Forty three uterine fibroids in 40 premenopausal women were included in this retrospective study. SSI of each fibroid was measured from the screening T2WI by standardizing its mean signal intensity to a 0-100 scale, using reference intensities of rectus abdominis muscle (0) and subcutaneous fat (100). Correlation between the SSI and the non-perfused volume (NPV) ratio (a measure for treatment success) was calculated. Pre-treatment SSI showed a significant inverse-correlation with post treatment NPV ratio (p < 0.05). When dichotomizing NPV ratio at 45 %, the optimal cut off value of the SSI was found to be 16.0. A fibroid with SSI value 16.0 or less can be expected to have optimal responses. The SSI of uterine fibroids in T2WI can be suggested as an objective parameter to help in patient selection for MRgFUS. • Signal intensity of fibroid in MR images predicts treatment response to MRgFUS. • Signal intensity is standardized into scaled form using adjacent tissues as references. • Fibroids with SSI less than 16.0 are expected to have optimal responses.

Decay analysis of compound nuclei formed in reactions with exotic neutron-rich 9Li projectile and the synthesis of 217At* within the dynamical cluster-decay model

NASA Astrophysics Data System (ADS)

Kaur, Arshdeep; Kaushal, Pooja; Hemdeep; Gupta, Raj K.

2018-01-01

The decay of various compound nuclei formed via exotic neutron-rich 9Li projectile is studied within the dynamical cluster-decay model (DCM). Following the earlier work of one of us (RKG) and collaborators (M. Kaur et al. (2015) [1]), for an empirically fixed neck-length parameter ΔRemp, the only parameter in the DCM, at a given incident laboratory energy ELab, we are able to fit almost exactly the (total) fusion cross section σfus =∑x=16σxn for 9Li projectile on 208Pb and other targets, with σfus depending strongly on the target mass of the most abundant isotope and its (magic) shell structure. This result shows the predictable nature of the DCM. The neck-length parameter ΔRemp is fixed empirically for the decay of 217At* formed in 9Li + 208Pb reaction at a fixed laboratory energy ELab, and then the total fusion cross section σfus calculated for all other reactions using 9Li as a projectile on different targets. Apparently, this procedure could be used to predict σfus for 9Li-induced reactions where experimental data are not available. Furthermore, optimum choice of "cold" target-projectile combinations, forming "hot" compact configurations, are predicted for the synthesis of compound nucleus 217At* with 8Li + 209Pb as one of the target-projectile combination, or another (t , p) combination 48Ca + 169Tb, with a doubly magic 48Ca, as the best possibility.

Fusidic Acid: A Bacterial Elongation Factor Inhibitor for the Oral Treatment of Acute and Chronic Staphylococcal Infections

PubMed Central

Fernandes, Prabhavathi

2016-01-01

Fusidic acid is an oral antistaphylococcal antibiotic that has been used in Europe for more than 40 years to treat skin infections as well as chronic bone and joint infections. It is a steroidal antibiotic and the only marketed member of the fusidane class. Fusidic acid inhibits protein synthesis by binding EF-G-GDP, which results in the inhibition of both peptide translocation and ribosome disassembly. It has a novel structure and novel mode of action and, therefore, there is little cross-resistance with other known antibiotics. Many mutations can occur in the FusA gene that codes for EF-G, and some of these mutations can result in high-level resistance (minimum inhibitory concentration [MIC] > 64 mg/L), whereas others result in biologically unfit staphylococci that require compensatory mutations to survive. Low-level resistance (<8 mg/L) is more common and is mediated by fusB, fusC, and fusD genes that code for small proteins that protect EF-G-GDP from binding fusidic acid. The genes for these proteins are spread by plasmids and can be selected mostly by topical antibiotic use. Reports of resistance have led to combination use of fusidic acid with rifampin, which is superseded by the development of a new dosing regimen for fusidic acid that can be used in monotherapy. It consists of a front-loading dose to decrease the potential for resistance development followed by a maintenance dose. This dosing regimen is now being used in clinical trials in the United States for skin and refractory bone and joint infections. PMID:26729758

Electron temperature response to ECRH on FTU tokamak in transient conditions.

NASA Astrophysics Data System (ADS)

Jacchia, A.; Bruschi, A.; Cirant, S.; Granucci, G.; Sozzi, C.; de Luca, F.; Amadeo, P.; Bracco, G.; Tudisco, O.

2001-10-01

Steady-state electron heat transport analysis of FTU high density plasmas under Electron Cyclotron Heating (ECRH) shows "stiff" electron temperature profiles [1,2,3]. Plasma response to off-axis EC heating, in fact, exibits a lower limit to electron temperature gradient length, Lc , below which electron thermal conductivity switches to higher values. Stiffness, however, is attenuated in the plasma core of saw-tooth free discharges with flat-hollow temperature profile and during current ramp-up [3,4,5], in which cases the temperature gradient length can be brought to very low values by means of on-axis ECH. Steady and current ramp-up discharges probed by steady and modulated ECH are analyzed in terms of stiffnes. Critical gradient length dependence on local features of computed current density profile is discussed. [1] Sozzi, C. et al., Paper EXP5/13, Plasma Phys. Contr. Fus. Res., Proc.18th IAEA Conf., Sorrento, 2000. [2] Jacchia, A. et al. Topical Conference on Radio Frequency Power in Plasmas, Oxnard, USA, (2001). [3] Cirant, S. et al. Topical Conference on Radio Frequency Power in Plasmas, Oxnard, USA, (2001). [4] Sozzi, C. et al., EPS, Madeira 2001. [5] Bracco, G. et al.,Plasma Phys. Contr. Fus. Res., Proc.18th IAEA Conf., Sorrento, 2000.

Non-invasive transcranial stimulation of rat abducens nerve by focused ultrasound

PubMed Central

Kim, Hyungmin; Taghados, Seyed Javid; Fischer, Krisztina; Maeng, Lee-So; Park, Shinsuk; Yoo, Seung-Schik

2012-01-01

Non-pharmacological and non-surgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidance. The abductive eyeball movement ipsilateral to the side of sonication was observed at 350 kHz, using the 0.36 msec tone burst duration (TBD), 1.5 kHz pulse repetition frequency (PRF), and the overall sonication duration of 200 msec. Histological and behavioral monitoring showed no signs of disruption in the blood brain barrier (BBB) as well as no damage to the nerves and adjacent brain tissue resulting from the sonication. As a novel functional neuro-modulatory modality, the pulsed application of FUS has potential in diagnostic and therapeutic applications in diseases of the peripheral nervous system. PMID:22763009

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping.

PubMed

Wu, Shih-Ying; Aurup, Christian; Sanchez, Carlos Sierra; Grondin, Julien; Zheng, Wenlan; Kamimura, Hermes; Ferrera, Vincent P; Konofagou, Elisa E

2018-05-22

Brain diseases including neurological disorders and tumors remain under treated due to the challenge to access the brain, and blood-brain barrier (BBB) restricting drug delivery which, also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with microbubbles is the sole method to open the BBB noninvasively, locally, and transiently and facilitate drug delivery, while translation to the clinic is challenging due to long procedure, targeting limitations, or invasiveness of current systems. In order to provide rapid, flexible yet precise applications, we have designed a noninvasive FUS and monitoring system with the protocol tested in monkeys (from in silico preplanning and simulation, real-time targeting and acoustic mapping, to post-treatment assessment). With a short procedure (30 min) similar to current clinical imaging duration or radiation therapy, the achieved targeting (both cerebral cortex and subcortical structures) and monitoring accuracy was close to the predicted 2-mm lower limit. This system would enable rapid clinical transcranial FUS applications outside of the MRI system without a stereotactic frame, thereby benefiting patients especially in the elderly population.

Complex adenovirus-vectored vaccine protects guinea pigs from three strains of Marburg virus challenges.

PubMed

Wang, Danher; Hevey, Michael; Juompan, Laure Y; Trubey, Charles M; Raja, Nicholas U; Deitz, Stephen B; Woraratanadharm, Jan; Luo, Min; Yu, Hong; Swain, Benjamin M; Moore, Kevin M; Dong, John Y

2006-09-30

The Marburg virus (MARV), an African filovirus closely related to the Ebola virus, causes a deadly hemorrhagic fever in humans, with up to 90% mortality. Currently, treatment of disease is only supportive, and no vaccines are available to prevent spread of MARV infections. In order to address this need, we have developed and characterized a novel recombinant vaccine that utilizes a single complex adenovirus-vectored vaccine (cAdVax) to overexpress a MARV glycoprotein (GP) fusion protein derived from the Musoke and Ci67 strains of MARV. Vaccination with the cAdVaxM(fus) vaccine led to efficient production of MARV-specific antibodies in both mice and guinea pigs. Significantly, guinea pigs vaccinated with at least 5 x 10(7) pfu of cAdVaxM(fus) vaccine were 100% protected against lethal challenges by the Musoke, Ci67 and Ravn strains of MARV, making it a vaccine with trivalent protective efficacy. Therefore, the cAdVaxM(fus) vaccine serves as a promising vaccine candidate to prevent and contain multi-strain infections by MARV.

Analytical estimation of ultrasound properties, thermal diffusivity, and perfusion using magnetic resonance-guided focused ultrasound temperature data

PubMed Central

Dillon, C R; Borasi, G; Payne, A

2016-01-01

For thermal modeling to play a significant role in treatment planning, monitoring, and control of magnetic resonance-guided focused ultrasound (MRgFUS) thermal therapies, accurate knowledge of ultrasound and thermal properties is essential. This study develops a new analytical solution for the temperature change observed in MRgFUS which can be used with experimental MR temperature data to provide estimates of the ultrasound initial heating rate, Gaussian beam variance, tissue thermal diffusivity, and Pennes perfusion parameter. Simulations demonstrate that this technique provides accurate and robust property estimates that are independent of the beam size, thermal diffusivity, and perfusion levels in the presence of realistic MR noise. The technique is also demonstrated in vivo using MRgFUS heating data in rabbit back muscle. Errors in property estimates are kept less than 5% by applying a third order Taylor series approximation of the perfusion term and ensuring the ratio of the fitting time (the duration of experimental data utilized for optimization) to the perfusion time constant remains less than one. PMID:26741344

Functional ultrasound imaging of intrinsic connectivity in the living rat brain with high spatiotemporal resolution

PubMed Central

Osmanski, Bruno-Félix; Pezet, Sophie; Ricobaraza, Ana; Lenkei, Zsolt; Tanter, Mickael

2014-01-01

Long-range coherences in spontaneous brain activity reflect functional connectivity. Here we propose a novel, highly resolved connectivity mapping approach, using ultrafast functional ultrasound (fUS), which enables imaging of cerebral microvascular haemodynamics deep in the anaesthetized rodent brain, through a large thinned-skull cranial window, with pixel dimensions of 100 μm × 100 μm in-plane. The millisecond-range temporal resolution allows unambiguous cancellation of low-frequency cardio-respiratory noise. Both seed-based and singular value decomposition analysis of spatial coherences in the low-frequency (<0.1 Hz) spontaneous fUS signal fluctuations reproducibly report, at different coronal planes, overlapping high-contrast, intrinsic functional connectivity patterns. These patterns are similar to major functional networks described in humans by resting-state fMRI, such as the lateral task-dependent network putatively anticorrelated with the midline default-mode network. These results introduce fUS as a powerful novel neuroimaging method, which could be extended to portable systems for three-dimensional functional connectivity imaging in awake and freely moving rodents. PMID:25277668

Complex adenovirus-vectored vaccine protects guinea pigs from three strains of Marburg virus challenges

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Danher; Hevey, Michael; Juompan, Laure Y.

2006-09-30

The Marburg virus (MARV), an African filovirus closely related to the Ebola virus, causes a deadly hemorrhagic fever in humans, with up to 90% mortality. Currently, treatment of disease is only supportive, and no vaccines are available to prevent spread of MARV infections. In order to address this need, we have developed and characterized a novel recombinant vaccine that utilizes a single complex adenovirus-vectored vaccine (cAdVax) to overexpress a MARV glycoprotein (GP) fusion protein derived from the Musoke and Ci67 strains of MARV. Vaccination with the cAdVaxM(fus) vaccine led to efficient production of MARV-specific antibodies in both mice and guineamore » pigs. Significantly, guinea pigs vaccinated with at least 5 x 10{sup 7} pfu of cAdVaxM(fus) vaccine were 100% protected against lethal challenges by the Musoke, Ci67 and Ravn strains of MARV, making it a vaccine with trivalent protective efficacy. Therefore, the cAdVaxM(fus) vaccine serves as a promising vaccine candidate to prevent and contain multi-strain infections by MARV.« less

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

PubMed Central

Ciryam, Prajwal; Lambert-Smith, Isabella A.; Bean, Daniel M.; Freer, Rosie; Cid, Fernando; Tartaglia, Gian Gaetano; Saunders, Darren N.; Wilson, Mark R.; Morimoto, Richard I.; Dobson, Christopher M.; Vendruscolo, Michele; Favrin, Giorgio; Yerbury, Justin J.

2017-01-01

Amyotrophic lateral sclerosis (ALS) is a heterogeneous degenerative motor neuron disease linked to numerous genetic mutations in apparently unrelated proteins. These proteins, including SOD1, TDP-43, and FUS, are highly aggregation-prone and form a variety of intracellular inclusion bodies that are characteristic of different neuropathological subtypes of the disease. Contained within these inclusions are a variety of proteins that do not share obvious characteristics other than coaggregation. However, recent evidence from other neurodegenerative disorders suggests that disease-affected biochemical pathways can be characterized by the presence of proteins that are supersaturated, with cellular concentrations significantly greater than their solubilities. Here, we show that the proteins that form inclusions of mutant SOD1, TDP-43, and FUS are not merely a subset of the native interaction partners of these three proteins, which are themselves supersaturated. To explain the presence of coaggregating proteins in inclusions in the brain and spinal cord, we observe that they have an average supersaturation even greater than the average supersaturation of the native interaction partners in motor neurons, but not when scores are generated from an average of other human tissues. These results suggest that inclusion bodies in various forms of ALS result from a set of proteins that are metastable in motor neurons, and thus prone to aggregation upon a disease-related progressive collapse of protein homeostasis in this specific setting. PMID:28396410

Cost comparison between uterine-sparing fibroid treatments one year following treatment

PubMed Central

2014-01-01

Background To compare one-year all-cause and uterine fibroid (UF)-related direct costs in patients treated with one of the following three uterine-sparing procedures: magnetic resonance-guided focused ultrasound (MRgFUS), uterine artery embolization (UAE) and myomectomy. Methods This retrospective observational cohort study used healthcare claims for several million individuals with healthcare coverage from employers in the MarketScan Database for the period 2003–2010. UF patients aged 25–54 on their first UF procedure (index) date with 366-day baseline experience, 366-day follow-up period, continuous health plan enrollment during baseline and follow-up, and absence of any baseline UF procedures were included in the final sample. Cost outcomes were measured by allowed charges (sum of insurer-paid and patient-paid amounts). UF-related cost was defined as difference in mean cost between study cohorts and propensity-score-matched control cohorts without UF. Multivariate adjustment of cost outcomes was conducted using generalized linear models. Results The study sample comprised 14,426 patients (MRgFUS = 14; UAE = 4,092; myomectomy = 10,320) with a higher percent of older patients in MRgFUS cohort (71% vs. 50% vs. 12% in age-group 45–54, P < 0.001). Adjusted all-cause mean cost was lowest for MRgFUS ($19,763; 95% CI: $10,425-$38,694) followed by myomectomy ($20,407; 95% CI: $19,483-$21,381) and UAE ($25,019; 95% CI: $23,738-$26,376) but without statistical significance. Adjusted UF-related costs were also not significantly different between the three procedures. Conclusions Adjusted all-cause and UF-related costs at one year were not significantly different between patients undergoing MRgFUS, myomectomy and UAE. PMID:25512868

Duplex Real-Time PCR Method for the Differentiation of Cronobacter sakazakii and Cronobacter malonaticus.

PubMed

Li, Xiaofang; Cui, Jinghua; Du, Xiaoli; Cui, Zhigang; Huang, Yibing; Kan, Biao

2017-01-01

Cronobacter sakazakii and Cronobacter malonaticus are the most common species of Cronobacter , so it is necessary to detect the two species as soon as possible in surveillance programs. We developed a real-time PCR method for identifying C. sakazakii and C. malonaticus from the genus Cronobacter . In this study, the two pairs of primers and probes were designed, targeting 16S rRNA and fusA, respectively. The specificity of the real-time PCR assay was validated with 112 strains of Cronobacter , including 56 C. sakazakii , 32 C. malonaticus , 16 Cronobacter dublinensis , 6 Cronobacter turicensis , and 2 Cronobacter muytjensii . The results showed that C. sakazakii and C. malonaticus were all correctly identified, consistent with the results of another method by analyzing the clustering of the fusA sequence. The detection limit for pure culture was 10 2 CFU/ml and 10 3 CFU/g for artificially contaminated rehydrated powdered infant formula. Therefore, the developed real-time PCR was a rapid, sensitive, and reliable method for the identification of C. sakazakii and C. malonaticus .

Thermodynamic Investigation of Carbamazepine-Saccharin Co-Crystal Polymorphs.

PubMed

Pagire, Sudhir K; Jadav, Niten; Vangala, Venu R; Whiteside, Benjamin; Paradkar, Anant

2017-08-01

Polymorphism in active pharmaceutical ingredients can be regarded as critical for the potential that crystal form can have on the quality, efficacy, and safety of the final drug product. The current contribution aims to characterize thermodynamic interrelationship of a dimorphic co-crystal, FI and FII, involving carbamazepine (CBZ) and saccharin (SAC) molecules. Supramolecular synthesis of CBZ-SAC FI and FII has been performed using thermokinetic methods and systematically characterized by differential scanning calorimetry, powder X-ray diffraction, solubility, and slurry measurements. According to the heat of fusion rule by Burger and Ramberger, FI (ΔH fus  = 121.1 J/g; melting point, 172.5°C) and FII (ΔH fus  = 110.3 J/g; melting point, 164.7°C) are monotropically related. The solubility and van't Hoff plot results suggest FI stable and FII metastable forms. This study reveals that CBZ-SAC co-crystal phases, FI or FII, could be stable to heat-induced stresses; however, FII converts to FI during solution-mediated transformation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound.

PubMed

Kobus, Thiele; Vykhodtseva, Natalia; Pilatou, Magdalini; Zhang, Yongzhi; McDannold, Nathan

2016-02-01

The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound.

PubMed

Kim, Hyungmin; Taghados, Seyed Javid; Fischer, Krisztina; Maeng, Lee-So; Park, Shinsuk; Yoo, Seung-Schik

2012-09-01

Nonpharmacologic and nonsurgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidance. The abductive eyeball movement ipsilateral to the side of sonication was observed at 350 kHz, using the 0.36-msec tone burst duration (TBD), 1.5-kHz pulse repetition frequency (PRF), and the overall sonication duration of 200 msec. Histologic and behavioral monitoring showed no signs of disruption in the blood brain barrier (BBB), as well as no damage to the nerves and adjacent brain tissue resulting from the sonication. As a novel functional neuro-modulatory modality, the pulsed application of FUS has potential for diagnostic and therapeutic applications in diseases of the peripheral nervous system. Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Improved survival in rats with glioma using MRI-guided focused ultrasound and microbubbles to disrupt the blood-brain barrier and deliver Doxil

NASA Astrophysics Data System (ADS)

Aryal, Muna; Zhi Zhang, Yong; Vykhodtseva, Natalia; Park, Juyoung; Power, Chanikarn; McDannold, Nathan

2012-02-01

Blood-brain-barrier (BBB) limits the transportation of most neuropeptides, proteins (enzymes, antibodies), chemotherapeutic agents, and genes that have therapeutic potential for the treatment of brain diseases. Different methods have been used to overcome this limitation, but they are invasive, non-targeted, or require the development of new drugs. We have developed a method that uses MRI-guided focused ultrasound (FUS) combined with circulating microbubbles to temporarily open BBB in and around brain tumors to deliver chemotherapy agents. Here, we tested whether this noninvasive technique could enhance the effectiveness of a chemotherapy agent (Doxil). Using 690 kHz FUS transducer and microbubble (Definity), we induced BBB disruption in intracranially-implanted 9L glioma tumors in rat's brain in three weekly sessions. Animals who received BBB disruption and Doxil had a median survival time of 34.5 days, which was significantly longer than that found in control animals which is 16, 18.5, 21 days who received no treatment, BBB disruption only and Doxil only respectively This work demonstrates that FUS technique has promise in overcoming barriers to drug delivery, which are particularly stark in the brain due to the BBB.

Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins.

PubMed

Ratti, Antonia; Buratti, Emanuele

2016-08-01

The multiple roles played by RNA binding proteins in neurodegeneration have become apparent following the discovery of TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) involvement in amyotrophic lateral sclerosis and frontotemporal lobar dementia. In these two diseases, the majority of patients display the presence of aggregated forms of one of these proteins in their brains. The study of their functional properties currently represents a very promising target for developing the effective therapeutic options that are still lacking. This aim, however, must be preceded by an accurate evaluation of TDP-43 and FUS/TLS biological functions, both in physiological and disease conditions. Recent findings have uncovered several aspects of RNA metabolism that can be affected by misregulation of these two proteins. Progress has also been made in starting to understand how the aggregation of these proteins occurs and spreads from cell to cell. The aim of this review will be to provide a general overview of TDP-43 and FUS/TLS proteins and to highlight their physiological functions. At present, the emerging picture is that TDP-43 and FUS/TLS control several aspects of an mRNA's life, but they can also participate in DNA repair processes and in non-coding RNA metabolism. Although their regulatory activities are similar, they regulate mainly distinct RNA targets and show different pathogenetic mechanisms in amyotrophic lateral sclerosis/frontotemporal lobar dementia diseases. The identification of key events in these processes represents today the best chance of finding targetable options for therapeutic approaches that might actually make a difference at the clinical level. The two major RNA Binding Proteins involved in Amyotrophic Lateral Sclerosisi and Frontotemporal Dementia are TDP-43 and FUST/TLS. Both proteins are involved in regulating all aspects of RNA and RNA life cycle within neurons, from transcription, processing, and transport/stability to the formation of cytoplasmic and nuclear stress granules. For this reason, the aberrant aggregation of these factors during disease can impair multiple RNA metabolic pathways and eventually lead to neuronal death/inactivation. The purpose of this review is to provide an up-to-date perspective on what we know about this issue at the molecular level. This article is part of the Frontotemporal Dementia special issue. © 2016 International Society for Neurochemistry.

Immediate-type hypersensitivity reaction to ingestion of mycoprotein (Quorn) in a patient allergic to molds caused by acidic ribosomal protein P2.

PubMed

Hoff, Michael; Trüeb, Ralph M; Ballmer-Weber, Barbara K; Vieths, Stefan; Wuethrich, Brunello

2003-05-01

Quorn is the brand name for a line of foods made with so-called "mycoprotein," which springs from the mold Fusarium venenatum. Since the introduction on the food market, there have been complaints from consumers reporting adverse gastrointestinal reactions after ingestion of mycoprotein. To date, it is not clear whether the reported symptoms are IgE-mediated. The aim of the study was to describe for the first time a case history of an asthmatic patient with severe hypersensitivity reactions to ingested mycoprotein and to identify and characterize the potential allergen that might be responsible for this. The sensitization pattern of the asthmatic subject was characterized, and food allergy to mycoprotein was assessed by double-blinded placebo-controlled food challenge. Afterward, specific IgE antibodies of the serum of this patient were used to screen a Fusarium culmorum cDNA expression library. The coding sequence of one enriched cDNA-clone was expressed in Escherichia coli to produce a recombinant protein that was further purified and immunologically characterized. The patient showed high sensitization to many known aeroallergens but apart from Quorn not to any other tested food samples. The deduced amino acid sequence of the enriched cDNA-clone (Fus c 1) showed large identity to the 60S acidic ribosomal protein P2 which is highly conserved among several species and also described as minor allergen in other mold species. The frequency of IgE reactivity of sera from F culmorum -sensitized subjects to rFus c 1 was approximately 35%. By enzyme allergosorbent test inhibition, we found 65% inhibition of mycoprotein IgE reactivity by rFus c 1. On the opposite we found reduced IgE reactivity of rFus c 1 of 68% by using mycoprotein as inhibitor. Sensitization to mold allergens by the respiratory tract and subsequent oral ingestion of cross-reactive proteins may lead to severe food-allergic reactions. Thus, the 60S acidic ribosomal protein P2 of F venenatum probably is the reason for the described severe hypersensitivity reactions of the patient to Quorn-mycoprotein because of its potential cross-reactivity to the F culmorum allergen Fus c 1.

Stress granules at the intersection of autophagy and ALS

PubMed Central

Monahan, Zachary; Shewmaker, Frank; Pandey, Udai Bhan

2016-01-01

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease caused by loss of upper and lower motor neurons. The majority of ALS cases are classified as sporadic (80-90%), with the remaining considered familial based on patient history. The last decade has seen a surge in the identification of ALS-causing genes – including TARDBP (TDP-43), FUS, MATR3 (Matrin-3), C9ORF72 and several others – providing important insights into the molecular pathways involved in pathogenesis. Most of the protein products of ALS-linked genes fall into two functional categories: RNA-binding/homeostasis and protein-quality control (i.e. autophagy and proteasome). The RNA-binding proteins tend to be aggregation-prone with low-complexity domains similar to the prion-forming domains of yeast. Many also incorporate into stress granules (SGs), which are cytoplasmic ribonucleoprotein complexes that form in response to cellular stress. Mutant forms of TDP-43 and FUS perturb SG dynamics, lengthening their cytoplasmic persistence. Recent evidence suggests that SGs are regulated by the autophagy pathway, suggesting a unifying connection between many of the ALS-linked genes. Persistent SGs may give rise to intractable aggregates that disrupt neuronal homeostasis, thus failure to clear SGs by autophagic processes may promote ALS pathogenesis. PMID:27181519

Spatial and Time Dynamics of Non-Linear Vortices in Plasma Lens for High-Current Ion Beam Focusing

NASA Astrophysics Data System (ADS)

Goncharov, Alexei A.; Maslov, Vasyl I.; Onishchenko, Ivan N.; Tretyakov, Vitalij N.

2002-11-01

It is known from numerical simulation (see, for example, [1]) and from experiments (see, for example, [2]), that an electron density bunches as discrete vortices are long - living structures in vacuum. However, in laboratory experiments [2] it has been shown that the vortices are changed faster, when they are submersed in electrons, distributed around them. The charged plasma lens intended for a focussing of high-current ion beams, has the same crossed configuration of a radial electrical and longitudinal magnetic field [3], as only electron plasma. In this lens the vortical turbulence is excited [3]. The vortex - bunch and vortex - hole are rotated in the inverse directions in system of their rest. The instability development in initially homogeneous plasma causes that the vortices are excited by pairs. Namely, if the vortex - bunch of electrons is generated, near the vortex - hole of electrons is also generated. It is shown, that in nonuniform plasma the vortices behave is various in time. Namely, the vortex - bunch goes to area of larger electron density, and the vortex - hole goes to area of smaller electron density. The speed of the vortex - hole is less than speed of the vortex - bunch. It is shown, that the electron vortices, generated in the plasma lens, can result in to formation of spiral distribution of electron density. The physical mechanism of coalescence of electron vortices - bunches is proposed. 1.Driscoll C.F. et al. Plasma Phys. Contr. Fus. Res. 3 (1989) 507. 2.Kiwamoto Y. et al. Non-neutral plasma physics. Princeton. 1999. P. 99-105. 3.Goncharov A. et al. Plasma Phys. Rep. 20 (1994) 499.

Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring.

PubMed

Konofagou, Elisa E; Maleke, Caroline; Vappou, Jonathan

2012-01-01

Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring.

Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring

PubMed Central

Maleke, Caroline; Vappou, Jonathan

2014-01-01

Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring. PMID:25364321

Comparison of 4th-Generation HIV Antigen/Antibody Combination Assay With 3rd-Generation HIV Antibody Assays for the Occurrence of False-Positive and False-Negative Results.

PubMed

Muthukumar, Alagarraju; Alatoom, Adnan; Burns, Susan; Ashmore, Jerry; Kim, Anne; Emerson, Brian; Bannister, Edward; Ansari, M Qasim

2015-01-01

To assess the false-positive and false-negative rates of a 4th-generation human immunodeficiency virus (HIV) assay, the Abbott ARCHITECT, vs 2 HIV 3rd-generation assays, the Siemens Centaur and the Ortho-Clinical Diagnostics Vitros. We examined 123 patient specimens. In the first phase of the study, we compared 99 specimens that had a positive screening result via the 3rd-generation Vitros assay (10 positive, 82 negative, and 7 indeterminate via confirmatory immunofluorescent assay [IFA]/Western blot [WB] testing). In the second phase, we assessed 24 HIV-1 RNA-positive (positive result via the nuclear acid amplification test [NAAT] and negative/indeterminate results via the WB test) specimens harboring acute HIV infection. The 4th-generation ARCHITECT assay yielded fewer false-positive results (n = 2) than the 3rd-generation Centaur (n = 9; P = .02) and Vitros (n = 82; P <.001) assays. One confirmed positive case had a false-negative result via the Centaur assay. When specimens from the 24 patients with acute HIV-1 infection were tested, the ARCHITECT assay yielded fewer false-negative results (n = 5) than the Centaur (n = 10) (P = .13) and the other 3rd-generation tests (n = 16) (P = .002). This study indicates that the 4th-generation ARCHITECT HIV assay yields fewer false-positive and false-negative results than the 3rd-generation HIV assays we tested. Copyright© by the American Society for Clinical Pathology (ASCP).

Magnetic Resonance Imaging-Guided Focused Ultrasound Surgery for the Treatment of Symptomatic Uterine Fibroids.

PubMed

Geraci, Laura; Napoli, Alessandro; Catalano, Carlo; Midiri, Massimo; Gagliardo, Cesare

2017-01-01

Uterine fibroids, the most common benign tumor in women of childbearing age, may cause symptoms including pelvic pain, menorrhagia, dysmenorrhea, pressure, urinary symptoms, and infertility. Various approaches are available to treat symptomatic uterine fibroids. Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) represents a recently introduced noninvasive safe and effective technique that can be performed without general anesthesia, in an outpatient setting. We review the principles of MRgFUS, describing patient selection criteria for the treatments performed at our center and we present a series of five selected patients with symptomatic uterine fibroids treated with this not yet widely known technique, showing its efficacy in symptom improvement and fibroid volume reduction.

Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles

NASA Astrophysics Data System (ADS)

Baseri, Babak; Choi, James J.; Deffieux, Thomas; Samiotaki, Gesthimani; Tung, Yao-Sheng; Olumolade, Oluyemi; Small, Scott A.; Morrison, Barclay, III; Konofagou, Elisa E.

2012-04-01

The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.

Focusing through the rib cage for MR-guided transcostal FUS

NASA Astrophysics Data System (ADS)

Gao, J.; Volovick, A.; Pekelny, Y.; Huang, ZH.; Cochran, S.; Melzer, A.

2012-10-01

The rib cage presents a significant obstacle in transcostal focused ultrasound surgery (FUS). This paper proposes a geometric solution, based on central projection from the focus to identify transducer elements affected by ribs shadowing which should be switched off. Its effectiveness in phantom experiments and simulations is reported, and ways are discussed to further reduce energy deposition on the ribs while enhancing heating at the focus. A tissue-mimicking phantom with phantom of ribs was sonicated using a 208-element 1.15 MHz bowl transducer and a 1000-element 550 kHz planar matrix transducer (both ExAblate, InSightec, Israel). The temperature evolution was monitored with real-time MRI thermometry (GE, USA). Numerical simulations were performed with FEA software (PZFlex, Weidlinger Associates, USA) to investigate different skin-focus and transducer-rib distances. The temperature rise near the ribs was reduced to 16°C and 4°C for the 1.15 MHz and 550 kHz transducers respectively. With the 1.15 MHz transducer, the focal temperature reached the ablation threshold. These measurements are in good agreement with simulations. The proposed method shows promising results for transcostal FUS. Residual temperature rise on the ribs can be further reduced by active cooling, allowing the higher energies essential for efficient ablation.

Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound

PubMed Central

Miller, G. Wilson; Song, Ji; Louttit, Cameron; Klibanov, Alexander L; Shih, Ting-Yu; Swaminathan, Ganesh; Tamargo, Rafael J.; Woodworth, Graeme F.; Hanes, Justin; Price, Richard J.

2014-01-01

The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer’s, Parkinson’s and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a noninvasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPN in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60 nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain. PMID:24979210

WE-H-209-01: Advances in Ultrasound Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hynynen, K.

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi-frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives:more » Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniques This research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments.« less

WE-H-209-00: Carson/Zagzebski Distinguished Lectureship: Image Guided Ultrasound Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi-frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives:more » Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniques This research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments.« less

Real-Time Monitoring Of Regional Tissue Elasticity During FUS Focused Ultrasound Therapy Using Harmonic Motion Imaging

NASA Astrophysics Data System (ADS)

Maleke, Caroline; Pernot, Mathieu; Konofagou, Elisa

2006-05-01

The feasibility of the Harmonic Motion Imaging (HMI) technique for simultaneous monitoring and generation of focused ultrasound therapy using two separate focused ultrasound transducer elements has previously been shown. In this study, a new HMI technique is described that images tissue displacement induced by a harmonic radiation force induced using a single focused ultrasound element. First, wave propagation simulation models were used to compare the use of a single Amplitude-Modulated (AM) focused beam versus two overlapping focused beams as previously implemented for HMI. Simulation results indicated that, unlike in the two-beam configuration, the AM beam produced a consistent, stable focus for the applied harmonic radiation force. The AM beam thus offered the unique advantage of sustaining the application of the spatially-invariant radiation force. Experiments were then performed on gelatin gel phantoms and tissue in vitro bovine liver. The radiation force was generated by a 4.68 MHz focused transducer using a low-frequency Amplitude-Modulated (AM) RF-signal. RF data were acquired at 7.5 MHz with a PRF of 6.5 kHz and displacements were estimated using a 1D cross-correlation algorithm on successive RF signals. Furthermore, taking advantage of the real-time capability of our method, the change in the elastic properties was monitored during focused ultrasound (FUS) ablation of tissue in vitro bovine liver. Based on the harmonic displacements, their temperature-dependence, and the calculated acoustic radiation force, the change in the relative, regional stiffness could be monitored during heating and ablation, both using the displacement amplitude and the resulting phase shift change of the displacement relative to the radiation force temporal profile. In conclusion, the feasibility of using an AM radiation force for HMI for simultaneous monitoring and treatment during ultrasound therapy was demonstrated in phantoms and tissues in vitro. Further study of this method will include, ex vivo and in vivo, stiffness and temperature.

Quantitative Magnetic Resonance Thermometry and Its Use with MR-Guided Focused Ultrasound

NASA Astrophysics Data System (ADS)

Pauly, Kim

2014-03-01

Focused ultrasound (FUS) uses a large area array, typically outside the body, that is geometrically or electronically focused to a point deep in the body. Such focusing provides amplification of the ultrasound intensity, thereby allowing heating of tissue to the point of coagulation at the focus, without damage to the intervening tissue. Guidance of FUS treatments deep in the body can be done quantitatively with magnetic resonance (MR) thermometry, termed MRgFUS. The physics behind MR thermometry lie in the changes in hydrogen bonding with temperature. As tissue temperature rises, hydrogen bonds break, allowing the return of the electron cloud to shield water protons, reducing the magnetic field seen by the protons, and the resonant frequency. The change in resonant frequency is -0.01 ppm per degree C and is the same for all aqueous tissues. The result of the shift in proton resonant frequency is seen in the phase of gradient echo images. Subtraction of the phase of images acquired before and during heating allows the removal of background phase from other sources, yielding quantitative temperature maps. Temperature standard deviations less than 1 degree C are readily achievable and thermal dose maps are easily calculated. Thermal dose is found from a conversion of the whole temperature-time curve to an equivalent number of minutes at 43 degrees C. A thermal dose of 240 minutes is often taken as the threshold for tissue damage. MR thermometry is complicated by the motion of the target tissue and/or motion of other organs such as occurs during respiration. More sophisticated algorithms than the simple baseline subtraction take advantage of the facts that motion can be repetitive (in the case of respiratory motion) and/or the fact that the focal region in MRgFUS is small, allowing for extraction of the heat from the phase profile without subtraction of a background phase.

Megasessions for Robotic Hair Restoration.

