Effects of Coating a Titanium Alloy with Fibronectin on the Expression of Osteoblast Gene Markers in the MC3T3 Osteoprogenitor Cell Line

PubMed Central

Rapuano, Bruce E.; Hackshaw, Kyle M.; Schniepp, Hannes C.; MacDonald, Daniel E.

2013-01-01

Purpose A number of environmental and patient-related factors contribute to implant failure. A significant fraction of these failures can be attributed to limited osseointegration resulting from poor bone healing responses. The overall goal of this study was to determine whether surface treatment of a titanium-aluminum-vanadium alloy (Ti-6Al-4V) implant material with a biomimetic protein coating could promote the differentiation of attached osteoblastic cells. The specific aims of the study were to investigate whether osteoprogenitor cells cultured on a rigorously cleaned implant specimen showed a normal pattern of differentiation and whether preadsorbed fibronectin accelerated or enhanced osteoblast differentiation. Materials and Methods Ti-6Al-4V disks were rigorously cleaned, passivated in nitric acid, and dry heat–sterilized; some of the disks were then coated with 1 nmol/L fibronectin. MC3T3 osteoprogenitor cells were then cultured on the pretreated disks for several weeks. Quantitative real-time polymerase chain reaction was performed to measure changes over time in the mRNA levels of osteoblast genes. Results Fibronectin increased the peak expression of all analyzed osteoblast gene markers. “Early” genes that normally mark the proliferative phase (0 to 10 days) of osteoblastic development showed peak expression within the first 10 days after cell attachment to the titanium alloy. In contrast, “late” genes that normally mark the differentiation (10 to 20 days) and mineralization (20 to 36 days) phases of osteoblastogenesis achieved peak expression only after approximately 3 to 4 weeks of culture. Conclusions Osteoprogenitors cultured on a rigorously cleaned Ti-6Al-4V alloy were found to demonstrate a normal pattern of osteoblast differentiation. Preadsorbed fibronectin was observed to stimulate osteoblast differentiation during the mineralization phase of osteoblastogenesis. PMID:23057020

A marked response to icotinib in a patient with large cell neuroendocrine carcinoma harboring an EGFR mutation: A case report.

PubMed

Wang, Yuehong; Shen, Yi Hong; Ma, Shanni; Zhou, Jianying

2015-09-01

The present study reports the case of an 84-year-old male with primary pulmonary large cell neuroendocrine carcinoma (LCNEC) harboring an epidermal growth factor receptor (EGFR) gene mutation that exhibited a long-lasting response to the EGFR-tyrosine kinase inhibitor (EGFR-TKI) icotinib. The patient had an extensive smoking history, a poor performance status, and presented with an irregular mass in the middle lobe of the right lung on computed tomography (CT) and an enlarged left supraclavicular lymph node on physical examination. Right middle lobe bronchial brushing during fiberoptic bronchoscopy identified poorly-differentiated cancer cells. The left supraclavicular lymph node was biopsied and a diagnosis of metastatic LCNEC was determined. Furthermore, an EGFR exon 19 deletion was identified by DNA sequencing. Following diagnosis, icotinib was administered at a dose of 125 mg three times a day. Chest CT scans were performed after 1 month of treatment, which indicated that the tumor was in partial remission. This marked response to icotinib lasted for 8 months. Thus, the present case illustrates the possibility of identifying EGFR mutations in LCNEC and indicates that EGFR-tyrosine kinase inhibitors may be an alternative treatment strategy for patients with LCNEC harboring activating EGFR mutations.

Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis.

PubMed

Hunter, Karen E; Quick, Marsha L; Sadanandam, Anguraj; Hanahan, Douglas; Joyce, Johanna A

2013-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a relatively rare but clinically challenging tumor type. In particular, high grade, poorly-differentiated PanNETs have the worst patient prognosis, and the underlying mechanisms of disease are poorly understood. In this study we have identified and characterized a previously undescribed class of poorly differentiated PanNETs in the RIP1-Tag2 mouse model. We found that while the majority of tumors in the RIP1-Tag2 model are well-differentiated insulinomas, a subset of tumors had lost multiple markers of beta-cell differentiation and were highly invasive, leading us to term them poorly differentiated invasive carcinomas (PDICs). In addition, we found that these tumors exhibited a high mitotic index, resembling poorly differentiated (PD)-PanNETs in human patients. Interestingly, we identified expression of Id1, an inhibitor of DNA binding gene, and a regulator of differentiation, specifically in PDIC tumor cells by histological analysis. The identification of PDICs in this mouse model provides a unique opportunity to study the pathology and molecular characteristics of PD-PanNETs.

Asthma-specific health-related quality of life of people in Great Britain: A national survey.

PubMed

Upton, Jane; Lewis, Carine; Humphreys, Emily; Price, David; Walker, Samantha

2016-11-01

Although the ultimate goal of asthma treatment is to improve asthma-specific Health-Related Quality-Of-Life (HRQOL), in the UK population this is insufficiently studied. National asthma-specific HRQOL data is needed to inform strategies to address this condition. To benchmark asthma-specific HRQOL in a national survey of adults with asthma, and explore differences in this measure within subsections of the population. We analysed answers to the Marks Asthma Quality-of-Life Questionnaire (AQLQ-M) from a representative sample of 658 adults with asthma. Respondents answered asthma-specific questions to assess control, previous hospital admissions, asthma attacks and an indicator of severity. Higher scores indicate poorer HRQOL (maximum = 60). The highest quintile formed a subgroup 'Poor HRQOL'. Data were weighted to correct for any biases caused by differential non-response. Chi-square analyses were used to determine differences between good and poor quality of life and regression analyses performed to determine what factors are associated with poor HRQOL. The response rate was 49%. AQLQ-M median (IQR) scores were 5 (2-13) for the total sample (poor HRQOL = 21, good HRQOL = 3). Significant differences between good and poor HRQOL were observed in smoking status, SES, employment status and co-morbidities, but no differences were found between age groups. Those with poorly controlled asthma were significantly more likely to have poor HRQOL, ≥1 breathing related hospital admission or ≥1 asthma attack. This article provides benchmarking data on asthma-specific HRQOL. Improved strategies are needed to target interventions towards people experiencing poor HRQOL.

Radiation-Induced Oral Mucositis

PubMed Central

Maria, Osama Muhammad; Eliopoulos, Nicoletta; Muanza, Thierry

2017-01-01

Radiation-induced oral mucositis (RIOM) is a major dose-limiting toxicity in head and neck cancer patients. It is a normal tissue injury caused by radiation/radiotherapy (RT), which has marked adverse effects on patient quality of life and cancer therapy continuity. It is a challenge for radiation oncologists since it leads to cancer therapy interruption, poor local tumor control, and changes in dose fractionation. RIOM occurs in 100% of altered fractionation radiotherapy head and neck cancer patients. In the United Sates, its economic cost was estimated to reach 17,000.00 USD per patient with head and neck cancers. This review will discuss RIOM definition, epidemiology, impact and side effects, pathogenesis, scoring scales, diagnosis, differential diagnosis, prevention, and treatment. PMID:28589080

Microcephalic osteodysplastic primordial dwarfism type I/III in sibs.

PubMed

Meinecke, P; Passarge, E

1991-11-01

The clinical and radiological findings in a pair of sibs with microcephalic osteodysplastic primordial dwarfism (MOPD) are described, a boy who survived for 5 1/2 years and his more severely affected younger sister, who died at the age of 6 months. Neuropathological studies in this girl showed marked micrencephaly with severely hypoplastic, poorly gyrated frontal lobes and absent corpus callosum. Our observation supports the hypothesis that types I and III MOPD probably constitute a spectrum of one and the same entity and published data together with this report are consistent with autosomal recessive inheritance. The pathogenesis of this condition is as yet unknown, but its characteristics indicate a basic defect affecting cell proliferation and tissue differentiation.

The Text Marking Patterns of College Students.

ERIC Educational Resources Information Center

Nist, Sherrie L.; Kirby, Katie

1989-01-01

Examines patterns in college students' text markings using texts from three content areas: history, political science, and sociology. Indicates little differential marking between various text-types. Concludes that students seem to have little idea how to mark text efficiently. (MG)

Glycolipids as indicators of tumorigenesis.

PubMed

Morré, D J; Kloppel, T M; Merritt, W D; Keenan, T W

1978-01-01

Hyperplastic liver nodules and hepatocellular carcinomas were induced in rats by oral administration of the carcinogen N-2-fluorenylacetamide. Neoplastic tissue was compared with control, fetal, neonatal, and precancerous liver tissues. The development of the tumors was slow, such that temporal changes in the biochemical and morphologic development of carcinogenesis could be identified. Ganglioside sialic acid levels were elevated in all but the most poorly differentiated tumors. Experiments to monitor individual enzymes suggested that the alterations in glycolipid composition were a direct effect of alterations in biosynthetic activities. The pattern during tumorigenesis was the inverse of that during normal development. Also, ganglioside patterns showed a progressive simplification from hyperplastic nodules to well-differentiated hepatomas and through two grades of poorly differentiated hepatomas. An increase in the activity of the branchpoint enzyme of ganglioside biosynthesis preceded both a decrease in the branchpoint enzyme of the disialoganglioside pathway and a marked increase in the galactosyltranferase of GM1 formation. The results indicate that ganglioside deletions are the end result of a cascade of events in the tumorigenic transformation. The onset of ganglioside deletions but not of the cascade per se may correlate with the onset of malignancy. Glycolipid levels are elevated early in certain surrounding tissues especially in the blood. In rats bearing transplantable hepatomas, serum levels of lipid-bound sialic acid were elevated 2.5-fold. Similar results were obtained with sera of mice bearing transplantable mammary carcinomas and of cancer patients. These findings provide new emphasis for gangliosides in both cancer detection and as regulatory signals for growth and multiplication of cells.

N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation

PubMed Central

Iborra, Salvador; Ramos, Manuel; Arana, David M.; Lázaro, Silvia; Aguilar, Francisco; Santos, Eugenio; López, Daniel

2013-01-01

Signals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras–deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)–AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras–deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate. PMID:23776078

Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190.

PubMed

Gardner, Samantha; Gross, Sean M; David, Larry L; Klimek, John E; Rotwein, Peter

2015-10-01

The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes regulated by these kinases remain poorly defined. Here we find that activity of p38α/β is important not only in early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treatment of C2 myoblasts with the promyogenic growth factor insulin-like growth factor (IGF)-I, the early block in differentiation imposed by the p38 chemical inhibitor SB202190 could be overcome. Yet, under these conditions, IGF-I could not prevent the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts reversed the fusion block, as multinucleated myofibers were detected several hours later and reached ∼90% of the culture within 30 h. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of upregulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion and should be useful in identifying specific steps regulated by p38 MAP kinase-mediated signaling in myogenesis. Copyright © 2015 the American Physiological Society.

Study of Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC)

ClinicalTrials.gov

2017-11-15

Well-differentiated Non-functional NET of Thoracic Origin; Well-differentiated Non-functional NET of Gastrointestinal Origin; Well-differentiated Non-functional NET of Pancreatic Origin; Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma

Microcephalic osteodysplastic primordial dwarfism type I/III in sibs.

PubMed Central

Meinecke, P; Passarge, E

1991-01-01

The clinical and radiological findings in a pair of sibs with microcephalic osteodysplastic primordial dwarfism (MOPD) are described, a boy who survived for 5 1/2 years and his more severely affected younger sister, who died at the age of 6 months. Neuropathological studies in this girl showed marked micrencephaly with severely hypoplastic, poorly gyrated frontal lobes and absent corpus callosum. Our observation supports the hypothesis that types I and III MOPD probably constitute a spectrum of one and the same entity and published data together with this report are consistent with autosomal recessive inheritance. The pathogenesis of this condition is as yet unknown, but its characteristics indicate a basic defect affecting cell proliferation and tissue differentiation. Images PMID:1770539

Characterization of Apoptosis Signaling Cascades During the Differentiation Process of Human Neural ReNcell VM Progenitor Cells In Vitro.

PubMed

Jaeger, Alexandra; Fröhlich, Michael; Klum, Susanne; Lantow, Margareta; Viergutz, Torsten; Weiss, Dieter G; Kriehuber, Ralf

2015-11-01

Apoptosis is an essential physiological process accompanying the development of the central nervous system and human neurogenesis. However, the time scale and the underlying molecular mechanisms are yet poorly understood. Due to this fact, we investigated the functionality and general inducibility of apoptosis in the human neural ReNcell VM progenitor cell line during differentiation and also after exposure to staurosporine (STS) and ultraviolet B (UVB) irradiation. Transmission light microscopy, flow cytometry, and Western-/Immunoblot analysis were performed to compare proliferating and differentiating, in addition to STS- and UVB-treated cells. In particular, from 24 to 72 h post-initiation of differentiation, G0/G1 cell cycle arrest, increased loss of apoptotic cells, activation of pro-apoptotic BAX, Caspase-3, and cleavage of its substrate PARP were observed during cell differentiation and, to a higher extent, after treatment with STS and UVB. We conclude that redundant or defective cells are eliminated by apoptosis, while otherwise fully differentiated cells were less responsive to apoptosis induction by STS than proliferating cells, likely as a result of reduced APAF-1 expression, and increased levels of BCL-2. These data provide the evidence that apoptotic mechanisms in the neural ReNcell VM progenitor cell line are not only functional, but also inducible by external stimuli like growth factor withdrawal or treatment with STS and UVB, which marks this cell line as a suitable model to investigate apoptosis signaling pathways in respect to the differentiation processes of human neural progenitor cells in vitro.

Neuroanatomy of the Marine Jurassic Turtle Plesiochelys etalloni (Testudinata, Plesiochelyidae)

PubMed Central

Carabajal, Ariana Paulina; Sterli, Juliana; Müller, Johannes; Hilger, André

2013-01-01

Turtles are one of the least explored clades regarding endocranial anatomy with few available descriptions of the brain and inner ear of extant representatives. In addition, the paleoneurology of extinct turtles is poorly known and based on only a few natural cranial endocasts. The main goal of this study is to provide for the first time a detailed description of the neuroanatomy of an extinct turtle, the Late Jurassic Plesiochelysetalloni , including internal carotid circulation, cranial endocast and inner ear, based on the first digital 3D reconstruction using micro CT scans. The general shape of the cranial endocast of P. etalloni is tubular, with poorly marked cephalic and pontine flexures. Anteriorly, the olfactory bulbs are clearly differentiated suggesting larger bulbs than in any other described extinct or extant turtle, and indicating a higher capacity of olfaction in this taxon. The morphology of the inner ear of P . etalloni is comparable to that of extant turtles and resembles those of slow-moving terrestrial vertebrates, with markedly low, short and robust semicircular canals, and a reduced lagena. In P . etalloni the arterial pattern is similar to that found in extant cryptodires, where all the internal carotid branches are protected by bone. As the knowledge of paleoneurology in turtles is scarce and the application of modern techniques such as 3D reconstructions based on CT scans is almost unexplored in this clade, we hope this paper will trigger similar investigations of this type in other turtle taxa. PMID:23844257

Neuroanatomy of the marine Jurassic turtle Plesiochelys etalloni (Testudinata, Plesiochelyidae).

PubMed

Carabajal, Ariana Paulina; Sterli, Juliana; Müller, Johannes; Hilger, André

2013-01-01

Turtles are one of the least explored clades regarding endocranial anatomy with few available descriptions of the brain and inner ear of extant representatives. In addition, the paleoneurology of extinct turtles is poorly known and based on only a few natural cranial endocasts. The main goal of this study is to provide for the first time a detailed description of the neuroanatomy of an extinct turtle, the Late Jurassic Plesiochelysetalloni, including internal carotid circulation, cranial endocast and inner ear, based on the first digital 3D reconstruction using micro CT scans. The general shape of the cranial endocast of P. etalloni is tubular, with poorly marked cephalic and pontine flexures. Anteriorly, the olfactory bulbs are clearly differentiated suggesting larger bulbs than in any other described extinct or extant turtle, and indicating a higher capacity of olfaction in this taxon. The morphology of the inner ear of P. etalloni is comparable to that of extant turtles and resembles those of slow-moving terrestrial vertebrates, with markedly low, short and robust semicircular canals, and a reduced lagena. In P. etalloni the arterial pattern is similar to that found in extant cryptodires, where all the internal carotid branches are protected by bone. As the knowledge of paleoneurology in turtles is scarce and the application of modern techniques such as 3D reconstructions based on CT scans is almost unexplored in this clade, we hope this paper will trigger similar investigations of this type in other turtle taxa.

Role of neurotransmitter Substance P in progression of oral squamous cell carcinoma.

PubMed

Mehboob, Riffat; Tanvir, Imrana; Warraich, Riaz Ahmad; Perveen, Shahida; Yasmeen, Sehrish; Ahmad, Fridoon Jawad

2015-03-01

Oral squamous cell carcinoma (OSCC) is the most frequent type of head and neck cancers. In the present study, we evaluated the expression and distribution of Substance P (SP) in different grades of OSCC and role of SP in its proliferation and progression. Forty OSCC biopsies were immunohistochemically analyzed by using SP antibody, including 29 male and 11 female cases. 35% were well differentiated, 35% moderately differentiated and 30% poorly differentiated OSCC. The majority of patients were in the age range of 41-80 years. 62% of the cases were positive for SP. SP positivity was expressed in the cytoplasm of the tumor cells. Most of the positive cases were from the tongue region. 93% of moderately differentiated, 92% of poorly differentiated and 8% of well-differentiated carcinomas were SP-positive, but SP expression intensity was highest in poorly differentiated cases (+3). More positive patients were males (68.96% of all male patients) with moderately and poorly differentiated OSCC. Among all positive cases, 48% were poorly differentiated, 48% moderately differentiated and 4% well differentiated. Strong expression of SP in poorly and moderately differentiated cases suggests a role of SP in the progression and development of tumor. Expression of SP in the current study increased as the proliferation of cells increased. Prevalence of oral cancer in males may be due to the fact that they smoke and use pan, chewing gum, beetle nut etc. in this region. SP antagonists can help in the reduction and inhibition of oral cancer. SP has a diagnostic value with sensitivity of 92.5% and specificity of 93.7%. The positive predictive value is 96.2% and the negative predictive value 88.2%. Copyright © 2014 Elsevier GmbH. All rights reserved.

Improved intestinal absorption of a poorly water-soluble oral drug using mannitol microparticles containing a nanosolid drug dispersion.

PubMed

Nishino, Yukiko; Kubota, Aya; Kanazawa, Takanori; Takashima, Yuuki; Ozeki, Tetsuya; Okada, Hiroaki

2012-11-01

A nozzle for a spray dryer that can prepare microparticles of water-soluble carriers containing various nanoparticles in a single step was previously developed in our laboratory. To enhance the solubility and intestinal absorption of poorly water-soluble drugs, we used probucol (PBL) as a poorly water-soluble drug, mannitol (MAN) as a water-soluble carrier for the microparticles, and EUDRAGIT (EUD) as a polymer vehicle for the solid dispersion. PBL-EUD-acetone-methanol and aqueous MAN solutions were simultaneously supplied through different liquid passages of the spray nozzle and dried together. PBL-EUD solid dispersion was nanoprecipitated in the MAN solution using an antisolvent mechanism and rapidly dried by surrounding it with MAN. PBL in the dispersion vehicle was amorphous and had higher physical stability according to powder X-ray diffraction and differential scanning calorimetry analysis. The bioavailability of PBL in PBL-EUD S-100-MAN microparticles after oral administration in rats was markedly higher (14- and 6.2-fold, respectively) than that of the original PBL powder and PBL-MAN microparticles. These results demonstrate that the composite microparticles containing a nanosized solid dispersion of a poorly water-soluble drug prepared using the spray nozzle developed by us should be useful to increase the solubility and bioavailability of drugs after oral administration. Copyright © 2012 Wiley Periodicals, Inc.

Back to Basics: Incomplete Knowledge of Differential Object Marking in Spanish Heritage Speakers

ERIC Educational Resources Information Center

Montrul, Silvina; Bowles, Melissa

2009-01-01

The obligatory use of the preposition a with animate, specific direct objects in Spanish ("Juan conoce a Maria" "Juan knows Maria") is a well-known instance of Differential Object Marking (DOM; Torrego, 1998; Leonetti, 2004). Recent studies have documented the loss and/or incomplete acquisition of several grammatical features in Spanish heritage…

Adult attachment style. II: Its relationship to psychosocial depressive-vulnerability.

PubMed

Bifulco, A; Moran, P M; Ball, C; Lillie, A

2002-02-01

A range of studies show adult attachment style is associated with depressive-vulnerability factors such as low self-esteem, poor support and childhood adversity. However, there is wide inconsistency shown in the type of insecure style most highly associated. Few studies have examined attachment style in relation to clinical depression together with a range of such factors in epidemiological series. The present study uses an interview measure of adult attachment which differentiates type of attachment style and degree of insecurity of attachment, to see: (a) if it adds to other vulnerability in predicting depression and (b) if there is specificity of style to type of vulnerability. Two hundred and twenty-two high-risk and 80 comparison women were selected from questionnaire screenings of London GP patient lists and intensively interviewed. The Attachment Style Interview (ASI) differentiated five styles (Enmeshed, Fearful, Angry-dismissive, Withdrawn and Standard) as well as the degree to which attitudes and behaviour within such styles were dysfunctional ('non-standard'). Attachment style was examined in relation to low self-esteem, support and childhood experience of neglect or abuse, and all of these examined in relation to clinical depression in a 12-month period. The presence of any 'non-standard' style was significantly related to poor support, low self-esteem and childhood adversity. Some specificity of type of style and type of vulnerability was observed. Logistic regression showed that non-standard Enmeshed, Fearful and Angry-dismissive styles, poor support and childhood neglect/abuse provided the best model for clinical depression. Non-standard attachment in the form of markedly Enmeshed, Fearful or Angry-dismissive styles was shown to be associated with other depressive-vulnerability factors involving close relationships, self-esteem and childhood adversity and added to these in modelling depression.

Diacylglycerol kinase ζ generates dipalmitoyl-phosphatidic acid species during neuroblastoma cell differentiation.

PubMed

Mizuno, Satoru; Kado, Sayaka; Goto, Kaoru; Takahashi, Daisuke; Sakane, Fumio

2016-12-01

Phosphatidic acid (PA) is one of the phospholipids composing the plasma membrane and acts as a second messenger to regulate a wide variety of important cellular events, including mitogenesis, migration and differentiation. PA consists of various molecular species with different acyl chains at the sn- 1 and sn -2 positions. However, it has been poorly understood what PA molecular species are produced during such cellular events. Here we identified the PA molecular species generated during retinoic acid (RA)-induced neuroblastoma cell differentiation using a newly established liquid chromatography/mass spectrometry (LC/MS) method. Intriguingly, the amount of 32:0-PA species was dramatically and transiently increased in Neuro-2a neuroblastoma cells 24-48 h after RA-treatment. In addition, 30:0- and 34:0-PA species were also moderately increased. Moreover, similar results were obtained when Neuro-2a cells were differentiated for 24 h by serum starvation. MS/MS analysis revealed that 32:0-PA species contains two palmitic acids (16:0 s). RT-PCR analysis showed that diacylglycerol kinase (DGK) δ and DGKζ were highly expressed in Neuro-2a cells. The silencing of DGKζ expression significantly decreased the production of 32:0-PA species, whereas DGKδ-siRNA did not. Moreover, neurite outgrowth was also markedly attenuated by the deficiency of DGKζ. Taken together, these results indicate that DGKζ exclusively generates very restricted PA species, 16:0/16:0-PA, and up-regulates neurite outgrowth during the initial/early stage of neuroblastoma cell differentiation.

[Nineteen cases of school-aged children with degenerative or metabolic neurological disorders initially presenting with learning difficulty and/or behavior disturbance].

PubMed

Honzawa, Shiho; Sugai, Kenji; Akaike, Hiroto; Nakayama, Tojo; Fujikawa, Yoshinao; Komaki, Hirofumi; Nakagawa, Eiji; Sasaki, Masayuki

2012-07-01

We reported 19 cases of school-aged children. They were initially judged to have learning difficulty or school maladaptation because of attention deficits, hyperactive behaviors or poor school performance, followed by the diagnosis such as degenerative or metabolic neurological diseases. The patients consisted of 4 cases of adrenoleukodystrophy, 5 cases of dentatorubral-pallidoluysian atrophy, 3 cases of Sanfilippo syndrome, 3 cases of subacute sclerosing panencephalitis, and each one case of juvenile Gaucher disease, juvenile Huntington disease, juvenile metachromatic leukodystrophy and Leigh disease. They had markedly poor school performance, and/or abnormal behaviors, followed by seizures, character disorders or psychomotor regression. The diagnostic clues included brain CT scan and/or MRI, peculiar facial appearance and notable family histories. When the children were indicated to have learning difficulty or maladjustment to school life, we should make deliberate differential diagnoses before concluding that they have a learning disorder and/or attention-deficit/hyperactivity disorder. Instead they should be recommended to visit child neurologists, when they present with any problems as aforesaid.

Development of drug-loaded chitosan hollow nanoparticles for delivery of paclitaxel to human lung cancer A549 cells.

PubMed

Jiang, Jie; Liu, Ying; Wu, Chao; Qiu, Yang; Xu, Xiaoyan; Lv, Huiling; Bai, Andi; Liu, Xuan

2017-08-01

In this study, biodegradable chitosan hollow nanospheres (CHN) were fabricated using polystyrene nanospheres (PS) as templates. CHN were applied to increase the solubility of poorly water-soluble drugs. The lung cancer drug paclitaxel (PTX), which is used as a model drug, was loaded into CHN by the adsorption equilibrium method. The drug-loaded sample (PTX-CHN) offered sustained PTX release and good bioavailability. The state characterization of PTX by differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) showed that the PTX absorbed into CHN existed in an amorphous state. An in vitro toxicity experiment indicated that CHN were nontoxic as carriers of poorly water-soluble drugs. The PTX-CHN produced a marked inhibition of lung cancer A549 cells proliferation and encouraged apoptosis. A cell uptake experiment indicated that PTX-CHN was successfully taken up by lung cancer A549 cells. Furthermore, a degradation experiment revealed that CHN were readily biodegradable. These findings state clearly that CHN can be regarded as promising biomaterials for lung cancer treatment.

Distinctive striatal dopamine signaling after dieting and gastric bypass.

PubMed

Hankir, Mohammed K; Ashrafian, Hutan; Hesse, Swen; Horstmann, Annette; Fenske, Wiebke K

2015-05-01

Highly palatable and/or calorically dense foods, such as those rich in fat, engage the striatum to govern and set complex behaviors. Striatal dopamine signaling has been implicated in hedonic feeding and the development of obesity. Dieting and bariatric surgery have markedly different outcomes on weight loss, yet how these interventions affect central homeostatic and food reward processing remains poorly understood. Here, we propose that dieting and gastric bypass produce distinct changes in peripheral factors with known roles in regulating energy homeostasis, resulting in differential modulation of nigrostriatal and mesolimbic dopaminergic reward circuits. Enhancement of intestinal fat metabolism after gastric bypass may also modify striatal dopamine signaling contributing to its unique long-term effects on feeding behavior and body weight in obese individuals. Copyright © 2015 Elsevier Ltd. All rights reserved.

Epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China

PubMed Central

Liang, He; Fan, Jin-Hu; Qiao, You-Lin

2017-01-01

Esophageal cancer is one of the most fatal diseases worldwide mainly because of its rapid progression and poor prognosis. Although the incidence of esophageal adenocarcinoma has markedly risen in North America and Europe in the past several decades, esophageal squamous cell carcinoma is still the predominant subtype of esophageal cancer, especially in China. It accounts for more than 90% of all esophageal squamous cell carcinoma cases in China. Geographical differentiation is one of the most distinctive characteristics of esophageal cancer. The progression, risk factors, and prognosis of these two subtypes of esophageal cancer differ. This study reviews the epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China, thereby providing systematic references for policy-makers who will decide on issues of esophageal cancer prevention and control. PMID:28443201

Study of the 2H(p,γ)3He reaction in the Big Bang Nucleosynthesis energy range at LUNA

NASA Astrophysics Data System (ADS)

Mossa, Viviana

2018-01-01

Deuterium is the first nucleus produced in the Universe, whose accumulation marks the beginning of the so called Big Bang Nucleosynthesis (BBN). Its primordial abundance is very sensitive to some cosmological parameters like the baryon density and the number of the neutrino families. Presently the main obstacle to an accurate theoretical deuterium abundance evaluation is due to the poor knowledge of the 2H(p,γ)3He cross section at BBN energies. The aim of the present work is to describe the experimental approach proposed by the LUNA collaboration, whose goal is to measure, with unprecedented precision, the total and the differential cross section of the reaction in the 30 < Ec.m. [keV] < 300 energy range.

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

PubMed Central

Fernández, Agustín F.; Bayón, Gustavo F.; Urdinguio, Rocío G.; Toraño, Estela G.; García, María G.; Carella, Antonella; Petrus-Reurer, Sandra; Ferrero, Cecilia; Martinez-Camblor, Pablo; Cubillo, Isabel; García-Castro, Javier; Delgado-Calle, Jesús; Pérez-Campo, Flor M.; Riancho, José A.; Bueno, Clara; Menéndez, Pablo; Mentink, Anouk; Mareschi, Katia; Claire, Fabian; Fagnani, Corrado; Medda, Emanuela; Toccaceli, Virgilia; Brescianini, Sonia; Moran, Sebastián; Esteller, Manel; Stolzing, Alexandra; de Boer, Jan; Nisticò, Lorenza; Stazi, Maria A.

2015-01-01

In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type–independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors. PMID:25271306

Human Genome Replication Proceeds through Four Chromatin States

PubMed Central

Julienne, Hanna; Zoufir, Azedine; Audit, Benjamin; Arneodo, Alain

2013-01-01

Advances in genomic studies have led to significant progress in understanding the epigenetically controlled interplay between chromatin structure and nuclear functions. Epigenetic modifications were shown to play a key role in transcription regulation and genome activity during development and differentiation or in response to the environment. Paradoxically, the molecular mechanisms that regulate the initiation and the maintenance of the spatio-temporal replication program in higher eukaryotes, and in particular their links to epigenetic modifications, still remain elusive. By integrative analysis of the genome-wide distributions of thirteen epigenetic marks in the human cell line K562, at the 100 kb resolution of corresponding mean replication timing (MRT) data, we identify four major groups of chromatin marks with shared features. These states have different MRT, namely from early to late replicating, replication proceeds though a transcriptionally active euchromatin state (C1), a repressive type of chromatin (C2) associated with polycomb complexes, a silent state (C3) not enriched in any available marks, and a gene poor HP1-associated heterochromatin state (C4). When mapping these chromatin states inside the megabase-sized U-domains (U-shaped MRT profile) covering about 50% of the human genome, we reveal that the associated replication fork polarity gradient corresponds to a directional path across the four chromatin states, from C1 at U-domains borders followed by C2, C3 and C4 at centers. Analysis of the other genome half is consistent with early and late replication loci occurring in separate compartments, the former correspond to gene-rich, high-GC domains of intermingled chromatin states C1 and C2, whereas the latter correspond to gene-poor, low-GC domains of alternating chromatin states C3 and C4 or long C4 domains. This new segmentation sheds a new light on the epigenetic regulation of the spatio-temporal replication program in human and provides a framework for further studies in different cell types, in both health and disease. PMID:24130466

Pheromonal Cues Deposited by Mated Females Convey Social Information about Egg-Laying Sites in Drosophila Melanogaster.

PubMed

Duménil, Claire; Woud, David; Pinto, Francesco; Alkema, Jeroen T; Jansen, Ilse; Van Der Geest, Anne M; Roessingh, Sanne; Billeter, Jean-Christophe

2016-03-01

Individuals can make choices based on information learned from others, a phenomenon called social learning. How observers differentiate between which individual they should or should not learn from is, however, poorly understood. Here, we showed that Drosophila melanogaster females can influence the choice of egg-laying site of other females through pheromonal marking. Mated females mark territories of high quality food by ejecting surplus male sperm containing the aggregation pheromone cis-11-vaccenyl acetate (cVA) and, in addition, deposit several sex- and species-specific cuticular hydrocarbon (CHC) pheromones. These pheromonal cues affect the choices of other females, which respond by preferentially laying eggs on the marked food. This system benefits both senders and responders, as communal egg laying increases offspring survival. Virgin females, however, do not elicit a change in the egg-laying decision of mated females, even when food has been supplemented with ejected sperm from mated females, thus indicating the necessity for additional cues. Genetic ablation of either a female's CHC pheromones or those of their mate results in loss of ability of mated females to attract other females. We conclude that mated females use a pheromonal marking system, comprising cVA acquired from male ejaculate with sex- and species-specific CHCs produced by both mates, to indicate egg-laying sites. This system ensures information reliability because mated, but not virgin, females have both the ability to generate the pheromone blend that attracts other flies to those sites and a direct interest in egg-laying site quality.