PubMed

Pereira, Joa O Carlos; Pereira Filho, Joa O Carlos; Cabrera Pereira, Joa O Pedro

2016-11-01

A robotic system can select and remove individual hair follicles from the donor area with great precision and without fatigue. This report describes the use of the robotic system in a megasession for hair restoration. Patients were instructed to cut their hair to 1.0 to 1.2 mm before surgery. The robot selected and removed 600 to 800 grafts per hour so the follicular units (FU)s could be transplanted manually to recipient sites. The robot arm consists of a sharp inner punch and a blunt outer punch which together separate FUs from the sur- rounding tissue. Stereoscopic cameras controlled by image processing software allow the system to identify the angle and direction of hair growth. The physician and one assistant control the harvesting with a hand-held remote control and computer monitor while the patient is positioned in an adjustable chair. When the robot has harvested all the FUs they are removed by technicians with small forceps. Hairline design, creation of recipient sites, and graft placement are performed manually by the physician. Clinical photographs before and after surgery show that patients experience excellent outcomes with the robotic megasession. Phy- sician fatigue during graft extraction is reduced because the robot performs the repetitive movements without fatigue. Variability of graft extraction is minimized because the robot's optical system can be programmed to choose the best FUs. The transection rate is reduced because the robot's graft extraction system uses two needles, a sharp one to piece the skin and a blunt needle to dissect the root without trauma. A robotic megasession for hair restoration is minimally invasive, does not result in linear scars in the donor area, and is associated with minimal fatigue and discomfort for both patient and physician. Healing is rapid and patients experience a high level of satisfaction with the results. J Drugs Dermatol. 2016;15(11):1407-1412..

Barcode Sequencing Screen Identifies SUB1 as a Regulator of Yeast Pheromone Inducible Genes

PubMed Central

Sliva, Anna; Kuang, Zheng; Meluh, Pamela B.; Boeke, Jef D.

2016-01-01

The yeast pheromone response pathway serves as a valuable model of eukaryotic mitogen-activated protein kinase (MAPK) pathways, and transcription of their downstream targets. Here, we describe application of a screening method combining two technologies: fluorescence-activated cell sorting (FACS), and barcode analysis by sequencing (Bar-Seq). Using this screening method, and pFUS1-GFP as a reporter for MAPK pathway activation, we readily identified mutants in known mating pathway components. In this study, we also include a comprehensive analysis of the FUS1 induction properties of known mating pathway mutants by flow cytometry, featuring single cell analysis of each mutant population. We also characterized a new source of false positives resulting from the design of this screen. Additionally, we identified a deletion mutant, sub1Δ, with increased basal expression of pFUS1-GFP. Here, in the first ChIP-Seq of Sub1, our data shows that Sub1 binds to the promoters of about half the genes in the genome (tripling the 991 loci previously reported), including the promoters of several pheromone-inducible genes, some of which show an increase upon pheromone induction. Here, we also present the first RNA-Seq of a sub1Δ mutant; the majority of genes have no change in RNA, but, of the small subset that do, most show decreased expression, consistent with biochemical studies implicating Sub1 as a positive transcriptional regulator. The RNA-Seq data also show that certain pheromone-inducible genes are induced less in the sub1Δ mutant relative to the wild type, supporting a role for Sub1 in regulation of mating pathway genes. The sub1Δ mutant has increased basal levels of a small subset of other genes besides FUS1, including IMD2 and FIG1, a gene encoding an integral membrane protein necessary for efficient mating. PMID:26837954

Expression of dog1 in low-grade fibromyxoid sarcoma: A study of 19 cases and review of the literature.

PubMed

Vallejo-Benítez, Ana; Rodríguez-Zarco, Enrique; Carrasco, Sara Pabón; Pereira-Gallardo, Sofia; Brugal Molina, Javier; García-Escudero, Antonio; Robles Frías, Antonio; Marcilla, David; González-Cámpora, Ricardo

2017-10-01

DOG1 is a highly-sensitive marker often included in the immunohistochemical panel for the diagnosis of gastrointestinal stromal tumors (GISTs). Recent research has shown that DOG1 may also be expressed by low-grade fibromyxoid sarcomas (LGFMSs); this may give rise to diagnostic error when the sarcoma is located in the abdominal cavity. This paper reports on immnohistochemical expression of DOG1 in 19 LGFMSs using two different monoclonal antibodies: K9 (Leica, Novocastra Laboratories, Newcastle upon Tyne, UK) and SP31 (Thermo Scientific, Freemont, USA). All LGFMSs displayed the standard histological pattern of alternating myxoid and fibrous areas, low cellularity and bland spindle-cell morphology. Positive staining for MUC4 was observed in 18/19 cases (94.7%), while there was rearrangement of the FUS gene in 14/19 (73.7%) cases and of the EWR1 gene in 2/19 (10.5%). The sarcoma staining negative for MUC4 displayed FUS gene rearrangement. Whole-section immunohistochemistry revealed positive staining for DOG1 in 8/19 cases (42.1%), though only with clone K9. Cytoplasmic as well as membrane staining was observed in all cases; staining was focal (10-30%) and of varying intensity (1+ to 2+). In conclusion, DOG1 clone K9 exhibited low sensitivity (42.1%) for the diagnosis of LGFMS, although higher than clone SP31. Since the two clones display similar sensitivity and specificity for GIST diagnosis, SP31 would appear to be more specific for this purpose, since no reaction was observed here with LGFMS, a GIST-mimicking lesion. Copyright © 2017 Elsevier Inc. All rights reserved.

Investigation of standing wave formation in a human skull for a clinical prototype of a large-aperture, transcranial MR-guided Focused Ultrasound (MRgFUS) phased array: An experimental and simulation study

PubMed Central

Song, Junho; Pulkkinen, Aki; Huang, Yuexi; Hynynen, Kullervo

2014-01-01

Standing wave formation in an ex vivo human skull was investigated using a clinical prototype of a 30 cm diameter with 15 cm radius of curvature, low frequency (230 kHz), hemispherical transcranial Magnetic Resonance guided Focused Ultrasound (MRgFUS) phased-array. Experimental and simulation studies were conducted with changing aperture size and f-number configurations of the phased array, and qualitatively and quantitatively examined the acoustic pressure variation at the focus due to standing waves. The results demonstrated that the nodes and anti-nodes of standing wave produced by the small aperture array were clearly seen at approximately every 3 mm. The effect of the standing wave became more pronounced as the focus was moved closer to skull base. However, a sharp focus was seen for the full array, and there was no such standing wave pattern in the acoustic plane or near the skull base. This study showed that the fluctuation pressure amplitude would be greatly reduced by using a large-scale, hemispherical phased array with a low f-number. PMID:22049360

Design and validation of an MR-conditional robot for transcranial focused ultrasound surgery in infants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, Karl D., E-mail: karl.price@sickkids.ca

Purpose: Current treatment of intraventricular hemorrhage (IVH) involves cerebral shunt placement or an invasive brain surgery. Magnetic resonance-guided focused ultrasound (MRgFUS) applied to the brains of pediatric patients presents an opportunity to treat IVH in a noninvasive manner, termed “incision-less surgery.” Current clinical and research focused ultrasound systems lack the capability to perform neonatal transcranial surgeries due to either range of motion or dexterity requirements. A novel robotic system is proposed to position a focused ultrasound transducer accurately above the head of a neonatal patient inside an MRI machine to deliver the therapy. Methods: A clinical Philips Sonalleve MRgFUS systemmore » was expanded to perform transcranial treatment. A five degree-of-freedom MR-conditional robot was designed and manufactured using MR compatible materials. The robot electronics and control were integrated into existing Philips electronics and software interfaces. The user commands the position of the robot with a graphical user interface, and is presented with real-time MR imaging of the patient throughout the surgery. The robot is validated through a series of experiments that characterize accuracy, signal-to-noise ratio degeneration of an MR image as a result of the robot, MR imaging artifacts generated by the robot, and the robot’s ability to operate in a representative surgical environment inside an MR machine. Results: Experimental results show the robot responds reliably within an MR environment, has achieved 0.59 ± 0.25 mm accuracy, does not produce severe MR-imaging artifacts, has a workspace providing sufficient coverage of a neonatal brain, and can manipulate a 5 kg payload. A full system demonstration shows these characteristics apply in an application environment. Conclusions: This paper presents a comprehensive look at the process of designing and validating a new robot from concept to implementation for use in an MR environment. An MR conditional robot has been designed and manufactured to design specifications. The system has demonstrated its feasibility as a platform for MRgFUS interventions for neonatal patients. The success of the system in experimental trials suggests that it is ready to be used for validation of the transcranial intervention in animal studies.« less

Characterization and chromosomal mapping of the human TFG gene involved in thyroid carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mencinger, M.; Panagopoulos, I.; Andreasson, P.

1997-05-01

Homology searches in the Expressed Sequence Tag Database were performed using SPYGQ-rich regions as query sequences to find genes encoding protein regions similar to the N-terminal parts of the sarcoma-associated EWS and FUS proteins. Clone 22911 (T74973), encoding a SPYGQ-rich region in its 5{prime} end, and several other clones that overlapped 22911 were selected. The combined data made it possible to assemble a full-length cDNA sequence. This cDNA sequence is 1677 bp, containing an initiation codon ATG, an open reading frame of 400 amino acids, a poly(A) signal, and a poly(A) tail. We found 100% identity between the 5{prime} partmore » of the consensus sequence and the 598-bp-long sequence named TFG. The TFG sequence is fused to the 3{prime} end of NTRK1, generating the TRK-T3 fusion transcript found in papillary thyroid carcinoma. The cDNA therefore represents the full-length transcript of the TFG gene. TFG was localized to 3q11-q12 by fluorescence in situ hybridization. The 3{prime} and the 5{prime} ends of the TFG cDNA probe hybridized to a 2.2-kb band on Northern blot filters in all tissues examined. 28 refs., 5 figs., 1 tab.« less

Disruptions generated runaways in the FTU high field tokamak

NASA Astrophysics Data System (ADS)

Poli, F. M.; Esposito, B.; Maddaluno, G.; Martin-Solis, J. R.

2001-10-01

Disruptions in FTU are usually accompanied by the generation of a strong pulse of photoneutrons (YN 10^12n/s), resulting from photonuclear reactions induced by the bremsstrahlung radiation emitted when runaway electrons (REs) strike the plasma facing components. Measurements of YN during major disruptions on TS [1] showed variations of three orders of magnitude when the toroidal field Bt increases from 1.8T to 3.9T. Similar results were found on JT-60 [2], where no REs are produced for low Bt (<2.2T) and a large YN was measured for higher fields (up to 4T). The range of Bt available in FTU (4T-8T) allows to extend such analysis so that useful predictions can be obtained for operation in next-step high field tokamaks (IGNITOR, ITER). The dependence of YN on Bt is investigated in several FTU disruptions. YN increases with Bt for B_t=4T-6T, while no variation is found for B_t=6T-8T: the role played by ne and Ip on such trend is discussed. [1]P.Joyer,G.Martin,Contr.Fusion and Plasma Heating,Proc.17^thEPS Conf.Amsterdam(1990) [2]R.Yoshino et al.,Nucl.Fus.39 151 (1999)

Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets.

PubMed

Vyas, Urvi; Ghanouni, Pejman; Halpern, Casey H; Elias, Jeff; Pauly, Kim Butts

2016-09-01

In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen human subjects. Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. The simulated skull efficiency using individual-specific heterogeneous models predicts well (R(2) = 0.84) the experimental energy efficiency. This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible.

Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets

PubMed Central

Vyas, Urvi; Ghanouni, Pejman; Halpern, Casey H.; Elias, Jeff; Pauly, Kim Butts

2016-01-01

Purpose: In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen human subjects. Methods: Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. Results: The simulated skull efficiency using individual-specific heterogeneous models predicts well (R2 = 0.84) the experimental energy efficiency. Conclusions: This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible. PMID:27587047

Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vyas, Urvi, E-mail: urvi.vyas@gmail.com; Ghanouni,

Purpose: In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen humanmore » subjects. Methods: Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. Results: The simulated skull efficiency using individual-specific heterogeneous models predicts well (R{sup 2} = 0.84) the experimental energy efficiency. Conclusions: This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible.« less

Stress granules at the intersection of autophagy and ALS.

PubMed

Monahan, Zachary; Shewmaker, Frank; Pandey, Udai Bhan

2016-10-15

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease caused by loss of upper and lower motor neurons. The majority of ALS cases are classified as sporadic (80-90%), with the remaining considered familial based on patient history. The last decade has seen a surge in the identification of ALS-causing genes - including TARDBP (TDP-43), FUS, MATR3 (Matrin-3), C9ORF72 and several others - providing important insights into the molecular pathways involved in pathogenesis. Most of the protein products of ALS-linked genes fall into two functional categories: RNA-binding/homeostasis and protein-quality control (i.e. autophagy and proteasome). The RNA-binding proteins tend to be aggregation-prone with low-complexity domains similar to the prion-forming domains of yeast. Many also incorporate into stress granules (SGs), which are cytoplasmic ribonucleoprotein complexes that form in response to cellular stress. Mutant forms of TDP-43 and FUS perturb SG dynamics, lengthening their cytoplasmic persistence. Recent evidence suggests that SGs are regulated by the autophagy pathway, suggesting a unifying connection between many of the ALS-linked genes. Persistent SGs may give rise to intractable aggregates that disrupt neuronal homeostasis, thus failure to clear SGs by autophagic processes may promote ALS pathogenesis. This article is part of a Special Issue entitled SI:Autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

Short term efficacy of capacitive-resistive diathermy therapy in patients with low back pain: a prospective randomized controlled trial.

PubMed

Notarnicola, A; Maccagnano, G; Gallone, M F; Covelli, I; Tafuri, S; Moretti, B

2017-01-01

To compare the effectiveness of Doctor Tecar TherapyTM with that of laser therapy in the management of low back pain (LBP), a total of 60 patients with LBP were enrolled. The participants were randomly divided into two groups: a Tecar group (experimental group, 30 subjects), and a laser group (control group, 30 subjects). All the subjects received 10 sessions of therapy: one each day from Monday to Friday and the same again the following week. All the subjects were evaluated for pain (VAS) and disability (Roland and Morris score and Oswestry score) at baseline (T0), and 2 weeks (T1), 1 month (T2) and 2 months (T3) after the end of treatment. The pain and disability presented a trend to improvement over time in both groups. This improvement was statistically significant at all follow-ups (FUs) in the Tecar group but only at T1 for the Laser group (p less than 0.01). Comparing the two methods, there emerged a significant difference in favour of the Tecar group at T2 and T3 (p less than 0.01). The results show that Tecar therapy determined significant improvement already by the end of the treatment. Moreover, at the first and second month FUs, the Tecar therapy showed statistically better results than laser therapy.

Clinicopathological correlations in behavioural variant frontotemporal dementia.

PubMed

Perry, David C; Brown, Jesse A; Possin, Katherine L; Datta, Samir; Trujillo, Andrew; Radke, Anneliese; Karydas, Anna; Kornak, John; Sias, Ana C; Rabinovici, Gil D; Gorno-Tempini, Maria Luisa; Boxer, Adam L; De May, Mary; Rankin, Katherine P; Sturm, Virginia E; Lee, Suzee E; Matthews, Brandy R; Kao, Aimee W; Vossel, Keith A; Tartaglia, Maria Carmela; Miller, Zachary A; Seo, Sang Won; Sidhu, Manu; Gaus, Stephanie E; Nana, Alissa L; Vargas, Jose Norberto S; Hwang, Ji-Hye L; Ossenkoppele, Rik; Brown, Alainna B; Huang, Eric J; Coppola, Giovanni; Rosen, Howard J; Geschwind, Daniel; Trojanowski, John Q; Grinberg, Lea T; Kramer, Joel H; Miller, Bruce L; Seeley, William W

2017-12-01

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models.

PubMed

Wong, Andrew W; Fite, Brett Z; Liu, Yu; Kheirolomoom, Azadeh; Seo, Jai W; Watson, Katherine D; Mahakian, Lisa M; Tam, Sarah M; Zhang, Hua; Foiret, Josquin; Borowsky, Alexander D; Ferrara, Katherine W

2016-01-01

Magnetic resonance-guided focused ultrasound (MRgFUS) facilitates noninvasive image-guided conformal thermal therapy of cancer. Yet in many scenarios, the sensitive tissues surrounding the tumor constrain the margins of ablation; therefore, augmentation of MRgFUS with chemotherapy may be required to destroy remaining tumor. Here, we used 64Cu-PET-CT, MRI, autoradiography, and fluorescence imaging to track the kinetics of long-circulating liposomes in immunocompetent mammary carcinoma-bearing FVB/n and BALB/c mice. We observed a 5-fold and 50-fold enhancement of liposome and drug concentration, respectively, within MRgFUS thermal ablation-treated tumors along with dense accumulation within the surrounding tissue rim. Ultrasound-enhanced drug accumulation was rapid and durable and greatly increased total tumor drug exposure over time. In addition, we found that the small molecule gadoteridol accumulates around and within ablated tissue. We further demonstrated that dilated vasculature, loss of vascular integrity resulting in extravasation of blood cells, stromal inflammation, and loss of cell-cell adhesion and tissue architecture all contribute to the enhanced accumulation of the liposomes and small molecule probe. The locally enhanced liposome accumulation was preserved even after a multiweek protocol of doxorubicin-loaded liposomes and partial ablation. Finally, by supplementing ablation with concurrent liposomal drug therapy, a complete and durable response was obtained using protocols for which a sub-mm rim of tumor remained after ablation.

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models

PubMed Central

Wong, Andrew W.; Fite, Brett Z.; Liu, Yu; Kheirolomoom, Azadeh; Seo, Jai W.; Watson, Katherine D.; Mahakian, Lisa M.; Tam, Sarah M.; Zhang, Hua; Foiret, Josquin; Borowsky, Alexander D.; Ferrara, Katherine W.

2015-01-01

Magnetic resonance–guided focused ultrasound (MRgFUS) facilitates noninvasive image-guided conformal thermal therapy of cancer. Yet in many scenarios, the sensitive tissues surrounding the tumor constrain the margins of ablation; therefore, augmentation of MRgFUS with chemotherapy may be required to destroy remaining tumor. Here, we used 64Cu-PET-CT, MRI, autoradiography, and fluorescence imaging to track the kinetics of long-circulating liposomes in immunocompetent mammary carcinoma–bearing FVB/n and BALB/c mice. We observed a 5-fold and 50-fold enhancement of liposome and drug concentration, respectively, within MRgFUS thermal ablation–treated tumors along with dense accumulation within the surrounding tissue rim. Ultrasound-enhanced drug accumulation was rapid and durable and greatly increased total tumor drug exposure over time. In addition, we found that the small molecule gadoteridol accumulates around and within ablated tissue. We further demonstrated that dilated vasculature, loss of vascular integrity resulting in extravasation of blood cells, stromal inflammation, and loss of cell-cell adhesion and tissue architecture all contribute to the enhanced accumulation of the liposomes and small molecule probe. The locally enhanced liposome accumulation was preserved even after a multiweek protocol of doxorubicin-loaded liposomes and partial ablation. Finally, by supplementing ablation with concurrent liposomal drug therapy, a complete and durable response was obtained using protocols for which a sub-mm rim of tumor remained after ablation. PMID:26595815

Efficacy of sub-threshold focused ultrasound irradiation against pancreatic cancer xenografts evaluated using magnetic resonance imaging

PubMed Central

Chen, Yini; Gao, Yihui; Wu, Lei

2017-01-01

We investigated the efficacy and optimal period for using magnetic resonance imaging (MRI) to detect effects of sub-threshold focused ultrasound (FUS) irradiation. Nude mice bearing pancreatic cancer xenografts were subjected to MRI and pathology examnation before, and 24 h, 48 h, 2 weeks after irradiation, which were used to evaluate therapeutic effects of FUS. Tumor volumes were lower post-treatment than control group (P < 0.05). The T1WI turbo spin echo (T1WI-TSE) sequence was similar signal before and after treatment. On T1 enhanced scanning sequence (T1WI-SPIR) imaging, ablation lesions appeared as patchy areas of low signal after 24 h and 48 h. After 2 weeks, the ablation lesions contained low signal areas with clear borders. Hematoxylin and eosin (HE) staining revealed small vessels at ablation lesions with no obvious boundary between cell injury areas and normal tumor cells areas in early-stage, while revealed obvious boundaries 2 weeks post-treatment. Terminal deoxynucleotidyl transferase-modified, dUTP nick-end labeling (TUNEL) staining showed cell apoptosis in early-stage, and revealed reduced apoptotic cells and increased necrotic cell areas 2 weeks later. These findings indicate sub-threshold FUS induces pancreatic cancer cell apoptosis and inhibits tumor growth. Contrast-enhanced MRI delineated the ablation lesions better 2 weeks post-treatment than early stage. PMID:29113316

Investigation and Treatment of Fusidic Acid Resistance Among Methicillin-Resistant Staphylococcal Isolates from Egypt.

PubMed

Abouelfetouh, Alaa; Kassem, Mervat; Naguib, Marwa; El-Nakeeb, Moustafa

2017-01-01

Methicillin resistance among staphylococci isolated from patients in northern Egypt has escalated alarmingly in the past decade. Data about the prevalence of fusidic acid (FA) resistance in Egyptian clinical isolates are limited. This work investigates the prevalence and mechanism of FA resistance among 81 methicillin-resistant staphylococcal isolates from major hospitals of Alexandria, Egypt. Some combinations for treating infections due to resistant isolates were studied. Twenty-six isolates (32.1%) were FA resistant (minimum inhibitory concentrations [MICs] = 2-1,024 μg/ml), and fusB and fusC genes coding for FA resistance were detected in 30.77% and 34.62% of the FA-resistant strains, respectively. One highly resistant isolate, S502 (MIC = 1,024 μg/ml), possessed both genes. Plasmid curing resulted in fusB loss and MIC decrease by 16-64 folds. Conjugation caused acquisition of FA resistance among susceptible isolates. Serial passages in subinhibitory FA concentrations produced mutants with increased MIC by 4-32 folds. The combination of FA with rifampin, gentamicin, or ampicillin/sulbactam, in a subinhibitory concentration, was synergistic against the isolates, including serial passage mutants, decreasing number of survivors by an average of 2-4 logs. A relatively moderate rate of FA resistance was detected in Alexandria hospitals. Combination therapy with gentamicin, rifampin, or ampicillin/sulbactam is crucial to preserve the effectiveness of FA.

Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

NASA Astrophysics Data System (ADS)

Cho, Hongseok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-Ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

2016-08-01

Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

Glutamate release and uptake processes are altered in a new mouse model of amyotrophic lateral sclerosis.

PubMed

Grigoriev, V V; Efimova, A D; Ustyugov, A A; Shevchenko, V P; Bachurin, S O; Myasoedov, N F

2016-05-01

In this paper, we showed that in the cortex of mice expressing an abberant form of FUS protein that model amyotrophic lateral sclerosis (ALS), the processes of KCl-induced and basal [(3)H]glutamate release and uptake are altered at the presymptomatic stage as compared to the non-transgenic littermates. The change in these three parameters in transgenic animals causes excitotoxicity, which, in turn, may lead to massive loss of motor neurons and the onset of ALS symptoms.

Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

NASA Astrophysics Data System (ADS)

Etame, Arnold B.

The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non-transport permissive and intact BBB, we also assessed the role of magnetic resonance imaging (MRI) guided focused ultrasound (MRgFUS) disruption of the BBB in enhancing permeation of AuNPs across the intact BBB and tumor BBB in vivo. MRgFUS is a novel technique that can transiently increase BBB permeability thereby allowing delivery of therapeutics into the CNS. We demonstrated enhanced delivery of AuNPs with therapeutic potential into the CNS via MRgFUS. Our study was the first to establish a definitive role for MRgFUS in delivering AuNPs into the CNS. In summary, this thesis describes results from a series of research projects that have contributed to our understanding of the influence of design features on AuNP permeation through the BBB and also the potential role of MRgFUS in AuNP permeation across the BBB.

Evaluation of FUS-2000 urine analyzer: analytical properties and particle recognition.

PubMed

Beňovská, Miroslava; Wiewiorka, Ondřej; Pinkavová, Jana

This study evaluates the performance of microscopic part of a hybrid analyzer FUS-2000 (Dirui Industrial Co., Changchun, China), its analytical properties and particle recognition. The evaluation of trueness, repeatability, detection limit, carry-over, linearity range and analytical stability was performed according to Dirui protocol guidelines designed by Dirui Company to guarantee the quality of the instrument. Trueness for low, medium and high-value concentrations was calculated with bias of 15.5, 4.7 and -6.6%, respectively. Detection limit of 5 Ery/μl was confirmed. Coefficient of variation of 11.0, 5.2 and 3.8% was measured for within-run repeatability of low, medium and high concentration. Between-run repeatability for daily quality control had coefficient of variation of 3.0%. Carry-over did not exceed 0.05%. Linearity was confirmed for range of 0-16,000 particles/μl (R 2  = 0.9997). The analytical stability had coefficient of variation of 4.3%. Out of 1258 analyzed urine samples, 362 positive were subjected to light microscopy urine sediment analysis and compared to the analyzer results. Cohen's kappa coefficients were calculated to express the concordance. Squared kappa coefficient was 0.927 (red blood cells), 0.888 (white blood cells), 0.908 (squamous epithelia), 0.634 (transitional epithelia), 0.628 (hyaline casts), 0.843 (granular casts) and 0.623 (bacteria). Single kappa coefficients were 0.885 (yeasts) and 0.756 (crystals), respectively. Aforementioned results show good analytical performance of the analyzer and tight agreement with light microscopy of urine sediment.

Evolution of the Pseudomonas aeruginosa mutational resistome in an international Cystic Fibrosis clone.

PubMed

López-Causapé, Carla; Sommer, Lea Mette; Cabot, Gabriel; Rubio, Rosa; Ocampo-Sosa, Alain A; Johansen, Helle Krogh; Figuerola, Joan; Cantón, Rafael; Kidd, Timothy J; Molin, Soeren; Oliver, Antonio

2017-07-17

Emergence of epidemic clones and antibiotic resistance development compromises the management of Pseudomonas aeruginosa cystic fibrosis (CF) chronic respiratory infections. Whole genome sequencing (WGS) was used to decipher the phylogeny, interpatient dissemination, WGS mutator genotypes (mutome) and resistome of a widespread clone (CC274), in isolates from two highly-distant countries, Australia and Spain, covering an 18-year period. The coexistence of two divergent CC274 clonal lineages was revealed, but without evident geographical barrier; phylogenetic reconstructions and mutational resistome demonstrated the interpatient transmission of mutators. The extraordinary capacity of P. aeruginosa to develop resistance was evidenced by the emergence of mutations in >100 genes related to antibiotic resistance during the evolution of CC274, catalyzed by mutator phenotypes. While the presence of classical mutational resistance mechanisms was confirmed and correlated with resistance phenotypes, results also showed a major role of unexpected mutations. Among them, PBP3 mutations, shaping up β-lactam resistance, were noteworthy. A high selective pressure for mexZ mutations was evidenced, but we showed for the first time that high-level aminoglycoside resistance in CF is likely driven by mutations in fusA1/fusA2, coding for elongation factor G. Altogether, our results provide valuable information for understanding the evolution of the mutational resistome of CF P. aeruginosa.

A theranostic nrGO@MSN-ION nanocarrier developed to enhance the combination effect of sonodynamic therapy and ultrasound hyperthermia for treating tumor

NASA Astrophysics Data System (ADS)

Chen, Yu-Wei; Liu, Tse-Ying; Chang, Po-Hsueh; Hsu, Po-Hung; Liu, Hao-Li; Lin, Hong-Cheu; Chen, San-Yuan

2016-06-01

Sonodynamic therapy (SDT), which induces activation of sonosensitizers in cancer cells through ultrasound irradiation, has emerged as an alternative and promising noninvasive therapeutic approach to kill both superficial and deep parts of tumors. In this study, mesoporous silica (MSN) grown on reduced graphene oxide nanosheet (nrGO) capped with Rose Bengal (RB)-PEG-conjugated iron-oxide nanoparticles (IONs), nrGO@MSN-ION-PEG-RB, was strategically designed to have targeted functionality and therapeutic efficacy under magnetic guiding and focused ultrasound (FUS) irradiation, respectively. The singlet oxygen produced by ultrasound-activated RB and the ultrasound-induced heating effect was enhanced by rGO and IONs, which improved the cytotoxic effect in cancer cells. In an animal experiment, we demonstrated that the combination of sonodynamic/hyperthermia therapy with magnetic guidance using this nanocomposite therapeutic agent can produce remarkable efficacious therapy in tumor growth inhibition. Furthermore, the combination effect induced by FUS irradiation produces significant damage to both superficial and deep parts of the targeted tumor.Sonodynamic therapy (SDT), which induces activation of sonosensitizers in cancer cells through ultrasound irradiation, has emerged as an alternative and promising noninvasive therapeutic approach to kill both superficial and deep parts of tumors. In this study, mesoporous silica (MSN) grown on reduced graphene oxide nanosheet (nrGO) capped with Rose Bengal (RB)-PEG-conjugated iron-oxide nanoparticles (IONs), nrGO@MSN-ION-PEG-RB, was strategically designed to have targeted functionality and therapeutic efficacy under magnetic guiding and focused ultrasound (FUS) irradiation, respectively. The singlet oxygen produced by ultrasound-activated RB and the ultrasound-induced heating effect was enhanced by rGO and IONs, which improved the cytotoxic effect in cancer cells. In an animal experiment, we demonstrated that the combination of sonodynamic/hyperthermia therapy with magnetic guidance using this nanocomposite therapeutic agent can produce remarkable efficacious therapy in tumor growth inhibition. Furthermore, the combination effect induced by FUS irradiation produces significant damage to both superficial and deep parts of the targeted tumor. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07782f

A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: Results at the 2-year follow-up.

PubMed

Chang, Jin Woo; Park, Chang Kyu; Lipsman, Nir; Schwartz, Michael L; Ghanouni, Pejman; Henderson, Jaimie M; Gwinn, Ryder; Witt, Jennifer; Tierney, Travis S; Cosgrove, G Rees; Shah, Binit B; Abe, Keiichi; Taira, Takaomi; Lozano, Andres M; Eisenberg, Howard M; Fishman, Paul S; Elias, W Jeffrey

2018-01-01

Magnetic resonance guided focused ultrasound (MRgFUS) has recently been investigated as a new treatment modality for essential tremor (ET), but the durability of the procedure has not yet been evaluated. This study reports results at a 2- year follow-up after MRgFUS thalamotomy for ET. A total of 76 patients with moderate-to-severe ET, who had not responded to at least two trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor. Sixty-seven of the patients continued in the open-label extension phase of the study with monitoring for 2 years. Nine patients were excluded by 2 years, for example, because of alternative therapy such as deep brain stimulation (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed. Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55% at 6 months (8.6 ± 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53%; 8.9 ± 4.8; 70 patients) and at 2 years (56%; 8.8 ± 5.0; 67 patients). Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64% at 6 months (5.4 ± 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year-each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years. Tremor suppression after MRgFUS thalamotomy for ET is stably maintained at 2 years. Latent or delayed complications do not develop after treatment. Ann Neurol 2018;83:107-114. © 2017 American Neurological Association.

Passive Acoustic Mapping with the Angular Spectrum Method

PubMed Central

Crake, Calum; McDannold, Nathan; Clement, Gregory T.

2017-01-01

In the present proof of principle study, we evaluated the homogenous angular spectrum method for passive acoustic mapping (AS-PAM) of microbubble oscillations using simulated and experimental data. In the simulated data we assessed the ability of AS-PAM to form 3D maps of a single and multiple point sources. Then, in the two dimensional limit, we compared the 2D maps from AS-PAM with alternative frequency and time domain passive acoustic mapping (FD- and TD-PAM) approaches. Finally, we assessed the ability of AS-PAM to visualize microbubble activity in vivo with data obtained during 8 different experiments of FUS-induced blood-brain barrier disruption in 3 nonhuman primates, using a clinical MR-guided FUS system. Our in silico results demonstrate AS-PAM can be used to perform 3D passive acoustic mapping. 2D AS-PAM as compared to FD- PAM and TD-PAM is 10 and 200 times faster respectively and has similar sensitivity, resolution, and localization accuracy, even when the noise was 10-fold higher than the signal. In-vivo, the AS-PAM reconstructions of emissions at frequency bands pertinent to the different types of microbubble oscillations were also found to be more sensitive than TD-PAM. AS-PAM of harmonic-only components predicted safe blood-brain barrier disruption, whereas AS-PAM of broadband emissions correctly identified MR-evident tissue damage. The disparity (3.2mm) in the location of the cavitation activity between the three methods was within their resolution limits. These data clearly demonstrate that AS-PAM is a sensitive and fast approach for PAM, thus providing a clinically relevant method to guide therapeutic ultrasound procedures. PMID:28026755

A novel type of EWS-CHOP fusion gene in myxoid liposarcoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsui, Yoshito; Ueda, Takafumi; Kubo, Takahiro

2006-09-22

The cytogenetic hallmark of myxoid type and round cell type liposarcoma consists of reciprocal translocation of t(12;16)(q13;p11) and t(12;22)(q13;q12), which results in fusion of TLS/FUS and CHOP, and EWS and CHOP, respectively. Nine structural variations of the TLS/FUS-CHOP chimeric transcript have been reported, however, only two types of EWS-CHOP have been described. We describe here a case of myxoid liposarcoma containing a novel EWS-CHOP chimeric transcript and identified the breakpoint occurring in intron 13 of EWS. Reverse transcription-polymerase chain reaction and direct sequence showed that exon 13 of EWS was in-frame fused to exon 2 of CHOP. Genomic analysis revealedmore » that the breaks were located in intron 13 of EWS and intron 1 of CHOP.« less

The physiological and pathological biophysics of phase separation and gelation of RNA binding proteins in amyotrophic lateral sclerosis and fronto-temporal lobar degeneration.

PubMed

St George-Hyslop, Peter; Lin, Julie Qiaojin; Miyashita, Akinori; Phillips, Emma C; Qamar, Seema; Randle, Suzanne J; Wang, GuoZhen

2018-04-30

Many RNA binding proteins, including FUS, contain moderately repetitive, low complexity, intrinsically disordered domains. These sequence motifs have recently been found to underpin reversible liquid: liquid phase separation and gelation of these proteins, permitting them to reversibly transition from a monodispersed state to liquid droplet- or hydrogel-like states. This function allows the proteins to serve as scaffolds for the formation of reversible membraneless intracellular organelles such as nucleoli, stress granules and neuronal transport granules. Using FUS as an example, this review examines the biophysics of this physiological process, and reports on how mutations and changes in post-translational state alter phase behaviour, and lead to neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Copyright © 2018. Published by Elsevier B.V.

Breakdown of lung framework and an increase in pores of Kohn as initial events of emphysema and a cause of reduction in diffusing capacity.

PubMed

Yoshikawa, Akira; Sato, Shuntaro; Tanaka, Tomonori; Hashisako, Mikiko; Kashima, Yukio; Tsuchiya, Tomoshi; Yamasaki, Naoya; Nagayasu, Takeshi; Yamamoto, Hiroshi; Fukuoka, Junya

2016-01-01

Pulmonary emphysema is the pathological prototype of chronic obstructive pulmonary disease and is also associated with other lung diseases. We considered that observation with different approaches may provide new insights for the pathogenesis of emphysema. We reviewed tissue blocks of the lungs of 25 cases with/without emphysema and applied a three-dimensional observation method to the blocks. Based on the three-dimensional characteristics of the alveolar structure, we considered one face of the alveolar polyhedron as a structural unit of alveoli and called it a framework unit (FU). We categorized FUs based on their morphological characteristics and counted their number to evaluate the destructive changes in alveoli. We also evaluated the number and the area of pores of Kohn in FUs. We performed linear regression analysis to estimate the effect of these data on pulmonary function tests. In multivariable regression analysis, a decrease in the number of FUs without an alveolar wall led to a significant decrease in the diffusing capacity of the lung for carbon monoxide (DLCO) and DLCO per unit alveolar volume, and an increase in the area of pores of Kohn had a significant effect on an increase in residual capacity. A breakdown in the lung framework and an increase in pores of Kohn are associated with a decrease in DLCO and DLCO per unit alveolar volume with/without emphysema.

The intensity dependence of lesion position shift during focused ultrasound surgery.

PubMed

Meaney, P M; Cahill, M D; ter Haar, G R

2000-03-01

Knowledge of the spatial distribution of intensity loss from an ultrasonic beam is critical for predicting lesion formation in focused ultrasound (US) surgery (FUS). To date, most models have used linear propagation models to predict intensity profiles required to compute the temporally varying temperature distributions used to compute thermal dose contours. These are used to predict the extent of thermal damage. However, these simulations fail to describe adequately the abnormal lesion formation behaviour observed during ex vivo experiments in cases for which the transducer drive levels are varied over a wide range. In such experiments, the extent of thermal damage has been observed to move significantly closer to the transducer with increased transducer drive levels than would be predicted using linear-propagation models. The first set of simulations described herein use the KZK (Khokhlov-Zabolotskaya-Kuznetsov) nonlinear propagation model with the parabolic approximation for highly focused US waves to demonstrate that both the peak intensity and the lesion positions do, indeed, move closer to the transducer. This illustrates that, for accurate modelling of heating during FUS, nonlinear effects should be considered. Additionally, a first order approximation has been employed that attempts to account for the abnormal heat deposition distributions that accompany high transducer drive level FUS exposures where cavitation and boiling may be present. The results of these simulations are presented. It is suggested that this type of approach may be a useful tool in understanding thermal damage mechanisms.