Jitter model and signal processing techniques for pulse width modulation optical recording

NASA Technical Reports Server (NTRS)

Liu, Max M.-K.

1991-01-01

A jitter model and signal processing techniques are discussed for data recovery in Pulse Width Modulation (PWM) optical recording. In PWM, information is stored through modulating sizes of sequential marks alternating in magnetic polarization or in material structure. Jitter, defined as the deviation from the original mark size in the time domain, will result in error detection if it is excessively large. A new approach is taken in data recovery by first using a high speed counter clock to convert time marks to amplitude marks, and signal processing techniques are used to minimize jitter according to the jitter model. The signal processing techniques include motor speed and intersymbol interference equalization, differential and additive detection, and differential and additive modulation.

Role of diabetes- and obesity-related protein in the regulation of osteoblast differentiation

PubMed Central

Linares, Gabriel R.; Xing, Weirong; Burghardt, Hans; Baumgartner, Bernhard; Chen, Shin-Tai; Ricart, Wifredo; Fernández-Real, José Manuel; Zorzano, Antonio

2011-01-01

Although thyroid hormone (TH) is known to exert important effects on the skeleton, the nuclear factors constituting the TH receptor coactivator complex and the molecular pathways by which TH mediates its effects on target gene expression in osteoblasts remain poorly understood. A recent study demonstrated that the actions of TH on myoblast differentiation are dependent on diabetes- and obesity-related protein (DOR). However, the role of DOR in osteoblast differentiation is unknown. We found DOR expression increased during in vitro differentiation of bone marrow stromal cells into osteoblasts and also in MC3T3-E1 cells treated with TH. However, DOR expression decreased during cellular proliferation. To determine whether DOR acts as a modulator of TH action during osteoblast differentiation, we examined whether overexpression or knockdown of DOR in MC3T3-E1 cells affects the ability of TH to induce osteoblast differentiation by evaluating alkaline phosphatase (ALP) activity. ALP activity was markedly increased in DOR-overexpressing cells treated with TH. In contrast, loss of DOR dramatically reduced TH stimulation of ALP activity in MC3T3-E1 cells and primary calvaria osteoblasts transduced with lentiviral DOR shRNA. Consistent with reduced ALP activity, mRNA levels of osteocalcin, ALP, and Runx2 were decreased significantly in DOR shRNA cells. In addition, a common single nucleotide polymorphism (SNP), DOR1 found on the promoter of human DOR gene, was associated with circulating osteocalcin levels in nondiabetic subjects. Based on these data, we conclude that DOR plays an important role in TH-mediated osteoblast differentiation, and a DOR SNP associates with plasma osteocalcin in men. PMID:21467300

HMB-45 reactivity in conventional uterine leiomyosarcomas.

PubMed

Simpson, Karen W; Albores-Saavedra, Jorge

2007-01-01

We studied the human melanoma black-45 (HMB-45) reactivity in 25 uterine leiomyosarcomas including 23 conventional and 2 myxoid variants. Eleven tumors were poorly differentiated, and 14 were well to moderately differentiated. Nine uterine leiomyosarcomas labeled with HMB-45 in 10% or less of the tumor cells. Six were poorly differentiated and 3 were well differentiated. Our study indicates that 36% of conventional leiomyosarcomas focally express HMB-45. HMB-45 reactivity was more common in the poorly differentiated than in the well-differentiated group of leiomyosarcomas. In light of our findings and of those recently reported in the literature, we believe that the term PEComa should not be used for uterine leiomyosarcomas with clear cells or for conventional leiomyosarcomas that stain positively with HMB-45.

Monoamines differentially modulate neuropeptide release from distinct sites within a single neuron pair.

PubMed

Clark, Tobias; Hapiak, Vera; Oakes, Mitchell; Mills, Holly; Komuniecki, Richard

2018-01-01

Monoamines and neuropeptides often modulate the same behavior, but monoaminergic-peptidergic crosstalk remains poorly understood. In Caenorhabditis elegans, the adrenergic-like ligands, tyramine (TA) and octopamine (OA) require distinct subsets of neuropeptides in the two ASI sensory neurons to inhibit nociception. TA selectively increases the release of ASI neuropeptides encoded by nlp-14 or nlp-18 from either synaptic/perisynaptic regions of ASI axons or the ASI soma, respectively, and OA selectively increases the release of ASI neuropeptides encoded by nlp-9 asymmetrically, from only the synaptic/perisynaptic region of the right ASI axon. The predicted amino acid preprosequences of genes encoding either TA- or OA-dependent neuropeptides differed markedly. However, these distinct preprosequences were not sufficient to confer monoamine-specificity and additional N-terminal peptide-encoding sequence was required. Collectively, our results demonstrate that TA and OA specifically and differentially modulate the release of distinct subsets of neuropeptides from different subcellular sites within the ASIs, highlighting the complexity of monoaminergic/peptidergic modulation, even in animals with a relatively simple nervous system.

Monoamines differentially modulate neuropeptide release from distinct sites within a single neuron pair

PubMed Central

Oakes, Mitchell; Mills, Holly; Komuniecki, Richard

2018-01-01

Monoamines and neuropeptides often modulate the same behavior, but monoaminergic-peptidergic crosstalk remains poorly understood. In Caenorhabditis elegans, the adrenergic-like ligands, tyramine (TA) and octopamine (OA) require distinct subsets of neuropeptides in the two ASI sensory neurons to inhibit nociception. TA selectively increases the release of ASI neuropeptides encoded by nlp-14 or nlp-18 from either synaptic/perisynaptic regions of ASI axons or the ASI soma, respectively, and OA selectively increases the release of ASI neuropeptides encoded by nlp-9 asymmetrically, from only the synaptic/perisynaptic region of the right ASI axon. The predicted amino acid preprosequences of genes encoding either TA- or OA-dependent neuropeptides differed markedly. However, these distinct preprosequences were not sufficient to confer monoamine-specificity and additional N-terminal peptide-encoding sequence was required. Collectively, our results demonstrate that TA and OA specifically and differentially modulate the release of distinct subsets of neuropeptides from different subcellular sites within the ASIs, highlighting the complexity of monoaminergic/peptidergic modulation, even in animals with a relatively simple nervous system. PMID:29723289

Synchronous double primary cancers of the extrahepatic bile duct: A case report and literature review.

PubMed

Nishi, Takeshi; Sato, Yoshitoshi; Hanaoka, Takuya; Takahashi, Takuya; Miura, Hiroshi; Takubo, Kenji

2018-01-01

Double cancers of the biliary tract system are rare. Most of these cancers are synchronous double cancers of the gall bladder and bile duct, associated with pancreaticobiliary maljunction (PBM). Synchronous double cancers of the extrahepatic bile duct without PBM are especially rare, and only 4 cases have been reported. A 78-year-old woman was admitted to our hospital for examination of hyperbilirubinemia and liver dysfunction. Contrast-enhanced abdominal computed tomography, Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography revealed 2 stenotic regions in the common bile duct: at its junction with the cystic duct and in the distal bile duct. No findings suggested PBM, such as a markedly long common channel. The diagnosis based on endoscopic brush cytology from both stricture portions was adenocarcinoma. The patient had a pylorus-preserving pancreaticoduodenectomy with regional lymph node resection. Macroscopically, there were 2 stenotic regions at the cystic duct junction and in the distal bile duct. Microscopically, the tumor at the junction of the cystic duct was a well-to-moderately differentiated adenocarcinoma. On the other hand, the tumor of the distal bile duct was a poorly differentiated adenocarcinoma. There was no evidence of communication between these 2 cancers. Double cancers of the extrahepatic bile duct without PBM are very rare. Therefore, an accurate diagnosis prior to surgery is necessary. Furthermore, this rare condition seems to be associated with a poor prognosis. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Appropriate Bmp7 levels are required for the differentiation of midline guidepost cells involved in corpus callosum formation.

PubMed

Sánchez-Camacho, Cristina; Ortega, Juan Alberto; Ocaña, Inmaculada; Alcántara, Soledad; Bovolenta, Paola

2011-05-01

Guidepost cells are essential structures for the establishment of major axonal tracts. How these structures are specified and acquire their axon guidance properties is still poorly understood. Here, we show that in mouse embryos appropriate levels of Bone Morphogenetic Protein 7 (Bmp7), a member of the TGF-β superfamily of secreted proteins, are required for the correct development of the glial wedge, the indusium griseum, and the subcallosal sling, three groups of cells that act as guidepost cells for growing callosal axons. Bmp7 is expressed in the region occupied by these structures and its genetic inactivation in mouse embryos caused a marked reduction and disorganization of these cell populations. On the contrary, infusion of recombinant Bmp7 in the developing forebrain induced their premature differentiation. In both cases, changes were associated with the disruption of callosal axon growth and, in most animals fibers did not cross the midline forming typical Probst bundles. Addition of Bmp7 to cortical explants did not modify the extent of their outgrowth nor their directionality, when explants were exposed to a focalized source of the protein. Together, these results indicate that Bmp7 is indirectly required for corpus callosum formation by controlling the timely differentiation of its guidepost cells. Copyright © 2010 Wiley Periodicals, Inc.

Transmissible Gastroenteritis in Feeder Pigs: Observations on the Jejunal Epithelium of Normal Feeder Pigs and Feeder Pigs Infected with TGE Virus

PubMed Central

Morin, M.; Morehouse, L. G.

1974-01-01

Light and electron microscopy findings in the jejunal mucosa of the normal feeder pig and feeder pigs infected with transmissible gastroenteritis (TGE) virus are reported. Villi in the mid jejunum of the normal feeder pig were elongated, finger shaped and covered with a layer of columnar absorptive cells with a well developed and regular brush border. Severe lesions of villous atrophy were present in all jejunal segments of feeder swine killed 96 hours post infection with TGE virus. Atrophic villi were covered by flat to cuboidal cells with a poorly developed brush border in some areas. In other segments, cells varied in appearance from sub-columnar to columnar type of near normal appearance. The ultrastructure of the jejunal absorptive cells in the normal feeder pig was found to be similar to that described for the jejunal cells of other adult mammals. There were no significant indications of high pinocytotic activity. The epithelial cells covering the atrophic villi of TGE infected pigs had a fine structure similar to that described for the crypt cells, ranging in appearance from very immature to moderately differentiated cells. Microvilli were very short, decreased markedly in number and irregular in arrangement. The terminal web was poorly developed. Strands of rough endoplasmic reticulum were markedly diminished and an increase in free ribosomes was noted. The significance of these observations in explaining pathogenesis of TGE in feeder pigs is discussed. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4.Fig. 5.Fig. 6.Fig. 7.Fig. 8. PMID:4277743

Snap-lock bags with red band: A study of manufacturing characteristics, thermal and chemical properties.

PubMed

Sim, Yvonne Hui Ying; Koh, Alaric C W; Lim, Shing Min; Yew, Sok Yee

2015-10-01

Drug packaging is commonly submitted to the Forensic Chemistry and Physics Laboratory of the Health Sciences Authority, Singapore, for examination. The drugs seized are often packaged in plastic bags. These bags are examined for linkages to provide law enforcement with useful associations between the traffickers and drug abusers. The plastic bags submitted may include snap-lock bags, some with a red band located above the snap-lock closure and some without. Current techniques for examination involve looking at the physical characteristics (dimensions, thickness and polarising patterns) and manufacturing marks of these bags. In cases where manufacturing marks on the main body of the bags are poor or absent, the manufacturing characteristics present on the red band can be examined. A study involving approximately 1000 bags was conducted to better understand the variations in the manufacturing characteristics of the red band. This understanding is crucial in helping to determine associations/eliminations between bags. Two instrumental techniques, namely differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR) were explored to evaluate the effectiveness of examining the chemical composition to discriminate the bags. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells.

PubMed

Fernández, Agustín F; Bayón, Gustavo F; Urdinguio, Rocío G; Toraño, Estela G; García, María G; Carella, Antonella; Petrus-Reurer, Sandra; Ferrero, Cecilia; Martinez-Camblor, Pablo; Cubillo, Isabel; García-Castro, Javier; Delgado-Calle, Jesús; Pérez-Campo, Flor M; Riancho, José A; Bueno, Clara; Menéndez, Pablo; Mentink, Anouk; Mareschi, Katia; Claire, Fabian; Fagnani, Corrado; Medda, Emanuela; Toccaceli, Virgilia; Brescianini, Sonia; Moran, Sebastián; Esteller, Manel; Stolzing, Alexandra; de Boer, Jan; Nisticò, Lorenza; Stazi, Maria A; Fraga, Mario F

2015-01-01

In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors. © 2015 Fernández et al.; Published by Cold Spring Harbor Laboratory Press.

[Cognitive disorders in patients with chronic mercury intoxication].

PubMed

Katamanova, E V; Shevchenko, O I; Lakhman, O L; Denisova, I A

2014-01-01

To assess severity of cognitive disorders in chronic mercury intoxication, the authors performed claster and discrimination analysis of neuropsychologic and neurophysiologic research data from workers exposed to mercury during long length of service, from patients with early and marked stages of chronic mercurial intoxication. Cognitive disorders in chronic mercurial intoxication have three severity degrees, in the light degree disorders patients demonstrate lower amplitude of cognitive evoked potentials, poor long-term memory and associative thinking. Moderate cognitive disorders are characterized by decreased visual, long-term memory, concentration of attention, poor optic and spatial gnosis. Marked cognitive disorders with chronic mercurial intoxication present with more decreased long-term, short-term, picturesque memory, poor intellect, optic and spatial gnosis and associative thinking.

Dissecting Stages of Human Kidney Development and Tumorigenesis with Surface Markers Affords Simple Prospective Purification of Nephron Stem Cells.

PubMed

Pode-Shakked, Naomi; Pleniceanu, Oren; Gershon, Rotem; Shukrun, Rachel; Kanter, Itamar; Bucris, Efrat; Pode-Shakked, Ben; Tam, Gal; Tam, Hadar; Caspi, Revital; Pri-Chen, Sara; Vax, Einav; Katz, Guy; Omer, Dorit; Harari-Steinberg, Orit; Kalisky, Tomer; Dekel, Benjamin

2016-03-29

When assembling a nephron during development a multipotent stem cell pool becomes restricted as differentiation ensues. A faulty differentiation arrest in this process leads to transformation and initiation of a Wilms' tumor. Mapping these transitions with respective surface markers affords accessibility to specific cell subpopulations. NCAM1 and CD133 have been previously suggested to mark human renal progenitor populations. Herein, using cell sorting, RNA sequencing, in vitro studies with serum-free media and in vivo xenotransplantation we demonstrate a sequential map that links human kidney development and tumorigenesis; In nephrogenesis, NCAM1(+)CD133(-) marks SIX2(+) multipotent renal stem cells transiting to NCAM1(+)CD133(+) differentiating segment-specific SIX2(-) epithelial progenitors and NCAM1(-)CD133(+) differentiated nephron cells. In tumorigenesis, NCAM1(+)CD133(-) marks SIX2(+) blastema that includes the ALDH1(+) WT cancer stem/initiating cells, while NCAM1(+)CD133(+) and NCAM1(-)CD133(+) specifying early and late epithelial differentiation, are severely restricted in tumor initiation capacity and tumor self-renewal. Thus, negative selection for CD133 is required for defining NCAM1(+) nephron stem cells in normal and malignant nephrogenesis.

Current issues in determining dietary protein quality and metabolic utilization

USDA-ARS?s Scientific Manuscript database

In resource-limited settings, poor dietary quality has a marked negative impact on health, especially during the sensitive periods of pregnancy and first 2 years of life (the first 1000 days) when stunting, poor development and increased risk of later disease develop. Protein quality is often poor o...

Poorly Differentiated Thyroid Carcinoma.

PubMed

Setia, Namrata; Barletta, Justine A

2014-12-01

Poorly differentiated thyroid carcinoma (PDTC) has been recognized for the past 30 years as an entity showing intermediate differentiation and clinical behavior between well-differentiated thyroid carcinomas (ie, papillary thyroid carcinoma and follicular thyroid carcinoma) and anaplastic thyroid carcinoma; however, there has been considerable controversy around the definition of PDTC. In this review, the evolution in the definition of PDTC, current diagnostic criteria, differential diagnoses, potentially helpful immunohistochemical studies, and molecular alterations are discussed with the aim of highlighting where the diagnosis of PDTC currently stands. Published by Elsevier Inc.

Functional high-resolution time-course expression analysis of human embryonic stem cells undergoing cardiac induction.

PubMed

Piccini, Ilaria; Araúzo-Bravo, Marcos; Seebohm, Guiscard; Greber, Boris

2016-12-01

Cardiac induction of human embryonic stem cells (hESCs) is a process bearing increasing medical relevance, yet it is poorly understood from a developmental biology perspective. Anticipated technological progress in deriving stably expandable cardiac precursor cells or in advancing cardiac subtype specification protocols will likely require deeper insights into this fascinating system. Recent improvements in controlling hESC differentiation now enable a near-homogeneous induction of the cardiac lineage. This is based on an optimized initial stimulation of mesoderm-inducing signaling pathways such as Activin and/or FGF, BMP, and WNT, followed by WNT inhibition as a secondary requirement. Here, we describe a comprehensive data set based on varying hESC differentiation conditions in a systematic manner and recording high-resolution differentiation time-courses analyzed by genome-wide expression profiling (GEO accession number GSE67154). As a baseline, hESCs were differentiated into cardiomyocytes under optimal conditions. Moreover, in additional time-series, individual signaling factors were withdrawn from the initial stimulation cocktail to reveal their specific roles via comparison to the standard condition. Hence, this data set presents a rich resource for hypothesis generation in studying human cardiac induction, as we reveal numbers of known as well as uncharacterized genes prominently marking distinct intermediate stages in the process. These data will also be useful for identifying putative cardiac master regulators in the human system as well as for characterizing expandable cardiac stem cells.

Poorly Differentiated Squamous Cell Carcinoma Arising in Tattooed Skin

PubMed Central

Sarma, Deba P.; Dentlinger, Renee B.; Forystek, Amanda M.; Stevens, Todd; Huerter, Christopher

2010-01-01

Introduction. Tattoos have increasingly become accepted by mainstream Western society. As a result, the incidence of tattoo-associated dermatoses is on the rise. The presence of a poorly differentiated squamous cell carcinoma in an old tattooed skin is of interest as it has not been previously documented. Case Presentation. A 79-year-old white homeless man of European descent presented to the dermatology clinic with a painless raised nodule on his left forearm arising in a tattooed area. A biopsy of the lesion revealed a poorly differentiated squamous cell carcinoma infiltrating into a tattoo. The lesion was completely excised and the patient remains disease-free one year later. Conclusion. All previous reports of squamous cell carcinomas arising in tattoos have been well-differentiated low-grade type or keratoacanthoma-type and are considered to be coincidental rather than related to any carcinogenic effect of the tattoo pigments. Tattoo-associated poorly differentiated invasive carcinoma appears to be extremely rare. PMID:21274289

Poor stem cell harvest may not always be related to poor mobilization: lessons gained from a mobilization study in patients with β-thalassemia major.

PubMed

Constantinou, Varnavas C; Bouinta, Asimina; Karponi, Garyfalia; Zervou, Fani; Papayanni, Penelope-Georgia; Stamatoyannopoulos, George; Anagnostopoulos, Achilles; Yannaki, Evangelia

2017-04-01

Hematopoietic stem cell mobilization and leukapheresis in adult patients with β-thalassemia have recently been optimized in the context of clinical trials for obtaining hematopoietic stem cells for thalassemia gene therapy. In some patients, however, the yield of cluster of differentiation 34-positive (CD34+) cells was poor despite successful mobilization, and a modification of apheresis settings was mandatory for harvest rescue. Data were analyzed from 20 adult patients with β-thalassemia who were enrolled in a clinical trial of optimizing mobilization strategies for stem cell gene therapy. The aim of this post-hoc analysis was to assess how certain hematological and/or clinical parameters may correlate with low collection efficiency in the presence of adequate numbers of circulating stem cells after pharmacological mobilization and standard leukapheresis procedures. Among 19 patients who achieved optimal mobilization with Plerixafor, four who underwent splenectomy demonstrated disproportionately poor CD34+ cell harvests, as determined by their circulating CD34+ cell counts after mobilization. All four patients who underwent splenectomy presented at baseline and before first apheresis with lymphocytosis resulting in lymphocyte/neutrophil ratios well above 1 and marked reticulocytosis compared with patients who achieved optimal mobilization/CD34+ cell harvest. Such unexpected expansion of specific cell populations disrupted the normal cell layer separation and necessitated modification of the apheresis settings to rescue the harvests. By close examination of certain hematological and/or clinical parameters before leukapheresis, patients who, despite adequate mobilization, are at risk for poor CD34+ cell harvests may be identified, and harvest failure can be prevented by adjusting the apheresis settings. © 2016 AABB.

The effect of surface modification of glass fiber on the performance of poly(lactic acid) composites: Graphene oxide vs. silane coupling agents

NASA Astrophysics Data System (ADS)

Jing, Mengfan; Che, Junjin; Xu, Shuman; Liu, Zhenwei; Fu, Qiang

2018-03-01

In this work, a comparison study was carried out to investigate the efficacy of glass fiber (GF) in reinforcing poly(lactic acid) (PLA) by using traditional silane coupling agents (GF-S) and novel graphene oxide (GF-GO) as surface modifiers. The crystallization behavior of the PLA matrix was investigated by differential scanning calorimetry. The mechanical performances and the thermomechanical properties of the composites were evaluated by uniaxial tensile testing and dynamic mechanical analysis, respectively. For neat GF without any treatment, the poor interfacial adhesion and the sharp shortening of the GF length result in the relatively poor mechanical performances of PLA/GF composites. However, the incorporation of GF-S significantly improves the mechanical strength and keeps relatively good toughness of the composites, while GF-GO exhibits excellent nucleation ability for PLA and could moderately increase the modulus of the composites. The thermomechanical properties of the composites are improved markedly resulting from the crystallinity increase. The different surface modification of glass fiber influences the crystallinity of matrix, the interfacial interaction and the length of fiber, which altogether affect the mechanical performances of the prepared PLA/GF composites.

Is Grammar Instruction Beneficial for Heritage Language Learners? Dative Case Marking in Spanish

ERIC Educational Resources Information Center

Montrul, Silvina; Bowles, Melissa

2010-01-01

Spanish heritage speakers have been shown to have incomplete knowledge of dative case marking with both animate direct objects (also known as differential object marking (DOM) or "a-personal") and dative experiencers with "gustar"-psych verbs in oral and written modes (Montrul, 2004; Montrul & Bowles, in press). In general, Spanish objects that…

Safety and Tolerability of Everolimus as Second-line Treatment in Poorly Differentiated Neuroendocrine Carcinoma / Neuroendocrine Carcinoma G3 (WHO 2010) and Neuroendocrine Tumor G3 - an Investigator Initiated Phase II Study

ClinicalTrials.gov

2018-01-19

Poorly Differentiated Malignant Neuroendocrine Carcinoma; Neuroendocrine Carcinoma, Grade 3; Neuroendocrine Carcinoma, Grade 1 [Well-differentiated Neuroendocrine Carcinoma] That Switched to G3; Neuroendocrine Carcinoma, Grade 2 [Moderately Differentiated Neuroendocrine Carcinoma] That Switched to G3; Neuroendocrine Tumor, Grade 3 and Disease Progression as Measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)

Predictive factors for lymph node metastasis in poorly differentiated early gastric cancer and their impact on the surgical strategy

PubMed Central

Li, Hua; Lu, Ping; Lu, Yang; Liu, Cai-Gang; Xu, Hui-Mian; Wang, Shu-Bao; Chen, Jun-Qing

2008-01-01

AIM: To identify the predictive clinicopathological factors for lymph node metastasis (LNM) in poorly differentiated early gastric cancer (EGC) and to further expand the possibility of using endoscopic mucosal resection (EMR) for the treatment of poorly differentiated EGC. METHODS: Data were collected from 85 poorly-differentiated EGC patients who were surgically treated. Association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. RESULTS: Univariate analysis showed that tumor size (OR = 5.814, 95% CI = 1.050 - 32.172, P = 0.044), depth of invasion (OR = 10.763, 95% CI = 1.259 - 92.026, P = 0.030) and lymphatic vessel involvement (OR = 61.697, 95% CI = 2.144 - 175.485, P = 0.007) were the significant and independent risk factors for LNM. The LNM rate was 5.4%, 42.9% and 50%, respectively, in poorly differentiated EGC patients with one, two and three of the risk factors, respectively. No LNM was found in 25 patients without the three risk factors. Forty-four lymph nodes were found to have metastasis, 29 (65.9%) and 15 (34.1%) of the lymph nodes involved were within N1 and beyond N1, respectively, in 12 patients with LNM. CONCLUSION: Endoscopic mucosal resection alone may be sufficient to treat poorly differentiated intramucosal EGC (≤ 2.0 cm in diameter) with no histologically-confirmed lymphatic vessel involvement. When lymphatic vessels are involved, lymph node dissection beyond limited (D1) dissection or D1+ lymph node dissection should be performed depending on the tumor location. PMID:18636670

[Skeletal manifestations of primary and secondary hyperparathyroiditis. Differential radiological diagnostic problems].

PubMed

Melella, A; Basilico, L; Lupini, A; Renda, F

1978-10-31

Primary and secondary hyperparathyroidism are both marked by widespread skeletal demineralisation, subperiosteal erosion of the cortex, brown tumours, osteosclerosis, and extraosseous calcification. Differential diagnosis is guided by the different association of these findings. Brown tumours and more extensive erosion are marks of the primary form, whereas osteosclerosis and extra-osseous calcification are a prominent feature of secondary hyperparathyroidism. Radiologists, therefore, should direct their attention to features suggesting the presence of secondary forms in addition to looking for bone alterations associated with hyperparathyroidism.

CRM-1 knockdown inhibits extrahepatic cholangiocarcinoma tumor growth by blocking the nuclear export of p27Kip1.

PubMed

Luo, Jian; Chen, Yongjun; Li, Qiang; Wang, Bing; Zhou, Yanqiong; Lan, Hongzhen

2016-08-01

Cholangiocarcinoma is a deadly disease which responds poorly to surgery and conventional chemotherapy or radiotherapy. Early diagnosis is difficult due to the anatomical and biological characteristics of cholangiocarcinoma. Cyclin-dependent kinase inhibitor 1B (p27Kip1) is a cyclin‑dependent kinase inhibitor and in the present study, we found that p27Kip1 expression was suppressed in the nucleus and increased in the cytoplasm in 53 samples of cholangiocarcinoma from patients with highly malignant tumors (poorly-differentiated and tumor-node-metastsis (TNM) stage III-IV) compared with that in samples from 10 patients with chronic cholangitis. The expression of phosphorylated (p-)p27Kip1 (Ser10), one of the phosphorylated forms of p27Kip1, was increased in the patient samples with increasing malignancy and clinical stage. Coincidentally, chromosome region maintenance 1 (CRM-1; also referred to as exportin 1 or Xpo1), a critical protein responsible for protein translocation from the nucleus to the cytoplasm, was also overexpressed in the tumor samples which were poorly differentiated and of a higher clinical stage. Through specific short hairpin RNA (shRNA)-mediated knockdown of CRM-1 in the cholangiocarcinoma cell line QBC939, we identified an elevation of cytoplasmic p27Kip1 and a decrease of nuclear p27Kip1. Furthermore, the viability and colony formation ability of QBC939 cells was largely reduced with G1 arrest. Consistent with the findings of the in vitro experiments, in a xenograft mouse model, the tumors formed in the CRM-1 knockdown group were markedly smaller and weighed less than those in the control group in vivo. Taken together, these findings demonstrated that the interplay between CRM-1 and p27Kip1 may provide potentially potent biomarkers and functional targets for the development of future cholangiocarcinoma treatments.

CRM-1 knockdown inhibits extrahepatic cholangiocarcinoma tumor growth by blocking the nuclear export of p27Kip1

PubMed Central

Luo, Jian; Chen, Yongjun; Li, Qiang; Wang, Bing; Zhou, Yanqiong; Lan, Hongzhen

2016-01-01

Cholangiocarcinoma is a deadly disease which responds poorly to surgery and conventional chemotherapy or radiotherapy. Early diagnosis is difficult due to the anatomical and biological characteristics of cholangiocarcinoma. Cyclin-dependent kinase inhibitor 1B (p27Kip1) is a cyclin-dependent kinase inhibitor and in the present study, we found that p27Kip1 expression was suppressed in the nucleus and increased in the cytoplasm in 53 samples of cholangiocarcinoma from patients with highly malignant tumors (poorly-differentiated and tumor-node-metastsis (TNM) stage III–IV) compared with that in samples from 10 patients with chronic cholangitis. The expression of phosphorylated (p-)p27Kip1 (Ser10), one of the phosphorylated forms of p27Kip1, was increased in the patient samples with increasing malignancy and clinical stage. Coincidentally, chromosome region maintenance 1 (CRM-1; also referred to as exportin 1 or Xpo1), a critical protein responsible for protein translocation from the nucleus to the cytoplasm, was also overexpressed in the tumor samples which were poorly differentiated and of a higher clinical stage. Through specific short hairpin RNA (shRNA)-mediated knockdown of CRM-1 in the cholangiocarcinoma cell line QBC939, we identified an elevation of cytoplasmic p27Kip1 and a decrease of nuclear p27Kip1. Furthermore, the viability and colony formation ability of QBC939 cells was largely reduced with G1 arrest. Consistent with the findings of the in vitro experiments, in a xenograft mouse model, the tumors formed in the CRM-1 knockdown group were markedly smaller and weighed less than those in the control group in vivo. Taken together, these findings demonstrated that the interplay between CRM-1 and p27Kip1 may provide potentially potent biomarkers and functional targets for the development of future cholangiocarcinoma treatments. PMID:27279267

Post-transcriptional Regulation of Keratinocyte Progenitor Cell Expansion, Differentiation and Hair Follicle Regression by miR-22

PubMed Central

Meng, Qingyong; Zhao, Yiqiang; Chen, Lei; Zhang, Hongquan; Xue, Lixiang; Zhang, Xiuqing; Lengner, Christopher; Yu, Zhengquan

2015-01-01

Hair follicles (HF) undergo precisely regulated recurrent cycles of growth, cessation, and rest. The transitions from anagen (growth), to catagen (regression), to telogen (rest) involve a physiological involution of the HF. This process is likely coordinated by a variety of mechanisms including apoptosis and loss of growth factor signaling. However, the precise molecular mechanisms underlying follicle involution after hair keratinocyte differentiation and hair shaft assembly remain poorly understood. Here we demonstrate that a highly conserved microRNA, miR-22 is markedly upregulated during catagen and peaks in telogen. Using gain- and loss-of-function approaches in vivo, we find that miR-22 overexpression leads to hair loss by promoting anagen-to-catagen transition of the HF, and that deletion of miR-22 delays entry to catagen and accelerates the transition from telogen to anagen. Ectopic activation of miR-22 results in hair loss due to the repression a hair keratinocyte differentiation program and keratinocyte progenitor expansion, as well as promotion of apoptosis. At the molecular level, we demonstrate that miR-22 directly represses numerous transcription factors upstream of phenotypic keratin genes, including Dlx3, Foxn1, and Hoxc13. We conclude that miR-22 is a critical post-transcriptional regulator of the hair cycle and may represent a novel target for therapeutic modulation of hair growth. PMID:26020521

[New features in the 2014 WHO classification of uterine neoplasms].

PubMed

Lax, S F

2016-11-01

The 2014 World Health Organization (WHO) classification of uterine tumors revealed simplification of the classification by fusion of several entities and the introduction of novel entities. Among the multitude of alterations, the following are named: a simplified classification for precursor lesions of endometrial carcinoma now distinguishes between hyperplasia without atypia and atypical hyperplasia, the latter also known as endometrioid intraepithelial neoplasia (EIN). For endometrial carcinoma a differentiation is made between type 1 (endometrioid carcinoma with variants and mucinous carcinoma) and type 2 (serous and clear cell carcinoma). Besides a papillary architecture serous carcinomas may show solid and glandular features and TP53 immunohistochemistry with an "all or null pattern" assists in the diagnosis of serous carcinoma with ambiguous features. Neuroendocrine neoplasms are categorized in a similar way to the gastrointestinal tract into well differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas (small cell and large cell types). Leiomyosarcomas of the uterus are typically high grade and characterized by marked nuclear atypia and lively mitotic activity. Low grade stromal neoplasms frequently show gene fusions, such as JAZF1/SUZ12. High grade endometrial stromal sarcoma is newly defined by cyclin D1 overexpression and the presence of the fusion gene YWHAE/FAM22 and must be distinguished from undifferentiated uterine sarcoma. Carcinosarcomas (malignant mixed Mullerian tumors MMMT) show biological and molecular similarities to high-grade carcinomas.