MRI monitoring of focused ultrasound sonications near metallic hardware.

PubMed

Weber, Hans; Ghanouni, Pejman; Pascal-Tenorio, Aurea; Pauly, Kim Butts; Hargreaves, Brian A

2018-07-01

To explore the temperature-induced signal change in two-dimensional multi-spectral imaging (2DMSI) for fast thermometry near metallic hardware to enable MR-guided focused ultrasound surgery (MRgFUS) in patients with implanted metallic hardware. 2DMSI was optimized for temperature sensitivity and applied to monitor focus ultrasound surgery (FUS) sonications near metallic hardware in phantoms and ex vivo porcine muscle tissue. Further, we evaluated its temperature sensitivity for in vivo muscle in patients without metallic hardware. In addition, we performed a comparison of temperature sensitivity between 2DMSI and conventional proton-resonance-frequency-shift (PRFS) thermometry at different distances from metal devices and different signal-to-noise ratios (SNR). 2DMSI thermometry enabled visualization of short ultrasound sonications near metallic hardware. Calibration using in vivo muscle yielded a constant temperature sensitivity for temperatures below 43 °C. For an off-resonance coverage of ± 6 kHz, we achieved a temperature sensitivity of 1.45%/K, resulting in a minimum detectable temperature change of ∼2.5 K for an SNR of 100 with a temporal resolution of 6 s per frame. The proposed 2DMSI thermometry has the potential to allow MR-guided FUS treatments of patients with metallic hardware and therefore expand its reach to a larger patient population. Magn Reson Med 80:259-271, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Vaginal-sparing ventral buccal mucosal graft urethroplasty for female urethral stricture: A novel modification of surgical technique.

PubMed

Hoag, Nathan; Gani, Johan; Chee, Justin

2016-07-01

To present a novel modification of surgical technique to treat female urethral stricture (FUS) by a vaginal-sparing ventral buccal mucosal urethroplasty. Recurrent FUS represents an uncommon, though difficult clinical scenario to manage definitively. A variety of surgical techniques have been described to date, yet a lack of consensus on the optimal procedure persists. We present a 51-year-old female with urethral stricture involving the entire urethra. Suspected etiology was iatrogenic from cystoscopy 17 years prior. Since then, the patient had undergone at least 25 formal urethral dilations and periods of self-dilation. In lithotomy position, the urethra was dilated to accommodate forceps, and ventral urethrotomy carried out sharply, exposing a bed of periurethral tissue. Buccal mucosa was harvested, and a ventral inlay technique facilitated by a nasal speculum, was used to place the graft from the proximal urethra/bladder neck to urethral meatus without a vaginal incision. Graft was sutured into place, and urethral Foley catheter inserted. The vaginal-sparing ventral buccal mucosal graft urethroplasty was deemed successful as of last follow-up. Flexible cystoscopy demonstrated patency of the repair at 6 months. At 10 months of follow-up, the patient was voiding well, with no urinary incontinence. No further interventions have been required. This case describes a novel modification of surgical technique for performing buccal mucosal urethroplasty for FUS. By avoiding incision of the vaginal mucosa, benefits may include reduced: morbidity, urinary incontinence, and wound complications including urethro-vaginal fistula.

Elasticity mapping of murine abdominal organs in vivo using harmonic motion imaging (HMI)

NASA Astrophysics Data System (ADS)

Payen, Thomas; Palermo, Carmine F.; Sastra, Stephen A.; Chen, Hong; Han, Yang; Olive, Kenneth P.; Konofagou, Elisa E.

2016-08-01

Recently, ultrasonic imaging of soft tissue mechanics has been increasingly studied to image otherwise undetectable pathologies. However, many underlying mechanisms of tissue stiffening remain unknown, requiring small animal studies and adapted elasticity mapping techniques. Harmonic motion imaging (HMI) assesses tissue viscoelasticity by inducing localized oscillation from a periodic acoustic radiation force. The objective of this study was to evaluate the feasibility of HMI for in vivo elasticity mapping of abdominal organs in small animals. Pathological cases, i.e. chronic pancreatitis and pancreatic cancer, were also studied in vivo to assess the capability of HMI for detection of the change in mechanical properties. A 4.5 MHz focused ultrasound transducer (FUS) generated an amplitude-modulated beam resulting in 50 Hz harmonic tissue oscillations at its focus. Axial tissue displacement was estimated using 1D-cross-correlation of RF signals acquired with a 7.8 MHz diagnostic transducer confocally aligned with the FUS. In vitro results in canine liver and kidney showed the correlation between HMI displacement and Young’s moduli measured by rheometry compression testing. HMI was capable of providing reproducible elasticity maps of the mouse abdominal region in vivo allowing the identification of, from stiffest to softest, the murine kidney, pancreas, liver, and spleen. Finally, pancreata affected by pancreatitis and pancreatic cancer showed HMI displacements 1.7 and 2.2 times lower than in the control case, respectively, indicating higher stiffness. The HMI displacement amplitude was correlated with the extent of fibrosis as well as detecting the very onset of stiffening even before fibrosis could be detected on H&E. This work shows that HMI can produce reliable elasticity maps of mouse abdominal region in vivo, thus providing a potentially critical tool to assess pathologies affecting organ elasticity.

Elasticity mapping of murine abdominal organs in vivo using Harmonic Motion Imaging (HMI)

PubMed Central

Payen, Thomas; Palermo, Carmine F.; Sastra, Steve; Chen, Hong; Han, Yang; Olive, Kenneth P.; Konofagou, Elisa E.

2016-01-01

Recently, ultrasonic imaging of soft tissue mechanics has been increasingly studied to image otherwise undetectable pathologies. However, many underlying mechanisms of tissue stiffening remain unknown, requiring small animal studies and adapted elasticity mapping techniques. Harmonic motion imaging (HMI) assesses tissue viscoelasticity by inducing localized oscillation from a periodic acoustic radiation force. The objective of this study was to evaluate the feasibility of HMI for in vivo elasticity mapping of abdominal organs in small animals. Pathological cases, i.e. chronic pancreatitis and pancreatic cancer, were also studied in vivo to assess the capability of HMI for detection of the change in mechanical properties. A 4.5-MHz focused ultrasound transducer (FUS) generated an amplitude-modulated beam resulting in 50-Hz harmonic tissue oscillations at its focus. Axial tissue displacement was estimated using 1D-cross-correlation of RF signals acquired with a 7.8-MHz diagnostic transducer confocally aligned with the FUS. In vitro results in canine liver and kidney showed the correlation between HMI displacement and Young’s moduli measured by rheometry compression tests. HMI was able to provide reproducible elasticity maps of the mouse abdominal region in vivo allowing the identification of, from stiffest to softest, the murine kidney, pancreas, liver, and spleen. Finally, pancreata affected by pancreatitis and pancreatic cancer showed HMI displacements 1.7 and 2.2 times lower than in the control case, respectively, indicating higher stiffness. HMI displacement was correlated with the extent of fibrosis as well as detecting the very onset of stiffening even before fibrosis could be detected on H&E. This work shows that HMI can produce reliable elasticity maps of mouse abdominal region in vivo providing a crucial tool to understand pathologies affecting organ elasticity. PMID:27401609

Elasticity mapping of murine abdominal organs in vivo using harmonic motion imaging (HMI).

PubMed

Payen, Thomas; Palermo, Carmine F; Sastra, Stephen A; Chen, Hong; Han, Yang; Olive, Kenneth P; Konofagou, Elisa E

2016-08-07

Recently, ultrasonic imaging of soft tissue mechanics has been increasingly studied to image otherwise undetectable pathologies. However, many underlying mechanisms of tissue stiffening remain unknown, requiring small animal studies and adapted elasticity mapping techniques. Harmonic motion imaging (HMI) assesses tissue viscoelasticity by inducing localized oscillation from a periodic acoustic radiation force. The objective of this study was to evaluate the feasibility of HMI for in vivo elasticity mapping of abdominal organs in small animals. Pathological cases, i.e. chronic pancreatitis and pancreatic cancer, were also studied in vivo to assess the capability of HMI for detection of the change in mechanical properties. A 4.5 MHz focused ultrasound transducer (FUS) generated an amplitude-modulated beam resulting in 50 Hz harmonic tissue oscillations at its focus. Axial tissue displacement was estimated using 1D-cross-correlation of RF signals acquired with a 7.8 MHz diagnostic transducer confocally aligned with the FUS. In vitro results in canine liver and kidney showed the correlation between HMI displacement and Young's moduli measured by rheometry compression testing. HMI was capable of providing reproducible elasticity maps of the mouse abdominal region in vivo allowing the identification of, from stiffest to softest, the murine kidney, pancreas, liver, and spleen. Finally, pancreata affected by pancreatitis and pancreatic cancer showed HMI displacements 1.7 and 2.2 times lower than in the control case, respectively, indicating higher stiffness. The HMI displacement amplitude was correlated with the extent of fibrosis as well as detecting the very onset of stiffening even before fibrosis could be detected on H&E. This work shows that HMI can produce reliable elasticity maps of mouse abdominal region in vivo, thus providing a potentially critical tool to assess pathologies affecting organ elasticity.

Harmonic motion imaging for focused ultrasound (HMIFU): a fully integrated technique for sonication and monitoring of thermal ablation in tissues.

PubMed

Maleke, C; Konofagou, E E

2008-03-21

FUS (focused ultrasound), or HIFU (high-intensity-focused ultrasound) therapy, a minimally or non-invasive procedure that uses ultrasound to generate thermal necrosis, has been proven successful in several clinical applications. This paper discusses a method for monitoring thermal treatment at different sonication durations (10 s, 20 s and 30 s) using the amplitude-modulated (AM) harmonic motion imaging for focused ultrasound (HMIFU) technique in bovine liver samples in vitro. The feasibility of HMI for characterizing mechanical tissue properties has previously been demonstrated. Here, a confocal transducer, combining a 4.68 MHz therapy (FUS) and a 7.5 MHz diagnostic (pulse-echo) transducer, was used. The therapy transducer was driven by a low-frequency AM continuous signal at 25 Hz, producing a stable harmonic radiation force oscillating at the modulation frequency. A pulser/receiver was used to drive the pulse-echo transducer at a pulse repetition frequency (PRF) of 5.4 kHz. Radio-frequency (RF) signals were acquired using a standard pulse-echo technique. The temperature near the ablation region was simultaneously monitored. Both RF signals and temperature measurements were obtained before, during and after sonication. The resulting axial tissue displacement was estimated using one-dimensional cross correlation. When temperature at the focal zone was above 48 degrees C during heating, the coagulation necrosis occurred and tissue damage was irreversible. The HMI displacement profiles in relation to the temperature and sonication durations were analyzed. At the beginning of heating, the temperature at the focus increased sharply, while the tissue stiffness decreased resulting in higher HMI displacements. This was confirmed by an increase of 0.8 microm degrees C(-1)(r=0.93, p<.005). After sustained heating, the tissue became irreversibly stiffer, followed by an associated decrease in the HMI displacement (-0.79 microm degrees C(-1), r=-0.92, p<0.001). Repeated experiments showed a reproducible pattern of the HMI displacement changes with a temperature at a slope equal to 0.8+/-0.11 and -0.79+/-0.14 microm degrees C(-1), prior to and after lesion formation in seven bovine liver samples, respectively. This technique was thus capable of following the protein-denatured lesion formation based on the variation of the HMI displacements. This method could, therefore, be applied for real-time monitoring of temperature-related stiffness changes of tissues during FUS, HIFU or other thermal therapies.

Preclinical evaluation of a low-frequency transcranial MRI-guided focused ultrasound system in a primate model

NASA Astrophysics Data System (ADS)

McDannold, Nathan; Livingstone, Margaret; Barış Top, Can; Sutton, Jonathan; Todd, Nick; Vykhodtseva, Natalia

2016-11-01

This study investigated thermal ablation and skull-induced heating with a 230 kHz transcranial MRI-guided focused ultrasound (TcMRgFUS) system in nonhuman primates. We evaluated real-time acoustic feedback and aimed to understand whether cavitation contributed to the heating and the lesion formation. In four macaques, we sonicated thalamic targets at acoustic powers of 34-560 W (896-7590 J). Tissue effects evaluated with MRI and histology were compared to MRI-based temperature and thermal dose measurements, acoustic emissions recorded during the experiments, and acoustic and thermal simulations. Peak temperatures ranged from 46 to 57 °C, and lesions were produced in 5/8 sonicated targets. A linear relationship was observed between the applied acoustic energy and both the focal and brain surface heating. Thermal dose thresholds were 15-50 cumulative equivalent minutes at 43 °C, similar to prior studies at higher frequencies. Histology was also consistent with earlier studies of thermal effects in the brain. The system successfully controlled the power level and maintained a low level of cavitation activity. Increased acoustic emissions observed in 3/4 animals occurred when the focal temperature rise exceeded approximately 16 °C. Thresholds for thermally-significant subharmonic and wideband emissions were 129 and 140 W, respectively, corresponding to estimated pressure amplitudes of 2.1 and 2.2 MPa. Simulated focal heating was consistent with the measurements for sonications without thermally-significant acoustic emissions; otherwise it was consistently lower than the measurements. Overall, these results suggest that the lesions were produced by thermal mechanisms. The detected acoustic emissions, however, and their association with heating suggest that cavitation might have contributed to the focal heating. Compared to earlier work with a 670 kHz TcMRgFUS system, the brain surface heating was substantially reduced and the focal heating was higher with this 230 kHz system, suggesting that a reduced frequency can increase the treatment envelope for TcMRgFUS and potentially reduce the risk of skull heating.

Acoustic Cavitation-Based Monitoring of the Reversibility and Permeability of Ultrasound-Induced Blood-Brain Barrier Opening

PubMed Central

Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C.; Konofagou, Elisa E.

2015-01-01

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n = 60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 days thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: 1) the duration of the BBB opening (r2 = 0.77); 2) the permeability of the opened BBB (r2 = 0.82); 3) the likelihood of safe opening (P < 0.05, safe opening compared to cases of damage; P < 0.0001, no opening compared to safe opening). The inertial cavitation dose was correlated with the resulting BBB permeability (r2 = 0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the BBB opening duration, enabling thus control of opening according to the drug circulation time. In addition, avoiding adverse effects in the brain and assessing the pharmacokinetics of the compounds delivered can also be achieved by monitoring and controlling the stable cavitation emissions. PMID:26562661

Custom molded thermal MRg-FUS phantom

NASA Astrophysics Data System (ADS)

Eames, Matthew D. C.; Snell, John W.; Hananel, Arik; Kassell, Neal F.

2012-11-01

This article describes a method for creating custom-molded thermal phantoms for use with MR-guided focused ultrasound systems. The method is defined here for intracranial applications, though it may be modified for other anatomical targets.

MR-guided Focused Ultrasound for Uterine Fibroids

MedlinePlus

... Professions Site Index A-Z MR-guided Focused Ultrasound for Uterine Fibroids Magnetic Resonance-guided Focused Ultrasound ( ... are the limitations of MRgFUS? What is Focused Ultrasound of Uterine Fibroids? Magnetic Resonance-guided Focused Ultrasound ( ...

Development of High-Activity Para- to Ortho-Hydrogen Conversion Catalysts. Volume 2

DTIC Science & Technology

1989-09-28

Proc. Roy. Soc. London AllO, 464 (1925). 2 1929 Para- and ortho-hydrogen, Barmois, E., La Nature No. 2820, 400-1 (1929) C.A. 24,, 1020b. K. F...U.S. At. Energy Comm. LA -2719, 40 pp. (1962); cf. 3. Chem. Eng. Data 7, 179(1962). C.A. 58, 10750g. Schmidt number for normal hydrogen and...A-L);- p 181-9; in Eng. Briones, A. G.; Garcia de la Banda, J. F.; Inst. Quim. Fis. Quim., Madrid, Anales Real. Soc. Espan. Fis. Quim. (Madrid); Ser

Vulvar Myxoid Liposarcoma and Well Differentiated Liposarcoma With Molecular Cytogenetic Confirmation: Case Reports With Review of Malignant Lipomatous Tumors of the Vulva.

PubMed

Schoolmeester, John Kenneth; Leifer, Aaron J; Wang, Lu; Hameed, Meera R

2015-07-01

Malignant lipomatous tumors of the vulva are uncommon. We present 2 cases of liposarcoma arising in the vulva: a myxoid liposarcoma harboring DDIT3 and FUS rearrangements and a well differentiated liposarcoma/atypical lipomatous tumor harboring MDM2 amplification detected by fluorescence in situ hybridization. Both cases are the first liposarcomas of this site to be confirmed by molecular cytogenetic analysis. We also review the literature's cases of liposarcoma to further examine the clinicopathologic features of these tumors.

A feasibility study of soft embalmed human breast tissue for preclinical trials of HIFU- preliminary results

NASA Astrophysics Data System (ADS)

Joy, Joyce; Yang, Yang; Purdie, Colin; Eisma, Roos; Melzer, Andreas; Cochran, Sandy; Vinnicombe, Sarah

2017-03-01

Breast cancer is the commonest cancer in women in the UK, accounting for 30% of all new cancers in women, with an estimated 49,500 new cases in 20101. With the widespread negative publicity around over-diagnosis and over-treatment of low risk breast cancers, interest in the application of non-invasive treatments such as magnetic resonance imaging (MRI) guided high intensity focused ultrasound (HIFU) has increased. Development has begun of novel US transducers and platforms specifically designed for use with breast lesions, so as to improve the range of breast lesions that can be safely treated. However, before such transducers can be evaluated in patients in clinical trials, there is a need to establish their efficacy. A particular issue is the accuracy of temperature monitoring of FUS with MRI in the breast, since the presence of large amounts of surrounding fat can hinder temperature measurement. An appropriate anatomical model that imposes similar physical constraints to the breast and that responds to FUS in the same way would be extremely advantageous. The aim of this feasibility study is to explore the use of Thiel embalmed cadaveric tissue for these purposes. We report here the early results of laboratory-based experiments sonicating dissected breast samples from a Thiel embalmed soft human cadaver with high body mass index (BMI). A specially developed MRI compatible chamber and sample holder was developed to secure the sample and ensure reproducible sonications at the transducer focus. The efficacy of sonication was first studied with chicken breast and porcine tissue. The experiments were then repeated with the dissected fatty breast tissue samples from the soft-embalmed human cadavers. The sonicated Thiel breast tissue was examined histopathologically, which confirmed the absence of any discrete lesion. To investigate further, fresh chicken breast tissue was embalmed and the embalmed tissue was sonicated with the same parameters. The results confirmed the inability to produce a discrete lesion in any of the Thiel embalmed samples.

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

PubMed Central

Murakami, Takashi; Singh, Arun S.; Kiyuna, Tasuku; Dry, Sarah M.; Li, Yunfeng; James, Aaron W.; Igarashi, Kentaro; Kawaguchi, Kei; DeLong, Jonathan C.; Zhang, Yong; Hiroshima, Yukihiko; Russell, Tara; Eckardt, Mark A.; Yanagawa, Jane; Federman, Noah; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C.; Hoffman, Robert M.

2016-01-01

Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer. PMID:27286459

ABA-dependent inhibition of the ubiquitin proteasome system during germination at high temperature in Arabidopsis.

PubMed

Chiu, Rex Shun; Pan, Shiyue; Zhao, Rongmin; Gazzarrini, Sonia

2016-12-01

During germination, endogenous and environmental factors trigger changes in the transcriptome, translatome and proteome to break dormancy. In Arabidopsis thaliana, the ubiquitin proteasome system (UPS) degrades proteins that promote dormancy to allow germination. While research on the UPS has focused on the identification of proteasomal substrates, little information is known about the regulation of its activity. Here we characterized the activity of the UPS during dormancy release and maintenance by monitoring protein ubiquitination and degradation of two proteasomal substrates: Suc-LLVY-AMC, a well characterized synthetic substrate, and FUSCA3 (FUS3), a dormancy-promoting transcription factor degraded by the 26S proteasome. Our data indicate that proteasome activity and protein ubiquitination increase during imbibition at optimal temperature (21°C), and are required for seed germination. However, abscisic acid (ABA) and supraoptimal temperature (32°C) inhibit germination by dampening both protein ubiquitination and proteasome activity. Inhibition of UPS function by high temperature is reduced by the ABA biosynthesis inhibitor, fluridone, and in ABA biosynthetic mutants, suggesting that it is ABA dependent. Accordingly, inhibition of FUS3 degradation at 32°C is also dependent on ABA. Native gels show that inhibition of proteasome activity is caused by interference with the 26S/30S ratio as well as free 19S and 20S levels, impacting the proteasome degradation cycle. Transfer experiments show that ABA-mediated inhibition of proteasome activity at 21°C is restricted to the first 2 days of germination, a time window corresponding to seed sensitivity to environmental and ABA-mediated growth inhibition. Our data show that ABA and high temperature inhibit germination under unfavourable growth conditions by repressing the UPS. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.

PubMed

Murakami, Takashi; Singh, Arun S; Kiyuna, Tasuku; Dry, Sarah M; Li, Yunfeng; James, Aaron W; Igarashi, Kentaro; Kawaguchi, Kei; DeLong, Jonathan C; Zhang, Yong; Hiroshima, Yukihiko; Russell, Tara; Eckardt, Mark A; Yanagawa, Jane; Federman, Noah; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

2016-07-26

Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.

Intracranial inertial cavitation threshold and thermal ablation lesion creation using MRI-guided 220-kHz focused ultrasound surgery: preclinical investigation.

PubMed

Xu, Zhiyuan; Carlson, Carissa; Snell, John; Eames, Matt; Hananel, Arik; Lopes, M Beatriz; Raghavan, Prashant; Lee, Cheng-Chia; Yen, Chun-Po; Schlesinger, David; Kassell, Neal F; Aubry, Jean-Francois; Sheehan, Jason

2015-01-01

In biological tissues, it is known that the creation of gas bubbles (cavitation) during ultrasound exposure is more likely to occur at lower rather than higher frequencies. Upon collapsing, such bubbles can induce hemorrhage. Thus, acoustic inertial cavitation secondary to a 220-kHz MRI-guided focused ultrasound (MRgFUS) surgery is a serious safety issue, and animal studies are mandatory for laying the groundwork for the use of low-frequency systems in future clinical trials. The authors investigate here the in vivo potential thresholds of MRgFUS-induced inertial cavitation and MRgFUS-induced thermal coagulation using MRI, acoustic spectroscopy, and histology. Ten female piglets that had undergone a craniectomy were sonicated using a 220-kHz transcranial MRgFUS system over an acoustic energy range of 5600-14,000 J. For each piglet, a long-duration sonication (40-second duration) was performed on the right thalamus, and a short sonication (20-second duration) was performed on the left thalamus. An acoustic power range of 140-300 W was used for long-duration sonications and 300-700 W for short-duration sonications. Signals collected by 2 passive cavitation detectors were stored in memory during each sonication, and any subsequent cavitation activity was integrated within the bandwidth of the detectors. Real-time 2D MR thermometry was performed during the sonications. T1-weighted, T2-weighted, gradient-recalled echo, and diffusion-weighted imaging MRI was performed after treatment to assess the lesions. The piglets were killed immediately after the last series of posttreatment MR images were obtained. Their brains were harvested, and histological examinations were then performed to further evaluate the lesions. Two types of lesions were induced: thermal ablation lesions, as evidenced by an acute ischemic infarction on MRI and histology, and hemorrhagic lesions, associated with inertial cavitation. Passive cavitation signals exhibited 3 main patterns identified as follows: no cavitation, stable cavitation, and inertial cavitation. Low-power and longer sonications induced only thermal lesions, with a peak temperature threshold for lesioning of 53°C. Hemorrhagic lesions occurred only with high-power and shorter sonications. The sizes of the hemorrhages measured on macroscopic histological examinations correlated with the intensity of the cavitation activity (R2 = 0.74). The acoustic cavitation activity detected by the passive cavitation detectors exhibited a threshold of 0.09 V·Hz for the occurrence of hemorrhages. This work demonstrates that 220-kHz ultrasound is capable of inducing a thermal lesion in the brain of living swines without hemorrhage. Although the same acoustic energy can induce either a hemorrhage or a thermal lesion, it seems that low-power, long-duration sonication is less likely to cause hemorrhage and may be safer. Although further study is needed to decrease the likelihood of ischemic infarction associated with the 220-kHz ultrasound, the threshold established in this work may allow for the detection and prevention of deleterious cavitations.

Ultrasound-Induced Blood-Brain Barrier Opening

PubMed Central

Konofagou, Elisa E.; Tung, Yao-Sheng; Choi, James; Deffieux, Thomas; Baseri, Babak; Vlachos, Fotios

2014-01-01

Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions. PMID:22201586

Membrane fusion triggers rapid degradation of two gamete-specific, fusion-essential proteins in a membrane block to polygamy in Chlamydomonas.

PubMed

Liu, Yanjie; Misamore, Michael J; Snell, William J

2010-05-01

The plasma membranes of gametes are specialized for fusion, yet, once fusion occurs, in many organisms the new zygote becomes incapable of further membrane fusion reactions. The molecular mechanisms that underlie this loss of fusion capacity (block to polygamy) remain unknown. During fertilization in the green alga Chlamydomonas, the plus gamete-specific membrane protein FUS1 is required for adhesion between the apically localized sites on the plasma membranes of plus and minus gametes that are specialized for fusion, and the minus-specific membrane protein HAP2 is essential for completion of the membrane fusion reaction. HAP2 (GCS1) family members are also required for fertilization in Arabidopsis, and for the membrane fusion reaction in the malaria organism Plasmodium berghei. Here, we tested whether Chlamydomonas gamete fusion triggers alterations in FUS1 and HAP2 and renders the plasma membranes of the cells incapable of subsequent fusion. We find that, even though the fusogenic sites support multi-cell adhesions, triploid zygotes are rare, indicating a fusion-triggered block to the membrane fusion reaction. Consistent with the extinction of fusogenic capacity, both FUS1 and HAP2 are degraded upon fusion. The rapid, fusion-triggered cleavage of HAP2 in zygotes is distinct from degradation occurring during constitutive turnover in gametes. Thus, gamete fusion triggers specific degradation of fusion-essential proteins and renders the zygote incapable of fusion. Our results provide the first molecular explanation for a membrane block to polygamy in any organism.

Vaginal-sparing ventral buccal mucosal graft urethroplasty for female urethral stricture: A novel modification of surgical technique

PubMed Central

Gani, Johan; Chee, Justin

2016-01-01

Purpose To present a novel modification of surgical technique to treat female urethral stricture (FUS) by a vaginal-sparing ventral buccal mucosal urethroplasty. Recurrent FUS represents an uncommon, though difficult clinical scenario to manage definitively. A variety of surgical techniques have been described to date, yet a lack of consensus on the optimal procedure persists. Materials and Methods We present a 51-year-old female with urethral stricture involving the entire urethra. Suspected etiology was iatrogenic from cystoscopy 17 years prior. Since then, the patient had undergone at least 25 formal urethral dilations and periods of self-dilation. In lithotomy position, the urethra was dilated to accommodate forceps, and ventral urethrotomy carried out sharply, exposing a bed of periurethral tissue. Buccal mucosa was harvested, and a ventral inlay technique facilitated by a nasal speculum, was used to place the graft from the proximal urethra/bladder neck to urethral meatus without a vaginal incision. Graft was sutured into place, and urethral Foley catheter inserted. Results The vaginal-sparing ventral buccal mucosal graft urethroplasty was deemed successful as of last follow-up. Flexible cystoscopy demonstrated patency of the repair at 6 months. At 10 months of follow-up, the patient was voiding well, with no urinary incontinence. No further interventions have been required. Conclusions This case describes a novel modification of surgical technique for performing buccal mucosal urethroplasty for FUS. By avoiding incision of the vaginal mucosa, benefits may include reduced: morbidity, urinary incontinence, and wound complications including urethro-vaginal fistula. PMID:27437540

TU-G-210-03: Acoustic Simulations in Transcranial MRgFUS: Treatment Prediction and Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vyas, U.

Modeling can play a vital role in predicting, optimizing and analyzing the results of therapeutic ultrasound treatments. Simulating the propagating acoustic beam in various targeted regions of the body allows for the prediction of the resulting power deposition and temperature profiles. In this session we will apply various modeling approaches to breast, abdominal organ and brain treatments. Of particular interest is the effectiveness of procedures for correcting for phase aberrations caused by intervening irregular tissues, such as the skull in transcranial applications or inhomogeneous breast tissues. Also described are methods to compensate for motion in targeted abdominal organs such asmore » the liver or kidney. Douglas Christensen – Modeling for Breast and Brain HIFU Treatment Planning Tobias Preusser – TRANS-FUSIMO - An Integrative Approach to Model-Based Treatment Planning of Liver FUS Urvi Vyas – Acoustic Simulations in Transcranial MRgFUS: Treatment Prediction and Analysis Learning Objectives: Understand the role of acoustic beam modeling for predicting the effectiveness of therapeutic ultrasound treatments. Apply acoustic modeling to specific breast, liver, kidney and transcranial anatomies. Determine how to obtain appropriate acoustic modeling parameters from clinical images. Understand the separate role of absorption and scattering in energy delivery to tissues. See how organ motion can be compensated for in ultrasound therapies. Compare simulated data with clinical temperature measurements in transcranial applications. Supported by NIH R01 HL172787 and R01 EB013433 (DC); EU Seventh Framework Programme (FP7/2007-2013) under 270186 (FUSIMO) and 611889 (TRANS-FUSIMO)(TP); and P01 CA159992, GE, FUSF and InSightec (UV)« less

Quantitative assessment of cerebral glucose metabolic rates after blood-brain barrier disruption induced by focused ultrasound using FDG-MicroPET.

PubMed

Yang, Feng-Yi; Chang, Wen-Yuan; Chen, Jyh-Cheng; Lee, Lin-Chien; Hung, Yi-Shun

2014-04-15

The goal of this study was to evaluate the pharmacokinetics of (18)F-2-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the expression of glucose transporter 1 (GLUT1) protein after blood-brain barrier (BBB) disruption of normal rat brains by focused ultrasound (FUS). After delivery of an intravenous bolus of ~37 MBq (1 mCi) (18)F-FDG, dynamic positron emission tomography scans were performed on rats with normal brains and those whose BBBs had been disrupted by FUS. Arterial blood sampling was collected throughout the scanning procedure. A 2-tissue compartmental model was used to estimate (18)F-FDG kinetic parameters in brain tissues. The rate constants Ki, K1, and k3 were assumed to characterize the uptake, transport, and hexokinase activity, respectively, of (18)F-FDG. The uptake of (18)F-FDG in brains significantly decreased immediately after the blood-brain barrier was disrupted. At the same time, the derived values of Ki, K1, and k3 for the sonicated brains were significantly lower than those for the control brains. In agreement with the reduction in glucose, Western blot analyses confirmed that focused ultrasound exposure significantly reduced the expression of GLUT1 protein in the brains. Furthermore, the effect of focused ultrasound on glucose uptake was transient and reversible 24h after sonication. Our results indicate that focused ultrasound may inhibit GLUT1 expression to decrease the glucose uptake in brain tissue during the period of BBB disruption. Copyright © 2013 Elsevier Inc. All rights reserved.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function.

PubMed

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2013-11-01

Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging-guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity--and thus a low microbubble concentration--some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function

PubMed Central

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2014-01-01

Object Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging–guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. Methods In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Results Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. Conclusions This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity—and thus a low microbubble concentration—some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures. PMID:24010975

Inverse effects of flowing phase-shift nanodroplets and lipid-shelled microbubbles on subsequent cavitation during focused ultrasound exposures.

PubMed

Zhang, Siyuan; Cui, Zhiwei; Xu, Tianqi; Liu, Pan; Li, Dapeng; Shang, Shaoqiang; Xu, Ranxiang; Zong, Yujin; Niu, Gang; Wang, Supin; He, Xijing; Wan, Mingxi

2017-01-01

This paper compared the effects of flowing phase-shift nanodroplets (NDs) and lipid-shelled microbubbles (MBs) on subsequent cavitation during focused ultrasound (FUS) exposures. The cavitation activity was monitored using a passive cavitation detection method as solutions of either phase-shift NDs or lipid-shelled MBs flowed at varying velocities through a 5-mm diameter wall-less vessel in a transparent tissue-mimicking phantom when exposed to FUS. The intensity of cavitation for the phase-shift NDs showed an upward trend with time and cavitation for the lipid-shelled MBs grew to a maximum at the outset of the FUS exposure followed by a trend of decreases when they were static in the vessel. Meanwhile, the increase of cavitation for the phase-shift NDs and decrease of cavitation for the lipid-shelled MBs had slowed down when they flowed through the vessel. During two discrete identical FUS exposures, while the normalized inertial cavitation dose (ICD) value for the lipid-shelled MB solution was higher than that for the saline in the first exposure (p-value <0.05), it decreased to almost the same level in the second exposure. For the phase-shift NDs, the normalized ICD was 0.71 in the first exposure and increased to 0.97 in the second exposure. At a low acoustic power, the normalized ICD values for the lipid-shelled MBs tended to increase with increasing velocities from 5 to 30cm/s (r>0.95). Meanwhile, the normalized ICD value for the phase-shift NDs was 0.182 at a flow velocity of 5cm/s and increased to 0.188 at a flow velocity of 15cm/s. As the flow velocity increased to 20cm/s, the normalized ICD was 0.185 and decreased to 0.178 at a flow velocity of 30cm/s. At high acoustic power, the normalized ICD values for both the lipid-shelled MBs and the phase-shift NDs increased with increasing flow velocities from 5 to 30cm/s (r>0.95). The effects of the flowing phase-shift NDs vaporized into gas bubbles as cavitation nuclei on the subsequent cavitation were inverse to those of the flowing lipid-shelled MBs destroyed after focused ultrasound exposures. Copyright © 2016 Elsevier B.V. All rights reserved.

Intergenerational Relationship Quality Across Three Generations

PubMed Central

Tighe, Lauren A.; Fingerman, Karen L.; Zarit, Steven H.

2012-01-01

Objectives. Studies of intergenerational relationship quality often include one or two generations. This study examined within-family differences and similarities or transmission of positive and negative relationship quality across three generations. Method. Participants included 633 middle-aged individuals (G2; 52% women, ages 40–60 years), 592 of their offspring (G3; 53% daughters; ages 18–41 years), and 337 of their parents (i.e., grandparents; G1; 69% women; ages 59–96 years). Results. Multilevel models revealed differences and similarities in relationship quality across generations. The oldest generation (G1) reported greater positive and less negative quality relationships than the middle (G2) and the younger (G3) generations. There was limited evidence of transmission. Middle-aged respondents who reported more positive and less negative ties with their parents (G1) reported more positive and less negative ties with their own children (G3). Grandmother (G1) reports of more positive relationship quality were associated with G3 reports of more positive relationship quality with G2. Discussion. Findings are consistent with the intergenerational stake hypothesis and only partially consistent with the theory of intergenerational transmission. Overall, this study suggests that there is greater within-family variability than similarities in how family members feel about one another. PMID:22628478

DAGON: a 3D Maxwell-Bloch code

NASA Astrophysics Data System (ADS)

Oliva, Eduardo; Cotelo, Manuel; Escudero, Juan Carlos; González-Fernández, Agustín.; Sanchís, Alberto; Vera, Javier; Vicéns, Sergio; Velarde, Pedro

2017-05-01

The amplification of UV radiation and high order harmonics (HOH) in plasmas is a subject of raising interest due to its different potential applications in several fields like environment and security (detection at distance), biology, materials science and industry (3D imaging) and atomic and plasma physics (pump-probe experiments). In order to develop these sources, it is necessary to properly understand the amplification process. Being the plasma an inhomogeneous medium which changes with time, it is desirable to have a full time-dependent 3D description of the interaction of UV and XUV radiation with plasmas. For these reasons, at the Instituto de Fusíon Nuclear we have developed DAGON, a 3D Maxwell-Bloch code capable of studying the full spationtemporal structure of the amplification process abovementioned.