A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

PubMed Central

Sadanandam, Anguraj; Wullschleger, Stephan; Lyssiotis, Costas A.; Grötzinger, Carsten; Barbi, Stefano; Bersani, Samantha; Körner, Jan; Wafy, Ismael; Mafficini, Andrea; Lawlor, Rita T.; Simbolo, Michele; Asara, John M.; Bläker, Hendrik; Cantley, Lewis C.; Wiedenmann, Bertram; Scarpa, Aldo; Hanahan, Douglas

2016-01-01

Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. SIGNIFICANCE This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. PMID:26446169

A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics.

PubMed

Sadanandam, Anguraj; Wullschleger, Stephan; Lyssiotis, Costas A; Grötzinger, Carsten; Barbi, Stefano; Bersani, Samantha; Körner, Jan; Wafy, Ismael; Mafficini, Andrea; Lawlor, Rita T; Simbolo, Michele; Asara, John M; Bläker, Hendrik; Cantley, Lewis C; Wiedenmann, Bertram; Scarpa, Aldo; Hanahan, Douglas

2015-12-01

Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation-enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. ©2015 American Association for Cancer Research.

Sox9 overexpression in uterine epithelia induces endometrial gland hyperplasia

PubMed Central

Gonzalez, Gabriel; Mehra, Shyamin; Wang, Ying; Akiyama, Haruhiko

2016-01-01

SOX9 is a high mobility group transcription factor that is required in many biological processes, including cartilage differentiation, endoderm progenitor maintenance, hair differentiation, and testis determination. SOX9 has also been linked to colorectal, prostate, and lung cancer. We found that SOX9 is expressed in the epithelium of the adult mouse and human uterus, predominantly marking the uterine glands. To determine if SOX9 plays a role in the development of endometrial cancer we overexpressed Sox9 in the uterine epithelium using a progesterone receptor-Cre mouse model. Sox9 overexpression in the uterine epithelium led to the formation of simple and complex cystic glandular structures in the endometrium of aged-females. Histological analysis revealed that these structures appeared morphologically similar to structures present in patients with endometrial hyperplastic lesions and endometrial polyps that are thought to be precursors of endometrial cancer. The molecular mechanisms that cause the glandular epithelium to become hyperplastic, leading to endometrial cancer are still poorly understood. These findings indicate that chronic overexpression of Sox9 in the uterine epithelium can induce the development of endometrial hyperplastic lesions. Thus, SOX9 expression may be a factor in the formation of endometrial cancer. PMID:27262401

Effects of lisdexamfetamine alone and in combination with s-citalopram on acetylcholine and histamine efflux in the rat pre-frontal cortex and ventral hippocampus.

PubMed

Hutson, Peter H; Heins, Mariette S; Folgering, Joost H A

2015-08-01

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by poor attention, impulse control and hyperactivity. A significant proportion of ADHD patients are also co-morbid for other psychiatric problems including mood disorders and these patients may be managed with a combination of psychostimulants and anti-depressants. While it is generally accepted that enhanced catecholamine signalling via the action of psychostimulants is likely responsible for the cognitive improvement in ADHD, other neurotransmitters including acetylcholine and histamine may be involved. In the present study, we have examined the effect of lisdexamfetamine dimesylate (LDX), an amphetamine pro-drug that is approved for the treatment of ADHD on acetylcholine and histamine efflux in pre-frontal cortex and hippocampus alone and in combination with the anti-depressant s-citalopram. LDX increased cortical acetylcholine efflux, an effect that was not significantly altered by co-administration of s-citalopram. Cortical and hippocampal histamine were markedly increased by LDX, an effect that was attenuated in the hippocampus but not in pre-frontal cortex when co-administered with s-citalopram. Taken together, these results suggest that efflux of acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially influenced by the co-administration of s-citalopram. Attention deficit hyperactivity disorder (ADHD) is characterized by poor attention, impulse control and hyperactivity. Some ADHD patients are also co-morbid for mood disorders and may be managed with psychostimulants (e.g. lisdexamfetamine, LDX) and anti-depressants (e.g. s-citalopram). LDX increased the efflux of acetylcholine and histamine, neurotransmitters involved in cognitive function, which were differentially influenced when co-administered with s-citalopram. Acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially affected by the co-administration of s-citalopram. © 2015 International Society for Neurochemistry.

Trajectories of child externalizing problems between ages 3 and 10 years: Contributions of children's early effortful control, theory of mind, and parenting experiences.

PubMed

Olson, Sheryl L; Choe, Daniel Ewon; Sameroff, Arnold J

2017-10-01

Preventing problem behavior requires an understanding of earlier factors that are amenable to intervention. The main goals of our prospective longitudinal study were to trace trajectories of child externalizing behavior between ages 3 and 10 years, and to identify patterns of developmentally significant child and parenting risk factors that differentiated pathways of problem behavior. Participants were 218 3-year-old boys and girls who were reassessed following the transition to kindergarten (age 5-6 years) and during the late school-age years (age 10). Mothers contributed ratings of children's externalizing behavior at all three time points. Children's self-regulation abilities and theory of mind were assessed during a laboratory visit, and parenting risk (frequent corporal punishment and low maternal warmth) was assessed using interview-based and questionnaire measures. Four developmental trajectories of externalizing behavior yielded the best balance of parsimony and fit with our longitudinal data and latent class growth analysis. Most young children followed a pathway marked by relatively low levels of symptoms that continued to decrease across the school-age years. Atypical trajectories marked chronically high, increasing, and decreasing levels of externalizing problems across early and middle childhood. Three-year-old children with low levels of effortful control were far more likely to show the chronic pattern of elevated externalizing problems than changing or low patterns. Early parental corporal punishment and maternal warmth, respectively, differentiated preschoolers who showed increasing and decreasing patterns of problem behavior compared to the majority of children. The fact that children's poor effortful regulation skills predicted chronic early onset problems reinforces the need for early childhood screening and intervention services.

Evaluation and differential diagnosis of marked, persistent eosinophilia

PubMed Central

Nutman, Thomas B.

2007-01-01

Synopsis: Hyperosinophilic syndromes (HES) are a group of heterogeneous disorders many of which remain ill-defined. By definition, the HES must be distinguished from other disorders with persistently elevated eosinophilia with a defined cause. Although marked eosinophilia worldwide is most commonly caused by helminth (worm) infections, the diagnostic approach must include non-infectious (non-parasitic) causes of marked eosinophilia as well. PMID:17868863

Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: A novel mechanism in muscle-bone communication.

PubMed

Qin, Yiwen; Peng, Yuanzhen; Zhao, Wei; Pan, Jianping; Ksiezak-Reding, Hanna; Cardozo, Christopher; Wu, Yingjie; Divieti Pajevic, Paola; Bonewald, Lynda F; Bauman, William A; Qin, Weiping

2017-06-30

Muscle and bone are closely associated in both anatomy and function, but the mechanisms that coordinate their synergistic action remain poorly defined. Myostatin, a myokine secreted by muscles, has been shown to inhibit muscle growth, and the disruption of the myostatin gene has been reported to cause muscle hypertrophy and increase bone mass. Extracellular vesicle-exosomes that carry microRNA (miRNA), mRNA, and proteins are known to perform an important role in cell-cell communication. We hypothesized that myostatin may play a crucial role in muscle-bone interactions and may promote direct effects on osteocytes and on osteocyte-derived exosomal miRNAs, thereby indirectly influencing the function of other bone cells. We report herein that myostatin promotes expression of several bone regulators such as sclerostin (SOST), DKK1, and RANKL in cultured osteocytic (Ocy454) cells, concomitant with the suppression of miR-218 in both parent Ocy454 cells and derived exosomes. Exosomes produced by Ocy454 cells that had been pretreated with myostatin could be taken up by osteoblastic MC3T3 cells, resulting in a marked reduction of Runx2, a key regulator of osteoblastic differentiation, and in decreased osteoblastic differentiation via the down-regulation of the Wnt signaling pathway. Importantly, the inhibitory effect of myostatin-modified osteocytic exosomes on osteoblast differentiation is completely reversed by expression of exogenous miR-218, through a mechanism involving miR-218-mediated inhibition of SOST. Together, our findings indicate that myostatin directly influences osteocyte function and thereby inhibits osteoblastic differentiation, at least in part, through the suppression of osteocyte-derived exosomal miR-218, suggesting a novel mechanism in muscle-bone communication. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

[Categorization of uterine cervix tumors : What's new in the 2014 WHO classification].

PubMed

Lax, S F; Horn, L-C; Löning, T

2016-11-01

In the 2014 WHO classification, squamous cell precursor lesions are classified as low-grade and high-grade intraepithelial lesions. LSIL corresponds to CIN1, HSIL includes CIN2 and CIN3. Only adenocarcinoma in situ (AIS) is accepted as precursor of adenocarcinoma and includes the stratified mucin-producing intraepithelial lesion (SMILE). Although relatively rare, adenocarcinoma and squamous cell carcinoma can be mixed with a poorly differentiated neuroendocrine carcinoma. Most cervical adenocarcinomas are low grade and of endocervical type. Mucinous carcinomas show marked intra- and extracellular mucin production. Almost all squamous cell carcinomas, the vast majority of adenocarcinomas, and many rare carcinoma types are HPV related. For low grade endocervical adenocarcinomas, the pattern-based classification according to Silva should be reported. Neuroendocrine tumors are rare and are classified into low-grade and high-grade, whereby the term carcinoid is still used.

Methylation interactions in Arabidopsis hybrids require RNA-directed DNA methylation and are influenced by genetic variation

PubMed Central

Zhang, Qingzhu; Wang, Dong; Lang, Zhaobo; He, Li; Yang, Lan; Zeng, Liang; Li, Yanqiang; Zhao, Cheng; Huang, Huan; Zhang, Heng; Zhang, Huiming; Zhu, Jian-Kang

2016-01-01

DNA methylation is a conserved epigenetic mark in plants and many animals. How parental alleles interact in progeny to influence the epigenome is poorly understood. We analyzed the DNA methylomes of Arabidopsis Col and C24 ecotypes, and their hybrid progeny. Hybrids displayed nonadditive DNA methylation levels, termed methylation interactions, throughout the genome. Approximately 2,500 methylation interactions occurred at regions where parental DNA methylation levels are similar, whereas almost 1,000 were at differentially methylated regions in parents. Methylation interactions were characterized by an abundance of 24-nt small interfering RNAs. Furthermore, dysfunction of the RNA-directed DNA methylation pathway abolished methylation interactions but did not affect the increased biomass observed in hybrid progeny. Methylation interactions correlated with altered genetic variation within the genome, suggesting that they may play a role in genome evolution. PMID:27382183

Chlamydia trachomatis-induced Fitz-Hugh-Curtis syndrome: a case report.

PubMed

Ekabe, Cyril Jabea; Kehbila, Jules; Njim, Tsi; Kadia, Benjamin Momo; Tendonge, Celestine Ntemlefack; Monekosso, Gottlieb Lobe

2017-01-03

Fitz-Hugh-Curtis syndrome is defined as perihepatitis associated with pelvic inflammatory disease. Chlamydia trachomatis is one of its most common aetiologies. This syndrome usually presents with right upper quadrant abdominal pain mimicking other hepatobiliary and gastrointestinal pathologies, hence, posing a diagnostic dilemma in settings with limited diagnostic tools. A 32 year old African female presented with acute right upper quadrant abdominal pain and vaginal discharge, for which she had previously received treatment in another health center with no improvement. Clinical and laboratory findings were suggestive of Fitz-Hugh-Curtis syndrome. Five days after treatment with oral doxycycline, the patient showed marked clinical improvement. Fitz-Hugh-Curtis syndrome is a common cause of right upper quadrant pain which is often under diagnosed in poor communities. Hence, it should be included as a differential diagnosis in patients presenting with right upper quadrant pain, especially in females of reproductive age.

Lymphocytic Mural Folliculitis Resembling Epitheliotropic Lymphoma in Tigers ( Panthera tigris).

PubMed

Sula, Mee-Ja M; Frank, Linda A; Ramsay, Edward C

2018-01-01

A striking form of lymphocytic mural folliculitis is described in 6 tigers ( Panthera tigris). Clinically, all tigers exhibited regionally extensive chronic, variably waxing and waning alopecia with minimal scaling and crusting most pronounced over the head, neck, and shoulders. More severely affected tigers exhibited marked hyperpigmentation and lichenification. Pruritus was not a feature. Tigers generally lacked signs of systemic illness and clinical pathology findings were unremarkable. Histologic examination of skin biopsies revealed infiltrative lymphocytic mural folliculitis extending the length of the hair follicle. Mild epidermal lymphocytic infiltrates were frequent. The surrounding dermis was histologically unremarkable in 4 of 6 tigers or associated with mild perifollicular and periadnexal mixed inflammation in 2 of 6 tigers. The cause of the mural folliculitis was not identified, and tigers responded poorly to immunomodulatory therapy. Lymphocytic mural folliculitis might be a nonspecific hypersensitivity reaction pattern in tigers, and care should be taken to differentiate this reaction pattern from epitheliotropic T-cell lymphoma.

Myasthenia gravis: long-term prognostic value of thymus lactate dehydrogenase isoenzyme pattern of hyperplastic thymus and thymoma.

PubMed Central

Szathmáry, I; Selmeci, L; Pósch, E; Szobor, A; Molnár, J

1985-01-01

Lactate dehydrogenase (LDH) isoenzyme pattern and the percent of H-subunit content were determined in the thymus of 62 patients (55 with hyperplasia, 7 with tumours) after thymectomy. An increase in LDH1 relative activity indicates that in the thymus of patients with myasthenia gravis the ratio of mature differentiated thymocytes was higher than in the thymus of control subjects. LDH isoenzyme profiles of thymus tumours were similar to those described in other neoplasms, except that thymomas with apparent predominance of epithelial cells and with minimal lymphocytic reaction exhibited a marked elevation only in LDH2 relative activity, presumably associated with the specific (secretory) function of epithelial cells. The elevation of H-subunit content, a parameter characteristic of both thymic components (lymphoid and epithelial), correlated closely with a poor clinical condition in patients several years after surgery. PMID:4031927

Who Are the Low-Performing Students? PISA in Focus. No. 60

ERIC Educational Resources Information Center

OECD Publishing, 2016

2016-01-01

Far too many students around the world are trapped in a vicious cycle of poor performance and demotivation that leads only to more bad marks and further disengagement from school. Students who perform poorly at age 15 face a high risk of dropping out of school altogether. By the time they become young adults, poor proficiency in numeracy and…

Differentiation of original and regenerated skeletal muscle fibres in mdx dystrophic muscles.

PubMed

Earnshaw, John C; Kyprianou, Phillip; Krishan, Kewal; Dhoot, Gurtej K

2002-07-01

The differentiation of both original muscle fibres and the regenerated muscle fibres following necrosis in mdx muscles was investigated using immunoblotting and immunocytochemical procedures. Before the onset of necrosis, postnatal skeletal muscles in mdx mouse differentiated well with only a slight delay in differentiation indicated by the level of developmental isoforms of troponin T. Prior to the onset of apparent myopathic change, both fast and slow skeletal muscle fibre types in mdx leg muscles also differentiated well when investigated by analysis of specific myosin heavy chain expression pattern. While the original muscle fibres in mdx leg muscles developed well, the differentiation of regenerated myotubes into both slow and distinct fast muscle fibre types, however, was markedly delayed or inhibited as indicated by several clusters of homogeneously staining fibres even at 14 weeks of age. The number of slow myosin heavy chain-positive myotubes amongst the regenerated muscle clusters was quite small even in soleus. This study thus established that while muscle fibres initially develop normally with only a slight delay in the differentiation process, the differentiation of regenerated myotubes in mdx muscles is markedly compromised and consequently delayed.

Cancer stem cell markers in patterning differentiation and in prognosis of oral squamous cell carcinoma.