The rice GERMINATION DEFECTIVE 1, encoding a B3 domain transcriptional repressor, regulates seed germination and seedling development by integrating GA and carbohydrate metabolism

PubMed Central

Guo, Xiaoli; Hou, Xiaomei; Fang, Jun; Wei, Piwei; Xu, Bo; Chen, Mingluan; Feng, Yuqi; Chu, Chengcai

2013-01-01

It has been shown that seed development is regulated by a network of transcription factors in Arabidopsis including LEC1 (LEAFY COTYLEDON1), L1L (LEC1-like) and the B3 domain factors LEC2, FUS3 (FUSCA3) and ABI3 (ABA-INSENSITIVE3); however, molecular and genetic regulation of seed development in cereals is poorly understood. To understand seed development and seed germination in cereals, a large-scale screen was performed using our T–DNA mutant population, and a mutant germination-defective1 (gd1) was identified. In addition to the severe germination defect, the gd1 mutant also shows a dwarf phenotype and abnormal flower development. Molecular and biochemical analyses revealed that GD1 encodes a B3 domain-containing transcription factor with repression activity. Consistent with the dwarf phenotype of gd1, expression of the gibberelic acid (GA) inactivation gene OsGA2ox3 is increased dramatically, accompanied by reduced expression of GA biosynthetic genes including OsGA20ox1, OsGA20ox2 and OsGA3ox2 in gd1, resulting in a decreased endogenous GA4 level. Exogenous application of GA not only induced GD1 expression, but also partially rescued the dwarf phenotype of gd1. Furthermore, GD1 binds to the promoter of OsLFL1, a LEC2/FUS3-like gene of rice, via an RY element, leading to significant up-regulation of OsLFL1 and a large subset of seed maturation genes in the gd1 mutant. Plants over-expressing OsLFL1 partly mimic the gd1 mutant. In addition, expression of GD1 was induced under sugar treatment, and the contents of starch and soluble sugar are altered in the gd1 mutant. These data indicate that GD1 participates directly or indirectly in regulating GA and carbohydrate homeostasis, and further regulates rice seed germination and seedling development. PMID:23581288

Sparsely-distributed organization of face and limb activations in human ventral temporal cortex

PubMed Central

Weiner, Kevin S.; Grill-Spector, Kalanit

2011-01-01

Functional magnetic resonance imaging (fMRI) has identified face- and body part-selective regions, as well as distributed activation patterns for object categories across human ventral temporal cortex (VTC), eliciting a debate regarding functional organization in VTC and neural coding of object categories. Using high-resolution fMRI, we illustrate that face- and limb-selective activations alternate in a series of largely nonoverlapping clusters in lateral VTC along the inferior occipital gyrus (IOG), fusiform gyrus (FG), and occipitotemporal sulcus (OTS). Both general linear model (GLM) and multivoxel pattern (MVP) analyses show that face- and limb-selective activations minimally overlap and that this organization is consistent across experiments and days. We provide a reliable method to separate two face-selective clusters on the middle and posterior FG (mFus and pFus), and another on the IOG using their spatial relation to limb-selective activations and retinotopic areas hV4, VO-1/2, and hMT+. Furthermore, these activations show a gradient of increasing face selectivity and decreasing limb selectivity from the IOG to the mFus. Finally, MVP analyses indicate that there is differential information for faces in lateral VTC (containing weakly- and highly-selective voxels) relative to non-selective voxels in medial VTC. These findings suggest a sparsely-distributed organization where sparseness refers to the presence of several face- and limb-selective clusters in VTC, and distributed refers to the presence of different amounts of information in highly-, weakly-, and non-selective voxels. Consequently, theories of object recognition should consider the functional and spatial constraints of neural coding across a series of nonoverlapping category-selective clusters that are themselves distributed. PMID:20457261

TU-G-210-02: TRANS-FUSIMO - An Integrative Approach to Model-Based Treatment Planning of Liver FUS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Preusser, T.

Modeling can play a vital role in predicting, optimizing and analyzing the results of therapeutic ultrasound treatments. Simulating the propagating acoustic beam in various targeted regions of the body allows for the prediction of the resulting power deposition and temperature profiles. In this session we will apply various modeling approaches to breast, abdominal organ and brain treatments. Of particular interest is the effectiveness of procedures for correcting for phase aberrations caused by intervening irregular tissues, such as the skull in transcranial applications or inhomogeneous breast tissues. Also described are methods to compensate for motion in targeted abdominal organs such asmore » the liver or kidney. Douglas Christensen – Modeling for Breast and Brain HIFU Treatment Planning Tobias Preusser – TRANS-FUSIMO – An Integrative Approach to Model-Based Treatment Planning of Liver FUS Tobias Preusser – TRANS-FUSIMO – An Integrative Approach to Model-Based Treatment Planning of Liver FUS Learning Objectives: Understand the role of acoustic beam modeling for predicting the effectiveness of therapeutic ultrasound treatments. Apply acoustic modeling to specific breast, liver, kidney and transcranial anatomies. Determine how to obtain appropriate acoustic modeling parameters from clinical images. Understand the separate role of absorption and scattering in energy delivery to tissues. See how organ motion can be compensated for in ultrasound therapies. Compare simulated data with clinical temperature measurements in transcranial applications. Supported by NIH R01 HL172787 and R01 EB013433 (DC); EU Seventh Framework Programme (FP7/2007-2013) under 270186 (FUSIMO) and 611889 (TRANS-FUSIMO)(TP); and P01 CA159992, GE, FUSF and InSightec (UV)« less

Oxidative stress in follicular units during hair transplantation surgery.

PubMed

Crisóstomo, Márcio Rocha; Guimarães, Sérgio Botelho; de Vasconcelos, Paulo Roberto Leitão; Crisóstomo, Marília Gabriela Rocha; Benevides, André Nunes

2011-02-01

Hair transplantation surgery currently is a well-established procedure in plastic surgery. It consists of harvesting a strip of scalp from the back of the head, then obtaining grafts called follicular units (FUs) from this strip and implanting them in the bald area. The FUs undergo oxidative stress during cold ischemia and after their implantation. Surgery was performed for 18 patients between April and July 2008. Follicular units were preserved in solutions containing different growth-stimulating hormone (GSH) concentrations (5, 10, and 20 mmol). Saline solution was used as a control condition. Spectrophotometry was used to measure the thiobarbituric acid-reactive substance (TBARS) and GSH concentrations before ischemia (control group) in the FUs preserved in the four proposed solutions, then after 30 min of cold ischemia and 30 min after grafting. The data obtained were submitted to analysis of variance, t test, and linear regression analysis. The TBARS (μmol of malondialdehyde [MDA]/g) and GSH (μmol/g) concentrations were not significantly different between the four solutions in either the ischemia or grafting group. The GSH concentration did not differ significantly between the control (59.801 ± 30.639 μmol/g) and ischemia (56.284 ± 28.404 μmol/g) groups. The GSH concentrations were significantly greater (p < 0.05) in the postgrafting group (63.815 ± 28.404 μmol/g) than in the group subjected to ischemia. Increasing the GSH concentrations used in FU preservation solutions does not reduce the oxidative effects of cold ischemia and reperfusion injury during hair transplantation surgery.

Stand-alone error characterisation of microwave satellite soil moisture using a Fourier method

USDA-ARS?s Scientific Manuscript database

Error characterisation of satellite-retrieved soil moisture (SM) is crucial for maximizing their utility in research and applications in hydro-meteorology and climatology. Error characteristics can provide insights for retrieval development and validation, and inform suitable strategies for data fus...

Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood-brain-barrier opening in a rat model

NASA Astrophysics Data System (ADS)

Wang, Po-Hsun; Liu, Hao-Li; Hsu, Po-Hung; Lin, Chia-Yu; Chris Wang, Churng-Ren; Chen, Pin-Yuan; Wei, Kuo-Chen; Yen, Tzu-Chen; Li, Meng-Lin

2012-06-01

In this study, we develop a novel photoacoustic imaging technique based on gold nanorods (AuNRs) for quantitatively monitoring focused-ultrasound (FUS) induced blood-brain barrier (BBB) opening in a rat model in vivo. This study takes advantage of the strong near-infrared absorption (peak at ~800 nm) of AuNRs and the extravasation tendency from BBB opening foci due to their nano-scale size to passively label the BBB disruption area. Experimental results show that AuNR contrast-enhanced photoacoustic microscopy (PAM) successfully reveals the spatial distribution and temporal response of BBB disruption area in the rat brains. The quantitative measurement of contrast enhancement has potential to estimate the local concentration of AuNRs and even the dosage of therapeutic molecules when AuNRs are further used as nano-carrier for drug delivery or photothermal therapy. The photoacoustic results also provide complementary information to MRI, being helpful to discover more details about FUS induced BBB opening in small animal models.

The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation.

PubMed

Buratti, Emanuele; Baralle, Francisco Ernesto

2010-01-01

Heterogeneous ribonucleoproteins (hnRNPs) are multifunctional RNA-binding proteins (RBPs) involved in many cellular processes. They participate in most gene expression pathways, from DNA replication and repair to mRNA translation. Among this class of proteins, TDP-43 (and more recently FUS/TLS) have received considerable attention due to their involvement in several neurodegenerative diseases. This finding has prompted many research groups to focus on the gene expression pathways that are regulated by these proteins. The results have uncovered a considerable complexity of TDP-43 and FUS/TLS functions due to the many independent mechanisms by which they may act to influence various cellular processes (such as DNA transcription, pre-mRNA splicing, mRNA export/import). The aim of this chapter will be to review especially some of the novel functions that have been uncovered, such as role in miRNA synthesis, regulation of transcript levels, and potential autoregulatory mechanisms in order to provide the basis for further investigations.

Fusion and elastic scattering of 6Li + 58Ni at low energies

NASA Astrophysics Data System (ADS)

Aguilera, Elí F.; Amador-Valenzuela, Paulina; Martinez-Quiroz, Enrique; Lizcano, David; Garcia-Flores, Araceli; Kolata, James J.

2017-11-01

Sub-barrier fusion cross sections (σfus) for the 6Li + 58Ni system, obtained from the respective evaporation protons, are examined in the present work. With respect to expectations of a simple one-dimensional barrier penetration model, a large enhancement of the data is observed. Good consistency with equivalent data reported previously for similar systems is found. A comparison with total reaction cross sections (σR), deduced from elastic scattering measurements reported previously, indicates that σfus is close to σR within the measured energy range. To estimate the contribution of complete fusion (CF), an optical model analysis of the elastic scattering data is performed where CF is identified with the absorption in a short range volume potential. A surface polarization potential is added to the bare nuclear potential to simulate the effect of peripheral reactions. The results obtained indicate that other mechanisms different from CF may be dominant, especially in the lower energy region.

Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: Potential for targeting experimental brain tumors

PubMed Central

Diaz, Roberto Jose; McVeigh, Patrick Z.; O’Reilly, Meaghan A.; Burrell, Kelly; Bebenek, Matthew; Smith, Christian; Etame, Arnold; Zadeh, Gelareh; Hynynen, Kullervo; Wilson, Brian C.; Rutka, James T.

2014-01-01

Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50 nm or 120 nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120 nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors. PMID:24374363

Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening

NASA Astrophysics Data System (ADS)

Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C.; Konofagou, Elisa E.

2015-12-01

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n  =  60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 d thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: (1) the duration of the BBB opening (r2  =  0.77) (2) the permeability of the opened BBB (r2  =  0.82) (3) the likelihood of safe opening (P  <  0.05, safe opening compared to cases of damage; P  <  0.0001, no opening compared to safe opening). The inertial cavitation dose was correlated with the resulting BBB permeability (r2  =  0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the BBB opening duration, enabling thus control of opening according to the drug circulation time. In addition, avoiding adverse effects in the brain and assessing the pharmacokinetics of the compounds delivered can also be achieved by monitoring and controlling the stable cavitation emissions.

Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening.

PubMed

Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C; Konofagou, Elisa E

2015-12-07

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n  =  60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 d thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: (1) the duration of the BBB opening (r(2)  =  0.77); (2) the permeability of the opened BBB (r(2)  =  0.82); (3) the likelihood of safe opening (P  <  0.05, safe opening compared to cases of damage; P  <  0.0001, no opening compared to safe opening). The inertial cavitation dose was correlated with the resulting BBB permeability (r(2)  =  0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the BBB opening duration, enabling thus control of opening according to the drug circulation time. In addition, avoiding adverse effects in the brain and assessing the pharmacokinetics of the compounds delivered can also be achieved by monitoring and controlling the stable cavitation emissions.

The Transcription Factor Ste12 Mediates the Regulatory Role of the Tmk1 MAP Kinase in Mycoparasitism and Vegetative Hyphal Fusion in the Filamentous Fungus Trichoderma atroviride

PubMed Central

Gruber, Sabine; Zeilinger, Susanne

2014-01-01

Mycoparasitic species of the fungal genus Trichoderma are potent antagonists able to combat plant pathogenic fungi by direct parasitism. An essential step in this mycoparasitic fungus-fungus interaction is the detection of the fungal host followed by activation of molecular weapons in the mycoparasite by host-derived signals. The Trichoderma atroviride MAP kinase Tmk1, a homolog of yeast Fus3/Kss1, plays an essential role in regulating the mycoparasitic host attack, aerial hyphae formation and conidiation. However, the transcription factors acting downstream of Tmk1 are hitherto unknown. Here we analyzed the functions of the T. atroviride Ste12 transcription factor whose orthologue in yeast is targeted by the Fus3 and Kss1 MAP kinases. Deletion of the ste12 gene in T. atroviride not only resulted in reduced mycoparasitic overgrowth and lysis of host fungi but also led to loss of hyphal avoidance in the colony periphery and a severe reduction in conidial anastomosis tube formation and vegetative hyphal fusion events. The transcription of several orthologues of Neurospora crassa hyphal fusion genes was reduced upon ste12 deletion; however, the Δste12 mutant showed enhanced expression of mycoparasitism-relevant chitinolytic and proteolytic enzymes and of the cell wall integrity MAP kinase Tmk2. Based on the comparative analyses of Δste12 and Δtmk1 mutants, an essential role of the Ste12 transcriptional regulator in mediating outcomes of the Tmk1 MAPK pathway such as regulation of the mycoparasitic activity, hyphal fusion and carbon source-dependent vegetative growth is suggested. Aerial hyphae formation and conidiation, in contrast, were found to be independent of Ste12. PMID:25356841

The transcription factor Ste12 mediates the regulatory role of the Tmk1 MAP kinase in mycoparasitism and vegetative hyphal fusion in the filamentous fungus Trichoderma atroviride.

PubMed

Gruber, Sabine; Zeilinger, Susanne

2014-01-01

Mycoparasitic species of the fungal genus Trichoderma are potent antagonists able to combat plant pathogenic fungi by direct parasitism. An essential step in this mycoparasitic fungus-fungus interaction is the detection of the fungal host followed by activation of molecular weapons in the mycoparasite by host-derived signals. The Trichoderma atroviride MAP kinase Tmk1, a homolog of yeast Fus3/Kss1, plays an essential role in regulating the mycoparasitic host attack, aerial hyphae formation and conidiation. However, the transcription factors acting downstream of Tmk1 are hitherto unknown. Here we analyzed the functions of the T. atroviride Ste12 transcription factor whose orthologue in yeast is targeted by the Fus3 and Kss1 MAP kinases. Deletion of the ste12 gene in T. atroviride not only resulted in reduced mycoparasitic overgrowth and lysis of host fungi but also led to loss of hyphal avoidance in the colony periphery and a severe reduction in conidial anastomosis tube formation and vegetative hyphal fusion events. The transcription of several orthologues of Neurospora crassa hyphal fusion genes was reduced upon ste12 deletion; however, the Δste12 mutant showed enhanced expression of mycoparasitism-relevant chitinolytic and proteolytic enzymes and of the cell wall integrity MAP kinase Tmk2. Based on the comparative analyses of Δste12 and Δtmk1 mutants, an essential role of the Ste12 transcriptional regulator in mediating outcomes of the Tmk1 MAPK pathway such as regulation of the mycoparasitic activity, hyphal fusion and carbon source-dependent vegetative growth is suggested. Aerial hyphae formation and conidiation, in contrast, were found to be independent of Ste12.

Adjustable under-expression of yeast mating pathway proteins in Saccharomyces cerevisiae using a programmed ribosomal frameshift.

PubMed

Choi, Min-Yeon; Park, Sang-Hyun

2016-06-01

Experimental research in molecular biology frequently relies on the promotion or suppression of gene expression, an important tool in the study of its functions. Although yeast is among the most studied model systems with the ease of maintenance and manipulation, current experimental methods are mostly limited to gene deletion, suppression or overexpression of genes. Therefore, the ability to reduce protein expressions and then observing the effects would promote a better understanding of the exact functions and their interactions. Reducing protein expression is mainly limited by the difficulties associated with controlling the reduction level, and in some cases, the initial endogenous abundance is too low. For the under-expression to be useful as an experimental tool, repeatability and stability of reduced expression is important. We found that cis-elements in programmed -1 ribosomal frameshifting (-1RFS) of beet western yellow virus (BWYV) could be utilized to reduced protein expression in Saccharomyces cerevisiae. The two main advantages of using -1RFS are adjustable reduction rates and ease of use. To demonstrate the utility of this under-expression system, examples of reduced protein abundance were shown using yeast mating pathway components. The abundance of MAP kinase Fus3 was reduced to approximately 28-75 % of the wild-type value. Other MAP kinase mating pathway components, including Ste5, Ste11, and Ste7, were also under-expressed to verify that the -1RFS system works with different proteins. Furthermore, reduced Fus3 abundance altered the overall signal transduction outcome of the mating pathway, demonstrating the potential for further studies of signal transduction adjustment via under-expression.

Phase aberration simulation study of MRgFUS breast treatments

PubMed Central

Farrer, Alexis I.; Almquist, Scott; Dillon, Christopher R.; Neumayer, Leigh A.; Parker, Dennis L.; Christensen, Douglas A.; Payne, Allison

2016-01-01

Purpose: This simulation study evaluates the effects of phase aberration in breast MR-guided focused ultrasound (MRgFUS) ablation treatments performed with a phased-array transducer positioned laterally to the breast. A quantification of these effects in terms of thermal dose delivery and the potential benefits of phase correction is demonstrated in four heterogeneous breast numerical models. Methods: To evaluate the effects of varying breast tissue properties on the quality of the focus, four female volunteers with confirmed benign fibroadenomas were imaged using 3T MRI. These images were segmented into numerical models with six tissue types, with each tissue type assigned standard acoustic properties from the literature. Simulations for a single-plane 16-point raster-scan treatment trajectory centered in a fibroadenoma in each modeled breast were performed for a breast-specific MRgFUS system. At each of the 16 points, pressure patterns both with and without applying a phase correction technique were determined with the hybrid-angular spectrum method. Corrected phase patterns were obtained using a simulation-based phase aberration correction technique to adjust each element’s transmit phase to obtain maximized constructive interference at the desired focus. Thermal simulations were performed for both the corrected and uncorrected pressure patterns using a finite-difference implementation of the Pennes bioheat equation. The effect of phase correction was evaluated through comparison of thermal dose accumulation both within and outside a defined treatment volume. Treatment results using corrected and uncorrected phase aberration simulations were compared by evaluating the power required to achieve a 20 °C temperature rise at the first treatment location. The extent of the volumes that received a minimum thermal dose of 240 CEM at 43 °C inside the intended treatment volume as well as the volume in the remaining breast tissues was also evaluated in the form of a dose volume ratio (DVR), a DVR percent change between corrected and uncorrected phases, and an additional metric that measured phase spread. Results: With phase aberration correction applied, there was an improvement in the focus for all breast anatomies as quantified by a reduction in power required (13%–102%) to reach 20 °C when compared to uncorrected simulations. Also, the DVR percent change increased by 5%–77% in seven out of eight cases, indicating an improvement to the treatment as measured by a reduction in thermal dose deposited to the nontreatment tissues. Breast compositions with a higher degree of heterogeneity along the ultrasound beam path showed greater reductions in thermal dose delivered outside of the treatment volume with correction applied than beam trajectories that propagated through more homogeneous breast compositions. An increasing linear trend was observed between the DVR percent change and the phase-spread metric (R2 = 0.68). Conclusions: These results indicate that performing phase aberration correction for breast MRgFUS treatments is beneficial for the small-aperture transducer (14.4 × 9.8 cm) evaluated in this work. While all breast anatomies could benefit from phase aberration correction, greater benefits are observed in more heterogeneous anatomies. PMID:26936722

Magnetic Enhancement of Stem Cell-Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood-Brain Barrier.

PubMed

Shen, Wei-Bin; Anastasiadis, Pavlos; Nguyen, Ben; Yarnell, Deborah; Yarowsky, Paul J; Frenkel, Victor; Fishman, Paul S

2017-07-01

Focused ultrasound (FUS)-mediated blood-brain barrier disruption (BBBD) can enable even large therapeutics such as stem cells to enter the brain from the bloodstream. However, the efficiency is relatively low. Our previous study showed that human neural progenitor cells (hNPCs) loaded with superparamagnetic iron oxide nanoparticles (SPIONs) in culture were attracted by an external magnetic field. In vivo, enhanced brain retention was observed near a magnet mounted on the skull in a rat model of traumatic brain injury, where BBBD also occurs. The goal of the current study was to determine whether magnetic attraction of SPION-loaded hNPCs would also enhance their retention in the brain after FUS-mediated BBBD. A small animal magnetic resonance imaging (MRI)-guided FUS system operating at 1.5 MHz was used to treat rats (∼120 g) without tissue damage or hemorrhage. Evidence of successful BBBD was validated with both radiologic enhancement of gadolinium on postsonication TI MRI and whole brain section visualization of Evans blue dye. The procedure was then combined with the application of a powerful magnet to the head directly after intravenous injection of the hNPCs. Validation of cells within the brain was performed by staining with Perls' Prussian blue for iron and by immunohistochemistry with a human-specific antigen. By injecting equal numbers of iron oxide (SPIONs) and noniron oxide nanoparticles-loaded hNPCs, each labeled with a different fluorophore, we found significantly greater numbers of SPIONs-loaded cells retained in the brain at the site of BBBD as compared to noniron loaded cells. This result was most pronounced in regions of the brain closest to the skull (dorsal cortex) in proximity to the magnet surface. A more powerful magnet and a Halbach magnetic array resulted in more effective retention of SPION-labeled cells in even deeper brain regions such as the striatum and ventral cortex. There, up to 90% of hNPCs observed contained SPIONs compared to 60% to 70% with the less powerful magnet. Fewer cells were observed at 24 h posttreatment compared to 2 h (primarily in the dorsal cortex). These results demonstrate that magnetic attraction can substantially enhance the retention of stem cells after FUS-mediated BBBD. This procedure could provide a safer and less invasive approach for delivering stem cells to the brain, compared to direct intracranial injections, substantially reducing the risk of bleeding and infection.

Diversity and evolution of Lactobacillus casei group isolated from fermented dairy products in Tibet.

PubMed

Feng, Jing; Jiang, Yujun; Li, Mingyu; Zhao, Siyu; Zhang, Yanming; Li, Xuesong; Wang, Hui; Lin, Guangen; Wang, Hao; Li, Tiejing; Man, Chaoxin

2018-05-25

Bacteria in Lactobacillus casei group, including Lactobacillus casei (L. casei), Lactobacillus paracasei (L. paracasei), and Lactobacillus rhamnosus (L. rhamnosus) are important lactic acid bacteria in the production of fermented dairy products and are faced with the controversial nomenclatural status due to their close phylogenetic similarity. To probe the evolution and phylogeny of L. casei group, 100 isolates of lactic acid bacteria originated from naturally fermented dairy products in Tibet of China were subjected to multilocus sequence typing (MLST). The MLST scheme, based on analysis of the housekeeping genes fusA, ileS, lepA, leuS, pyrG, recA and recG, revealed that all the isolates belonged to a group containing the L. paracasei reference strains and were clearly different from the strains of L. casei and L. rhamnosus. Although nucleotide diversity (π) was low for the seven genes (ranging from 0.00341 for fusA to 0.01307 for recG), high genetic diversity represented by 83 sequence types (STs) with a discriminatory index of 0.98 was detected. A network-like structure based on split decomposition analysis, and the high values of the relative effect of recombination and mutation in the diversification of the lineages (r/m = 4.76) and the relative frequency of occurrence of recombination and mutation (ρ/θ = 2.62) indicated that intra-species recombination occurred frequently and homologous recombination played a key role in generating genotypic diversity amongst L. paracasei strains in Tibet. The discovery of 51 new STs and the results of STRUCTURE analysis suggested that the L. casei group in Tibet had an individual and particular population structure in comparison to European isolates. Overall, this research might be the first report about genetic diversity and population structure of Lactobacillus populations isolated from naturally fermented dairy products in Tibet based on MLST scheme.

Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas.

PubMed

Specht, Katja; Zhang, Lei; Sung, Yun-Shao; Nucci, Marisa; Dry, Sarah; Vaiyapuri, Sumathi; Richter, Gunther H S; Fletcher, Christopher D M; Antonescu, Cristina R

2016-04-01

Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose because of overlapping morphologic, immunohistochemical, and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4-related fusions, whereas another small subset shows BCOR-CCNB3 X-chromosomal paracentric inversion. Applying paired-end RNA sequencing to an SBRCT index case of a 44-year-old man, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by reverse transcription polymerase chain reaction and fluorescence in situ hybridization techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC, and BCOR-CCNB3 abnormalities for BCOR break-apart probes by fluorescence in situ hybridization to detect potential recurrent BCOR gene rearrangements outside the typical X-chromosomal inversion. Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, whereas no fusion partner was detected in the remaining 4 cases. Gene expression of the BCOR-MAML3-positive index case showed a distinct transcriptional profile with upregulation of HOX-gene signature, compared with classic Ewing's sarcoma or CIC-DUX4-positive SBRCTs. The clinicopathologic features of the SBRCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion-positive cases, combining 11 from our files with a meta-analysis of 42 published cases. The BCOR-CCNB3-positive tumors occurred preferentially in children and in bone, in contrast to alternative BCOR-rearranged SBRCTs, which presented in young adults, with a variable anatomic distribution. Furthermore, BCOR-rearranged tumors often displayed spindle cell areas, either well defined in intersecting fascicles or blending with the round cell component, which appears distinct from most other fusion-positive SBRCTs and shares histologic overlap with poorly differentiated synovial sarcoma.

Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas

PubMed Central

Specht, Katja; Zhang, Lei; Sung, Yun-Shao; Nucci, Marisa; Dry, Sarah; Vaiyapuri, Sumathi; Richter, Gunther HS; Fletcher, Christopher DM; Antonescu, Cristina R

2015-01-01

Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose due to overlapping morphologic, immunohistochemical and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4 related fusions, while another small subset shows BCOR-CCNB3 X-chromosomal paracentric inversion. Applying paired-end RNA sequencing to an SBRCT index case of a 44 year-old male, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by RT-PCR and FISH techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC and BCOR-CCNB3 abnormalities, for BCOR break-apart probes by FISH to detect potential recurrent BCOR gene rearrangements, outside the typical X-chromosomal inversion. Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, while no fusion partner was detected in the remaining 4 cases. Gene expression of the BCOR-MAML3 positive index case showed a distinct transcriptional profile with upregulation of HOX-gene signature, compared to classic Ewing sarcoma or CIC-DUX4-positive SBRCTs. The clinicopathologic features of the SRBCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion positive cases, combining 11 from our files with a meta-analysis of 42 published cases. The BCOR-CCNB3-positive tumors occurred preferentially in children and in bone, in contrast to alternative BCOR-rearranged SBRCTs which presented in young adults, with a variable anatomic distribution. Furthermore BCOR-rearranged tumors often displayed spindle cell areas, either well-defined in intersecting fascicles or blending with the round cell component, which appears distinct from most other fusion-positive SBRCTs and shares histologic overlap with poorly differentiated synovial sarcoma. PMID:26752546

Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies

PubMed Central

Arvanitis, Costas D.; McDannold, Nathan

2013-01-01

Purpose: Ultrasound can be used to noninvasively produce different bioeffects via viscous heating, acoustic cavitation, or their combination, and these effects can be exploited to develop a wide range of therapies for cancer and other disorders. In order to accurately localize and control these different effects, imaging methods are desired that can map both temperature changes and cavitation activity. To address these needs, the authors integrated an ultrasound imaging array into an MRI-guided focused ultrasound (MRgFUS) system to simultaneously visualize thermal and mechanical effects via passive acoustic mapping (PAM) and MR temperature imaging (MRTI), respectively. Methods: The system was tested with an MRgFUS system developed for transcranial sonication for brain tumor ablation in experiments with a tissue mimicking phantom and a phantom-filled ex vivo macaque skull. In experiments on cavitation-enhanced heating, 10 s continuous wave sonications were applied at increasing power levels (30–110 W) until broadband acoustic emissions (a signature for inertial cavitation) were evident. The presence or lack of signal in the PAM, as well as its magnitude and location, were compared to the focal heating in the MRTI. Additional experiments compared PAM with standard B-mode ultrasound imaging and tested the feasibility of the system to map cavitation activity produced during low-power (5 W) burst sonications in a channel filled with a microbubble ultrasound contrast agent. Results: When inertial cavitation was evident, localized activity was present in PAM and a marked increase in heating was observed in MRTI. The location of the cavitation activity and heating agreed on average after registration of the two imaging modalities; the distance between the maximum cavitation activity and focal heating was −3.4 ± 2.1 mm and −0.1 ± 3.3 mm in the axial and transverse ultrasound array directions, respectively. Distortions and other MRI issues introduced small uncertainties in the PAM/MRTI registration. Although there was substantial variation, a nonlinear relationship between the average intensity of the cavitation maps, which was relatively constant during sonication, and the peak temperature rise was evident. A fit to the data to an exponential had a correlation coefficient (R2) of 0.62. The system was also found to be capable of visualizing cavitation activity with B-mode imaging and of passively mapping cavitation activity transcranially during cavitation-enhanced heating and during low-power sonication with an ultrasound contrast agent. Conclusions: The authors have demonstrated the feasibility of integrating an ultrasound imaging array into an MRgFUS system to simultaneously map localized cavitation activity and temperature. The authors anticipate that this integrated approach can be utilized to develop controllers for cavitation-enhanced ablation and facilitate the optimization and development of this and other ultrasound therapies. The integrated system may also provide a useful tool to study the bioeffects of acoustic cavitation. PMID:24320468

Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies.

PubMed

Arvanitis, Costas D; McDannold, Nathan

2013-11-01

Ultrasound can be used to noninvasively produce different bioeffects via viscous heating, acoustic cavitation, or their combination, and these effects can be exploited to develop a wide range of therapies for cancer and other disorders. In order to accurately localize and control these different effects, imaging methods are desired that can map both temperature changes and cavitation activity. To address these needs, the authors integrated an ultrasound imaging array into an MRI-guided focused ultrasound (MRgFUS) system to simultaneously visualize thermal and mechanical effects via passive acoustic mapping (PAM) and MR temperature imaging (MRTI), respectively. The system was tested with an MRgFUS system developed for transcranial sonication for brain tumor ablation in experiments with a tissue mimicking phantom and a phantom-filled ex vivo macaque skull. In experiments on cavitation-enhanced heating, 10 s continuous wave sonications were applied at increasing power levels (30-110 W) until broadband acoustic emissions (a signature for inertial cavitation) were evident. The presence or lack of signal in the PAM, as well as its magnitude and location, were compared to the focal heating in the MRTI. Additional experiments compared PAM with standard B-mode ultrasound imaging and tested the feasibility of the system to map cavitation activity produced during low-power (5 W) burst sonications in a channel filled with a microbubble ultrasound contrast agent. When inertial cavitation was evident, localized activity was present in PAM and a marked increase in heating was observed in MRTI. The location of the cavitation activity and heating agreed on average after registration of the two imaging modalities; the distance between the maximum cavitation activity and focal heating was -3.4 ± 2.1 mm and -0.1 ± 3.3 mm in the axial and transverse ultrasound array directions, respectively. Distortions and other MRI issues introduced small uncertainties in the PAM∕MRTI registration. Although there was substantial variation, a nonlinear relationship between the average intensity of the cavitation maps, which was relatively constant during sonication, and the peak temperature rise was evident. A fit to the data to an exponential had a correlation coefficient (R(2)) of 0.62. The system was also found to be capable of visualizing cavitation activity with B-mode imaging and of passively mapping cavitation activity transcranially during cavitation-enhanced heating and during low-power sonication with an ultrasound contrast agent. The authors have demonstrated the feasibility of integrating an ultrasound imaging array into an MRgFUS system to simultaneously map localized cavitation activity and temperature. The authors anticipate that this integrated approach can be utilized to develop controllers for cavitation-enhanced ablation and facilitate the optimization and development of this and other ultrasound therapies. The integrated system may also provide a useful tool to study the bioeffects of acoustic cavitation.

Analysis of Four Automated Urinalysis Systems Compared to Reference Methods.

PubMed

Bartosova, Kamila; Kubicek, Zdenek; Franekova, Janka; Louzensky, Gustav; Lavrikova, Petra; Jabor, Antonin

2016-11-01

The aim of this study was to compare four automated urinalysis systems: the Iris iQ200 Sprint (Iris Diagnostics, U.S.A.) combined with the Arkray AUTION MAX AX 4030, Iris + AUTION, Arkray AU 4050 (Arkray Global Business, Inc., Japan), Dirui FUS 2000 (Dirui Industrial Co., P.R.C.), and Menarini sediMAX (Menarini, Italy). Urine concentrations of protein and glucose (Iris, Dirui) were compared using reference quantitative analysis on an Abbott Architect c16000. Leukocytes, erythrocytes, epithelia, and casts (Iris, Arkray, Diuri, Menarini) were compared to urine sediment under reference light microscopy, Leica DM2000 (Leica Microsystems GmbH, Germany) with calibrated FastRead plates (Biosigma S.r.l., Italy), using both native and stained preparations. Total protein and glucose levels were measured using the Iris + AUTION system with borderline trueness, while the Dirui analysis revealed worse performances for the protein and glucose measurements. True classifications of leukocytes and erythrocytes were above 85% and 72%, respectively. Kappa statistics revealed a nearly perfect evaluation of leukocytes for all tested systems; the erythrocyte evaluation was nearly perfect for the Iris, Dirui and Arkray analyzers and substantial for the Menarini analyzer. The epithelia identification was connected to high false negativity (above 15%) in the Iris, Arkray, and Menarini analyses. False-negative casts were above 70% for all tested systems. The use of automated urinalysis demonstrated some weaknesses and should be checked by experienced laboratory staff using light microscopy.

A simulation technique for 3D MR-guided acoustic radiation force imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Payne, Allison, E-mail: apayne@ucair.med.utah.edu; Bever, Josh de; Farrer, Alexis

2015-02-15

Purpose: In magnetic resonance-guided focused ultrasound (MRgFUS) therapies, the in situ characterization of the focal spot location and quality is critical. MR acoustic radiation force imaging (MR-ARFI) is a technique that measures the tissue displacement caused by the radiation force exerted by the ultrasound beam. This work presents a new technique to model the displacements caused by the radiation force of an ultrasound beam in a homogeneous tissue model. Methods: When a steady-state point-source force acts internally in an infinite homogeneous medium, the displacement of the material in all directions is given by the Somigliana elastostatic tensor. The radiation forcemore » field, which is caused by absorption and reflection of the incident ultrasound intensity pattern, will be spatially distributed, and the tensor formulation takes the form of a convolution of a 3D Green’s function with the force field. The dynamic accumulation of MR phase during the ultrasound pulse can be theoretically accounted for through a time-of-arrival weighting of the Green’s function. This theoretical model was evaluated experimentally in gelatin phantoms of varied stiffness (125-, 175-, and 250-bloom). The acoustic and mechanical properties of the phantoms used as parameters of the model were measured using independent techniques. Displacements at focal depths of 30- and 45-mm in the phantoms were measured by a 3D spin echo MR-ARFI segmented-EPI sequence. Results: The simulated displacements agreed with the MR-ARFI measured displacements for all bloom values and focal depths with a normalized RMS difference of 0.055 (range 0.028–0.12). The displacement magnitude decreased and the displacement pattern broadened with increased bloom value for both focal depths, as predicted by the theory. Conclusions: A new technique that models the displacements caused by the radiation force of an ultrasound beam in a homogeneous tissue model theory has been rigorously validated through comparison with experimentally obtained 3D displacement data in homogeneous gelatin phantoms using a 3D MR-ARFI sequence. The agreement of the experimentally measured and simulated results demonstrates the potential to use MR-ARFI displacement data in MRgFUS therapies.« less

A pernicious agent affecting avocado in Israel: a novel symbiotic Fusarium sp. associated with the ambrosia beetle Euwallacea fornicatus

USDA-ARS?s Scientific Manuscript database

Since first recorded in Israel in 2009, the ambrosia beetle, Euwallacea fornicatus Eichhoff, has been shown to vector a fusarial pathogen of avocado (Persea Americana Miller) in its mandibular mycangia. Multilocus molecular phylogenetic analyses indicate the pathogen represents a novel symbiotic Fus...

Phytotoxicity Evaluation of Type B Trichothecenes Using a Chlamydomonas reinhardtii Model System

PubMed Central

Suzuki, Tadahiro; Iwahashi, Yumiko

2014-01-01

Type B trichothecenes, which consist of deoxynivalenol (DON) and nivalenol (NIV) as the major end products, are produced by phytotoxic fungi, such as the Fusarium species, and pollute arable fields across the world. The DON toxicity has been investigated using various types of cell systems or animal bioassays. The evaluation of NIV toxicity, however, has been relatively restricted because of its lower level compared with DON. In this study, the Chlamydomonas reinhardtii testing system, which has been reported to have adequate NIV sensitivity, was reinvestigated under different mycotoxin concentrations and light conditions. The best concentration of DON and NIV, and their derivatives, for test conditions was found to be 25 ppm (2.5 × 10−2 mg/mL). In all light test conditions, DON, NIV, and fusarenon-X (FusX) indicated significant growth inhibition regardless of whether a light source existed, or under differential wavelength conditions. FusX growth was also influenced by changes in photon flux density. These results suggest that C. reinhardtii is an appropriate evaluation system for type B trichothecenes. PMID:24476708

Prion-like domains in RNA binding proteins are essential for building subnuclear paraspeckles

PubMed Central

Hennig, Sven; Kong, Geraldine; Mannen, Taro; Sadowska, Agata; Kobelke, Simon; Blythe, Amanda; Knott, Gavin J.; Iyer, K. Swaminathan; Ho, Diwei; Newcombe, Estella A.; Hosoki, Kana; Goshima, Naoki; Kawaguchi, Tetsuya; Hatters, Danny; Trinkle-Mulcahy, Laura; Hirose, Tetsuro; Bond, Charles S.

2015-01-01

Prion-like domains (PLDs) are low complexity sequences found in RNA binding proteins associated with the neurodegenerative disorder amyotrophic lateral sclerosis. Recently, PLDs have been implicated in mediating gene regulation via liquid-phase transitions that drive ribonucleoprotein granule assembly. In this paper, we report many PLDs in proteins associated with paraspeckles, subnuclear bodies that form around long noncoding RNA. We mapped the interactome network of paraspeckle proteins, finding enrichment of PLDs. We show that one protein, RBM14, connects key paraspeckle subcomplexes via interactions mediated by its PLD. We further show that the RBM14 PLD, as well as the PLD of another essential paraspeckle protein, FUS, is required to rescue paraspeckle formation in cells in which their endogenous counterpart has been knocked down. Similar to FUS, the RBM14 PLD also forms hydrogels with amyloid-like properties. These results suggest a role for PLD-mediated liquid-phase transitions in paraspeckle formation, highlighting this nuclear body as an excellent model system for understanding the perturbation of such processes in neurodegeneration. PMID:26283796

Transducer design and characterization for dorsal-based ultrasound exposure and two-photon imaging of in vivo blood-brain barrier disruption in a rat model.

PubMed

Nhan, Tam; Burgess, Alison; Hynynen, Kullervo

2013-07-01

Focused ultrasound (FUS) and microbubbles have been used effectively for transient, noninvasive blood¿ brain barrier disruption (BBBD). The use of two-photon microscopy (2PM) imaging of BBBD can provide valuable insights into the associated cellular mechanisms and fundamental biological effects. Coupling a thin ring-shaped transducer to a coverslip offers a robust solution for simultaneous dorsal application of FUS for BBBD and in vivo 2PM imaging of the cerebral microvasculature under treatment conditions. Two modes of vibration (thickness and height) from the transducer configuration were investigated for BBBD in an animal model. With the transducer operating in the thickness mode at 1.2 MHz frequency, shallow and localized BBBD near the cortical surface of animal brain was detected via 2PM and confirmed by Evans blue (EB) extravasation. Acoustic pressures ranging from 0.2 to 0.8 MPa were tested and the probability for successful BBBD was identified. Two distinct types of disruption characterized by different leakage kinetics were observed and appeared to be dependent on acoustic pressure.

Primary low-grade fibromyxoid sarcoma of breast: A rare case report with immunohistochemical and fluorescence in situ hybridization detection.

PubMed

Master, Yutao Zhang; Master, Dan Wan; Master, Fuping Gao

2018-02-24

Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor with a bland histological appearance but malignant biological behavior. Primary LGFMS of breast has not been described in the English-language literature. Here, we report a 58-year-old Chinese female patient who presented with a painless mass in the right breast for more than 30 years. The tumor consists of spindle cells resembling fibroblasts and includes two kinds of morphological change, which are alternating collagenized hypocellular zone and cell-rich myxoid area. There are more arcades of curvilinear blood vessels. The spindle cells are not heteromorphic and mitotic figures are scarce. Immunostaining shows tumor cells are positive for vimentin, mucin4, CD99 and Bcl-2, but negative for SMA, desmin, S100, CD34, ALK and myogenin. FUS gene rearrangement is positively detected by FISH. The patient has been followed up for 59 months and is in a favorable condition. This rare location of LGFMS should be noted. Copyright © 2018. Published by Elsevier Inc.

The reduction in treatment efficiency at high acoustic powers during MR-guided transcranial focused ultrasound thalamotomy for Essential Tremor.

PubMed

Hughes, Alec; Huang, Yuexi; Schwartz, Michael L; Hynynen, Kullervo

2018-05-14

To analyze clinical data indicating a reduction in the induced energy-temperature efficiency relationship during transcranial focused ultrasound (FUS) Essential Tremor (ET) thalamotomy treatments at higher acoustic powers, establish its relationship with the spatial distribution of the focal temperature elevation, and explore its cause. A retrospective observational study of patients (n = 19) treated between July 2015 and August 2016 for (ET) by FUS thalamotomy was performed. These data were analyzed to compare the relationships between the applied power, the applied energy, the resultant peak temperature achieved in the brain, and the dispersion of the focal volume. Full ethics approval was received and all patients provided signed informed consent forms before the initiation of the study. Computer simulations, animal experiments, and clinical system tests were performed to determine the effects of skull heating, changes in brain properties and transducer acoustic output, respectively. All animal procedures were approved by the Animal Care and Use Committee and conformed to the guidelines set out by the Canadian Council on Animal Care. MATLAB was used to perform statistical analysis. The reduction in the energy efficiency relationship during treatment correlates with the increase in size of the focal volume at higher sonication powers. A linear relationship exists showing that a decrease in treatment efficiency correlates positively with an increase in the focal size over the course of treatment (P < 0.01), supporting the hypothesis of transient skull and tissue heating causing acoustic aberrations leading to a decrease in efficiency. Changes in thermal conductivity, perfusion, absorption rates in the brain, as well as ultrasound transducer acoustic output levels were found to have minimal effects on the observed reduction in efficiency. The reduction in energy-temperature efficiency during high-power FUS treatments correlated with observed increases in the size of the focal volume and is likely caused by transient changes in the tissue and skull during heating. © 2018 American Association of Physicists in Medicine.

Analysis of lower limb work-energy patterns in world-class race walkers.

PubMed

Hanley, Brian; Bissas, Athanassios

2017-05-01

The aim of this study was to analyse lower limb work patterns in world-class race walkers. Seventeen male and female athletes race walked at competitive pace. Ground reaction forces (1000 Hz) and high-speed videos (100 Hz) were recorded and normalised joint moments, work and power, stride length, stride frequency and speed estimated. The hip flexors and extensors were the main generators of energy (24.5 J (±6.9) and 40.3 J (±8.3), respectively), with the ankle plantarflexors (16.3 J (±4.3)) contributing to the energy generated during late stance. The knee generated little energy but performed considerable negative work during swing (-49.1 J (±8.7)); the energy absorbed by the knee extensors was associated with smaller changes in velocity during stance (r = .783, P < .001), as was the energy generated by the hip flexors (r = -.689, P = .002). The knee flexors did most negative work (-38.6 J (±5.8)) and the frequent injuries to the hamstrings are probably due to this considerable negative work. Coaches should note the important contributions of the hip and ankle muscles to energy generation and the need to develop knee flexor strength in reducing the risk of injury.

The safest parameters for FUS-induced blood-brain barrier opening without effects on the opening volume

NASA Astrophysics Data System (ADS)

Tung, Yao-Sheng; Olumolade, Yemi; Wang, Shutao; Wu, Shih-Ying; Konofagou, Elisa E.

2012-11-01

Acoustic cavitation has been identified as the main physical mechanism for the focused ultrasound (FUS) induced blood-brain barrier (BBB) opening. In this paper, the mechanism of stable cavitation (SC) and inertial cavitation (IC) responsible for BBB opening was investigated. Thirty-three (n=33) mice were intravenously injected with bubbles of 4-5 μm in diameter. The right hippocampus was then sonicated using focused 1.5-MHz ultrasound and three different studies were carried out. First, pulse lengths (PLs) of 0.1, 0.5, 2, and 5 ms at 0.18- MPa peak rarefactional pressure with 5-Hz pulse repetition frequency (PRF) and 5-minute duration were used to identify the threshold of PL using SC. Second, the effects of the duty cycle and exposure time were investigated. Third, the BBB opening size was compared between the SC and the IC. In the case of IC-induced BBB opening, a burst sequence (3-cycles PL; 5-Hz burst repetition frequency (BRF); 30 s duration) at 0.45 MPa was applied. Passive cavitation detection was performed with each sonication to detect whether a broadband response was obtained, i.e., if IC occurred, during BBB opening. The properties of BBB opening were measured through MRI. The threshold of PL for BBB opening was identified between 0.1 and 0.5 ms using SC, but the BBB can be opened in few cycles using IC. The BBB opening volume and normalized intensity increased with the PL, but reached saturation when the PL was above 2 ms. Once the PL threshold was reached, the same exposure time induced a similar BBB opening volume, but longer sonication duration induced higher MR intensity. The duty cycle was found not to play an important role on the BBB opening. Comparable BBB opening volume (20-25 mm3) could be reached between long PL (7500 cycles, i.e., 5 ms) at 0.18 MPa and 3 cycles at 0.45 MPa. 3-kDa fluorescently tagged dextran may be able to diffuse to the parenchyma after IC-induced BBB opening at 0.45 MPa but not after SC-induced BBB opening at 0.18 MPa.

Casualty Evacuation in the Contemporary Operating Environment

DTIC Science & Technology

2002-05-20

HIFU ), or Focused Ultrasound ( FUS ), can be used to rapidly kill tissue (directly applicable to cancer treatment, for example) and to stop internal...132 Peter Kaczkowski, Development of a High-Intensity Focused Ultrasound System for Image-guided Ultrasound Surgery...spatial dimension, with acquisition and display occurring nearly in real time.135 Recent research has shown that High Intensity Focused Ultrasound

[Negative air ions generated by plants upon pulsed electric field stimulation applied to soil].

PubMed

Wu, Ren-ye; Deng, Chuan-yuan; Yang, Zhi-jian; Weng, Hai-yong; Zhu, Tie-jun-rong; Zheng, Jin-gui

2015-02-01

This paper investigated the capacity of plants (Schlumbergera truncata, Aloe vera var. chinensis, Chlorophytum comosum, Schlumbergera bridgesii, Gymnocalycium mihanovichii var. friedrichii, Aspidistra elatior, Cymbidium kanran, Echinocactus grusonii, Agave americana var. marginata, Asparagus setaceus) to generate negative air ions (NAI) under pulsed electric field stimulation. The results showed that single plant generated low amounts of NAI in natural condition. The capacity of C. comosum and G. mihanovichii var. friedrichii generated most NAI among the above ten species, with a daily average of 43 ion · cm(-3). The least one was A. americana var. marginata with the value of 19 ion · cm(-3). When proper pulsed electric field stimulation was applied to soil, the NAI of ten plant species were greatly improved. The effect of pulsed electric field u3 (average voltage over the pulse period was 2.0 x 10(4) V, pulse frequency was 1 Hz, and pulse duration was 50 ms) was the greatest. The mean NAI concentration of C. kanran was the highest 1454967 ion · cm(-3), which was 48498.9 times as much as that in natural condition. The lowest one was S. truncata with the value of 34567 ion · cm(-3), which was 843.1 times as much as that in natural condition. The capacity of the same plants to generate negative air ion varied extremely under different intensity pulsed electric fields.

Effect of Zn2+ on halohydrin dehalogenase expression and accumulation through multi-parameter correlation research with Escherichia coli P84A/MC1061

PubMed Central

Li, Xiao; Luo, Yu-Di; Pan, Dong-Rui; Shi, Xiao-Dan; Tan, Ya-Li; Li, Zhi-Hong

2017-01-01

ABSTRACT Using 5 Zn2+ supplementation strategies in a 50 L batch bioreactor named FUS-50L(A), possible correlations among Zn2+ content and addition timing, physiologic activity (PA), halohydrin dehalogenase (HheC) accumulation of Escherichia coli P84A/MC1061 were systematically investigated. First, Zn2+ was confirmed as the significant factor, and its optimal concentration for HheC expression was 3.87 mg/L through fermentation experiments in shaking flasks. Second, based on experimental results from the different strategies, it was found that PA, nutrient consumption rate (NCR) and specific growth rate (μ) for E. coli P84A/MC1061 were promoted in the log phase (4–8 h) under appropriate Zn2+ concentrations in the lag phase and late log phase. Furthermore cell biomass was also increased to a higher level and the maximum HheC activity (i.e. HheCmax) was increased by 9.80%, and the time to reach HheCmax was reduced from 16 to 12 hours. Furthermore, appropriate supplementation of Zn2+ caused higher μ for E. coli P84A/MC1061, which resulted in more rapid accumulation of increased acetic acid concentrations, leading to higher acetic acid consumption avoiding any negative effects on producing HheC because of carbon source being exhausted prematurely and acetic acid being consumed rapidly. PMID:28282255

Three Fusarium oxysporum mitogen-activated protein kinases (MAPKs) have distinct and complementary roles in stress adaptation and cross-kingdom pathogenicity.

PubMed

Segorbe, David; Di Pietro, Antonio; Pérez-Nadales, Elena; Turrà, David

2017-09-01

Mitogen-activated protein kinase (MAPK) cascades mediate cellular responses to environmental signals. Previous studies in the fungal pathogen Fusarium oxysporum have revealed a crucial role of Fmk1, the MAPK orthologous to Saccharomyces cerevisiae Fus3/Kss1, in vegetative hyphal fusion and plant infection. Here, we genetically dissected the individual and combined contributions of the three MAPKs Fmk1, Mpk1 and Hog1 in the regulation of development, stress response and virulence of F. oxysporum on plant and animal hosts. Mutants lacking Fmk1 or Mpk1 were affected in reactive oxygen species (ROS) homeostasis and impaired in hyphal fusion and aggregation. Loss of Mpk1 also led to increased sensitivity to cell wall and heat stress, which was exacerbated by simultaneous inactivation of Fmk1, suggesting that both MAPKs contribute to cellular adaptation to high temperature, a prerequisite for mammalian pathogens. Deletion of Hog1 caused increased sensitivity to hyperosmotic stress and resulted in partial rescue of the restricted colony growth phenotype of the mpk1Δ mutant. Infection assays on tomato plants and the invertebrate animal host Galleria mellonella revealed distinct and additive contributions of the different MAPKs to virulence. Our results indicate that positive and negative cross-talk between the three MAPK pathways regulates stress adaptation, development and virulence in the cross-kingdom pathogen F. oxysporum. © 2016 BSPP AND JOHN WILEY & SONS LTD.

Impact of Focused Ultrasound-enhanced Drug Delivery on Survival in Rats with Glioma

NASA Astrophysics Data System (ADS)

Treat, Lisa Hsu; Zhang, Yongzhi; McDannold, Nathan; Hynynen, Kullervo

2009-04-01

Malignancies of the brain remain difficult to treat with chemotherapy because the selective permeability of the blood-brain barrier (BBB) blocks many potent agents from reaching their target. Previous studies have illustrated the feasibility of drug and antibody delivery across the BBB using MRI-guided focused ultrasound. In this study, we investigated the impact of focused ultrasound-enhanced delivery of doxorubicin on survival in rats with aggressive glioma. Sprague-Dawley rats were implanted with 9 L gliosarcoma cells in the brain. Eight days after implantation, each rat received one of the following: (1) no treatment (control), (2) a single treatment with microbubble-enhanced MRI-guided focused ultrasound (FUS only), (3) a single treatment with i.v. liposomal doxorubicin (DOX only), or (4) a single treatment with microbubble-enhanced MRI-guided focused ultrasound and concurrent i.v. injections of liposomal doxorubicin (FUS+DOX). The survival time from implantation to death or euthanasia was recorded. We observed a modest but significant increase in median survival time in rats treated with combined MRI-guided focused ultrasound chemotherapy, compared to chemotherapy alone (p<0.001). There was no significant improvement in survival between those who received stand-alone chemotherapy and those who did not receive any treatment (p>0.10). Our study demonstrates for the first time a therapeutic benefit achieved with ultrasound-enhanced drug delivery across the blood-brain barrier. This confirmation of efficacy in an in vivo tumor model indicates that targeted drug delivery using MRI-guided focused ultrasound has the potential to have a major impact on the treatment of patients with brain tumors and other neurological disorders.

Multi-resolution simulation of focused ultrasound propagation through ovine skull from a single-element transducer

NASA Astrophysics Data System (ADS)

Yoon, Kyungho; Lee, Wonhye; Croce, Phillip; Cammalleri, Amanda; Yoo, Seung-Schik

2018-05-01

Transcranial focused ultrasound (tFUS) is emerging as a non-invasive brain stimulation modality. Complicated interactions between acoustic pressure waves and osseous tissue introduce many challenges in the accurate targeting of an acoustic focus through the cranium. Image-guidance accompanied by a numerical simulation is desired to predict the intracranial acoustic propagation through the skull; however, such simulations typically demand heavy computation, which warrants an expedited processing method to provide on-site feedback for the user in guiding the acoustic focus to a particular brain region. In this paper, we present a multi-resolution simulation method based on the finite-difference time-domain formulation to model the transcranial propagation of acoustic waves from a single-element transducer (250 kHz). The multi-resolution approach improved computational efficiency by providing the flexibility in adjusting the spatial resolution. The simulation was also accelerated by utilizing parallelized computation through the graphic processing unit. To evaluate the accuracy of the method, we measured the actual acoustic fields through ex vivo sheep skulls with different sonication incident angles. The measured acoustic fields were compared to the simulation results in terms of focal location, dimensions, and pressure levels. The computational efficiency of the presented method was also assessed by comparing simulation speeds at various combinations of resolution grid settings. The multi-resolution grids consisting of 0.5 and 1.0 mm resolutions gave acceptable accuracy (under 3 mm in terms of focal position and dimension, less than 5% difference in peak pressure ratio) with a speed compatible with semi real-time user feedback (within 30 s). The proposed multi-resolution approach may serve as a novel tool for simulation-based guidance for tFUS applications.

Improving Thermal Dose Accuracy in Magnetic Resonance-Guided Focused Ultrasound Surgery: Long-Term Thermometry Using a Prior Baseline as a Reference

PubMed Central

Bitton, Rachel R.; Webb, Taylor D.; Pauly, Kim Butts; Ghanouni, Pejman

2015-01-01

Purpose To investigate thermal dose volume (TDV) and non-perfused volume (NPV) of magnetic resonance-guided focused ultrasound (MRgFUS) treatments in patients with soft tissue tumors, and describe a method for MR thermal dosimetry using a baseline reference. Materials and Methods Agreement between TDV and immediate post treatment NPV was evaluated from MRgFUS treatments of five patients with biopsy-proven desmoid tumors. Thermometry data (gradient echo, 3T) were analyzed over the entire course of the treatments to discern temperature errors in the standard approach. The technique searches previously acquired baseline images for a match using 2D normalized cross-correlation and a weighted mean of phase difference images. Thermal dose maps and TDVs were recalculated using the matched baseline and compared to NPV. Results TDV and NPV showed between 47%–91% disagreement, using the standard immediate baseline method for calculating TDV. Long-term thermometry showed a nonlinear local temperature accrual, where peak additional temperature varied between 4–13°C (mean = 7.8°C) across patients. The prior baseline method could be implemented by finding a previously acquired matching baseline 61% ± 8% (mean ± SD) of the time. We found 7%–42% of the disagreement between TDV and NPV was due to errors in thermometry caused by heat accrual. For all patients, the prior baseline method increased the estimated treatment volume and reduced the discrepancies between TDV and NPV (P = 0.023). Conclusion This study presents a mismatch between in-treatment and post treatment efficacy measures. The prior baseline approach accounts for local heating and improves the accuracy of thermal dose-predicted volume. PMID:26119129

Improving thermal dose accuracy in magnetic resonance-guided focused ultrasound surgery: Long-term thermometry using a prior baseline as a reference.

PubMed

Bitton, Rachel R; Webb, Taylor D; Pauly, Kim Butts; Ghanouni, Pejman

2016-01-01

To investigate thermal dose volume (TDV) and non-perfused volume (NPV) of magnetic resonance-guided focused ultrasound (MRgFUS) treatments in patients with soft tissue tumors, and describe a method for MR thermal dosimetry using a baseline reference. Agreement between TDV and immediate post treatment NPV was evaluated from MRgFUS treatments of five patients with biopsy-proven desmoid tumors. Thermometry data (gradient echo, 3T) were analyzed over the entire course of the treatments to discern temperature errors in the standard approach. The technique searches previously acquired baseline images for a match using 2D normalized cross-correlation and a weighted mean of phase difference images. Thermal dose maps and TDVs were recalculated using the matched baseline and compared to NPV. TDV and NPV showed between 47%-91% disagreement, using the standard immediate baseline method for calculating TDV. Long-term thermometry showed a nonlinear local temperature accrual, where peak additional temperature varied between 4-13°C (mean = 7.8°C) across patients. The prior baseline method could be implemented by finding a previously acquired matching baseline 61% ± 8% (mean ± SD) of the time. We found 7%-42% of the disagreement between TDV and NPV was due to errors in thermometry caused by heat accrual. For all patients, the prior baseline method increased the estimated treatment volume and reduced the discrepancies between TDV and NPV (P = 0.023). This study presents a mismatch between in-treatment and post treatment efficacy measures. The prior baseline approach accounts for local heating and improves the accuracy of thermal dose-predicted volume. © 2015 Wiley Periodicals, Inc.

Multi-resolution simulation of focused ultrasound propagation through ovine skull from a single-element transducer.

PubMed

Yoon, Kyungho; Lee, Wonhye; Croce, Phillip; Cammalleri, Amanda; Yoo, Seung-Schik

2018-05-10

Transcranial focused ultrasound (tFUS) is emerging as a non-invasive brain stimulation modality. Complicated interactions between acoustic pressure waves and osseous tissue introduce many challenges in the accurate targeting of an acoustic focus through the cranium. Image-guidance accompanied by a numerical simulation is desired to predict the intracranial acoustic propagation through the skull; however, such simulations typically demand heavy computation, which warrants an expedited processing method to provide on-site feedback for the user in guiding the acoustic focus to a particular brain region. In this paper, we present a multi-resolution simulation method based on the finite-difference time-domain formulation to model the transcranial propagation of acoustic waves from a single-element transducer (250 kHz). The multi-resolution approach improved computational efficiency by providing the flexibility in adjusting the spatial resolution. The simulation was also accelerated by utilizing parallelized computation through the graphic processing unit. To evaluate the accuracy of the method, we measured the actual acoustic fields through ex vivo sheep skulls with different sonication incident angles. The measured acoustic fields were compared to the simulation results in terms of focal location, dimensions, and pressure levels. The computational efficiency of the presented method was also assessed by comparing simulation speeds at various combinations of resolution grid settings. The multi-resolution grids consisting of 0.5 and 1.0 mm resolutions gave acceptable accuracy (under 3 mm in terms of focal position and dimension, less than 5% difference in peak pressure ratio) with a speed compatible with semi real-time user feedback (within 30 s). The proposed multi-resolution approach may serve as a novel tool for simulation-based guidance for tFUS applications.

Force-Free Time-Harmonic Plasmoids

DTIC Science & Technology

1992-10-01

effect of currents or vortical motion are absolutely required for stability. What makes the present model attractive is the minimization of the body ...radiative-mode effects may be very fruitful in the future. For example: Rigid non-radiative composite "particles" containing large numbers of fus- able...12 7. The neutral plasma .......... .......................... 12 8. Forces on a moving electron ....... ......... .............. 13 9. Effects of

An MBS-Assisted Femtocell Transmit Power Control Scheme with Mobile User QoS Guarantee in 2-Tier Heterogeneous Femtocell Networks

PubMed Central

Yang, Chih-Cheng; Sheu, Shiann-Tsong

2013-01-01

This study investigates how to adjust the transmit power of femto base station (FBS) to mitigate interference problems between the FBSs and mobile users (MUs) in the 2-tier heterogeneous femtocell networks. A common baseline of deploying the FBS to increase the indoor access bandwidth requires that the FBS operation will not affect outdoor MUs operation with their quality-of-service (QoS) requirements. To tackle this technical problem, an FBS transmit power adjustment (FTPA) algorithm is proposed to adjust the FBS transmit power (FTP) to avoid unwanted cochannel interference (CCI) with the neighboring MUs in downlink transmission. FTPA reduces the FTP to serve its femto users (FUs) according to the QoS requirements of the nearest neighboring MUs to the FBS so that the MU QoS requirement is guaranteed. Simulation results demonstrate that FTPA can achieve a low MU outage probability as well as serve FUs without violating the MU QoS requirements. Simulation results also reveal that FTPA has better performance on voice and video services which are the major trend of future multimedia communication in the NGN. PMID:24391461

Riluzole does not improve lifespan or motor function in three ALS mouse models.

PubMed

Hogg, Marion C; Halang, Luise; Woods, Ina; Coughlan, Karen S; Prehn, Jochen H M

2018-08-01

Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1 G93A model, the TDP-43 A315T model, and the recently developed FUS (1-359) model. Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset. Lifespan was assessed and motor function tests were carried out twice weekly to determine whether riluzole slowed disease progression. Riluzole treatment had no significant benefit on lifespan in any of the ALS mouse models tested. Riluzole had no significant impact on decline in motor performance in the FUS (1-359) and SOD1 G93A transgenic mice as assessed by Rotarod and stride length analysis. Riluzole is widely prescribed for ALS patients despite questions surrounding its efficacy. Our data suggest that if riluzole was identified as a therapeutic candidate today it would not progress past pre-clinical assessment. This raises questions about the standards used in pre-clinical assessment of therapeutic candidates for the treatment of ALS.

Changes in cat urinary glycosaminoglycans with age and in feline urologic syndrome.

PubMed

Pereira, Daionety A; Aguiar, Jair A K; Hagiwara, Mitika K; Michelacci, Yara M

2004-04-07

The aim of the present study was to characterize the urinary excretion of glycosaminoglycans in kittens and adult healthy cats, as well as in cats with a low urinary tract disease, the feline urologic syndrome (FUS). The main urinary glycosaminoglycan in cats was found to be chondroitin sulfate, with smaller amounts of dermatan sulfate and heparan sulfate. There was no difference in the urinary glycosaminoglycan concentration with sex, but a marked decrease occurred with age, due to chondroitin sulfate. Trace amounts of keratan sulfate were also detected in the urine of kittens, but not of healthy adult cats. Dermatan sulfate and heparan sulfate were the only glycosaminoglycans found in the urinary tract and kidney, and chondroitin sulfate was the only glycosaminoglycan found in the plasma. These data suggest that the main urinary glycosaminoglycan chondroitin sulfate is of systemic origin and filtered in the kidney, while the minor components dermatan sulfate and heparan sulfate may come from the urinary tract. The urinary glycosaminoglycan concentration was greatly decreased in animals with FUS, as compared to normal adults. We hypothesize that these low glycosaminoglycan levels reflect a damage to the bladder surface, resulting in absorption and/or degradation of the endogenous urinary glycosaminoglycans.

Improvement of constraint-based flux estimation during L-phenylalanine production with Escherichia coli using targeted knock-out mutants.

PubMed

Weiner, Michael; Tröndle, Julia; Albermann, Christoph; Sprenger, Georg A; Weuster-Botz, Dirk

2014-07-01

Fed-batch production of the aromatic amino acid L-phenylalanine was studied with recombinant Escherichia coli strains on a 15 L-scale using glycerol as carbon source. Flux Variability Analysis (FVA) was applied for intracellular flux estimation to obtain an insight into intracellular flux distribution during L-phenylalanine production. Variability analysis revealed great flux uncertainties in the central carbon metabolism, especially concerning malate consumption. Due to these results two recombinant strains were genetically engineered differing in the ability of malate degradation and anaplerotic reactions (E. coli FUS4.11 ΔmaeA pF81kan and E. coli FUS4.11 ΔmaeA ΔmaeB pF81kan). Applying these malic enzyme knock-out mutants in the standardized L-phenylalanine production process resulted in almost identical process performances (e.g., L-phenylalanine concentration, production rate and byproduct formation). This clearly highlighted great redundancies in central metabolism in E. coli. Uncertainties of intracellular flux estimations by constraint-based analyses during fed-batch production of L-phenylalanine were drastically reduced by application of the malic enzyme knock-out mutants. © 2014 Wiley Periodicals, Inc.

An MBS-assisted femtocell transmit power control scheme with mobile user QoS guarantee in 2-tier heterogeneous femtocell networks.

PubMed

Chen, Jenhui; Yang, Chih-Cheng; Sheu, Shiann-Tsong

2013-01-01

This study investigates how to adjust the transmit power of femto base station (FBS) to mitigate interference problems between the FBSs and mobile users (MUs) in the 2-tier heterogeneous femtocell networks. A common baseline of deploying the FBS to increase the indoor access bandwidth requires that the FBS operation will not affect outdoor MUs operation with their quality-of-service (QoS) requirements. To tackle this technical problem, an FBS transmit power adjustment (FTPA) algorithm is proposed to adjust the FBS transmit power (FTP) to avoid unwanted cochannel interference (CCI) with the neighboring MUs in downlink transmission. FTPA reduces the FTP to serve its femto users (FUs) according to the QoS requirements of the nearest neighboring MUs to the FBS so that the MU QoS requirement is guaranteed. Simulation results demonstrate that FTPA can achieve a low MU outage probability as well as serve FUs without violating the MU QoS requirements. Simulation results also reveal that FTPA has better performance on voice and video services which are the major trend of future multimedia communication in the NGN.

Improved Design of Stellarator Coils for Current Carrying Plasmas

NASA Astrophysics Data System (ADS)

Drevlak, M.; Strumberger, E.; Hirshman, S.; Boozer, A.; Brooks, A.; Valanju, P.

1998-11-01

The method of automatic optimization (P. Merkel, Nucl. Fus. 27), (1987) 867; P. Merkel, M. Drevlak, Proc 25th EPS Conf. on Cont. Fus. and Plas. Phys., Prague, in print. for the design of stellarator coils consists essentially of determining filaments such that the average relative field error int dS [ (B_coil + B_j) \\cdot n]^2/B^2_coil is minimized on the prescribed plasma boundary. Bj is the magnetic field produced by the plasma currents of the given finite β fixed boundary equilibrium. For equilibria of the W7-X type, Bj can be neglected, because of the reduced parallel plasma currents. This is not true for quasi-axisymmetric stellarator (QAS) configurations (A. Reiman, et al., to be published.) with large equilibrium and net plasma (bootstrap) currents. Although the coils for QAS exhibit low values of the field error, free boundary calculations indicate that the shape of the plasma is usually not accurately reproduced , particularly when saddle coils are used. We investigate if the surface reconstruction can be improved by introducing a modified measure of the field error based on a measure of the resonant components of the normal field.

A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping

NASA Astrophysics Data System (ADS)

Deng, Lulu; O'Reilly, Meaghan A.; Jones, Ryan M.; An, Ran; Hynynen, Kullervo

2016-12-01

Focused ultrasound (FUS) phased arrays show promise for non-invasive brain therapy. However, the majority of them are limited to a single transmit/receive frequency and therefore lack the versatility to expose and monitor the treatment volume. Multi-frequency arrays could offer variable transmit focal sizes under a fixed aperture, and detect different spectral content on receive for imaging purposes. Here, a three-frequency (306, 612, and 1224 kHz) sparse hemispherical ultrasound phased array (31.8 cm aperture; 128 transducer modules) was constructed and evaluated for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. The array is able to perform effective electronic beam steering over a volume spanning (-40, 40) and (-30, 50) mm in the lateral and axial directions, respectively. The focal size at the geometric center is approximately 0.9 (2.1) mm, 1.7 (3.9) mm, and 3.1 (6.5) mm in lateral (axial) pressure full width at half maximum (FWHM) at 1224, 612, and 306 kHz, respectively. The array was also found capable of dual-frequency excitation and simultaneous multi-foci sonication, which enables the future exploration of more complex exposure strategies. Passive acoustic mapping of dilute microbubble clouds demonstrated that the point spread function of the receive array has a lateral (axial) intensity FWHM between 0.8-3.5 mm (1.7-11.7 mm) over a volume spanning (-25, 25) mm in both the lateral and axial directions, depending on the transmit/receive frequency combination and the imaging location. The device enabled both half and second harmonic imaging through the intact skull, which may be useful for improving the contrast-to-tissue ratio or imaging resolution, respectively. Preliminary in vivo experiments demonstrated the system’s ability to induce blood-brain barrier opening and simultaneously spatially map microbubble cavitation activity in a rat model. This work presents a tool to investigate optimal strategies for non-thermal FUS brain therapy and concurrent microbubble cavitation monitoring through the availability of multiple frequencies.

A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping

PubMed Central

Deng, Lulu; O'Reilly, Meaghan A.; Jones, Ryan M.; An, Ran; Hynynen, Kullervo

2016-01-01

Focused ultrasound (FUS) phased arrays show promise for non-invasive brain therapy. However, the majority of them are limited to a single transmit/receive frequency and therefore lack the versatility to expose and monitor the treatment volume. Multi-frequency arrays could offer variable transmit focal sizes under a fixed aperture, and detect different spectral content on receive for imaging purposes. Here, a three-frequency (306, 612 and 1224 kHz) sparse hemispherical ultrasound phased array (31.8 cm aperture; 128 transducer modules) was constructed and evaluated for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. The array is able to perform effective electronic beam steering over a volume spanning [−40, 40] and [−30, 50] mm in the lateral and axial directions, respectively. The focal size at the geometric center is approximately 0.9 (2.1) mm, 1.7 (3.9) mm, and 3.1 (6.5) mm in lateral (axial) pressure full width at half maximum (FWHM) at 1224, 612, and 306 kHz, respectively. The array was also found capable of dual-frequency excitation and simultaneous multi–foci sonication, which enables the future exploration of more complex exposure strategies. Passive acoustic mapping of dilute microbubble clouds demonstrated that the point spread function of the receive array has a lateral (axial) intensity FWHM between 0.8-3.5 mm (1.7-11.7 mm) over a volume spanning [−25, 25] mm in both the lateral and axial directions, depending on the transmit/receive frequency combination and the imaging location. The device enabled both half and second harmonic imaging through the intact skull, which may be useful for improving the contrast-to-tissue ratio or imaging resolution, respectively. Preliminary in-vivo experiments demonstrated the system's ability to induce blood-brain barrier opening and simultaneously spatially map microbubble cavitation activity in a rat model. This work presents a tool to investigate optimal strategies for non-thermal FUS brain therapy and concurrent microbubble cavitation monitoring through the availability of multiple frequencies. PMID:27845920

A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping.

PubMed

Deng, Lulu; O'Reilly, Meaghan A; Jones, Ryan M; An, Ran; Hynynen, Kullervo

2016-12-21

Focused ultrasound (FUS) phased arrays show promise for non-invasive brain therapy. However, the majority of them are limited to a single transmit/receive frequency and therefore lack the versatility to expose and monitor the treatment volume. Multi-frequency arrays could offer variable transmit focal sizes under a fixed aperture, and detect different spectral content on receive for imaging purposes. Here, a three-frequency (306, 612, and 1224 kHz) sparse hemispherical ultrasound phased array (31.8 cm aperture; 128 transducer modules) was constructed and evaluated for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. The array is able to perform effective electronic beam steering over a volume spanning (-40, 40) and (-30, 50) mm in the lateral and axial directions, respectively. The focal size at the geometric center is approximately 0.9 (2.1) mm, 1.7 (3.9) mm, and 3.1 (6.5) mm in lateral (axial) pressure full width at half maximum (FWHM) at 1224, 612, and 306 kHz, respectively. The array was also found capable of dual-frequency excitation and simultaneous multi-foci sonication, which enables the future exploration of more complex exposure strategies. Passive acoustic mapping of dilute microbubble clouds demonstrated that the point spread function of the receive array has a lateral (axial) intensity FWHM between 0.8-3.5 mm (1.7-11.7 mm) over a volume spanning (-25, 25) mm in both the lateral and axial directions, depending on the transmit/receive frequency combination and the imaging location. The device enabled both half and second harmonic imaging through the intact skull, which may be useful for improving the contrast-to-tissue ratio or imaging resolution, respectively. Preliminary in vivo experiments demonstrated the system's ability to induce blood-brain barrier opening and simultaneously spatially map microbubble cavitation activity in a rat model. This work presents a tool to investigate optimal strategies for non-thermal FUS brain therapy and concurrent microbubble cavitation monitoring through the availability of multiple frequencies.