PubMed

Mohanta, Simple; Siddappa, Gangotri; Valiyaveedan, Sindhu Govindan; Dodda Thimmasandra Ramanjanappa, Ravindra; Das, Debashish; Pandian, Ramanan; Khora, Samanta Sekhar; Kuriakose, Moni Abraham; Suresh, Amritha

2017-06-01

Differentiation is a major histological parameter determining tumor aggressiveness and prognosis of the patient; cancer stem cells with their slow dividing and undifferentiated nature might be one of the factors determining the same. This study aims to correlate cancer stem cell markers (CD44 and CD147) with tumor differentiation and evaluate their subsequent effect on prognosis. Immunohistochemical analysis in treatment naïve oral cancer patients (n = 53) indicated that the expression of CD147 was associated with poorly differentiated squamous cell carcinoma and moderately differentiated squamous cell carcinoma (p < 0.01). Furthermore, co-expression analysis showed that 45% each of moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma patients were CD44 high /CD147 high as compared to only 10% of patients with well-differentiated squamous cell carcinoma. A three-way analysis indicated that differentiation correlated with recurrence and survival (p < 0.05) in only the patients with CD44 high /CD147 high cohort. Subsequently, relevance of these cancer stem cell markers in patterning the differentiation characteristics was evaluated in oral squamous cell carcinoma cell lines originating from different grades of oral cancer. Flowcytometry-based analysis indicated an increase in CD44 + /CD147 + cells in cell lines of poorly differentiated squamous cell carcinoma (94.35 ± 1.14%, p < 0.001) and moderately differentiated squamous cell carcinoma origin (93.49 ± 0.47%, p < 0.001) as compared to cell line of well-differentiated squamous cell carcinoma origin (23.12% ± 0.49%). Expression profiling indicated higher expression of cancer stem cell and epithelial-mesenchymal transition markers in SCC029B (poorly differentiated squamous cell carcinoma originated; p ≤ 0.001), which was further translated into increased spheroid formation, migration, and invasion (p < 0.001) as compared to cell line of well-differentiated squamous cell carcinoma origin. This study suggests that CD44 and CD147 together improve the prognostic efficacy of tumor differentiation; in vitro results further point out that these markers might be determinant of differentiation characteristics, imparting properties of increased self-renewal, migration, and invasion.

Elevated serum alpha-fetoprotein in poorly differentiated adenocarcinoma with neuroendocrine differentiation of the ascending colon: a case report.

PubMed

Lin, Hung-Hsin; Chang, Chia-Chu; Yang, Shung-Haur; Chang, Shih-Ching; Chen, Wei-Shone; Liang, Wen-Yih; Lin, Jen-Kou; Jiang, Jeng-Kai

2016-03-15

Colorectal cancer (CRC) is the most common form of cancer and the third leading cause of death in Taiwan. Serum alpha-fetoprotein (AFP) has been extensively used as a biomarker for hepatocellular carcinoma (HCC) and yolk sac tumors. This case report presents a 90-year-old woman with right abdominal pain and poor appetite for 1 week. The computed tomography (CT) showed wall thickening in the proximal ascending colon with ruptured appendicitis. Preoperative serum AFP was high. There was no definite liver metastasis or other abnormal findings in the hepatobiliary systems. After initial empirical antibiotic treatment, we performed laparoscopic right hemicolectomy. The pathological assessment was poorly differentiated adenocarcinoma with neuroendocrine differentiation in the ascending colon. The tumor cells did not produce AFP. Amazingly, the follow-up serum AFP level 1 month after the surgery declined to normal range. The patient had an uneventful course after the surgery and was free of recurrence or metastasis within 5 months of follow-up. AFP may be a useful tumor marker in poorly differentiated colorectal cancer with neuroendocrine component patients and a prediction of early treatment response.

Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status.

PubMed

Hanyuda, Akiko; Cao, Yin; Hamada, Tsuyoshi; Nowak, Jonathan A; Qian, Zhi Rong; Masugi, Yohei; da Silva, Annacarolina; Liu, Li; Kosumi, Keisuke; Soong, Thing Rinda; Jhun, Iny; Wu, Kana; Zhang, Xuehong; Song, Mingyang; Meyerhardt, Jeffrey A; Chan, Andrew T; Fuchs, Charles S; Giovannucci, Edward L; Ogino, Shuji; Nishihara, Reiko

2017-05-01

Previous studies suggest that abnormal energy balance status may dysregulate intestinal epithelial homeostasis and promote colorectal carcinogenesis, yet little is known about how host energy balance and obesity influence enterocyte differentiation during carcinogenesis. We hypothesized that the association between high body mass index (BMI) and colorectal carcinoma incidence might differ according to tumor histopathologic differentiation status. Using databases of the Nurses' Health Study and Health Professionals Follow-up Study, and duplication-method Cox proportional hazards models, we prospectively examined an association between BMI and the incidence of colorectal carcinoma subtypes classified by differentiation features. 120,813 participants were followed for 26 or 32 years and 1528 rectal and colon cancer cases with available tumor pathological data were documented. The association between BMI and colorectal cancer risk significantly differed depending on the presence or absence of poorly-differentiated foci (P heterogeneity  = 0.006). Higher BMI was associated with a higher risk of colorectal carcinoma without poorly-differentiated foci (≥30.0 vs. 18.5-22.4 kg/m 2 : multivariable-adjusted hazard ratio, 1.87; 95% confidence interval, 1.49-2.34; P trend  < 0.001), but not with risk of carcinoma with poorly-differentiated foci (P trend  = 0.56). This differential association appeared to be consistent in strata of tumor microsatellite instability or FASN expression status, although the statistical power was limited. The association between BMI and colorectal carcinoma risk did not significantly differ by overall tumor differentiation, mucinous differentiation, or signet ring cell component (P heterogeneity  > 0.03, with the adjusted α of 0.01). High BMI was associated with risk of colorectal cancer subtype containing no poorly-differentiated focus. Our findings suggest that carcinogenic influence of excess energy balance might be stronger for tumors that retain better intestinal differentiation throughout the tumor areas.

Epigenetic Modifications Unlock the Milk Protein Gene Loci during Mouse Mammary Gland Development and Differentiation

PubMed Central

Rijnkels, Monique; Freeman-Zadrowski, Courtneay; Hernandez, Joseph; Potluri, Vani; Wang, Liguo; Li, Wei; Lemay, Danielle G.

2013-01-01

Background Unlike other tissues, development and differentiation of the mammary gland occur mostly after birth. The roles of systemic hormones and local growth factors important for this development and functional differentiation are well-studied. In other tissues, it has been shown that chromatin organization plays a key role in transcriptional regulation and underlies epigenetic regulation during development and differentiation. However, the role of chromatin organization in mammary gland development and differentiation is less well-defined. Here, we have studied the changes in chromatin organization at the milk protein gene loci (casein, whey acidic protein, and others) in the mouse mammary gland before and after functional differentiation. Methodology/Principal Findings Distal regulatory elements within the casein gene cluster and whey acidic protein gene region have an open chromatin organization after pubertal development, while proximal promoters only gain open-chromatin marks during pregnancy in conjunction with the major induction of their expression. In contrast, other milk protein genes, such as alpha-lactalbumin, already have an open chromatin organization in the mature virgin gland. Changes in chromatin organization in the casein gene cluster region that are present after puberty persisted after lactation has ceased, while the changes which occurred during pregnancy at the gene promoters were not maintained. In general, mammary gland expressed genes and their regulatory elements exhibit developmental stage- and tissue-specific chromatin organization. Conclusions/Significance A progressive gain of epigenetic marks indicative of open/active chromatin on genes marking functional differentiation accompanies the development of the mammary gland. These results support a model in which a chromatin organization is established during pubertal development that is then poised to respond to the systemic hormonal signals of pregnancy and lactation to achieve the full functional capacity of the mammary gland. PMID:23301053

CT perfusion imaging of the stomach: a quantitative analysis according to different degrees of adenocarcinoma cell differentiation.

PubMed

Zongqiong, Sun; Xiaohong, Li; Wei, Cai; Jiangfeng, Zhou; Yuxi, Ge; Zhihui, Xie; Linfang, Jin; Yong, Pu; Gen, Yan

2016-01-01

To evaluate clinical usefulness of computed tomography perfusion imaging (CTPI) in gastric cancer. Twenty subjects without gastric diseases (control group) and fifty patients with gastric cancer were studied prospectively using CTPI examinations. Four perfusion parameter values, i.e., blood flow (BF), blood volume (BV), mean transit time, and permeability surface (PS), were calculated. The gastric cancer group was divided into three groups: well differentiated, moderately differentiated, and poorly differentiated gastric adenocarcinoma. Comparing the three groups, differences between the well-differentiated group and the moderately differentiated group or the poorly differentiated group were all statistically significant for BF, BV, and PS. The BF, BV, and PS values could serve as indicators of the degree of malignancy of gastric cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Thyroid cancer profile in Mures County (Romania): a 20 years study.

PubMed

Cătană, Ramona; Boilă, Adela; Borda, Angela

2012-01-01

The aim of the present study was to present data on frequency of thyroid cancer in Mures County (Romania) and border counties, a goiter endemic area, and to analyze its histopathological characteristics, over a 20 years period (1990-2009). Demographic, clinical and pathological data were obtained from database registries. Histological subtypes of thyroid cancer were classified according to the WHO criteria (sixth edition, 2004) in the following categories: papillary thyroid carcinoma with its histological subtypes, follicular thyroid carcinoma, poorly differentiated thyroid carcinoma, undifferentiated thyroid carcinoma, medullary carcinoma, lymphoma, metastatic tumors. Our analyze included 524 cases of thyroid cancer of the 3460 surgical thyroid specimens resected between 1990-2009: 410 (78.2%) cases of papillary carcinoma, 19 (3.6%) cases of follicular carcinoma, 24 (4.6%) cases of poorly differentiated carcinoma, 33 (6.3%) cases of undifferentiated carcinoma, 22 (4.1%) medullary carcinomas, eight (1.6%) lymphomas, and eight (1.6%) metastatic tumors. Papillary thyroid carcinoma is the most common histological form (78%) and an increasing incidence of this form was observed. A statistical significant increase in the incidence of the follicular variant of papillary carcinoma was noticed between 2000-2009, compared to 1990-2000. An increased incidence of small tumors was also found (6.66%, 1990-1999 vs. 23.5%, 2000-2009). The undifferentiated thyroid cancer had a marked decreasing trend (20%, 1990-1999 vs. 3.45%, 2000-2009). Our study demonstrates an increasing trend in the incidence of thyroid cancer in the last 20 years. This increase is mainly due to the small papillary cancers, by contrast to the undifferentiated thyroid cancers that have a decreasing trend. A better understanding and description of the morphological criteria could explained the increasing incidence of the follicular variant of papillary carcinoma.

Direct effects of mitochondrial dysfunction on poor bone health in Leigh syndrome.

PubMed

Kato, Hiroki; Han, Xu; Yamaza, Haruyoshi; Masuda, Keiji; Hirofuji, Yuta; Sato, Hiroshi; Pham, Thanh Thi Mai; Taguchi, Tomoaki; Nonaka, Kazuaki

2017-11-04

Mitochondrial diseases are the result of aberrant mitochondrial function caused by mutations in either nuclear or mitochondrial DNA. Poor bone health has recently been suggested as a symptom of mitochondrial diseases; however, a direct link between decreased mitochondrial function and poor bone health in mitochondrial disease has not been demonstrated. In this study, stem cells from human exfoliated deciduous teeth (SHED) were isolated from a child with Leigh syndrome (LS), a mitochondrial disease, and the effects of decreased mitochondrial function on poor bone health were analyzed. Compared with control SHED, LS SHED displayed decreased osteoblastic differentiation and calcium mineralization. The intracellular and mitochondrial calcium levels were lower in LS SHED than in control SHED. Furthermore, the mitochondrial activity of LS SHED was decreased compared with control SHED both with and without osteoblastic differentiation. Our results indicate that decreased osteoblast differentiation potential and osteoblast function contribute to poor bone health in mitochondrial diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

The Use of Platelet-Rich and Platelet-Poor Plasma to Enhance Differentiation of Skeletal Myoblasts: Implications for the Use of Autologous Blood Products for Muscle Regeneration.

PubMed

Miroshnychenko, Olga; Chang, Wen-Teh; Dragoo, Jason L

2017-03-01

Platelet-rich plasma (PRP) has been used to augment tissue repair and regeneration after musculoskeletal injury. However, there is increasing clinical evidence that PRP does not show a consistent clinical effect. Purpose/Hypothesis: This study aimed to compare the effects of the following non-neutrophil-containing (leukocyte-poor) plasma fractions on human skeletal muscle myoblast (HSMM) differentiation: (1) PRP, (2) modified PRP (Mod-PRP), in which transforming growth factor β1 (TGF-β1) and myostatin (MSTN) were depleted, and (3) platelet-poor plasma (PPP). The hypothesis was that leukocyte-poor PRP would lead to myoblast proliferation (not differentiation), whereas certain modifications of PRP preparations would increase myoblast differentiation, which is necessary for skeletal muscle regeneration. Controlled laboratory study. Blood from 7 human donors was individually processed to simultaneously create leukocyte-poor fractions: PRP, Mod-PRP, PPP, and secondarily spun PRP and Mod-PRP (PRP ss and Mod-PRP ss , respectively). Mod-PRP was produced by removing TGF-β1 and MSTN from PRP using antibodies attached to sterile beads, while a second-stage centrifugal spin of PRP was performed to remove platelets. The biologics were individually added to cell culture groups. Analysis for induction into myoblast differentiation pathways included Western blot analysis, reverse-transcription polymerase chain reaction, and immunohistochemistry, as well as confocal microscopy to assess polynucleated myotubule formation. HSMMs cultured with PRP showed an increase in proliferation but no evidence of differentiation. Western blot analysis confirmed that MSTN and TGF-β1 could be decreased in Mod-PRP using antibody-coated beads, but this modification mildly improved myoblast differentiation. However, cell culture with PPP, PRP ss , and Mod-PRP ss led to a decreased proliferation rate but a significant induction of myoblast differentiation verified by increased multinucleated myotubule formation and myosin heavy chain expression (mean 8-fold change in mRNA level; P < .05), which was comparable with 2% horse serum, the positive control. PPP and leukocyte-poor PRP preparations subjected to a second spin to remove the platelets led to induction of myoblast cells into the muscle differentiation pathway, whereas unmodified leukocyte-poor PRP led to myoblast proliferation. These results indicate that traditionally formulated PRP may not be appropriate to induce muscle regeneration. Laboratory evidence suggests that PPP or non-neutrophil-containing PRP ss , subjected to an additional spin to remove platelets, should be used to stimulate myoblast differentiation, which is necessary for skeletal muscle regeneration. Clinical studies will be required to confirm the effect of these biologics on muscle regeneration.

Magnetic resonance imaging and immunohistochemistry of primary vertebral hemangiosarcoma in a dog and implications for diagnosis and therapy

PubMed Central

Pérez-Martínez, Claudia; Regueiro-Purriños, Marta; Fernández-Martínez, Beatriz; Altónaga, José R.; Gonzalo-Orden, José M.; García-Iglesias, María J.

2016-01-01

A vertebral mass in a dog with an acute onset paraparesis was identified by magnetic resonance imaging. A poorly differentiated hemangiosarcoma was diagnosed by histopathology and immunohistochemistry. Endothelial nitric oxide synthase could be a new differential marker for poorly differentiated hemangiosarcoma in dogs. Immunohistochemical detection of p53 phosphorylated at Serine392, p53, CD117, and CD44 suggest targets for design of therapeutic strategies. PMID:27928170

Magnetic resonance imaging and immunohistochemistry of primary vertebral hemangiosarcoma in a dog and implications for diagnosis and therapy.

PubMed

Pérez-Martínez, Claudia; Regueiro-Purriños, Marta; Fernández-Martínez, Beatriz; Altónaga, José R; Gonzalo-Orden, José M; García-Iglesias, María J

2016-12-01

A vertebral mass in a dog with an acute onset paraparesis was identified by magnetic resonance imaging. A poorly differentiated hemangiosarcoma was diagnosed by histopathology and immunohistochemistry. Endothelial nitric oxide synthase could be a new differential marker for poorly differentiated hemangiosarcoma in dogs. Immunohistochemical detection of p53 phosphorylated at Serine 392 , p53, CD117, and CD44 suggest targets for design of therapeutic strategies.

Inter-island movements and population differentiation in a pelagic seabird.