Effects of different blasting materials on charge generation and decay on titanium surface after sandblasting.

PubMed

Guo, Cecilia Yan; Hong Tang, Alexander Tin; Hon Tsoi, James Kit; Matinlinna, Jukka Pekka

2014-04-01

It has been reported that sandblasting titanium with alumina (Al2O3) powder could generate a negative electric charge on titanium surface. This has been proven to promote osteoblast activities and possibly osseointegration. The purpose of this pilot study was to investigate the effects of different blasting materials, in terms of the grit sizes and electro-negativity, on the generation of a negative charge on the titanium surface. The aim was also to make use of these results to deduct the underlying mechanism of charge generation by sandblasting. Together 60 c.p. 2 titanium plates were machine-cut and polished for sandblasting, and divided into 6 groups with 10 plates in each. Every plate in the study groups was sandblasted with one of the following 6 powder materials: 110µm Al2O3 grits, 50µm Al2O3 grits, 150-300µm glass beads, 45-75µm glass beads, 250µm Al powder and 44µm Al powder. The static voltage on the surface of every titanium plate was measured immediately after sandblasting. The static voltages of the titanium plates were recorded and processed using statistical analysis. The results suggested that only sandblasting with 45-75µm glass beads generated a positive charge on titanium, while using all other blasting materials lead to a negative charge. Furthermore, blasting grits of the same powder material but of different sizes might lead to different amount and polarity of the charges. This triboelectric effect is likely to be the main mechanism for charge generation through sandblasting. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Interactomic Analysis Reveals Pathogenic Protein Networks in Phomopsis longicolla Underlying Seed Decay of Soybean.

PubMed

Li, Shuxian; Musungu, Bryan; Lightfoot, David; Ji, Pingsheng

2018-01-01

Phomopsis longicolla T. W. Hobbs (syn. Diaporthe longicolla ) is the primary cause of Phomopsis seed decay (PSD) in soybean, Glycine max (L.) Merrill. This disease results in poor seed quality and is one of the most economically important seed diseases in soybean. The objectives of this study were to infer protein-protein interactions (PPI) and to identify conserved global networks and pathogenicity subnetworks in P. longicolla including orthologous pathways for cell signaling and pathogenesis. The interlog method used in the study identified 215,255 unique PPIs among 3,868 proteins. There were 1,414 pathogenicity related genes in P. longicolla identified using the pathogen host interaction (PHI) database. Additionally, 149 plant cell wall degrading enzymes (PCWDE) were detected. The network captured five different classes of carbohydrate degrading enzymes, including the auxiliary activities, carbohydrate esterases, glycoside hydrolases, glycosyl transferases, and carbohydrate binding molecules. From the PPI analysis, novel interacting partners were determined for each of the PCWDE classes. The most predominant class of PCWDE was a group of 60 glycoside hydrolases proteins. The glycoside hydrolase subnetwork was found to be interacting with 1,442 proteins within the network and was among the largest clusters. The orthologous proteins FUS3, HOG, CYP1, SGE1, and the g5566t.1 gene identified in this study could play an important role in pathogenicity. Therefore, the P. longicolla protein interactome (PiPhom) generated in this study can lead to a better understanding of PPIs in soybean pathogens. Furthermore, the PPI may aid in targeting of genes and proteins for further studies of the pathogenicity mechanisms.

Mutational analysis of STE5 in the yeast Saccharomyces cerevisiae: Application of a differential interaction trap assay for examining protein-protein interactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inouye, C.; Dhillon, N.; Durfee, T.

1997-10-01

Ste5 is essential for the yeast mating pheromone response pathway and is thought to function as a scaffold that organized the components of the mitogen-activated protein kinase (MAKP) cascade. A new method was developed to isolate missense mutations in Ste5 that differentially affect the ability of Ste5 to interact with either of two MAPK cascade constituents, the MEKK (Ste11) and the MEK (Ste7). Mutations that affect association with Ste7 or with Ste11 delineate discrete regions of Ste5 that are critical for each interaction. Co-immunoprecipitation analysis, examining the binding in vitro of Ste5 to Ste11, Ste7, Ste4 (G protein {beta} subunit),more » and Fus3 (MAPK), confirmed that each mutation specifically affects the interaction of Ste5 with only one protein. When expressed in a ste5{delta} cell, mutant Ste5 proteins that are defective in their ability to interact with either Ste11 or Ste7 result in a markedly reduced mating proficiency. One mutation that clearly weakened (but did not eliminate) interaction of Ste5 with Ste7 permitted mating at wild-type efficiency, indicating that an efficacious signal is generated even when Ste5 associates with only a small fraction of (or only transiently with) Ste7. Ste5 mutants defective in association with Ste11 or Ste7 showed strong interallelic complementation when co-expressed, suggesting that the functional form of Ste5 in vivo is an oligomer. 69 refs., 6 figs., 3 tabs.« less

The Interactomic Analysis Reveals Pathogenic Protein Networks in Phomopsis longicolla Underlying Seed Decay of Soybean

PubMed Central

Li, Shuxian; Musungu, Bryan; Lightfoot, David; Ji, Pingsheng

2018-01-01

Phomopsis longicolla T. W. Hobbs (syn. Diaporthe longicolla) is the primary cause of Phomopsis seed decay (PSD) in soybean, Glycine max (L.) Merrill. This disease results in poor seed quality and is one of the most economically important seed diseases in soybean. The objectives of this study were to infer protein–protein interactions (PPI) and to identify conserved global networks and pathogenicity subnetworks in P. longicolla including orthologous pathways for cell signaling and pathogenesis. The interlog method used in the study identified 215,255 unique PPIs among 3,868 proteins. There were 1,414 pathogenicity related genes in P. longicolla identified using the pathogen host interaction (PHI) database. Additionally, 149 plant cell wall degrading enzymes (PCWDE) were detected. The network captured five different classes of carbohydrate degrading enzymes, including the auxiliary activities, carbohydrate esterases, glycoside hydrolases, glycosyl transferases, and carbohydrate binding molecules. From the PPI analysis, novel interacting partners were determined for each of the PCWDE classes. The most predominant class of PCWDE was a group of 60 glycoside hydrolases proteins. The glycoside hydrolase subnetwork was found to be interacting with 1,442 proteins within the network and was among the largest clusters. The orthologous proteins FUS3, HOG, CYP1, SGE1, and the g5566t.1 gene identified in this study could play an important role in pathogenicity. Therefore, the P. longicolla protein interactome (PiPhom) generated in this study can lead to a better understanding of PPIs in soybean pathogens. Furthermore, the PPI may aid in targeting of genes and proteins for further studies of the pathogenicity mechanisms. PMID:29666630

Altered Fruit and Seed Development of Transgenic Rapeseed (Brassica napus) Over-Expressing MicroRNA394

PubMed Central

Song, Jian Bo; Shu, Xia Xia; Shen, Qi; Li, Bo Wen; Song, Jun; Yang, Zhi Min

2015-01-01

Fruit and seed development in plants is a complex biological process mainly involved in input and biosynthesis of many storage compounds such as proteins and oils. Although the basic biochemical pathways for production of the storage metabolites in plants are well characterized, their regulatory mechanisms are not fully understood. In this study, we functionally identified rapeseed (Brassica napus) miR394 with its target gene Brassica napus LEAF CURLING RESPONSIVENESS (BnLCR) to dissect a role of miR394 during the fruit and seed development. Transgenic rapeseed plants over-expressing miR394 under the control of the cauliflower mosaic virus 35S promoter were generated. miR394 over-expression plants exhibited a delayed flowering time and enlarged size of plants, leaf blade, pods and seed body, but developed seeds with higher contents of protein and glucosinolates (GLS) and lower levels of oil accumulation as compared to wild-type. Over-expression of miR394 altered the fatty acid (FA) composition by increasing several FA species such as C16:0 and C18:0 and unsaturated species of C20:1 and C22:1 but lowering C18:3. This change was accompanied by induction of genes coding for transcription factors of FA synthesis including LEAFY COTYLEDON1 (BnLEC1), BnLEC2, and FUSCA3 (FUS3). Because the phytohormone auxin plays a crucial role in fruit development and seed patterning, the DR5-GUS reporter was used for monitoring the auxin response in Arabidopsis siliques and demonstrated that the DR5 gene was strongly expressed. These results suggest that BnmiR394 is involved in rapeseed fruit and seed development. PMID:25978066

Generation mechanism of negative permittivity and Kramers-Kronig relations in BaTiO3/Y3Fe5O12 multiferroic composites

NASA Astrophysics Data System (ADS)

Wang, Zhongyang; Sun, Kai; Xie, Peitao; Liu, Yao; Fan, Runhua

2017-09-01

Recently, negative parameters such as negative permittivity and negative permeability have been attracting extensive attention for their unique electromagnetic properties. Usually, negative permittivity is well achieved by plasma oscillation of free electrons in conductor-insulator composites or metamaterials, while some attention has been paid to attaining negative permittivity in ceramics to reduce dielectric loss. In this paper, negative permittivity in barium titanate and yttrium iron garnet composites are reported which was well fitted by the Lorentz model. Further, negative permittivity behavior was verified via Kramers-Kronig relations, and it revealed that the causal principle still valid for negative permittivity resulted from dielectric resonance. The interrelationships among negative permittivity, capacitive-inductive transition and ac conductivity are discussed.

Negative Capacitance in BaTiO3/BiFeO3 Bilayer Capacitors.

PubMed

Hou, Ya-Fei; Li, Wei-Li; Zhang, Tian-Dong; Yu, Yang; Han, Ren-Lu; Fei, Wei-Dong

2016-08-31

Negative capacitances provide an approach to reduce heat generations in field-effect transistors during the switch processes, which contributes to further miniaturization of the conventional integrated circuits. Although there are many studies about negative capacitances using ferroelectric materials, the direct observation of stable ferroelectric negative capacitances has rarely been reported. Here, we put forward a dc bias assistant model in bilayer capacitors, where one ferroelectric layer with large dielectric constant and the other ferroelectric layer with small dielectric constant are needed. Negative capacitances can be obtained when external dc bias electric fields are larger than a critical value. Based on the model, BaTiO3/BiFeO3 bilayer capacitors are chosen as study objects, and negative capacitances are observed directly. Additionally, the upward self-polarization effect in the ferroelectric layer reduces the critical electric field, which may provide a method for realizing zero and/or small dc bias assistant negative capacitances.

Litter Ammonia Generation: Moisture Content and Organic vs. Inorganic Bedding Materials

USDA-ARS?s Scientific Manuscript database

Negative impacts on the environment, bird well-being, and farm worker health indicate the need for abatement strategies for poultry litter NH3 generation. Type of bedding affects many parameters related to poultry production including NH3 losses. Broiler excrement was mixed with pine wood shavings, ...

The citrus postharvest pathogen Penicillium digitatum depends on the PdMpkB kinase for developmental and virulence functions.

PubMed

Ma, Haijie; Sun, Xuepeng; Wang, Mingshuang; Gai, Yunpeng; Chung, Kuang-Ren; Li, Hongye

2016-11-07

The postharvest pathogen Penicillium digitatum causes green mold decay on citrus fruit, resulting in severe economic losses. To explore possible factors involved in fungal pathogenesis, phenotypic characterization of the budding yeast Fus3/Kiss1 mitogen-activated protein (MAP) kinase homolog was carried out. The P. digitatum MAP kinase B coding gene, designated PdMpkB, was functionally inactivated via homologous recombination. The fungal strain (∆PdMpkB) carrying a PdMpkBdeletion demonstrated altered gene expression profiles, reduced growth and conidiogenesis, elevated resistance to osmotic stress, and failed to induce green mold decay on citrus fruit. ∆PdMpkB was more resistant to CaCl2, NaCl and sorbitol than its progenitor strain, indicating a negative regulatory function of PdMpkB in osmotic stress adaptation. Fungal infection assays on citrus fruit revealed that ∆PdMpkB proliferated poorly within host tissues, induced water-soaking lesions, failed to break through host cuticle layers and thus, failed to produce aerial hyphae and conidia. Introduction of a functional copy of PdMpkB into a null mutant restored all defective phenotypes. Transcriptome analysis revealed that inactivation of PdMpkB impacted expression of the genes associated with cell wall-degrading enzyme activities, carbohydrate and amino acid metabolisms, conidial formation, and numerous metabolic processes. Our results define pivotal roles of the PdMpkB-mediated signaling pathway in developmental and pathological functions in the citrus postharvest pathogen P. digitatum. Copyright © 2016 Elsevier B.V. All rights reserved.

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

PubMed

Morgan, Sarah; Shatunov, Aleksey; Sproviero, William; Jones, Ashley R; Shoai, Maryam; Hughes, Deborah; Al Khleifat, Ahmad; Malaspina, Andrea; Morrison, Karen E; Shaw, Pamela J; Shaw, Christopher E; Sidle, Katie; Orrell, Richard W; Fratta, Pietro; Hardy, John; Pittman, Alan; Al-Chalabi, Ammar

2017-06-01

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Investigation of the High, Finite n Ballooning Mode Limit for Compact Quasi-Axially Symmetric Stellarators

NASA Astrophysics Data System (ADS)

Redi, Martha; Canik, John; Fredrickson, E.; Fu, G.; Nuehrenberg, C.; Boozer, A. H.

2000-10-01

The standard ballooning-mode beta limit comes from an infinite-n, radially local, ideal magnetohydrodynamic (MHD) calculation. Finite-n ballooning modes have been observed in tokamak plasmas [1]. Investigations of optimized quasiaxially symmetric stellarators with three dimensional, global, ideal MHD codes have recently shown good stability for the external kink, ``vertical" and infinite-n ballooning modes [2,3]. However, infinite-n ballooning stability may be too restrictive, due to its sensitivity to features in the local shear and curvature. The CAS3D [4] code is being used to compare the stability of the high-n ballooning modes to the infinite-n calculations from TERPSICHORE [5]. [1] E. Fredrickson, et al. Phys. Plas. 3 (1996) 2620. [2] G. Fu, Phys. Plas. 7 (2000)1079; Phys. Plas. 7 (2000) 1809. M. Redi, et al. Phys. Plas 7 (2000)1911. [3] A. Reiman, et al., Plas. Phys. Cont. Fus. 41 (1999) B273. [4] C. Nuehrenberg, Phys. Plas. 6 (1999) 275. C. Nuehrenberg, Phys. Plas. 3 (1996) 2401. C. Schwab, Phys. Fluids B5 (1993) 3195. [5] W. A. Cooper, Phys. Plas. 3 (1996) 275.

Physico-chemical studies on the interaction of dendrimers with lipid bilayers. 1. Effect of dendrimer generation and liposome surface charge.

PubMed

Roy, Biplab; Panda, Amiya Kumar; Parimi, Srinivas; Ametov, Igor; Barnes, Timothy; Prestidge, Clive A

2014-01-01

Studies on the interaction of different generation poly (amido amine) (PAMAM) dendrimers (2G, 4G and 6G) and liposomes of different compositions were carried out by a combined turbidity, dynamic light scattering and atomic force microscopic measurements. Liposomes comprising soy lecithin (SLC, negative surface charge), 1, 2-palmitoyl-sn-glycero-3-phosphatidylcholine (DPPC, mildly positive surface charge), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol (DPPG, negatively charged) and a biologically simulated mixture of DPPC + DPPG (7:3, M/M, negatively charged) were used as model bilayers. 30 wt% cholesterol was used in each combination as it is known to control the fluidity of membrane bilayers. Silica was used as a negatively charged hard sphere model with an aim to compare the results. Both the turbidity and hydrodynamic diameter values of all the liposomes, except DPPC, passed through maxima upon the progressive addition of PAMAM; the effect was insignificant in case of DPPC. Formation of dendriosome, a complex formed between dendrimer and liposome, resulted in the charge reversal of the negatively charged liposomes. Interaction between PAMAM and liposome was found to be governed by electrostatic as well as hydrogen bonding. Generation dependent PAMAM activity followed the order: 6G >4G>2G in terms of overall dendrimer concentration. However, interestingly, the order was reverse when PAMAM activity was considered in terms of total end group concentrations. AFM studies reveal the rupture of bilayer structure upon addition of dendrimer.

Effect of milling on DSC thermogram of excipient adipic acid.

PubMed

Ng, Wai Kiong; Kwek, Jin Wang; Yuen, Aaron; Tan, Chin Lee; Tan, Reginald

2010-03-01

The purpose of this research was to investigate why and how mechanical milling results in an unexpected shift in differential scanning calorimetry (DSC) measured fusion enthalpy (Delta(fus)H) and melting point (T(m)) of adipic acid, a pharmaceutical excipient. Hyper differential scanning calorimetry (hyper-DSC) was used to characterize adipic acid before and after ball-milling. An experimental study was conducted to evaluate previous postulations such as electrostatic charging using the Faraday cage method, crystallinity loss using powder X-ray diffraction (PXRD), thermal annealing using DSC, impurities removal using thermal gravimetric analysis (TGA) and Karl Fischer titration. DSC thermograms showed that after milling, the values of Delta(fus)H and T(m) were increased by approximately 9% and 5 K, respectively. Previous suggestions of increased electrostatic attraction, change in particle size distribution, and thermal annealing during measurements did not explain the differences. Instead, theoretical analysis and experimental findings suggested that the residual solvent (water) plays a key role. Water entrapped as inclusions inside adipic acid during solution crystallization was partially evaporated by localized heating at the cleaved surfaces during milling. The correlation between the removal of water and melting properties measured was shown via drying and crystallization experiments. These findings show that milling can reduce residual solvent content and causes a shift in DSC results.

Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: potential for targeting experimental brain tumors.

PubMed

Diaz, Roberto Jose; McVeigh, Patrick Z; O'Reilly, Meaghan A; Burrell, Kelly; Bebenek, Matthew; Smith, Christian; Etame, Arnold B; Zadeh, Gelareh; Hynynen, Kullervo; Wilson, Brian C; Rutka, James T

2014-07-01

Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50nm or 120nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors. This study demonstrates the use of magnetic resonance image-guided transcranial focused ultrasound to open the BBB and enable spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS)-based molecular imaging for experimental tumor tracking. Copyright © 2014 Elsevier Inc. All rights reserved.

Fontes binárias supermoles de raios X

NASA Astrophysics Data System (ADS)

Pires, A. M.; Janot Pacheco, E.

2003-08-01

Estuda-se as características físicas das fontes supermoles (de raios X (SSS), utilizando dados ópticos e em altas energias, no âmbito de um trabalho de IC. Trata-se de binárias que apresentam espectro X muito mole, baixas temperaturas e altas luminosidades bolométricas. Esse sistemas são compostos por uma anã branca realizando fusão em sua superfície, a partir de matéria perdida pela estrela companheira. Os resíduos de fusão se acumulam na superfície da anã branca, e essa pode ultrapassar o limite de Chadrasekhar, produzir um colapso gravitacional, sendo esse um dos cenários propostos para as explosões de SN Ia. Apresentamos nesta comunicação o estado da arte das características físicas das fontes SSS, situando-as no âmbito das VCs. Procuramos também situar esses objetos em relação às variáveis galácticas V Sge, na medida em que os dois grupos apresentam certas caracerísticas bastante semelhantes.A metodologia adotada é aquela pedagógico-cognitiva clássica de um trabalho de IC na área de ciências exatas.

Can trans-generational experiments be used to enhance species resilience to ocean warming and acidification?

PubMed

Chakravarti, Leela J; Jarrold, Michael D; Gibbin, Emma M; Christen, Felix; Massamba-N'Siala, Gloria; Blier, Pierre U; Calosi, Piero

2016-10-01

Human-assisted, trans-generational exposure to ocean warming and acidification has been proposed as a conservation and/or restoration tool to produce resilient offspring. To improve our understanding of the need for and the efficacy of this approach, we characterized life-history and physiological responses in offspring of the marine polychaete Ophryotrocha labronica exposed to predicted ocean warming (OW: + 3°C), ocean acidification (OA: pH -0.5) and their combination (OWA: + 3°C, pH -0.5), following the exposure of their parents to either control conditions ( within-generational exposure ) or the same conditions ( trans-generational exposure ). Trans-generational exposure to OW fully alleviated the negative effects of within-generational exposure to OW on fecundity and egg volume and was accompanied by increased metabolic activity. While within-generational exposure to OA reduced juvenile growth rates and egg volume, trans-generational exposure alleviated the former but could not restore the latter. Surprisingly, exposure to OWA had no negative impacts within- or trans-generationally. Our results highlight the potential for trans-generational laboratory experiments in producing offspring that are resilient to OW and OA. However, trans-generational exposure does not always appear to improve traits and therefore may not be a universally useful tool for all species in the face of global change.

Effect of incorporation of nitrogen atoms in Al2O3 gate dielectric of wide-bandgap-semiconductor MOSFET on gate leakage current and negative fixed charge

NASA Astrophysics Data System (ADS)

Kojima, Eiji; Chokawa, Kenta; Shirakawa, Hiroki; Araidai, Masaaki; Hosoi, Takuji; Watanabe, Heiji; Shiraishi, Kenji

2018-06-01

We performed first-principle calculations to investigate the effect of incorporation of N atoms into Al2O3 gate dielectrics. Our calculations show that the defect levels generated by VO in Al2O3 are the origin of the stress-induced gate leakage current and that VOVAl complexes in Al2O3 cause negative fixed charge. We revealed that the incorporation of N atoms into Al2O3 eliminates the VO defect levels, reducing the stress-induced gate leakage current. Moreover, this suppresses the formation of negatively charged VOVAl complexes. Therefore, AlON can reduce both stress-induced gate leakage current and negative fixed charge in wide-bandgap-semiconductor MOSFETs.

Emergence of a Staphylococcus aureus Clone Resistant to Mupirocin and Fusidic Acid Carrying Exotoxin Genes and Causing Mainly Skin Infections

PubMed Central

Spiliopoulou, Iris; Spyridis, Nikolaos; Giormezis, Nikolaos; Kopsidas, John; Militsopoulou, Maria; Lebessi, Evangelia; Tsolia, Maria

2017-01-01

ABSTRACT Skin and soft tissue infections (SSTIs) caused by mupirocin-resistant Staphylococcus aureus strains have recently increased in number in our settings. We sought to evaluate the characteristics of these cases over a 43-month period. Data for all community-acquired staphylococcal infections caused by mupirocin-resistant strains were retrospectively reviewed. Genes encoding products producing high-level resistance (HLR) to mupirocin (mupA), fusidic acid resistance (fusB), resistance to macrolides and lincosamides (ermC and ermA), Panton-Valentine leukocidin (PVL) (lukS/lukF-PV), exfoliative toxins (eta and etb), and fibronectin binding protein A (fnbA) were investigated by PCRs in 102 selected preserved strains. Genotyping was performed by SCCmec and agr typing, whereas clonality was determined by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). A total of 437 cases among 2,137 staphylococcal infections were recorded in 2013 to 2016; they were all SSTIs with the exception of 1 case of primary bacteremia. Impetigo was the predominant clinical entity (371 cases [84.9%]), followed by staphylococcal scalded skin syndrome (21 cases [4.8%]), and there were no abscesses. The number of infections detected annually increased during the study years. All except 3 isolates were methicillin susceptible. The rates of HLR to mupirocin and constitutive resistance to clindamycin were 99% and 20.1%, respectively. Among the 102 tested strains, 100 (98%) were mupA positive and 97 (95%) were fusB positive, 26/27 clindamycin-resistant strains (96.3%) were ermA positive, 83 strains (81.4%) were lukS/lukF positive, 95 (93%) carried both eta and etb genes, and 99 (97%) were fnbA positive. Genotyping of methicillin-sensitive S. aureus (MSSA) strains revealed that 96/99 (96.7%) belonged to one main pulsotype, pulsotype 1, classified as sequence type 121 (ST121). The emergence of a single MSSA clone (ST121) causing impetigo was documented. Resistance to topical antimicrobials and a rich toxinogenic profile confer to this clone adaptability for spread in the community. PMID:28592549

Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry.

PubMed

Johansson, Bente B; Irgens, Henrik U; Molnes, Janne; Sztromwasser, Paweł; Aukrust, Ingvild; Juliusson, Petur B; Søvik, Oddmund; Levy, Shawn; Skrivarhaug, Torild; Joner, Geir; Molven, Anders; Johansson, Stefan; Njølstad, Pål R

2017-04-01

MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes. Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic). We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3-5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p = 1.6 × 10 -5 ). HNF1A showed the strongest enrichment of class 3-5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5. This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.

Radiative forcing from aircraft NOx emissions: Mechanisms and seasonal dependence

NASA Astrophysics Data System (ADS)

Stevenson, David S.; Doherty, Ruth M.; Sanderson, Michael G.; Collins, William J.; Johnson, Colin E.; Derwent, Richard G.

2004-09-01

A chemistry-climate model has been applied to study the radiative forcings generated by aircraft NOx emissions through changes in ozone and methane. Four numerical experiments, where an extra pulse of aircraft NOx was emitted into the model atmosphere for a single month (January, April, July, or October), were compared to a control experiment, allowing the aircraft impact to be isolated. The extra NOx produces a short-lived (few months) pulse of ozone that generates a positive radiative forcing. However, the NOx and O3 both generate OH, which leads to a reduction in CH4. A detailed analysis of the OH budget reveals the spatial structure and chemical reactions responsible for the generation of the OH perturbation. Methane's long lifetime means that the CH4 anomaly decays slowly (perturbation lifetime of 11.1 years). The negative CH4 anomaly also has an associated negative O3 anomaly, and both of these introduce a negative radiative forcing. There are important seasonal differences in the response of O3 and CH4 to aircraft NOx, related to the annual cycle in photochemistry; the O3 radiative forcing calculations also have a seasonal dependence. The long-term globally integrated annual mean net forcing calculated here is approximately zero, although earlier work suggests a small net positive forcing. The model design (e.g., upper tropospheric chemistry, convection parameterization) and experimental setup (pulse magnitude and duration) may somewhat influence the results: further work with a range of models is required to confirm these results quantitatively.

The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy.

PubMed

Miyake, Kentaro; Murakami, Takashi; Kiyuna, Tasuku; Igarashi, Kentaro; Kawaguchi, Kei; Miyake, Masuyo; Li, Yunfeng; Nelson, Scott D; Dry, Sarah M; Bouvet, Michael; Elliott, Irmina A; Russell, Tara A; Singh, Arun S; Eckardt, Mark A; Hiroshima, Yukihiko; Momiyama, Masashi; Matsuyama, Ryusei; Chishima, Takashi; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

2017-11-28

The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing's sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm 3 : untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician's request and were used for third-line therapy of the patient.

Osteoid osteoma: Magnetic resonance guided high intensity focused ultrasound for entirely non-invasive treatment. A prospective developmental study

NASA Astrophysics Data System (ADS)

Napoli, A.; de Soccio, V.; Cartocci, G.; Boni, F.; Anzidei, M.; Catalano, C.

2017-03-01

To determine the effect of acoustic energy delivered during MR guided Focused Ultrasound (MRgFUS) treatment of symptomatic osteoid osteomas. This prospective, IRB approved study involved 15 consecutive patients (11 m; 4f; mean age, 21) with clinical and imaging diagnosis of Osteoid Osteoma; all patients underwent MRgFUS ablation (ExAblate, InSightec; Discovery 750 MR unit, GE). Lesions located in the vertebral body were excluded, while lesions in proximity to joints or neurovascular bundles were included. Treatment success was determined at clinical and imaging follow-up at 1, 6 and 12 months post-treatment. A visual Analog Pain Score (VAS) was used to assess changes in symptoms. Bone changes at nidus site were evaluated on the basis of CT and dynamic ce-MR imaging (Gd-Bopta; Bracco) pre- and post-treatment. Treatment was carried out using a variable number of sonications (mean 4±1.8) with a mean energy deposition of 866±211 J. There were no treatment- or anesthesia-related complications. A statistically significant (p=0.001) difference was noted between the overall pre- and post-treatment mean VAS scores (8.3±1.6 and 0.6±1.5, respectively). Two treatments were conducted in patients with prior CTgRFA failure and needed two different session for achieving complete clinical successful. At imaging, edema and hyperemia associated with typical osteoid osteoma, gradually disappeared in all lesions. No apparent relationship between nidus vascular extinction and successful outcome was found. Variable reabsorption degree of sclerotic reaction was observed with nidus disappearance in 4 cases (27%). Treatment of osteoid osteoma using MR guided Focused Ultrasound can be performed safely with a high rate of success and without treatment related morbidity; our results indicated also a positive trend to bone rearrangement after treatment.

Minimizing eddy currents induced in the ground plane of a large phased-array ultrasound applicator for echo-planar imaging-based MR thermometry.

PubMed

Lechner-Greite, Silke M; Hehn, Nicolas; Werner, Beat; Zadicario, Eyal; Tarasek, Matthew; Yeo, Desmond

2016-01-01

The study aims to investigate different ground plane segmentation designs of an ultrasound transducer to reduce gradient field induced eddy currents and the associated geometric distortion and temperature map errors in echo-planar imaging (EPI)-based MR thermometry in transcranial magnetic resonance (MR)-guided focused ultrasound (tcMRgFUS). Six different ground plane segmentations were considered and the efficacy of each in suppressing eddy currents was investigated in silico and in operando. For the latter case, the segmented ground planes were implemented in a transducer mockup model for validation. Robust spoiled gradient (SPGR) echo sequences and multi-shot EPI sequences were acquired. For each sequence and pattern, geometric distortions were quantified in the magnitude images and expressed in millimeters. Phase images were used for extracting the temperature maps on the basis of the temperature-dependent proton resonance frequency shift phenomenon. The means, standard deviations, and signal-to-noise ratios (SNRs) were extracted and contrasted with the geometric distortions of all patterns. The geometric distortion analysis and temperature map evaluations showed that more than one pattern could be considered the best-performing transducer. In the sagittal plane, the star (d) (3.46 ± 2.33 mm) and star-ring patterns (f) (2.72 ± 2.8 mm) showed smaller geometric distortions than the currently available seven-segment sheet (c) (5.54 ± 4.21 mm) and were both comparable to the reference scenario (a) (2.77 ± 2.24 mm). Contrasting these results with the temperature maps revealed that (d) performs as well as (a) in SPGR and EPI. We demonstrated that segmenting the transducer ground plane into a star pattern reduces eddy currents to a level wherein multi-plane EPI for accurate MR thermometry in tcMRgFUS is feasible.

Magnetic resonance-guided motorized transcranial ultrasound system for blood-brain barrier permeabilization along arbitrary trajectories in rodents.

PubMed

Magnin, Rémi; Rabusseau, Fabien; Salabartan, Frédéric; Mériaux, Sébastien; Aubry, Jean-François; Le Bihan, Denis; Dumont, Erik; Larrat, Benoit

2015-01-01

Focused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB). Magnetic resonance imaging (MRI) guidance enables to plan, monitor, and characterize the BBB disruption. Being able to precisely and remotely control the permeabilization location is of great interest to perform reproducible drug delivery protocols. In this study, we developed an MR-guided motorized focused ultrasound (FUS) system allowing the transducer displacement within preclinical MRI scanners, coupled with real-time transfer and reconstruction of MRI images, to help ultrasound guidance. Capabilities of this new device to deliver large molecules to the brain on either single locations or along arbitrary trajectories were characterized in vivo on healthy rats and mice using 1.5 MHz ultrasound sonications combined with microbubble injection. The efficacy of BBB permeabilization was assessed by injecting a gadolinium-based MR contrast agent that does not cross the intact BBB. The compact motorized FUS system developed in this work fits into the 9-cm inner diameter of the gradient insert installed on our 7-T preclinical MRI scanners. MR images acquired after contrast agent injection confirmed that this device can be used to enhance BBB permeability along remotely controlled spatial trajectories of the FUS beam in both rats and mice. The two-axis motor stage enables reaching any region of interest in the rodent brain. The positioning error when targeting the same anatomical location on different animals was estimated to be smaller than 0.5 mm. Finally, this device was demonstrated to be useful for testing BBB opening at various acoustic pressures (0.2, 0.4, 0.7, and 0.9 MPa) in the same animal and during one single ultrasound session. Our system offers the unique possibility to move the transducer within a high magnetic field preclinical MRI scanner, thus enabling the delivery of large molecules to virtually any rodent brain area in a non-invasive manner. It results in time-saving and reproducibility and could be used to either deliver drugs over large parts of the brain or test different acoustic conditions on the same animal during the same session, therefore reducing physiological variability.

Focal therapy for localized unifocal and multifocal prostate cancer: A prospective development study using real time MR guided focused ultrasound

NASA Astrophysics Data System (ADS)

Napoli, A.; Caliolo, G.; Boni, F.; Anzidei, M.; Catalano, C.

2017-03-01

To assess safety and feasibility of non-invasive high intensity 3T MR guided focused ultrasound (MRgFUS) treatment of localized prostate cancer in an exploratory designed study. Men aged 45-80 years were eligible for this prospective study if they had low-risk localized prostate cancer (prostate specific antigen [PSA] ≤10 ng/mL, Gleason score ≤ 3 + 3), with no previous androgen deprivation or treatment for prostate cancer, and who could safely undergo multiparametric MRI (Discovery 750, GE; Gd-Bopta, Bracco) and have a spinal anesthetic. Patients underwent focal therapy using real time MR guided high intensity focused ultrasound (MRgFUS), delivered to all known cancer lesions, with a margin of normal tissue. Primary endpoints were adverse events (serious and otherwise) and urinary symptoms and erectile function assessed using patient questionnaires. 8 men were recruited between June 2011 and June 2012. After treatment, one man was admitted to hospital for acute urinary retention. Another patient had self-resolving, mild, intermittent dysuria (median duration 5.0 days). Urinary tract infection was not reported. Urinary debris occurred in 6 men (75%), with a median duration of 12 days. Median overall International Index of Erectile Function-15 (IIEF-15) scores were similar at baseline and at 6 to 12 months (p=0.060), as were median IIEF-15 scores for intercourse satisfaction (p=0.433), sexual desire (p=0.622), and overall satisfaction (p=0.256). There was an improvement in lower urinary tract symptoms, assessed by International Prostate Symptom Score (IPSS), between baseline and 6 to 12 months (p=0.026). All 8 men with no baseline urinary incontinence were leak-free and pad-free by 9 months. No histological evidence of cancer was identified in 7 of 8 men biopsied at 6 months (87,5%); overall, the entire population (8 patients) was free of clinically significant cancer and had no evidence of disease on multi-parametric MRI at 6 to 12 months. MR guided Focused Ultrasound focal therapy of individual prostate cancer lesions, whether multifocal or unifocal, leads to a low rate of genitourinary side-effects and an encouraging rate of early absence of clinically significant prostate cancer.

Establishment of a new method to quantitatively evaluate hyphal fusion ability in Aspergillus oryzae.

PubMed

Tsukasaki, Wakako; Maruyama, Jun-Ichi; Kitamoto, Katsuhiko

2014-01-01

Hyphal fusion is involved in the formation of an interconnected colony in filamentous fungi, and it is the first process in sexual/parasexual reproduction. However, it was difficult to evaluate hyphal fusion efficiency due to the low frequency in Aspergillus oryzae in spite of its industrial significance. Here, we established a method to quantitatively evaluate the hyphal fusion ability of A. oryzae with mixed culture of two different auxotrophic strains, where the ratio of heterokaryotic conidia growing without the auxotrophic requirements reflects the hyphal fusion efficiency. By employing this method, it was demonstrated that AoSO and AoFus3 are required for hyphal fusion, and that hyphal fusion efficiency of A. oryzae was increased by depleting nitrogen source, including large amounts of carbon source, and adjusting pH to 7.0.

Negative index of refraction in metallic metamaterial comprising split-ring resonators.

PubMed

Dong, Zheng-Gao; Lei, Shuang-Ying; Xu, Ming-Xiang; Liu, Hui; Li, Tao; Wang, Fu-Ming; Zhu, Shi-Ning

2008-05-01

We numerically investigate the negative index of refraction in a metamaterial composed of metallic split-ring resonators, which exhibits simultaneously negative permittivity and permeability without resorting to additional metallic wires. It is confirmed that, in the left-handed band, negative permittivity is generated in analogy to the cut-wire metamaterial and negative permeability comes from the antisymmetric resonant mode, which occurs at a frequency band about 3 times higher than the fundamental magnetic resonance proposed by Pendry [IEEE Trans. Microwave Theory Tech. 47, 2075 (1999)].

Cotargeting the lncRNA-PIP3 Interaction and AKT/PI3K Signaling Axis: A Novel Paradigm for Treating Triple-Negative Breast Cancer

DTIC Science & Technology

2017-10-01

Model Core Facility at MD Anderson has generated a genomic deletion of LINK-A using CRISPR /Cas9 technology based on collaboration. The single...Generation of LINK-A deletion mutant using CRISPR /Cas9 technology. A, Illustration of genomic deletion region of LINK-A (Chr1: 238644075-238644134

A multi-dimensional approach to insight and its evolution in first-episode psychosis: a 1-year outcome naturalistic study.

PubMed

Capdevielle, Delphine; Norton, Joanna; Jaussent, Isabelle; Prud'homme, Cindy; Raffard, Stéphane; Gelly, Françoise; Boulenger, Jean-Philippe; Ritchie, Karen

2013-12-30

The aim of the study was to describe the evolution of the different dimensions of insight at 1 year and its associations with psychopathology and symptomatic remission. Participants included 55 patients hospitalized for a first psychosis episode and followed up at 6 and 12 months after discharge. Measures included the Scale to Assess Unawareness of Mental Disorder and the Positive and Negative Syndrome Scale (PANSS). Six dimensions of insight were evaluated, for current episode at hospital discharge and at 6 and 12 month FUs and past episode (at 6 and 12 month follow-ups). Our results show that concerning the current episode, only awareness of the social consequences and of the positive symptoms significantly improved during follow-up. Insight into the past episode improved for awareness of having a mental disorder, the social consequences and the positive symptoms of mental illness. Cross-sectional associations between insight and PANSS show weak to moderate, albeit significant, associations. Most of the dimensions of insight are positively and significantly associated with remission. Our findings suggest that the main underlying dimensions of insight evolve differently over time, which could suggest different inherent processes. This could be useful for developing psychotherapeutic programmes acting upon the different aspects of insight. © 2013 Elsevier Ireland Ltd. All rights reserved.

Contrast-enhanced ultrasound evaluation of pancreatic cancer xenografts in nude mice after irradiation with sub-threshold focused ultrasound for tumor ablation

PubMed Central

Wang, Rui; Guo, Qian; Chen, Yi Ni; Hu, Bing; Jiang, Li Xin

2017-01-01

We evaluated the efficacy of contrast-enhanced ultrasound for assessing tumors after irradiation with sub-threshold focused ultrasound (FUS) ablation in pancreatic cancer xenografts in nude mice. Thirty tumor-bearing nude mice were divided into three groups: Group A received sham irradiation, Group B received a moderate-acoustic energy dose (sub-threshold), and Group C received a high-acoustic energy dose. In Group B, B-mode ultrasound (US), color Doppler US, and dynamic contrast-enhanced ultrasound (DCE-US) studies were conducted before and after irradiation. After irradiation, tumor growth was inhibited in Group B, and the tumors shrank in Group C. In Group A, the tumor sizes were unchanged. In Group B, contrast-enhanced ultrasound (CEUS) images showed a rapid rush of contrast agent into and out of tumors before irradiation. After irradiation, CEUS revealed contrast agent perfusion only at the tumor periphery and irregular, un-perfused volumes of contrast agent within the tumors. DCE-US perfusion parameters, including peak intensity (PI) and area under the curve (AUC), had decreased 24 hours after irradiation. PI and AUC were increased 48 hours and 2weeks after irradiation. Time to peak (TP) and sharpness were increased 24 hours after irradiation. TP decreased at 48 hours and 2 weeks after irradiation. CEUS is thus an effective method for early evaluation after irradiation with sub-threshold FUS. PMID:28402267

Non-invasive transmission of sensorimotor information in humans using an EEG/focused ultrasound brain-to-brain interface

PubMed Central

Lee, Wonhye; Kim, Suji; Kim, Byeongnam; Lee, Chungki; Chung, Yong An; Kim, Laehyun; Yoo, Seung-Schik

2017-01-01

We present non-invasive means that detect unilateral hand motor brain activity from one individual and subsequently stimulate the somatosensory area of another individual, thus, enabling the remote hemispheric link between each brain hemisphere in humans. Healthy participants were paired as a sender and a receiver. A sender performed a motor imagery task of either right or left hand, and associated changes in the electroencephalogram (EEG) mu rhythm (8–10 Hz) originating from either hemisphere were programmed to move a computer cursor to a target that appeared in either left or right of the computer screen. When the cursor reaches its target, the outcome was transmitted to another computer over the internet, and actuated the focused ultrasound (FUS) devices that selectively and non-invasively stimulated either the right or left hand somatosensory area of the receiver. Small FUS transducers effectively allowed for the independent administration of stimulatory ultrasonic waves to somatosensory areas. The stimulation elicited unilateral tactile sensation of the hand from the receiver, thus establishing the hemispheric brain-to-brain interface (BBI). Although there was a degree of variability in task accuracy, six pairs of volunteers performed the BBI task in high accuracy, transferring approximately eight commands per minute. Linkage between the hemispheric brain activities among individuals suggests the possibility for expansion of the information bandwidth in the context of BBI. PMID:28598972

Transitiometric analysis of solid II/solid I transition in anhydrous theophylline.

PubMed

Legendre, Bernard; Randzio, Stanislaw L

2007-10-01

For the first time, with the use of a high sensitivity, low heating rate, scanning transitiometry, it was possible to distinguish and characterise the polymorphic equilibrium transition between forms II and I in anhydrous theophylline. In this manner it was univocally proved, that forms II and I in theophylline are enantiotropically related. The temperature and enthalpy for that transition are as follows: T(trs)(II/I)=536.8+/-2.2K; Delta(trs)H(II/I)=1.99+/-0.09 kJ/mol. Making use of advantages of very slow heating rate and of a high energetic sensitivity of the transitiometer it was possible to observe in detail the polymorphic transition followed by melting of high temperature form I and to stop the solid I-liquid transition at a desired point of equilibrium. Such a solid I-liquid equilibrium could be stabilised and then displaced back to the crystallisation of form I with an adequate use of a precise temperature programming. In such a way a pure single phase of form I of theophylline was prepared. This fact was confirmed by X-ray powder diffraction patterns and calorimetric traces of fusion of the crystallised product. The temperature and enthalpy of the form I-liquid transition are as follows: T(fus)(I)=546.5+/-0.2K and Delta(fus)H(I)=29.37+/-0.29 kJ/mol.

Recent progress in the genetics of motor neuron disease.

PubMed

Finsterer, Josef; Burgunder, Jean-Marc

2014-02-01

Genetic background and pathogenesis of motor neuron diseases (MNDs) have been increasingly elucidated over recent years. To give an overview about publications during the last year concerning the genetic background and phenotypic manifestations of MNDs, such as familial or sporadic amyotrophic lateral sclerosis (fALS, sALS), spinal muscular atrophies (SMA), bulbospinal muscular atrophy (BSMA), and unclassified MNDs. Pubmed search for literature about ALS, SMA, and BSMA for the period 10/2012 to 9/2013. An increasing number of mutated genes is recognised in fALS but also sALS patients. Genes mutated in sALS include C9orf72, SOD1, TARDBP, FUS, UBQL2, SQSTM1, DCTN1, and UNC13A. Juvenile (onset <20y) and adult ALS (early onset 20-60y, late onset >60y) are differentiated. Juvenile fALS is most frequently caused by mutations in ALS2, SETX, spatacsin, or Sigmar1 and adult fALS by mutations in C9orf72, SOD1, TARDBP, and FUS. Onset, phenotype, progression, and outcome of ALS are variable between different mutations, different genes, and different countries. Differentiation between sALS and fALS cases becomes artificial. Further progress has been made over the last year in the clarification and understanding of the aetiology and pathogenesis of MNDs. However, further effort is needed to answer the many remaining questions. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Phenomenology of Polymorphism, III: p, TDiagram and Stability of Piracetam Polymorphs

NASA Astrophysics Data System (ADS)

Céolin, R.; Agafonov, V.; Louër, D.; Dzyabchenko, V. A.; Toscani, S.; Cense, J. M.

1996-02-01

The nootropic drug Piracetam is known to crystallize in three phases. In order to obtain their stability hierarchy from sublimation pressure inequalities, the drawing of a topologicalp,Tdiagram was attempted. For such a purpose and also for quality control, crystallographic and thermodynamic data were required. Powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC) were used. Molecular energy calculations were performed. Phase I melts at 426 K (ΔfusH(I) = +180 J·g-1). Phase II transforms into Phase I at 399 K (Δ(II→I)H= +24 J·g-1). Phase III transforms into phase I at 392 K (Δ(III→I)H= +28 J·g-1) or melts at 412 K (ΔfusH(III) = +210 J·g-1). Thep,Tdiagram shows that phase I is stable at higher temperature and phase II at lower temperature, like phase III, which is stable under high pressure. At room temperature, phase II is the more stable form, and phase I the less stable one. This agrees with the spontaneous I → II transformation observed at 298 K within a few hours, and with lattice energies, calculated previously. Molecular energy calculations and crystal structure comparison show how intermolecular hydrogen bonds and H-bonded dimers, in phases II and III, may stabilize conformations higher in energy than those of the isolated molecule and of phase I.

Quasi-Axially Symmetric Stellarators with 3 Field Periods

NASA Astrophysics Data System (ADS)

Garabedian, Paul; Ku, Long-Poe

1998-11-01

Compact hybrid configurations with 2 field periods have been studied recently as candidates for a proof of principle experiment at PPPL, cf. A. Reiman et al., Physics design of a high beta quasi-axially symmetric stellarator, J. Plas. Fus. Res. SERIES 1, 429(1998). This enterprise has led us to the discovery of a family of quasi-axially symmetric stellarators with 3 field periods that seem to have significant advantages, although their aspect ratios are a little larger. They have reversed shear and perform better in a local analysis of ballooning modes. Nonlinear equilibrium and stability calculations predict that the average beta limit may be as high as 6% if the bootstrap current turns out to be as big as that expected in comparable tokamaks. The concept relies on a combination of helical fields and bootstrap current to achieve adequate rotational transform at low aspect ratio. A detailed manuscript describing some of this work will be published soon, cf. P.R. Garabedian, Quasi-axially symmetric stellarators, Proc. Natl. Acad. Sci. USA 95 (1998).

In vitro replication of poliovirus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lubinski, J.M.

1986-01-01

Poliovirus is a member of the Picornaviridae whose genome is a single stranded RNA molecule of positive polarity surrounded by a proteinaceous capsid. Replication of poliovirus occurs via negative strand intermediates in infected cells using a virally encoded RNA-dependent RNA polymerase and host cell proteins. The authors have exploited the fact that complete cDNA copies of the viral genome when transfected onto susceptible cells generate virus. Utilizing the bacteriophage SP6 DNA dependent RNA polymerase system to synthesize negative strands in vitro and using these in an in vitro reaction the authors have generated full length infectious plus strands. Mutagenesis ofmore » the 5' and 3' ends of the negative and positive strands demonstrated that replication could occur either de novo or be extensions of the templates from their 3' ends or from nicks occurring during replication. The appearance of dimeric RNA molecules generated in these reactions was not dependent upon the same protein required for de novo initiation. Full length dimeric RNA molecules using a 5' /sup 32/P end-labelled oligo uridylic acid primer and positive strand template were demonstrated in vitro containing only the 35,000 Mr host protein and the viral RNA-dependent RNA polymerase. A model for generating positive strands without protein priming by cleavage of dimeric RNA molecules was proposed.« less

Characteristics of EMI generated by negative metal-positive dielectric voltage stresses due to spacecraft charging

NASA Technical Reports Server (NTRS)

Chaky, R. C.; Inouye, G. T.

1985-01-01

Charging of spacecraft surfaces by the environmental plasma can result in differential potentials between metallic structure and adjacent dielectric surfaces in which the relative polarity of the voltage stress is either negative dielectric/positive metal or negative metal/positive dielectric. Negative metal/positive dielectric is a stress condition that may arise if relatively large areas of spacecraft surface metals are shadowed from solar UV and/or if the UV intensity is reduced as in the situation in which the spacecraft is entering into or leaving eclipse. The results of experimental studies of negative metal/positive dielectric systems are given. Information is given on: enhanced electron emission I-V curves; e(3) corona noise vs e(3) steady-state current; the localized nature of e(3) and negative metal arc discharge currents; negative metal arc discharges at stress thresholds below 1 kilovolt; negative metal arc discharge characteristics; dependence of blowoff arc discharge current on spacecraft capacitance to space (linear dimension); and damage to second surface mirrors due to negative metal arcs.

MicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3

PubMed Central

Zhang, Lingyun; Ke, Fang; Liu, Zhaoyuan; Bai, Jing; Liu, Jinlin; Yan, Sha; Xu, Zhenyao; Lou, Fangzhou; Wang, Hong; Zhu, Huiyuan; Sun, Yang; Cai, Wei; Gao, Yuanyuan; Li, Qun; Yu, Xue-Zhong; Qian, Youcun; Hua, Zichun; Deng, Jiong; Li, Qi-Jing; Wang, Honglin

2015-01-01

Peripherally derived regulatory T (pTreg) cell generation requires T-cell receptor (TCR) signalling and the cytokines TGF-β1 and IL-2. Here we show that TCR signalling induces the microRNA miR-31, which negatively regulates pTreg-cell generation. miR-31 conditional deletion results in enhanced induction of pTreg cells, and decreased severity of experimental autoimmune encephalomyelitis (EAE). Unexpectedly, we identify Gprc5a as a direct target of miR-31. Gprc5a is known as retinoic acid-inducible protein 3, and its deficiency leads to impaired pTreg-cell induction and increased EAE severity. By generating miR-31 and Gprc5a double knockout mice, we show that miR-31 promotes the development of EAE through inhibiting Gprc5a. Thus, our data identify miR-31 and its target Gprc5a as critical regulators for pTreg-cell generation, suggesting a previously unrecognized epigenetic mechanism for dysfunctional Treg cells in autoimmune diseases. PMID:26165721

Emergence of Sequence Type 779 Methicillin-Resistant Staphylococcus aureus Harboring a Novel Pseudo Staphylococcal Cassette Chromosome mec (SCCmec)-SCC-SCCCRISPR Composite Element in Irish Hospitals

PubMed Central

Kinnevey, Peter M.; Shore, Anna C.; Brennan, Grainne I.; Sullivan, Derek J.; Ehricht, Ralf; Monecke, Stefan; Slickers, Peter

2013-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) has been a major cause of nosocomial infection in Irish hospitals for 4 decades, and replacement of predominant MRSA clones has occurred several times. An MRSA isolate recovered in 2006 as part of a larger study of sporadic MRSA exhibited a rare spa (t878) and multilocus sequence (ST779) type and was nontypeable by PCR- and DNA microarray-based staphylococcal cassette chromosome mec (SCCmec) element typing. Whole-genome sequencing revealed the presence of a novel 51-kb composite island (CI) element with three distinct domains, each flanked by direct repeat and inverted repeat sequences, including (i) a pseudo SCCmec element (16.3 kb) carrying mecA with a novel mec class region, a fusidic acid resistance gene (fusC), and two copper resistance genes (copB and copC) but lacking ccr genes; (ii) an SCC element (17.5 kb) carrying a novel ccrAB4 allele; and (iii) an SCC element (17.4 kb) carrying a novel ccrC allele and a clustered regularly interspaced short palindromic repeat (CRISPR) region. The novel CI was subsequently identified by PCR in an additional 13 t878/ST779 MRSA isolates, six from bloodstream infections, recovered between 2006 and 2011 in 11 hospitals. Analysis of open reading frames (ORFs) carried by the CI showed amino acid sequence similarity of 44 to 100% to ORFs from S. aureus and coagulase-negative staphylococci (CoNS). These findings provide further evidence of genetic transfer between S. aureus and CoNS and show how this contributes to the emergence of novel SCCmec elements and MRSA strains. Ongoing surveillance of this MRSA strain is warranted and will require updating of currently used SCCmec typing methods. PMID:23147725

System integration of RF based negative ion experimental facility at IPR

NASA Astrophysics Data System (ADS)

Bansal, G.; Bandyopadhyay, M.; Singh, M. J.; Gahlaut, A.; Soni, J.; Pandya, K.; Parmar, K. G.; Sonara, J.; Chakraborty, A.

2010-02-01

The setting up of RF based negative ion experimental facility shall witness the beginning of experiments on the negative ion source fusion applications in India. A 1 MHz RF generator shall launch 100 kW RF power into a single driver on the plasma source to produce a plasma of density ~5 × 1012 cm-3. The source can deliver a negative ion beam of ~10 A with a current density of ~30 mA/cm2 and accelerated to 35 kV through an electrostatic ion accelerator. The experimental system is similar to a RF based negative ion source, BATMAN, presently operating at IPP. The subsystems for source operation are designed and procured principally from indigenous resources, keeping the IPP configuration as a base line. The operation of negative ion source is supported by many subsystems e.g. vacuum pumping system with gate valves, cooling water system, gas feed system, cesium delivery system, RF generator, high voltage power supplies, data acquisition and control system, and different diagnostics. The first experiments of negative ion source are expected to start at IPR from the middle of 2009.

Tritium Decay Helium-3 Effects in Tungsten

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shimada, M.; Merrill, B. J.

2016-06-01

A critical challenge for long-term operation of ITER and beyond to a Demonstration reactor (DEMO) and future fusion reactor will be the development of plasma-facing components (PFCs) that demonstrate erosion resistance to steady-state/transient heat fluxes and intense neutral/ion particle fluxes under the extreme fusion nuclear environment, while at the same time minimizing in-vessel tritium inventories and permeation fluxes into the PFC’s coolant. Tritium will diffuse in bulk tungsten at elevated temperatures, and can be trapped in radiation-induced trap site (up to 1 at. % T/W) in tungsten [1,2]. Tritium decay into helium-3 may also play a major role in microstructuralmore » evolution (e.g. helium embrittlement) in tungsten due to relatively low helium-4 production (e.g. He/dpa ratio of 0.4-0.7 appm [3]) in tungsten. Tritium-decay helium-3 effect on tungsten is hardly understood, and its database is very limited. Two tungsten samples (99.99 at. % purity from A.L.M.T. Co., Japan) were exposed to high flux (ion flux of 1.0x1022 m-2s-1 and ion fluence of 1.0x1026 m-2) 0.5%T2/D2 plasma at two different temperatures (200, and 500°C) in Tritium Plasma Experiment (TPE) at Idaho National Laboratory. Tritium implanted samples were stored at ambient temperature in air for more than 3 years to investigate tritium decay helium-3 effect in tungsten. The tritium distributions on plasma-exposed was monitored by a tritium imaging plate technique during storage period [4]. Thermal desorption spectroscopy was performed with a ramp rate of 10°C/min up to 900°C to outgas residual deuterium and tritium but keep helium-3 in tungsten. These helium-3 implanted samples were exposed to deuterium plasma in TPE to investigate helium-3 effect on deuterium behavior in tungsten. The results show that tritium surface concentration in 200°C sample decreased to 30 %, but tritium surface concentration in 500°C sample did not alter over the 3 years storage period, indicating possible tritium retention in helium-3 bubble. This paper reports the initial experimental observation of tritium-decay helium-3 in tungsten exposed to deuterium/tritium plasma along with electron microscope analysis and also discusses a Tritium Migration Analysis Program (TMAP) analysis of tritium-decay helium-3 effects on tritium retention in tungsten for DEMO and future fusion reactor. [1] Y. Hatano, et.al., Nucl. Fusion 53 (2013) 073006 [2] M. Shimada, et.al., Nucl. Fusion 55 (2015) 013008 [3] M. Sawan, Fus. Sci. Technol. 66 (2014) 272 [4] T. Otsuka, Fus. Sci. Technol. 60 (2011) 1539 This work was prepared for the U.S. Department of Energy, Office of Fusion Energy Sciences, under the DOE Idaho Field Office contract number DE-AC07-05ID14517.« less

SEPs to finger joint input lack the N20-P20 response that is evoked by tactile inputs: contrast between cortical generators in areas 3b and 2 in humans.

PubMed

Desmedt, J E; Ozaki, I

1991-01-01

A method using a DC servo motor is described to produce brisk angular movements at finger interphalangeal joints in humans. Small passive flexions of 2 degrees elicited sizable somatosensory evoked potentials (SEPs) starting with a contralateral positive P34 parietal response thought to reflect activation of a radial equivalent dipole generator in area 2 which receives joint inputs. By contrast, electric stimulation of tactile (non-joint) inputs from the distal phalanx evoked the usual contralateral negative N20 reflecting a tangential equivalent dipole generator in area 3b. Finger joint inputs also evoked a precentral positivity equivalent to the P22 of motor area 4, and a large frontal negativity equivalent to N30. It is suggested that natural stimulation allows human SEP components to be differentiated in conjunction with distinct cortical somatotopic projections.

Methane negative chemical ionization analysis of 1,3-dihydro-5-phenyl-1,4-benzodiazepin-2-ones.

PubMed Central

Garland, W A; Miwa, B J

1980-01-01

The methane negative chemical ionization (NCI) mass spectra of the medically important 1,3-dihydro-5-phenyl-1,4-benzodiazepin-2-ones generally consisted solely of M- and (M-H)- ions. Attempts to find the location of the H lost in the generation of the (M-H)- ion were unsuccessful, although many possibilities were eliminated. A Hammett correlation analysis of the relative sensitivities of a series of 7-substituted benzodiazepines suggested that the initial ionization takes place at the 4,5-imine bond. For certain benzodiazepines, the (M-H)- ion generated by methane NCI was 20 times more intense than the MH+ ion generated by methane positive chemical ionization (PCI). By using NCI, a sensitive and simple GC-MS assay for nordiazepam was developed that can quantitate this important metabolite of many of the clinically used benzodiazepines in the blood and brain of rats. PMID:6775944

Generation of CsI cluster ions for mass calibration in matrix-assisted laser desorption/ionization mass spectrometry.

PubMed

Lou, Xianwen; van Dongen, Joost L J; Meijer, E W

2010-07-01

A simple method was developed for the generation of cesium iodide (CsI) cluster ions up to m/z over 20,000 in matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). Calibration ions in both positive and negative ion modes can readily be generated from a single MALDI spot of CsI(3) with 2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2-enylidene] malononitrile (DCTB) matrix. The major cluster ion series observed in the positive ion mode is [(CsI)(n)Cs](+), and in the negative ion mode is [(CsI)(n)I](-). In both cluster series, ions spread evenly every 259.81 units. The easy method described here for the production of CsI cluster ions should be useful for MALDI MS calibrations. Copyright 2010 American Society for Mass Spectrometry. Published by Elsevier Inc. All rights reserved.

Scaling of the VASIMR thruster first stage operation

NASA Astrophysics Data System (ADS)

Molvig, Kim; Batishchev, Oleg

2002-11-01

An effective helicon plasma source [1,2] is used in the variable high specific impulse VASIMR plasma thruster [3]. Experimental prototypes - VX-3 and recently up-scaled VX-10 [4] configurations operate with hydrogen, deuterium and helium plasmas. A set of models [5-7] has been developed to study VASIMR light gases helicon discharge. Using zero-dimensional model incorporating energy and mass balance equations we study scaling of the plasma source efficiency with the increased mass flow rate, applied electrical power and dimensions of the quartz tube. We compare theoretical results with existing experimental data. [1] M.A.Lieberman, A.J.Lihtenberg, 'Principles of ..', Wiley, 1994; [2] F.F.Chen, Plas. Phys. Contr. Fus. 33, 339, 1991; [3] F.Chang-Diaz et al, Bull. APS 45 (7) 129, 2000; [4] J.Squire et al., Bull. APS 45 (7) 130, 2000; [5] O.Batishchev, K.Molvig, AIAA technical paper 2000-3754, 2001; [6] O.Batishchev, K.Molvig, IEPC-01-208 paper, 27th Int. Electrical Propulsion Conf., 2001; [7] O.Batishchev, K.Molvig, AIAA technical paper 2002-0347, 2002.

Comparison of Multispot EIA with Western blot for confirmatory serodiagnosis of HIV.

PubMed

Torian, Lucia V; Forgione, Lisa A; Punsalang, Amado E; Pirillo, Robert E; Oleszko, William R

2011-12-01

Recent improvements in the sensitivity of immunoassays (IA) used for HIV screening, coupled with increasing recognition of the importance of rapid point-of-care testing, have led to proposals to adjust the algorithm for serodiagnosis of HIV so that screening and confirmation can be performed using a dual or triple IA sequence that does not require Western blotting for confirmation. One IA that has been proposed as a second or confirmatory test is the Bio-Rad Multispot(®) Rapid HIV-1/HIV-2 Test. This test would have the added advantage of differentiating between HIV-1 and HIV-2 antibodies. To compare the sensitivity and type-specificity of an algorithm combining a 3rd generation enzyme immunoassay (EIA) followed by a confirmatory Multispot with the conventional algorithm that combines a 3rd generation EIA (Bio-Rad GS HIV-1/HIV-2 Plus O EIA) followed by confirmatory Western blot (Bio-Rad GS HIV-1 WB). 8760 serum specimens submitted for HIV testing to the New York City Public Health Laboratory between May 22, 2007, and April 30, 2010, tested repeatedly positive on 3rd generation HIV-1-2+O EIA screening and received parallel confirmatory testing by WB and Multispot (MS). 8678/8760 (99.1%) specimens tested WB-positive; 82 (0.9%) tested WB-negative or indeterminate (IND). 8690/8760 specimens (99.2%) tested MS-positive, of which 14 (17.1%) had been classified as negative or IND by WB. Among the HIV-1 WB-positive specimens, MS classified 26 (0.29%) as HIV-2. Among the HIV-1 WB negative and IND, MS detected 12 HIV-2. MS detected an additional 14 HIV-1 infections among WB negative or IND specimens, differentiated 26 HIV-1 WB positives as HIV-2, and detected 12 additional HIV-2 infections among WB negative/IND. A dual 3rd generation EIA algorithm incorporating MS had equivalent HIV-1 sensitivity to the 3rd generation EIA-WB algorithm and had the added advantage of detecting 12 HIV-2 specimens that were not HIV-1 WB cross-reactors. In this series an algorithm using EIA followed by MS would have resulted in the expedited referral of 38 specimens for HIV-2 testing and 40 specimens for nucleic acid confirmation. Further testing using a combined gold standard of nucleic acid detection and WB is needed to calculate specificity and validate the substitution of MS for WB in the diagnostic algorithm used by a large public health laboratory. Copyright © 2011. Published by Elsevier B.V.

Design of an Integrated Plasma Control System and Extension of XSCTools to Ignitor

NASA Astrophysics Data System (ADS)

Albanese, R.; Ambrosino, G.; Artaserse, G.; Pironti, A.; Rubinacci, G.; Villone, F.; Ramogida, G.

2010-11-01

The performance of the integrated system for vertical stability, shape and plasma current control for the Ignitor machine has been assessed by means of the CREATELlinearized model of plasma responseootnotetextR. Albanese, F. Villone, Nucl. Fusion 38, 723 (1998) against a set of disturbances for the reference 11 MA limiter configuration and the 9 MA Double Null configuration. A new design, based on the methodology of the eXtreme Shape Controller (XSC) at JET, has been tested : by using all the shape control circuits with the exception of those used to control the vertical stability is possible to control up to four independent linear combinations of the 36 plasma-wall gaps. The results point out a substantial improvement in shape recovery, especially in the presence of a disturbance in li. The new shape controller can also automatically generate, via feedback control, new plasma shapes in the proximity of a given equilibrium configuration. The XSC ToolsootnotetextG. Ambrosino, R. Albanese et al., Fus. Eng.& Des. 74, 521 (2005) have been adapted and extended to develop linearized Ignitor models including 2D eddy currents and to solve inverse linearized plasma equilibria.

Specific interaction between negative atmospheric ions and organic compounds in atmospheric pressure corona discharge ionization mass spectrometry.

PubMed

Sekimoto, Kanako; Sakai, Mami; Takayama, Mitsuo

2012-06-01

The interaction between negative atmospheric ions and various types of organic compounds were investigated using atmospheric pressure corona discharge ionization (APCDI) mass spectrometry. Atmospheric negative ions such as O(2)(-), HCO(3)(-), COO(-)(COOH), NO(2)(-), NO(3)(-), and NO(3)(-)(HNO(3)) having different proton affinities served as the reactant ions for analyte ionization in APCDI in negative-ion mode. The individual atmospheric ions specifically ionized aliphatic and aromatic compounds with various functional groups as atmospheric ion adducts and deprotonated analytes. The formation of the atmospheric ion adducts under certain discharge conditions is most likely attributable to the affinity between the analyte and atmospheric ion and the concentration of the atmospheric ion produced under these conditions. The deprotonated analytes, in contrast, were generated from the adducts of the atmospheric ions with higher proton affinity attributable to efficient proton abstraction from the analyte by the atmospheric ion.

Intergenerational Continuity of Hostile Parenting and Its Consequences: The Moderating Influence of Children's Negative Emotional Reactivity.

ERIC Educational Resources Information Center

Scaramella, Laura V.; Conger, Rand D.

2003-01-01

Examined intergenerational transmission of hostile parenting, moderating effects of child negative emotional reactivity, and links between second generation (G2) hostile parenting and G3 problem behaviors. Found that G1 mothers' hostile parenting when target participant was an adolescent (G2) predicted G2 hostile parenting toward their young child…

Helicon wave-generated plasmas for negative ion beams for fusion

NASA Astrophysics Data System (ADS)

Furno, Ivo; Agnello, Riccardo; Fantz, U.; Howling, Alan; Jacquier, Remy; Marini, Claudio; Plyushchev, Gennady; Guittienne, Philippe; Simonin, Alain

2017-10-01

In the next generation of fusion reactors, such as DEMO, neutral beam injectors (NBIs) of high energy (0.8-1 MeV) deuterium atoms with high wall-plug efficiency (>50%) will be required to reach burning plasma conditions and to provide a significant amount of current drive. The present NBI system for DEMO assumes that 50 MW is delivered to the plasma by 3 NBIs. In the Siphore NBI concept, negative deuterium ions are extracted from a long, thin ion source 3 m high and 15 cm wide, accelerated and subsequently photo-neutralized. This requires the development of a new generation of negative ion sources. At the Swiss Plasma Center, a novel radio frequency helicon plasma source, based on a resonant network antenna source delivering up to 10 kW at 13.56 MHz, has been developed and is presently under study on the Resonant Antenna Ion Device (RAID). RAID is a linear device (1.9 m total length, 0.4 m diameter) and is equipped with an extensive set of diagnostics for full plasma characterization. In this work, the principles of operation of resonant antennas as helicon sources are introduced. We present absolute spectroscopy, Langmuir probe, and interferometry measurements on helicon plasmas. We characterize the performance of the source in terms of hydrogen/deuterium dissociation and negative ion production as a function of the input power. Furthermore, first results with the helicon birdcage antenna installed on the Cybele negative ion source at CEA-IRFM are presented, as a first step towards the validation of the Siphore concept.

Exploring the spatio-temporal neural basis of face learning

PubMed Central

Yang, Ying; Xu, Yang; Jew, Carol A.; Pyles, John A.; Kass, Robert E.; Tarr, Michael J.

2017-01-01

Humans are experts at face individuation. Although previous work has identified a network of face-sensitive regions and some of the temporal signatures of face processing, as yet, we do not have a clear understanding of how such face-sensitive regions support learning at different time points. To study the joint spatio-temporal neural basis of face learning, we trained subjects to categorize two groups of novel faces and recorded their neural responses using magnetoencephalography (MEG) throughout learning. A regression analysis of neural responses in face-sensitive regions against behavioral learning curves revealed significant correlations with learning in the majority of the face-sensitive regions in the face network, mostly between 150–250 ms, but also after 300 ms. However, the effect was smaller in nonventral regions (within the superior temporal areas and prefrontal cortex) than that in the ventral regions (within the inferior occipital gyri (IOG), midfusiform gyri (mFUS) and anterior temporal lobes). A multivariate discriminant analysis also revealed that IOG and mFUS, which showed strong correlation effects with learning, exhibited significant discriminability between the two face categories at different time points both between 150–250 ms and after 300 ms. In contrast, the nonventral face-sensitive regions, where correlation effects with learning were smaller, did exhibit some significant discriminability, but mainly after 300 ms. In sum, our findings indicate that early and recurring temporal components arising from ventral face-sensitive regions are critically involved in learning new faces. PMID:28570739

Focal point determination in magnetic resonance-guided focused ultrasound using tracking coils.

PubMed

Svedin, Bryant T; Beck, Michael J; Hadley, J Rock; Merrill, Robb; de Bever, Joshua T; Bolster, Bradley D; Payne, Allison; Parker, Dennis L

2017-06-01

To develop a method for rapid prediction of the geometric focus location in MR coordinates of a focused ultrasound (US) transducer with arbitrary position and orientation without sonicating. Three small tracker coil circuits were designed, constructed, attached to the transducer housing of a breast-specific MR-guided focused US (MRgFUS) system with 5 degrees of freedom, and connected to receiver channel inputs of an MRI scanner. A one-dimensional sequence applied in three orthogonal directions determined the position of each tracker, which was then corrected for gradient nonlinearity. In a calibration step, low-level heating located the US focus in one transducer position orientation where the tracker positions were also known. Subsequent US focus locations were determined from the isometric transformation of the trackers. The accuracy of this method was verified by comparing the tracking coil predictions to thermal center of mass calculated using MR thermometry data acquired at 16 different transducer positions for MRgFUS sonications in a homogeneous gelatin phantom. The tracker coil predicted focus was an average distance of 2.1 ± 1.1 mm from the thermal center of mass. The one-dimensional locator sequence and prediction calculations took less than 1 s to perform. This technique accurately predicts the geometric focus for a transducer with arbitrary position and orientation without sonicating. Magn Reson Med 77:2424-2430, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

TUSC2(FUS1)-erlotinib Induced Vulnerabilities in Epidermal Growth Factor Receptor(EGFR) Wildtype Non-small Cell Lung Cancer(NSCLC) Targeted by the Repurposed Drug Auranofin.

PubMed

Xiaobo, Cao; Majidi, Mourad; Feng, Meng; Shao, Ruping; Wang, Jing; Zhao, Yang; Baladandayuthapani, Veerabhadran; Song, Juhee; Fang, Bingliang; Ji, Lin; Mehran, Reza; Roth, Jack A

2016-11-15

Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy. Addition of the thioredoxin reductase 1 inhibitor (TXNRD1) auranofin (AF) to NSCLC cells treated with combination of TUSC2 forced expression with erlotinib increased tumor cell apoptosis and inhibited colony formation. TXNRD1 overexpression rescued tumors from AF-TUSC2-erlotinib induced apoptosis. Neutralizing ROS with nordihydroguaiaretic acid (NDGA) abrogated cell death induced by AF-TUSC2-erlotinib, indicating a regulatory role for ROS in the efficacy of the three drug combination. Isobologram-based statistical analysis of this combination demonstrated superior synergism, compared with each individual treatment at lower concentrations. In NSCLC tumor xenografts, tumor growth was markedly inhibited and animal survival was prolonged over controls by AF-TUSC2-erlotinib. Microarray mRNA expression analysis uncovered oxidative stress and DNA damage gene signatures significantly upregulated by AF-TUSC2-erlotinib compared to TUSC2-erlotinib. Pathway analysis showed the highest positive z-score for the NRF2-mediated oxidative stress response. Taken together these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with AF.

Adaptation Genomics of a Small-Colony Variant in a Pseudomonas chlororaphis 30-84 Biofilm

PubMed Central

Dorosky, Robert J.; Han, Cliff S.; Lo, Chien-chi; Dichosa, Armand E. K.; Chain, Patrick S.; Yu, Jun Myoung; Pierson, Leland S.