PubMed

Dearborn, Donald C; Anders, Angela D; Schreiber, E A; Adams, Rachelle M M; Mueller, Ulrich G

2003-10-01

We used mark-resight data and amplified fragment length polymorphism (AFLP) markers to assess movements and gene flow between Central Pacific breeding colonies of the great frigatebird, Fregata minor. Of 715 adult frigatebirds marked on Tern Island and Johnston Atoll, 21.3% were resighted at other frigatebird colonies at least 582 km away. Mark-resight data indicated regular movement of males and females between Tern Island and Johnston Atoll (873 km apart), and less frequent movements to other islands; no birds marked on Tern or Johnston were seen on Christmas Island, but one was seen in the Philippines, 7627 km from where it was marked. Despite the regular occurrence of interisland movements, Bayesian analyses of AFLP data showed significant genetic differentiation between Tern Island and Johnston Atoll, and more pronounced differentiation between these two islands and the more distant Christmas Island. The AFLP profiles of three birds breeding on Tern Island fell within the profile-cluster typical for Christmas Island birds, both in a nonmetric multidimensional scaling analysis and in a population assignment test, suggesting dispersal events from Christmas Island to Tern Island. Several factors could explain the persistence of genetic structure despite frequent movements between colonies: many movements occurred during the nonbreeding season, many breeding-season movements did not involve mate-acquisition behaviours and individuals that do disperse may be selected against, as suggested by morphometric differences between colonies. The persistence of genetic structure among breeding colonies despite significant interisland movements suggests limits to the effectiveness of migration as a homogenizing force in this broadly distributed, extremely mobile species.

On service differentiation in mobile Ad Hoc networks.

PubMed

Zhang, Shun-liang; Ye, Cheng-qing

2004-09-01

A network model is proposed to support service differentiation for mobile Ad Hoc networks by combining a fully distributed admission control approach and the DIFS based differentiation mechanism of IEEE802.11. It can provide different kinds of QoS (Quality of Service) for various applications. Admission controllers determine a committed bandwidth based on the reserved bandwidth of flows and the source utilization of networks. Packets are marked when entering into networks by markers according to the committed rate. By the mark in the packet header, intermediate nodes handle the received packets in different manners to provide applications with the QoS corresponding to the pre-negotiated profile. Extensive simulation experiments showed that the proposed mechanism can provide QoS guarantee to assured service traffic and increase the channel utilization of networks.

The Processing of Case in Near-Native Spanish

ERIC Educational Resources Information Center

Jegerski, Jill

2015-01-01

This article reports a study that sought to determine whether non-native sentence comprehension can show sensitivity to two different types of Spanish case marking. Sensitivity to case violations was generally more robust with indirect objects in ditransitive constructions than with differential object marking of animate direct objects, even among…

Preoperative predictors of occult nodal disease in cT1N0 oral cavity squamous cell carcinoma: Review of 2623 cases.

PubMed

Zhan, Kevin Y; Morgan, Patrick F; Neskey, David M; Kim, Joanne J; Huang, Andrew T; Garrett-Mayer, Elizabeth; Day, Terry A

2018-05-14

Nodal disease predicts survival in oral cavity squamous cell carcinoma (SCC). Currently, no large studies on predictors of occult nodal disease in cT1N0 oral cavity SCC exist. The National Cancer Database (NCDB) review for cT1N0 oral cavity SCC with surgical resection and elective neck dissection (END). The number of patients found with occult nodal disease was 2623 (15.1%). In multivariable regression, female sex and tumor differentiation predict occult nodal disease. Occult nodal disease incidence was 5.9% in well-differentiated tumors, 17.4% in moderately differentiated tumors, and 28.5% in poorly differentiated tumor (P < .001). Women with oral tongue tumors had higher occult nodal disease (19.1%) than men (12%; P = .001). Adjusted odds ratios (aORs) for occult nodal disease in women were: aOR 1.26; 95% confidence interval (CI) 1.01-1.59; P = .045; moderately differentiated aOR 3.52; 95% CI 2.47-5.01; P < .001; and poorly differentiated aOR 6.25; 95% CI 4.17-9.38; P < .001. Sex and tumor differentiation significantly predict occult nodal disease. END is recommended for all moderately and poorly differentiated cT1N0 oral cavity SCC, regardless of the depth of invasion. One can consider not performing END in well-differentiated tumors. © 2018 Wiley Periodicals, Inc.

The Naval Enlisted Aviation Maintenance Manpower System: Advancing Readiness Through Improved Utilization of Intellectual Capital

DTIC Science & Technology

2011-09-01

human capital can be. The other 2 important aspect of human capital which differentiates it from any other form of capital is its requirement to...century, management has come to accept that people, not cash, buildings, or equipment, are the critical differentiators of a business enterprise. (Fitz...capital” as what has been referred to as a “critical differentiator .” Differentiator , from the word differentiate , is defined as “to form or mark

[Thyroid carcinoma--differentiated, poorly differentiated and anaplastic carcinoma].

PubMed

Kakudo, Kennichi; Bai, Yanhua; Li, Yaqiong; Wakasa, Tomoko; Mori, Ichiro

2007-11-01

The poorly differentiated carcinoma was first added as a new member in the lists of classification of thyroid carcinomas in the WHO 2004 edition. However its histological criteria include necrosis and increased mitoses in addition to the original definition by Sakamoto's proposal, solid, trabecular and schirrhous growth. This modification creates a significant change in the incidence and prognosis of this carcinoma. This carcinoma, defined by the new WHO classification, is about 1-5% of all thyroid malignancy and has more aggressive outcome than the previous definition.

Differential Lectin Binding Patterns Identify Distinct Heart Regions in Giant Danio (Devario aequipinnatus) and Zebrafish (Danio rerio) Hearts

PubMed Central

Manalo, Trina; May, Adam; Quinn, Joshua; Lafontant, Dominique S.; Shifatu, Olubusola; He, Wei; Gonzalez-Rosa, Juan M.; Burns, Geoffrey C.; Burns, Caroline E.; Burns, Alan R.; Lafontant, Pascal J.

2016-01-01

Lectins are carbohydrate-binding proteins commonly used as biochemical and histochemical tools to study glycoconjugate (glycoproteins, glycolipids) expression patterns in cells, tissues, including mammalian hearts. However, lectins have received little attention in zebrafish (Danio rerio) and giant danio (Devario aequipinnatus) heart studies. Here, we sought to determine the binding patterns of six commonly used lectins—wheat germ agglutinin (WGA), Ulex europaeus agglutinin, Bandeiraea simplicifolia lectin (BS lectin), concanavalin A (Con A), Ricinus communis agglutinin I (RCA I), and Lycopersicon esculentum agglutinin (tomato lectin)—in these hearts. Con A showed broad staining in the myocardium. WGA stained cardiac myocyte borders, with binding markedly stronger in the compact heart and bulbus. BS lectin, which stained giant danio coronaries, was used to measure vascular reconstruction during regeneration. However, BS lectin reacted poorly in zebrafish. RCA I stained the compact heart of both fish. Tomato lectin stained the giant danio, and while low reactivity was seen in the zebrafish ventricle, staining was observed in their transitional cardiac myocytes. In addition, we observed unique staining patterns in the developing zebrafish heart. Lectins’ ability to reveal differential glycoconjugate expression in giant danio and zebrafish hearts suggests they can serve as simple but important tools in studies of developing, adult, and regenerating fish hearts. PMID:27680670

Deterioration in Teachers' Performance: Causes and Some Remedies

ERIC Educational Resources Information Center

Yariv, Eliezer

2011-01-01

Why do teachers become poor performers? In semi-structured interviews, forty elementary school principals in Israel described the personal story of one poor-performing staff member. Half of the problematic teachers were veteran teachers who faced a marked internal and external shift in mid-career. The seeds of their problems were probably planted…

Blood Plasma-Derived Anti-Glycan Antibodies to Sialylated and Sulfated Glycans Identify Ovarian Cancer Patients

PubMed Central

Pochechueva, Tatiana; Chinarev, Alexander; Schoetzau, Andreas; Fedier, André; Bovin, Nicolai V.; Hacker, Neville F.; Jacob, Francis; Heinzelmann-Schwarz, Viola

2016-01-01

Altered levels of naturally occurring anti-glycan antibodies (AGA) circulating in human blood plasma are found in different pathologies including cancer. Here the levels of AGA directed against 22 negatively charged (sialylated and sulfated) glycans were assessed in high-grade serous ovarian cancer (HGSOC, n = 22) patients and benign controls (n = 31) using our previously developed suspension glycan array (SGA). Specifically, the ability of AGA to differentiate between controls and HGSOC, the most common and aggressive type of ovarian cancer with a poor outcome was determined. Results were compared to CA125, the commonly used ovarian cancer biomarker. AGA to seven glycans that significantly (P<0.05) differentiated between HGSOC and control were identified: AGA to top candidates SiaTn and 6-OSulfo-TF (both IgM) differentiated comparably to CA125. The area under the curve (AUC) of a panel of AGA to 5 glycans (SiaTn, 6-OSulfo-TF, 6-OSulfo-LN, SiaLea, and GM2) (0.878) was comparable to CA125 (0.864), but it markedly increased (0.985) when combined with CA125. AGA to SiaTn and 6-OSulfo-TF were also valuable predictors for HGSOC when CA125 values appeared inconclusive, i.e. were below a certain threshold. AGA-glycan binding was in some cases isotype-dependent and sensitive to glycosidic linkage switch (α2–6 vs. α2–3), to sialylation, and to sulfation of the glycans. In conclusion, plasma-derived AGA to sialylated and sulfated glycans including SiaTn and 6-OSulfo-TF detected by SGA present a valuable alternative to CA125 for differentiating controls from HGSOC patients and for predicting the likelihood of HGSOC, and may be potential HGSOC tumor markers. PMID:27764122

Blood Plasma-Derived Anti-Glycan Antibodies to Sialylated and Sulfated Glycans Identify Ovarian Cancer Patients.

PubMed

Pochechueva, Tatiana; Chinarev, Alexander; Schoetzau, Andreas; Fedier, André; Bovin, Nicolai V; Hacker, Neville F; Jacob, Francis; Heinzelmann-Schwarz, Viola

2016-01-01

Altered levels of naturally occurring anti-glycan antibodies (AGA) circulating in human blood plasma are found in different pathologies including cancer. Here the levels of AGA directed against 22 negatively charged (sialylated and sulfated) glycans were assessed in high-grade serous ovarian cancer (HGSOC, n = 22) patients and benign controls (n = 31) using our previously developed suspension glycan array (SGA). Specifically, the ability of AGA to differentiate between controls and HGSOC, the most common and aggressive type of ovarian cancer with a poor outcome was determined. Results were compared to CA125, the commonly used ovarian cancer biomarker. AGA to seven glycans that significantly (P<0.05) differentiated between HGSOC and control were identified: AGA to top candidates SiaTn and 6-OSulfo-TF (both IgM) differentiated comparably to CA125. The area under the curve (AUC) of a panel of AGA to 5 glycans (SiaTn, 6-OSulfo-TF, 6-OSulfo-LN, SiaLea, and GM2) (0.878) was comparable to CA125 (0.864), but it markedly increased (0.985) when combined with CA125. AGA to SiaTn and 6-OSulfo-TF were also valuable predictors for HGSOC when CA125 values appeared inconclusive, i.e. were below a certain threshold. AGA-glycan binding was in some cases isotype-dependent and sensitive to glycosidic linkage switch (α2-6 vs. α2-3), to sialylation, and to sulfation of the glycans. In conclusion, plasma-derived AGA to sialylated and sulfated glycans including SiaTn and 6-OSulfo-TF detected by SGA present a valuable alternative to CA125 for differentiating controls from HGSOC patients and for predicting the likelihood of HGSOC, and may be potential HGSOC tumor markers.

Diffusion-weighted imaging (DWI) of hepatocellular carcinomas: a retrospective analysis of the correlation between qualitative and quantitative DWI and tumour grade.

PubMed

Jiang, T; Xu, J H; Zou, Y; Chen, R; Peng, L R; Zhou, Z D; Yang, M

2017-06-01

To evaluate the application of qualitative and quantitative diffusion-weighted imaging (DWI) in predicting the histological grade of hepatocellular carcinoma (HCC). Two hundred and fifty-four patients with pathologically confirmed HCC who underwent hepatic DWI on a 1.5-T platform (b = 0, 600 s/mm 2 ) were evaluated retrospectively. HCCs were divided into well-, moderately, and poorly differentiated groups. The relationships between naked-eye signal intensity (SI), SI values, apparent diffusion coefficient (ADC) values on DWI, and the histopathological differentiation of HCC were analysed. Receiver operating characteristic (ROC) curves were drawn to determine the optimal operating points (OOPs) of the SI and ADC values to predict the tumour grade. A weak negative correlation (r=-0.350, p<0.05) was obtained between naked-eye SI and histological grade. There was a significant difference in mean SI values between well- (68.32±31.71) and moderately (102.39±45.55)/poorly (114.55±32.15) differentiated HCC but not between moderately and poorly differentiated HCC. The OOP of the SI value by ROC curve analysis was 66.5 to predict well-differentiated HCC. The mean ADC values of well-, moderately, and poorly differentiated HCC were 1.67±0.13×10 -3 , 1.31±0.16×10 -3 , and 1.08±0.11×10 -3  mm 2 /s, respectively, with significant differences between any two combinations of groups. The OOPs of ADC to diagnose well- and poorly differentiated HCC were 1.5×10 -3 and 1.24×10 -3  mm 2 /s, respectively. Qualitative and quantitative SI and ADC values at DWI may be useful to estimate the histological grade of HCC preoperatively and non-invasively. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

The Warburg effect: persistence of stem-cell metabolism in cancers as a failure of differentiation.

PubMed

Riester, M; Xu, Q; Moreira, A; Zheng, J; Michor, F; Downey, R J

2018-01-01

Two recent observations regarding the Warburg effect are that (i) the metabolism of stem cells is constitutive (aerobic) glycolysis while normal cellular differentiation involves a transition to oxidative phosphorylation and (ii) the degree of glucose uptake of a malignancy as imaged by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is associated with histologic measures of tumor differentiation. Combining these observations, we hypothesized that the high levels of glucose uptake observed in poorly differentiated cancers may reflect persistence of the glycolytic metabolism of stem cells in malignant cells that fail to fully differentiate. Tumor glucose uptake was measured by FDG-PET in 552 patients with histologically diverse cancers. We used normal mixture modeling to explore FDG-PET standardized uptake value (SUV) distributions and tested for associations between glucose uptake and histological differentiation, risk of lymph node metastasis, and survival. Using RNA-seq data, we carried out pathway and transcription factor analyses to compare tumors with high and low levels of glucose uptake. We found that well-differentiated tumors had low FDG uptake, while moderately and poorly differentiated tumors had higher uptake. The distribution of SUV for each histology was bimodal, with a low peak around SUV 2-5 and a high peak at SUV 8-14. The cancers in the two modes were clinically distinct in terms of the risk of nodal metastases and death. Carbohydrate metabolism and the pentose-related pathway were elevated in the poorly differentiated/high SUV clusters. Embryonic stem cell-related signatures were activated in poorly differentiated/high SUV clusters. Our findings support the hypothesis that the biological basis for the Warburg effect is a persistence of stem cell metabolism (i.e. aerobic glycolysis) in cancers as a failure to transition from glycolysis-utilizing undifferentiated cells to oxidative phosphorylation-utilizing differentiated cells. We found that cancers cluster along the differentiation pathway into two groups, utilizing either glycolysis or oxidative phosphorylation. Our results have implications for multiple areas of clinical oncology. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Automatic extraction of pavement markings on streets from point cloud data of mobile LiDAR

NASA Astrophysics Data System (ADS)

Gao, Yang; Zhong, Ruofei; Tang, Tao; Wang, Liuzhao; Liu, Xianlin

2017-08-01

Pavement markings provide an important foundation as they help to keep roads users safe. Accurate and comprehensive information about pavement markings assists the road regulators and is useful in developing driverless technology. Mobile light detection and ranging (LiDAR) systems offer new opportunities to collect and process accurate pavement markings’ information. Mobile LiDAR systems can directly obtain the three-dimensional (3D) coordinates of an object, thus defining spatial data and the intensity of (3D) objects in a fast and efficient way. The RGB attribute information of data points can be obtained based on the panoramic camera in the system. In this paper, we present a novel method process to automatically extract pavement markings using multiple attribute information of the laser scanning point cloud from the mobile LiDAR data. This method process utilizes a differential grayscale of RGB color, laser pulse reflection intensity, and the differential intensity to identify and extract pavement markings. We utilized point cloud density to remove the noise and used morphological operations to eliminate the errors. In the application, we tested our method process on different sections of roads in Beijing, China, and Buffalo, NY, USA. The results indicated that both correctness (p) and completeness (r) were higher than 90%. The method process of this research can be applied to extract pavement markings from huge point cloud data produced by mobile LiDAR.