2014-01-01

The rhizosphere-colonizing bacterium Pseudomonas chlororaphis 30-84 is an effective biological control agent against take-all disease of wheat. In this study, we characterize a small-colony variant (SCV) isolated from a P. chlororaphis 30-84 biofilm. The SCV exhibited pleiotropic phenotypes, including small cell size, slow growth and motility, low levels of phenazine production, and increased biofilm formation and resistance to antimicrobials. To better understand the genetic alterations underlying these phenotypes, RNA and whole-genome sequencing analyses were conducted comparing an SCV to the wild-type strain. Of the genome's 5,971 genes, transcriptomic profiling indicated that 1,098 (18.4%) have undergone substantial reprograming of gene expression in the SCV. Whole-genome sequence analysis revealed multiple alterations in the SCV, including mutations in yfiR (cyclic-di-GMP production), fusA (elongation factor), and cyoE (heme synthesis) and a 70-kb deletion. Genetic analysis revealed that the yfiR locus plays a major role in controlling SCV phenotypes, including colony size, growth, motility, and biofilm formation. Moreover, a point mutation in the fusA gene contributed to kanamycin resistance. Interestingly, the SCV can partially switch back to wild-type morphologies under specific conditions. Our data also support the idea that phenotypic switching in P. chlororaphis is not due to simple genetic reversions but may involve multiple secondary mutations. The emergence of these highly adherent and antibiotic-resistant SCVs within the biofilm might play key roles in P. chlororaphis natural persistence. PMID:25416762

Localized Harmonic Motion Imaging for Focused Ultrasound Surgery Targeting

PubMed Central

Curiel, Laura; Hynynen, Kullervo

2011-01-01

Recently, an in vivo real-time ultrasound-based monitoring technique that uses localized harmonic motion (LHM) to detect changes in tissues during focused ultrasound surgery (FUS) has been proposed to control the exposure. This technique can potentially be used as well for targeting imaging. In the present study we evaluated the potential of using LHM to detect changes in stiffness and the feasibility of using it for imaging purposes in phantoms and in vivo tumor detection. A single-element FUS transducer (80 mm focal length, 100 mm diameter, 1.485 MHz) was used for inducing a localized harmonic motion and a separate ultrasound diagnostic transducer excited by a pulser/receiver (5 kHz PRF, 5 MHz) was used to track motion. The motion was estimated using cross-correlation techniques on the acquired RF signal. Silicon phantom studies were performed in order to determine the size of inclusion that was possible to detect using this technique. Inclusions were discerned from the surroundings as a reduction on LHM amplitude and it was possible to depict inclusions as small as 4 mm. The amplitude of the induced LHM was always lower at the inclusions as compared with the one obtained at the surroundings. Ten New Zealand rabbits had VX2 tumors implanted on their thighs and LHM was induced and measured at the tumor region. Tumors (as small as 10 mm in length and 4 mm in width) were discerned from the surroundings as a reduction on LHM amplitude. PMID:21683514

Exploring the spatio-temporal neural basis of face learning.

PubMed

Yang, Ying; Xu, Yang; Jew, Carol A; Pyles, John A; Kass, Robert E; Tarr, Michael J

2017-06-01

Humans are experts at face individuation. Although previous work has identified a network of face-sensitive regions and some of the temporal signatures of face processing, as yet, we do not have a clear understanding of how such face-sensitive regions support learning at different time points. To study the joint spatio-temporal neural basis of face learning, we trained subjects to categorize two groups of novel faces and recorded their neural responses using magnetoencephalography (MEG) throughout learning. A regression analysis of neural responses in face-sensitive regions against behavioral learning curves revealed significant correlations with learning in the majority of the face-sensitive regions in the face network, mostly between 150-250 ms, but also after 300 ms. However, the effect was smaller in nonventral regions (within the superior temporal areas and prefrontal cortex) than that in the ventral regions (within the inferior occipital gyri (IOG), midfusiform gyri (mFUS) and anterior temporal lobes). A multivariate discriminant analysis also revealed that IOG and mFUS, which showed strong correlation effects with learning, exhibited significant discriminability between the two face categories at different time points both between 150-250 ms and after 300 ms. In contrast, the nonventral face-sensitive regions, where correlation effects with learning were smaller, did exhibit some significant discriminability, but mainly after 300 ms. In sum, our findings indicate that early and recurring temporal components arising from ventral face-sensitive regions are critically involved in learning new faces.

Transcranial passive acoustic mapping with hemispherical sparse arrays using CT-based skull-specific aberration corrections: a simulation study

PubMed Central

Jones, Ryan M.; O’Reilly, Meaghan A.; Hynynen, Kullervo

2013-01-01

The feasibility of transcranial passive acoustic mapping with hemispherical sparse arrays (30 cm diameter, 16 to 1372 elements, 2.48 mm receiver diameter) using CT-based aberration corrections was investigated via numerical simulations. A multi-layered ray acoustic transcranial ultrasound propagation model based on CT-derived skull morphology was developed. By incorporating skull-specific aberration corrections into a conventional passive beamforming algorithm (Norton and Won 2000 IEEE Trans. Geosci. Remote Sens. 38 1337–43), simulated acoustic source fields representing the emissions from acoustically-stimulated microbubbles were spatially mapped through three digitized human skulls, with the transskull reconstructions closely matching the water-path control images. Image quality was quantified based on main lobe beamwidths, peak sidelobe ratio, and image signal-to-noise ratio. The effects on the resulting image quality of the source’s emission frequency and location within the skull cavity, the array sparsity and element configuration, the receiver element sensitivity, and the specific skull morphology were all investigated. The system’s resolution capabilities were also estimated for various degrees of array sparsity. Passive imaging of acoustic sources through an intact skull was shown possible with sparse hemispherical imaging arrays. This technique may be useful for the monitoring and control of transcranial focused ultrasound (FUS) treatments, particularly non-thermal, cavitation-mediated applications such as FUS-induced blood-brain barrier disruption or sonothrombolysis, for which no real-time monitoring technique currently exists. PMID:23807573

Adaptive model-predictive controller for magnetic resonance guided focused ultrasound therapy.

PubMed

de Bever, Joshua; Todd, Nick; Payne, Allison; Christensen, Douglas A; Roemer, Robert B

2014-11-01

Minimising treatment time and protecting healthy tissues are conflicting goals that play major roles in making magnetic resonance image-guided focused ultrasound (MRgFUS) therapies clinically practical. We have developed and tested in vivo an adaptive model-predictive controller (AMPC) that reduces treatment time, ensures safety and efficacy, and provides flexibility in treatment set-up. The controller realises time savings by modelling the heated treatment cell's future temperatures and thermal dose accumulation in order to anticipate the optimal time to switch to the next cell. Selected tissues are safeguarded by a configurable temperature constraint. Simulations quantified the time savings realised by each controller feature as well as the trade-offs between competing safety and treatment time parameters. In vivo experiments in rabbit thighs established the controller's effectiveness and reliability. In all in vivo experiments the target thermal dose of at least 240 CEM43 was delivered everywhere in the treatment volume. The controller's temperature safety limit reliably activated and constrained all protected tissues to <9 CEM43. Simulations demonstrated the path independence of the controller, and that a path which successively proceeds to the hottest untreated neighbouring cell leads to significant time savings, e.g. when compared to a concentric spiral path. Use of the AMPC produced a compounding time-saving effect; reducing the treatment cells' heating times concurrently reduced heating of normal tissues, which eliminated cooling periods. Adaptive model-predictive control can automatically deliver safe, effective MRgFUS treatments while significantly reducing treatment times.

An examination of the thermodynamics of fusion, vaporization, and sublimation of (R,S)- and (R)-flurbiprofen by correlation gas chromatography.

PubMed

Umnahanant, Patamaporn; Hasty, Darrell; Chickos, James

2012-06-01

The vaporization, fusion, and sublimation enthalpies of (R,S)- and (R)-flurbiprofen at T = 298.15 K are reported and compared with literature values when available. Correlation gas chromatography experiments were first performed to identify appropriate standards that could be used for materials containing a single fluorine substituent. Subsequent correlations resulted in a vaporization enthalpy for (R,S)-flurbiprofen and (R)-flurbiprofen, ΔH(vap) (298.15 K), of (127.5 ± 5.5) and (127.4 ± 4.7) kJ mol, respectively. Fusion enthalpies, ΔH(fus) (387 K), of (28.2 ± and, ΔH(fus) (381 K), (22.8 ± kJ mol(-1) were also measured by differential scanning calorimetry for the racemic and chiral forms of flurbiprofen. Adjusted to T = 298.15 K and combined with the vaporization enthalpy resulted in sublimation enthalpies, ΔH(sub) (298.15 K), of (155.6 ± 5.8) and (145.1 ± 5.7) kJ mol(-1) for (R,S)- and (R)-flurbiprofen, respectively. The fusion enthalpy measured for the racemic form was in excellent agreement with the literature value, while the sublimation enthalpy varies substantially from previous work. Two weak solid-solid phase transitions were also observed for (R)-flurbiprofen at T = 353.9 K (0.30 ± 0.1) and 363.2 K (0.21 ± 0.03) kJ · mol(-1). Copyright © 2012 Wiley Periodicals, Inc.

Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound.

PubMed

Kaye, Elena A; Hertzberg, Yoni; Marx, Michael; Werner, Beat; Navon, Gil; Levoy, Marc; Pauly, Kim Butts

2012-10-01

To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set. The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat et al., "MR-guided adaptive focusing of ultrasound," IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734-1747 (2010)] was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients' phase aberrations. MR acoustic radiation force imaging (MR-ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patient's data were investigated. The benefits of the initial estimates in the Zernike-based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case. Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike-based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects. The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull-based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike-based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR-ARFI-based focusing for a clinical transcranial MRgFUS therapy.

Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound

PubMed Central

Kaye, Elena A.; Hertzberg, Yoni; Marx, Michael; Werner, Beat; Navon, Gil; Levoy, Marc; Pauly, Kim Butts

2012-01-01

Purpose: To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set. Methods: The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat , “MR-guided adaptive focusing of ultrasound,” IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734–1747 (2010)]10.1109/TUFFC.2010.1612 was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients’ phase aberrations. MR acoustic radiation force imaging (MR-ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patient's data were investigated. The benefits of the initial estimates in the Zernike-based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case. Results: Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike-based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects. Conclusions: The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull-based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike-based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR-ARFI-based focusing for a clinical transcranial MRgFUS therapy. PMID:23039661

Research progress on ionic plasmas generated in an intense hydrogen negative ion source

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takeiri, Y., E-mail: takeiri@nifs.ac.jp; Tsumori, K.; Nagaoka, K.

2015-04-08

Characteristics of ionic plasmas, observed in a high-density hydrogen negative ion source, are investigated with a multi-diagnostics system. The ionic plasma, which consists of hydrogen positive- and negative-ions with a significantly low-density of electrons, is generated in the ion extraction region, from which the negative ions are extracted through the plasma grid. The negative ion density, i.e., the ionic plasma density, as high as the order of 1×10{sup 17}m{sup −3}, is measured with cavity ring-down spectroscopy, while the electron density is lower than 1×10{sup 16}m{sup −3}, which is confirmed with millimeter-wave interferometer. Reduction of the negative ion density is observedmore » at the negative ion extraction, and at that time the electron flow into the ionic plasma region is observed to conserve the charge neutrality. Distribution of the plasma potential is measured in the extraction region in the direction normal to the plasma grid surface with a Langmuir probe, and the results suggest that the sheath is formed at the plasma boundary to the plasma grid to which the bias voltage is applied. The beam extraction should drive the negative ion transport in the ionic plasma across the sheath formed on the extraction surface. Larger reduction of the negative ions at the beam extraction is observed in a region above the extraction aperture on the plasma grid, which is confirmed with 2D image measurement of the Hα emission and cavity ring-down spectroscopy. The electron distribution is also measured near the plasma grid surface. These various properties observed in the ionic plasma are discussed.« less

Double exposure using 193nm negative tone photoresist

NASA Astrophysics Data System (ADS)

Kim, Ryoung-han; Wallow, Tom; Kye, Jongwook; Levinson, Harry J.; White, Dave

2007-03-01

Double exposure is one of the promising methods for extending lithographic patterning into the low k I regime. In this paper, we demonstrate double patterning of k 1-effective=0.25 with improved process window using a negative resist. Negative resist (TOK N- series) in combination with a bright field mask is proven to provide a large process window in generating 1:3 = trench:line resist features. By incorporating two etch transfer steps into the hard mask material, frequency doubled patterns could be obtained.

Use of the Abbott Architect HIV antigen/antibody assay in a low incidence population.

PubMed

Dubravac, Terry; Gahan, Thomas F; Pentella, Michael A

2013-12-01

With the availability of 4th generation HIV diagnostic tests which are capable of detecting acute infection, Iowa evaluated the 3rd and 4th generation HIV test and compared the performance of these products in a low incidence population. This study was conducted to evaluate the performance of an HIV antigen/antibody combination (4th generation) assay compared to an EIA 3rd generation assay. Over a 4 month period, 2037 specimens submitted for HIV screening were tested by Bio-Rad GS HIV-1/HIV-2 Plus O EIA and the Abbott Architect i1000SR HIV Ag/Ab Combo. The performance characteristics of sensitivity, specificity, positive predictive value and negative predictive value were determined. Of the 2037 specimens tested, there were 13 (0.64%) true positives detected. None of the positive specimens were from patients in the acute phase of infection. The Abbott antigen/antibody combo assay had a sensitivity, specificity, positive-predictive value and negative predictive value of 100%, 99.85%, 81.25%, and 100% respectively. The Bio-Rad EIA assay had a sensitivity, specificity, positive-predictive value and negative predictive value of 100%, 99.80%, 76.47% and 100%, respectively. The EIA had four false positive results which tested negative by the antigen/antibody assay and western blot. In a low-incidence state where early infections are less commonly encountered, the EIA assay and the antigen/antibody assay performed with near equivalency. The antigen/antibody assay had one less false positive result. While no patients were detected in the acute stage of infection, the use of the antigen/antibody assay presents the opportunity to detect an infected patient sooner and prevent transmission to others. Copyright © 2013 Elsevier B.V. All rights reserved.

Investigation of Dusts Effect and Negative Ion in DC Plasmas by Electric Probes

NASA Astrophysics Data System (ADS)

Oh, Hye Taek; Kang, Inje; Bae, Min-Keun; Park, Insun; Lee, Seunghwa; Jeong, Seojin; Chung, Kyu-Sun

2017-10-01

Dust is typically negatively charged by electron attachment whose thermal velocities are fast compared to that of the heavier ions. The negatively charged particles can play a role of negative ions which affect the quasi-neutrality of background plasma. To investigate effect of metal dusts and negative ion on plasma and materials, metal dusts are injected into background Ar plasma which is generated by tungsten filament using dust dispenser on Cubical Plasma Device (CPD). The CPD has following conditions: size =24x24x24cm3, plasma source =DC filament plasma (ne 1x10x1010, Te 2eV), background gas =Ar, dusts =tungsten powder (diameter 1.89micron). The dust dispenser is developed to quantitate of metal dust by ultrasonic transducer. Electronegative plasmas are generated by adding O2 + Ar plasma to compare negative ion and dust effect. A few grams of micron-sized dusts are placed in the dust dispenser which is located at the upper side of the Cubical Plasma Device. The falling particles by dust dispenser are mainly charged up by the collection of the background plasma. The change in parameters due to negative ion production are characterized by measuring the floating and plasma potential, electron temperature and negative ion density using electric probes.

An exposition on Friedmann cosmology with negative energy densities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nemiroff, Robert J.; Joshi, Ravi; Patla, Bijunath R., E-mail: nemiroff@mtu.edu, E-mail: rjoshimtu@gmail.com, E-mail: bijunath.patla@nist.gov

2015-06-01

How would negative energy density affect a classic Friedmann cosmology? Although never measured and possibly unphysical, certain realizations of quantum field theories leaves the door open for such a possibility. In this paper we analyze the evolution of a universe comprising varying amounts of negative energy forms. Negative energy components have negative normalized energy densities, Ω < 0. They include negative phantom energy with an equation of state parameter w < −1, negative cosmological constant: w=−1, negative domain walls: w = −2/3, negative cosmic strings: w=−1/3, negative mass: w = 0, negative radiation: w = 1/3 and negative ultralight: w > 1/3. Assuming that such energy forms generate pressure like perfect fluids,more » the attractive or repulsive nature of negative energy components are reviewed. The Friedmann equation is satisfied only when negative energy forms are coupled to a greater magnitude of positive energy forms or positive curvature. We show that the solutions exhibit cyclic evolution with bounces and turnovers.The future and fate of such universes in terms of curvature, temperature, acceleration, and energy density are reviewed. The end states are dubbed ''big crunch,' '' big void,' or ''big rip' and further qualified as ''warped',''curved', or ''flat',''hot' versus ''cold', ''accelerating' versus ''decelerating' versus ''coasting'. A universe that ends by contracting to zero energy density is termed ''big poof.' Which contracting universes ''bounce' in expansion and which expanding universes ''turnover' into contraction are also reviewed.« less

Recovering Old Stereoscopic Negatives and Producing Digital 3d Models of Former Appearances of Historic Buildings

NASA Astrophysics Data System (ADS)

Rodríguez Miranda, Á.; Valle Melón, J. M.

2017-02-01

Three-dimensional models with photographic textures have become a usual product for the study and dissemination of elements of heritage. The interest for cultural heritage also includes evolution along time; therefore, apart from the 3D models of the current state, it is interesting to be able to generate models representing how they were in the past. To that end, it is necessary to resort to archive information corresponding to the moments that we want to visualize. This text analyses the possibilities of generating 3D models of surfaces with photographic textures from old collections of analog negatives coming from works of terrestrial stereoscopic photogrammetry of historic buildings. The case studies presented refer to the geometric documentation of a small hermitage (done in 1996) and two sections of a wall (year 2000). The procedure starts with the digitization of the film negatives and the processing of the images generated, after which a combination of different methods for 3D reconstruction and texture wrapping are applied: techniques working simultaneously with several images (such as the algorithms of Structure from Motion - SfM) and single image techniques (such as the reconstruction based on vanishing points). Then, the features of the obtained models are described according to the geometric accuracy, completeness and aesthetic quality. In this way, it is possible to establish the real applicability of the models in order to be useful for the aforementioned historical studies and dissemination purposes. The text also wants to draw attention to the importance of preserving the documentary heritage available in the collections of negatives in archival custody and to the increasing difficulty of using them due to: (1) problems of access and physical conservation, (2) obsolescence of the equipment for scanning and stereoplotting and (3) the fact that the software for processing digitized photographs is discontinued.

Entanglement with negative Wigner function of almost 3,000 atoms heralded by one photon.

PubMed

McConnell, Robert; Zhang, Hao; Hu, Jiazhong; Ćuk, Senka; Vuletić, Vladan

2015-03-26

Quantum-mechanically correlated (entangled) states of many particles are of interest in quantum information, quantum computing and quantum metrology. Metrologically useful entangled states of large atomic ensembles have been experimentally realized, but these states display Gaussian spin distribution functions with a non-negative Wigner quasiprobability distribution function. Non-Gaussian entangled states have been produced in small ensembles of ions, and very recently in large atomic ensembles. Here we generate entanglement in a large atomic ensemble via an interaction with a very weak laser pulse; remarkably, the detection of a single photon prepares several thousand atoms in an entangled state. We reconstruct a negative-valued Wigner function--an important hallmark of non-classicality--and verify an entanglement depth (the minimum number of mutually entangled atoms) of 2,910 ± 190 out of 3,100 atoms. Attaining such a negative Wigner function and the mutual entanglement of virtually all atoms is unprecedented for an ensemble containing more than a few particles. Although the achieved purity of the state is slightly below the threshold for entanglement-induced metrological gain, further technical improvement should allow the generation of states that surpass this threshold, and of more complex Schrödinger cat states for quantum metrology and information processing. More generally, our results demonstrate the power of heralded methods for entanglement generation, and illustrate how the information contained in a single photon can drastically alter the quantum state of a large system.

A genome-wide inducible phenotypic screen identifies antisense RNA constructs silencing Escherichia coli essential genes

PubMed Central

Meng, Jia; Kanzaki, Gregory; Meas, Diane; Lam, Christopher K.; Crummer, Heather; Tain, Justina; Xu, H. Howard

2013-01-01

Regulated antisense RNA (asRNA) expression has been employed successfully in Gram-positive bacteria for genome-wide essential gene identification and drug target determination. However, there have been no published reports describing the application of asRNA gene silencing for comprehensive analyses of essential genes in Gram-negative bacteria. In this study, we report the first genome-wide identification of asRNA constructs for essential genes in Escherichia coli. We screened 250,000 library transformants for conditional growth-inhibitory recombinant clones from two shot-gun genomic libraries of E. coli using a paired-termini expression vector (pHN678). After sequencing plasmid inserts of 675 confirmed inducer-sensitive cell clones, we identified 152 separate asRNA constructs of which 134 inserts came from essential genes while 18 originated from non-essential genes (but share operons with essential genes). Among the 79 individual essential genes silenced by these asRNA constructs, 61 genes (77%) engage in processes related to protein synthesis. The cell-based assays of an asRNA clone targeting fusA (encoding elongation factor G) showed that the induced cells were sensitized 12 fold to fusidic acid, a known specific inhibitor. Our results demonstrate the utility of the paired-termini expression vector and feasibility of large-scale gene silencing in E. coli using regulated asRNA expression. PMID:22268863

Intergenerational continuity in economic hardship, parental positivity, and positive parenting: The association with child behavior

PubMed Central

Jeon, Shinyoung; Neppl, Tricia K.

2015-01-01

The current study examined intergenerational continuity in economic hardship, parental positivity, and positive parenting across generations based on both the Family Stress Model and the Family Resilience Framework. The study included 220 generation one (G1) parents, their target youth (generation two: G2) who participated from adolescence through adulthood, and the target’s child (generation three: G3). Assessments included observational and self-report measures. Results indicated that G1 economic hardship negatively influenced both G1 positivity and G1 positive parenting. Similarly, G2 economic hardship was negatively related to both G2 positivity and G2 positive parenting which, in turn, was associated with G3 positive behavior to G2. For both G1 and G2, parental positivity mediated the association between economic hardship and positive parenting. G2 economic hardship was indirectly related to G3 positive behavior through G2 parental positivity and positive parenting. An important finding is that the intergenerational continuity of economic hardship, positivity, and positive parenting were transmitted from G1 to G2. Results suggest that even in times of economic adversity, parental positivity and positive parenting were transmitted from G1 parents to their G2 youth during adulthood. Such continuity seems to influence the positive behavior of the G3 children. PMID:26371448

Generation and context memory.

PubMed

Mulligan, Neil W; Lozito, Jeffrey P; Rosner, Zachary A

2006-07-01

Generation enhances memory for occurrence but may not enhance other aspects of memory. The present study further delineates the negative generation effect in context memory reported in N. W. Mulligan (2004). First, the negative generation effect occurred for perceptual attributes of the target item (its color and font) but not for extratarget aspects of context (location and background color). Second, nonvisual generation tasks with either semantic or nonsemantic generation rules (antonym and rhyme generation, respectively) produced the same pattern of results. In contrast, a visual (or data-driven) generation task (letter transposition) did not disrupt context memory for color. Third, generating nonwords produced no effect on item memory but persisted in producing a negative effect on context memory for target attributes, implying that (a) the negative generation effect in context memory is not mediated by semantic encoding, and (b) the negative effect on context memory can be dissociated from the positive effect on item memory. The results are interpreted in terms of the processing account of generation. The original, perceptual-conceptual version of this account is too narrow, but a modified processing account, based on a more generic visual versus nonvisual processing distinction, accommodates the results. Copyright 2006 APA, all rights reserved.

Simulation of cesium injection and distribution in rf-driven ion sources for negative hydrogen ion generation.

PubMed

Gutser, R; Fantz, U; Wünderlich, D

2010-02-01

Cesium seeded sources for surface generated negative hydrogen ions are major components of neutral beam injection systems in future large-scale fusion experiments such as ITER. Stability and delivered current density depend highly on the cesium conditions during plasma-on and plasma-off phases of the ion source. The Monte Carlo code CSFLOW3D was used to study the transport of neutral and ionic cesium in both phases. Homogeneous and intense flows were obtained from two cesium sources in the expansion region of the ion source and from a dispenser array, which is located 10 cm in front of the converter surface.

A four-field model for collisionless reconnection: Hamiltonian structure and numerical simulations

NASA Astrophysics Data System (ADS)

Tassi, Emanuele; Grasso, Daniela; Pegoraro, Francesco

2008-11-01

A 4-field model for magnetic reconnection in collisionless plasmas is investigated both analytically and numerically. The model equations are shown to admit a non-canonical Hamiltonian formulation with four infinite families of Casimir invariants [1]. Numerical simulations show that, consistently with previously investigated models [2,3], in the absence of significant fluctuations along the toroidal direction, reconnection can lead to a macroscopic saturated state exhibiting filamentation on microsocopic scales, or to a secondary Kelvin-Helmholtz-like instability, depending on the value of a parameter measuring the compressibility of the electron fluid. The novel feature exhibited by the four-field model is the coexistence of significant filamentation with a secondary instability when magnetic and velocity perturbations along the toroidal direction are no longer negligible. An interpretation of this phenomenon in terms of Casimir invariants is given.[0pt] [1] E. Tassi et al., Plasma Phys. Contr. Fus., 50, 085014 (2008)[0pt] [2] D. Grasso et al., Phys. Rev. Lett. 86, 5051 (2001)[0pt] [3] D. Del Sarto, F. Califano and F. Pegoraro, Phys. Plasmas 12, 012317 (2005)

Molecular and epigenetic regulations and functions of the LAFL transcriptional regulators that control seed development.

PubMed

Lepiniec, L; Devic, M; Roscoe, T J; Bouyer, D; Zhou, D-X; Boulard, C; Baud, S; Dubreucq, B

2018-05-24

The LAFL (i.e. LEC1, ABI3, FUS3, and LEC2) master transcriptional regulators interact to form different complexes that induce embryo development and maturation, and inhibit seed germination and vegetative growth in Arabidopsis. Orthologous genes involved in similar regulatory processes have been described in various angiosperms including important crop species. Consistent with a prominent role of the LAFL regulators in triggering and maintaining embryonic cell fate, their expression appears finely tuned in different tissues during seed development and tightly repressed in vegetative tissues by a surprisingly high number of genetic and epigenetic factors. Partial functional redundancies and intricate feedback regulations of the LAFL have hampered the elucidation of the underpinning molecular mechanisms. Nevertheless, genetic, genomic, cellular, molecular, and biochemical analyses implemented during the last years have greatly improved our knowledge of the LALF network. Here we summarize and discuss recent progress, together with current issues required to gain a comprehensive insight into the network, including the emerging function of LEC1 and possibly LEC2 as pioneer transcription factors.

Cryptic Amyloidogenic Elements in the 3′ UTRs of Neurofilament Genes Trigger Axonal Neuropathy

PubMed Central

Rebelo, Adriana P.; Abrams, Alexander J.; Cottenie, Ellen; Horga, Alejandro; Gonzalez, Michael; Bis, Dana M.; Sanchez-Mejias, Avencia; Pinto, Milena; Buglo, Elena; Markel, Kasey; Prince, Jeffrey; Laura, Matilde; Houlden, Henry; Blake, Julian; Woodward, Cathy; Sweeney, Mary G.; Holton, Janice L.; Hanna, Michael; Dallman, Julia E.; Auer-Grumbach, Michaela; Reilly, Mary M.; Zuchner, Stephan

2016-01-01

Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3′ UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants. PMID:27040688

The Negative Testing and Negative Generation Effects Are Eliminated by Delay

ERIC Educational Resources Information Center

Mulligan, Neil W.; Peterson, Daniel J.

2015-01-01

Although retrieval often enhances subsequent memory (the testing effect), a negative testing effect has recently been documented in which prior retrieval harms later recall compared with restudying. The negative testing effect was predicated on the negative generation effect and the item-specific-relational framework. The present experiments…

Morphological, chemical and molecular differentiation of Fusarium equiseti isolated from Norwegian cereals.

PubMed

Kosiak, Elzbieta Barbara; Holst-Jensen, Arne; Rundberget, Thomas; Gonzalez Jaen, Maria Teresa; Torp, Mona

2005-03-15

The morphological variation, secondary metabolite profiles and restriction fragment length polymorphisms (RFLPs) of PCR amplified intergenic spacer (IGS) ribosomal DNA (rDNA) were studied in 27 isolates of Fusarium equiseti, 25 isolated from Norwegian cereals and 2 from soil obtained from the IBT culture collection (BioCentrum, Technical University of Denmark). All 27 isolates were tested for production of fusarochromanone (FUSCHR), zearalenone (ZEA) and the trichothecenes: 15-monoacetoxy-scirpentriol (MAS), diacetoxy-scirpenol (DAS), T-2 and HT-2 toxins, T2-triol, neosolaniol (NEO), deoxynivalenol (DON), nivalenol (NIV) and 4-acetylnivalenol (Fus-X). The trichothecenes were analysed by GC-MS in a selected ion monitoring mode, while FUSCHR was determined by ion pair HPLC with fluorometric detection and production of ZEA by TLC. For amplification of IGS rDNA primers CNL12 and CNS1 were applied. IGS rDNA was digested with the four restriction enzymes: AvaII, CfoI, EcoRI and Sau3A. In addition, we sequenced the IGS rDNA region of three of the Norwegian isolates. There were two morphological types among the Norwegian strains of F. equiseti, type I with short apical cells (dominating) and type II with long apical cells, with four haplotypes identified based on the RFLP data. Variation in secondary metabolite profiles within and between the morphological groups was observed and the levels of produced toxins were: FUSCHR 3000-42,500 and 25-30 ng/g, NIV 20-2500 and 120-700 ng/g, FUS-X 20-15,000 and 0 ng/g, DAS 30-7500 and 0-600 ng/g, and MAS 10-600 and 0-500 ng/g, for strains with short and long apical cells, respectively. NEO was detected in 16/27 strains tested (all morphotype I). All but four strains of type I (these four lacked a restriction site for EcoRI) had identical RFLP profiles. The isolates of type II had two haplotypes. The IGS sequence similarity data indicated differences between these morphotypes corresponding to two separate lineages apparently at the species level.

Negative branes, supergroups and the signature of spacetime

NASA Astrophysics Data System (ADS)

Dijkgraaf, Robbert; Heidenreich, Ben; Jefferson, Patrick; Vafa, Cumrun

2018-02-01

We study the realization of supergroup gauge theories using negative branes in string theory. We show that negative branes are intimately connected with the possibility of timelike compactification and exotic spacetime signatures previously studied by Hull. Isolated negative branes dynamically generate a change in spacetime signature near their worldvolumes, and are related by string dualities to a smooth M-theory geometry with closed timelike curves. Using negative D3-branes, we show that SU(0| N) supergroup theories are holographically dual to an exotic variant of type IIB string theory on {dS}_{3,2}× {\\overline{S}}^5 , for which the emergent dimensions are timelike. Using branes, mirror symmetry and Nekrasov's instanton calculus, all of which agree, we derive the Seiberg-Witten curve for N=2 SU( N | M ) gauge theories. Together with our exploration of holography and string dualities for negative branes, this suggests that supergroup gauge theories may be non-perturbatively well-defined objects, though several puzzles remain.

Mass spectrometric study of the negative and positive secondary ions emitted from ethanol microdroplets by MeV-energy heavy ion impact

NASA Astrophysics Data System (ADS)

Kitajima, Kensei; Majima, Takuya; Nishio, Tatsuya; Oonishi, Yoshiki; Mizutani, Shiori; Kohno, Jun-ya; Saito, Manabu; Tsuchida, Hidetsugu

2018-06-01

We have investigated the negative and positive secondary ions emitted from ethanol droplets by 4.0-MeV C3+ impact to reveal the characteristic features of the reaction processes induced by fast heavy ions at the liquid ethanol surface. Analysis of the secondary ions was performed by time-of-flight mass spectrometry for microdroplet targets in a high vacuum environment. Fragment ions, deprotonated cluster ions, and trace amounts of the reaction product ions are observed in the negative secondary ions. The main fragment anions are C2HmO- (m = 1, 3, and 5) and C2H- generated by loss of hydrogen and oxygen atoms. The reaction product anions include deprotonated glycols, larger alcohols, and their dehydrated and dehydrogenated forms generated by secondary reactions between fragments and radicals. Furthermore, C3Hm- (m = 0-2) and C4Hm- (m = 0 and 1) are observed, which could be produced through a plasma state generated in the heavy ion track. Deprotonated ethanol cluster ions, [(EtOH)n - H]-, are observed up to about n = 25. [(EtOH)n - H]- have smaller kinetic energies than the protonated cluster ions (EtOH)nH+. This probably represents the effect of the positive Coulomb potential transiently formed in the ion track. We also discuss the size distributions and structures of the water- and CH2OH-radical-attached ethanol cluster ions.

Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy.

PubMed

Chen, Yu-Hsiang; Hancock, Bradley A; Solzak, Jeffrey P; Brinza, Dumitru; Scafe, Charles; Miller, Kathy D; Radovich, Milan

2017-01-01

Next-generation sequencing to detect circulating tumor DNA is a minimally invasive method for tumor genotyping and monitoring therapeutic response. The majority of studies have focused on detecting circulating tumor DNA from patients with metastatic disease. Herein, we tested whether circulating tumor DNA could be used as a biomarker to predict relapse in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. In this study, we analyzed samples from 38 early-stage triple-negative breast cancer patients with matched tumor, blood, and plasma. Extracted DNA underwent library preparation and amplification using the Oncomine Research Panel consisting of 134 cancer genes, followed by high-coverage sequencing and bioinformatics. We detected high-quality somatic mutations from primary tumors in 33 of 38 patients. TP53 mutations were the most prevalent (82%) followed by PIK3CA (16%). Of the 33 patients who had a mutation identified in their primary tumor, we were able to detect circulating tumor DNA mutations in the plasma of four patients (three TP53 mutations, one AKT1 mutation, one CDKN2A mutation). All four patients had recurrence of their disease (100% specificity), but sensitivity was limited to detecting only 4 of 13 patients who clinically relapsed (31% sensitivity). Notably, all four patients had a rapid recurrence (0.3, 4.0, 5.3, and 8.9 months). Patients with detectable circulating tumor DNA had an inferior disease free survival ( p  < 0.0001; median disease-free survival: 4.6 mos. vs. not reached; hazard ratio = 12.6, 95% confidence interval: 3.06-52.2). Our study shows that next-generation circulating tumor DNA sequencing of triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy can predict recurrence with high specificity, but moderate sensitivity. For those patients where circulating tumor DNA is detected, recurrence is rapid.

Non-human primate skull effects on the cavitation detection threshold of FUS-induced blood-brain barrier opening

NASA Astrophysics Data System (ADS)

Wu, Shih-Ying; Tung, Yao-Sheng; Marquet, Fabrice; Chen, Cherry C.; Konofagou, Elisa E.

2012-11-01

Microbubble (MB)-assisted focused ultrasound is a promising technique for delivering drugs to the brain by noninvasively and transiently opening the blood-brain barrier (BBB), and monitoring BBB opening using passive cavitation detection (PCD) is critical in detecting its occurrence, extent as well as assessing its mechanism. One of the main obstacles in achieving those objectives in large animals is the transcranial attenuation. To study the effects, the cavitation response through the in-vitro non-human primate (NHP) skull was investigated. In-house manufactured lipid-shelled MB (medium diameter: 4-5 um) were injected into a 4-mm channel of a phantom below a degassed monkey skull. A hydrophone confocally aligned with the FUS transducer served as PCD during sonication (frequency: 0.50 MHz, peak rarefactional pressures: 0.05-0.60 MPa, pulse length: 100 cycles, PRF: 10 Hz, duration: 2 s) for four cases: water without skull, water with skull, MB without skull and MB with skull. A 5.1-MHz linear-array transducer was also used to monitor the MB disruption. The frequency spectra, spectrograms, stable cavitation dose (SCD) and inertial cavitation dose (ICD) were quantified. Results showed that the onset of stable cavitation and inertial cavitation in the experiments occurred at 50 kPa, and was detectable throught the NHP skull since the both the detection thresholds for stable cavitation and inertial cavitation remained unchanged compared to the non-skull case, and the SCD and ICD acquired transcranially may not adequately represent the true extent of stable and inertial cavitation due to the skull attenuation.

Quantification of intraventricular blood clot in MR-guided focused ultrasound surgery

NASA Astrophysics Data System (ADS)

Hess, Maggie; Looi, Thomas; Lasso, Andras; Fichtinger, Gabor; Drake, James

2015-03-01

Intraventricular hemorrhage (IVH) affects nearly 15% of preterm infants. It can lead to ventricular dilation and cognitive impairment. To ablate IVH clots, MR-guided focused ultrasound surgery (MRgFUS) is investigated. This procedure requires accurate, fast and consistent quantification of ventricle and clot volumes. We developed a semi-autonomous segmentation (SAS) algorithm for measuring changes in the ventricle and clot volumes. Images are normalized, and then ventricle and clot masks are registered to the images. Voxels of the registered masks and voxels obtained by thresholding the normalized images are used as seed points for competitive region growing, which provides the final segmentation. The user selects the areas of interest for correspondence after thresholding and these selections are the final seeds for region growing. SAS was evaluated on an IVH porcine model. SAS was compared to ground truth manual segmentation (MS) for accuracy, efficiency, and consistency. Accuracy was determined by comparing clot and ventricle volumes produced by SAS and MS, and comparing contours by calculating 95% Hausdorff distances between the two labels. In Two-One-Sided Test, SAS and MS were found to be significantly equivalent (p < 0.01). SAS on average was found to be 15 times faster than MS (p < 0.01). Consistency was determined by repeated segmentation of the same image by both SAS and manual methods, SAS being significantly more consistent than MS (p < 0.05). SAS is a viable method to quantify the IVH clot and the lateral brain ventricles and it is serving in a large-scale porcine study of MRgFUS treatment of IVH clot lysis.