Tumor differentiation as related to sentinel lymph node status in gastric cancer

PubMed Central

Lavy, Ron; Kapiev, Andronik; Hershkovitz, Yehuda; Poluksht, Natan; Rabin, Igor; Chikman, Bar; Shapira, Zahar; Wasserman, Ilan; Sandbank, Judith; Halevy, Ariel

2014-01-01

AIM: To investigate the influence of tumor grade on sentinel lymph node (SLN) status in patients with gastric cancer (GC). METHODS: We retrospectively studied 71 patients with GC who underwent SLN mapping during gastric surgery to evaluate the relationship between SLN status and tumor grade. RESULTS: Poorly differentiated tumors were detected in 50/71 patients, while the other 21 patients had moderately differentiated tumors. SLNs were identified in 58/71 patients (82%). In 41 of the 58 patients that were found to have stained nodes (70.7%), the tumor was of the poorly differentiated type (group I), while in the remaining patients with stained nodes 17/58 (29.3%), the tumor was of the moderately differentiated type (group II). Positive SLNs were found in 22/41 patients in group I (53.7%) and in 7/17 patients in group II (41.2%) (P = 0.325). The rate of positivity for the SLNs in the two groups (53.7% vs 41.2%) was not statistically significant (P = 0.514). CONCLUSION: Most of our patients were found to have poorly differentiated adenocarcinoma of the stomach and there was no correlation between tumor grade and SLN involvement. PMID:24627734

A patient with scirrhous stomach cancer treated with combination of hyperthermotherapy and 5-aminolevulinic acid (ALA).

PubMed

Saito, Masashi; Yano, Kazuhito; Kamigaki, Takashi; Goto, Shigenori

2013-07-01

A 35-year-old female with scirrhous stomach cancer (stage IV) was treated with a combination of 5-aminolevulinic acid (ALA), sodium dichloroacetate (DCA), hyperthermotherapy, and immunotherapy as terminal care. The patient survived for one year and seven months, during which her quality of life was markedly improved and she returned to work. The patient was diagnosed with poorly-differentiated adenocarcinoma and progressive signet-ring cell carcinoma, accompanied by left ovarian metastasis, peritoneal dissemination, and right hydronephrosis stage IV, and treated with combination chemotherapy with tegafur-gimeracil-oteracil potassium (TS-1) and docetaxel. Oral ALA and DCA were concomitantly administered at 50 mg each three times a day (150 mg/day, respectively). In addition, hyperthermotherapy using thermotron was concomitantly performed at 2- to 3-week intervals. Cellular immunotherapy with αβ T- and immature dendritic cells was also performed. The disease did not progress for 11 months, her quality of life was markedly improved, and she was able to return to work. However, the signs of enlargement of the ovarian metastatic lesion were noted later, for which chemotherapy with four cycles of second-line paclitaxel and a half dose of irinotecan and cisplatin as third-line treatment were performed. Combination of ALA/DCA, hyperthermotherapy, and cellular immunotherapy may be a low-invasive palliative therapy superior in maintaining quality of life of tumor-bearing terminally ill individuals.

Decreased expression of miR‑490‑3p in colorectal cancer predicts poor prognosis and promotes cell proliferation and invasion by targeting RAB14.

PubMed

Wang, Bo; Yin, Mujun; Cheng, Cheng; Jiang, Hongpeng; Jiang, Kewei; Shen, Zhanlong; Ye, Yingjiang; Wang, Shan

2018-06-19

Growing evidence indicates a potential role for miR‑490‑3p in tumorigenesis. However, its function in colorectal carcinoma (CRC) remains undefined. In this study, miR‑490‑3p was markedly downregulated in fifty colorectal cancer tissue samples compared with the corresponding adjacent non‑cancerous specimens, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression levels of miR‑490‑3p were closely associated with tumor differentiation and distant metastasis. In addition, both Kaplan-Meier and multivariate analyses indicated CRC patients with elevated miR‑490‑3p amounts had prolonged overall survival. Overexpression of miR‑490‑3p markedly reduced proliferation, colony formation and invasion in CRC cells by enhancing apoptosis and promoting G2/M phase arrest. Furthermore, ectopic expression of miR‑490‑3p resulted in decreased expression of RAB14, which was directly targeted by miR‑490‑3p, as shown by the dual-luciferase reporter gene assay. Finally, in a nude mouse model, miR‑490‑3p overexpression significantly suppressed the growth of CRC cells. The above results indicated that miR‑490‑3p might constitute a prognostic indicator and a novel molecular target for miRNA-based CRC therapy.

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

PubMed Central

Dozmorov, Mikhail G

2015-01-01

Although age-associated gene expression and methylation changes have been reported throughout the literature, the unifying epigenomic principles of aging remain poorly understood. Recent explosion in availability and resolution of functional/regulatory genome annotation data (epigenomic data), such as that provided by the ENCODE and Roadmap Epigenomics projects, provides an opportunity for the identification of epigenomic mechanisms potentially altered by age-associated differentially methylated regions (aDMRs) and regulatory signatures in the promoters of age-associated genes (aGENs). In this study we found that aDMRs and aGENs identified in multiple independent studies share a common Polycomb Repressive Complex 2 signature marked by EZH2, SUZ12, CTCF binding sites, repressive H3K27me3, and activating H3K4me1 histone modification marks, and a “poised promoter” chromatin state. This signature is depleted in RNA Polymerase II-associated transcription factor binding sites, activating H3K79me2, H3K36me3, H3K27ac marks, and an “active promoter” chromatin state. The PRC2 signature was shown to be generally stable across cell types. When considering the directionality of methylation changes, we found the PRC2 signature to be associated with aDMRs hypermethylated with age, while hypomethylated aDMRs were associated with enhancers. In contrast, aGENs were associated with the PRC2 signature independently of the directionality of gene expression changes. In this study we demonstrate that the PRC2 signature is the common epigenomic context of genomic regions associated with hypermethylation and gene expression changes in aging. PMID:25880792

The human phospholamban gene: structure and expression.

PubMed

McTiernan, C F; Frye, C S; Lemster, B H; Kinder, E A; Ogletree-Hughes, M L; Moravec, C S; Feldman, A M

1999-03-01

Phospholamban, through modulation of sarcoplasmic reticulum calcium-ATPase activity, is a key regulator of cardiac diastolic function. Alterations in phospholamban expression may define parameters of muscle relaxation. In experimental animals, phospholamban is differentially expressed in various striated and smooth muscles, and within the four chambers of the heart. Decreased phospholamban expression within the heart during heart failure has also been observed. Furthermore, regulatory elements of mammalian phospholamban genes remain poorly defined. To extend these studies to humans, we (1) characterized phospholamban expression in various human organs, (2) isolated genomic clones encoding the human phospholamban gene, and (3) prepared human phospholamban promoter/luciferase reporter constructs and performed transient transfection assays to begin identification of regulatory elements. We observed that human ventricle and quadriceps displayed high levels of phospholamban transcripts and proteins, with markedly lower expression observed in smooth muscles, while the right atria also expressed low levels of phospholamban. The human phospholamban gene structure closely resembles that reported for chicken, rabbit, rat, and mouse. Comparison of the human to other mammalian phospholamban genes indicates a marked conservation of sequence for at least 217 bp upstream of the transcription start site, which contains conserved motifs for GATA, CP1/NFY, M-CAT-like, and E-box elements. Transient transfection assays with a series of plasmids containing deleted 5' flanking regions (between -2530 and -66 through +85) showed that sequences between -169 and the CP1-box at -93 were required for maximal promoter activity in neonatal rat cardiomyocytes. Activity of these reporters in HeLa cells was markedly lower than that observed in rat cardiomyocytes, suggesting at least a partial tissue selectivity of these reporter constructs.

Quantitative proteome analysis reveals the correlation between endocytosis-associated proteins and hepatocellular carcinoma dedifferentiation.

PubMed

Naboulsi, Wael; Bracht, Thilo; Megger, Dominik A; Reis, Henning; Ahrens, Maike; Turewicz, Michael; Eisenacher, Martin; Tautges, Stephanie; Canbay, Ali E; Meyer, Helmut E; Weber, Frank; Baba, Hideo A; Sitek, Barbara

2016-11-01

The majority of poorly differentiated hepatocellular carcinomas (HCCs) develop from well-differentiated tumors. Endocytosis is a cellular function which is likely to take part in this development due to its important role in regulating the abundances of vital signaling receptors. Here, we aimed to investigate the abundance of endocytosis-associated proteins in HCCs with various differentiation grades. Therefore, we analyzed 36 tissue specimens from HCC patients via LC-MS/MS-based label-free quantitative proteomics including 19 HCC tissue samples with different degrees of histological grades and corresponding non-tumorous tissue controls. As a result, 277 proteins were differentially regulated between well-differentiated tumors and controls. In moderately and poorly differentiated tumors, 278 and 1181 proteins, respectively, were significantly differentially regulated compared to non-tumorous tissue. We explored the regulated proteins based on their functions and identified thirty endocytosis-associated proteins, mostly overexpressed in poorly differentiated tumors. These included proteins that have been shown to be up-regulated in HCC like clathrin heavy chain-1 (CLTC) as well as unknown proteins, such as secretory carrier-associated membrane protein 3 (SCAMP3). The abundances of SCAMP3 and CLTC were immunohistochemically examined in tissue sections of 84 HCC patients. We demonstrate the novel association of several endocytosis-associated proteins, in particular, SCAMP3 with HCC progression. Copyright © 2016 Elsevier B.V. All rights reserved.

What triggers differential DNA methylation of genes and TEs: contribution of body methylation?

PubMed

Inagaki, S; Kakutani, T

2012-01-01

Transposable elements (TEs) are epigenetically silenced with extensive DNA methylation. The silent epigenetic marks should, however, be excluded from active genes. By genetic approaches, we study mechanisms to remove the heterochromatin marks from transcribed genes. Based on our observations on control of TE transcription, we propose a possible trigger for the TE-specific accumulation of DNA methylation. A critical difference between TEs and genes could be their responses to the DNA methylation in the internal part of transcribed regions. When their internal region is methylated, genes are still transcribed, but TEs could be silenced, which may reflect the obligatory position of every critical cis-acting element within the TE itself. This initial difference of TEs and genes will be amplified by positive feedback loops to stabilize active or silent states. Thus, the mechanisms to accumulate heterochromatin marks within transcribed regions could provide a trigger to induce differential DNA methylation between genes and TEs.

The Differential Contributions of Auditory-Verbal and Visuospatial Working Memory on Decoding Skills in Children Who Are Poor Decoders

ERIC Educational Resources Information Center

Squires, Katie Ellen

2013-01-01

This study investigated the differential contribution of auditory-verbal and visuospatial working memory (WM) on decoding skills in second- and fifth-grade children identified with poor decoding. Thirty-two second-grade students and 22 fifth-grade students completed measures that assessed simple and complex auditory-verbal and visuospatial memory,…

Sialomucins are characteristically O-acylated in poorly differentiated and colloid prostatic adenocarcinomas.

PubMed

Sáez, C; Japón, M A; Conde, A F; Poveda, M A; Luna-Moré, S; Segura, D I

1998-12-01

Mucinous glycoproteins are secreted by prostatic adenocarcinomas and might play important roles in tumor invasion and metastasis. Their histochemical properties on routine biopsy specimens have not been fully characterized. We present a histochemical study of mucin in 21 prostatic adenocarcinomas, with particular focus on the demonstration of different types of sialomucins. We applied the following histochemical techniques to routinely processed, formalin-fixed, paraffin-embedded tissue sections: Alcian blue (pH 2.5) and periodic acid-Schiff to reveal both acidic and neutral mucins; high iron diamine and Alcian blue (pH 2.5) to show sulfated and acidic nonsulfated mucosubstances simultaneously; periodic acid borohydride, potassium hydroxide, and periodic acid-Schiff to demonstrate O-acylated sialic acids; periodic acid thionine-Schiff, potassium hydroxide, and periodic acid-Schiff to differentiate pre-existing glycols from those revealed after saponification procedures; and periodic acid borohydride and periodic acid-Schiff to show C9-O-acylated sialic acid. These techniques are useful tools for demonstrating neutral and acidic (sialo- and sulfo-) mucins and di(C8,C9- or C7,C9-)-O-acylated, tri(C7,C8,C9-)-O-acylated and mono(C9)-O-acylated sialomucins. Most prostatic adenocarcinomas showed acidic mucins, with sialomucins predominating over sulfomucins. Well-differentiated and moderately differentiated noncolloid tumors had non-O-acylated sialomucins. Poorly differentiated tumors contained mono-O-acylated (C9) sialomucins, and colloid-type tumors secreted mono-, di-, and tri-O-acylated sialoglycoproteins. Acidic mucins, mainly sialomucins, constitute the major secretory component in prostatic adenocarcinomas, and our results show that the O-acylation of these sialoglycoproteins inversely correlates with tumor differentiation. Well-differentiated and moderately differentiated tumors are not O-acylated, whereas the poorly differentiated ones characteristically have O-acylated sialomucins in C9. Adenocarcinomas of the colloid type, thought to bear a poor prognosis, are the most heavily O-acylated.

The relationship between histological differentiation and disease recurrence of primary oral squamous cell carcinoma

PubMed Central

Padma, Ramasamy; Kalaivani, Amitkumar; Sundaresan, Sivapatham; Sathish, Paulraj

2017-01-01

Background: Although advance techniques were available for diagnosis and prognosis of oral cancer, histopathology was used as major method in clinical routine. Of all oral subsites, buccal mucosa squamous cell carcinoma is aggressive in nature with poor survival. Therefore, the aim of the present study was to evaluate the relation of tumor histopathological grade with disease recurrence of buccal squamous cell mucosa carcinoma. Materials and Methods: A retrospective study was carried out in regional cancer research institute, Tamil Nadu. Demographic, histopathological and participant's follow-up details were collected from medical records. Results: Of 198 participants, high frequently encountered with well-differentiated squamous cell carcinoma (n = 98, 49.5%). The clinical characteristics of lymphovascular invasion (P = 0.031), perineural invasion (P = 0.019), tumor stage (P = 0.004), tumor depth (P = 0.048), lymph node (P = 0.02) and metastasis (P = 0.043) had significant association with histopathological grade. In addition, the treatment strategies (P = 0.014) also showed significance at P < 0.05. Further, multivariate revealed cell differentiation (P = 0.048), tumor size (P = 0.037) and depth (P = 0.021) as independent hazard risk of the development of disease using recurrence-free survival of participants at P < 0.05. Of 198 participants, 24 (12.1%) recurrences reported during 34-month follow-up period and the overall estimated recurrence-free survival was 52%. The high frequency of recurrence, 12 (50%), was identified with moderately differentiated tumor cells. However, poorly differentiated tumor showed significantly lower survival (28%) than moderate (54%) and well differentiated (81%) by Kaplan–Meier analysis using log-rank test (P = 0.004, P < 0.05). Conclusions: The present study concludes high frequency of recurrence observed in moderately differentiated and also revealed lower survival in poorly differentiated tumor. Hence, further treatment plans should focus on moderate and poorly differentiated tumors to improve survival outcome. PMID:29391735

TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

PubMed Central

Cammareri, Patrizia; Vincent, David F; Hodder, Michael C; Ridgway, Rachel A; Murgia, Claudio; Nobis, Max; Campbell, Andrew D; Varga, Julia; Huels, David J; Subramani, Chithra; Prescott, Katie L H; Nixon, Colin; Hedley, Ann; Barry, Simon T; Greten, Florian R; Inman, Gareth J; Sansom, Owen J

2017-01-01

Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment. PMID:28622298

Math Anxiety--Contributing School and Individual Level Factors

ERIC Educational Resources Information Center

Radišic, Jelena; Videnovic, Marina; Baucal, Aleksander

2015-01-01

PISA 2003 survey data indicate high levels of mathematics anxiety among students in Serbia. More than a half of Serbian students are concerned with whether they will have difficulties in a mathematics class or earn poor marks. At the same time, the achievement on the mathematical literacy scale is very poor. Building on control-value theory, the…

Analysis of FY 1990 Budget Proposals and Their Impact on Low Income Programs.

ERIC Educational Resources Information Center

Center on Budget and Policy Priorities, Washington, DC.

Despite claims that benefits for the needy have not been reduced, the Reagan Administration's final budget for fiscal year 1990 is marked by substantial reductions in programs for the poor. Actual spending for low-income programs would be sliced $6.75 billion below current levels. Medicaid, which provides health care coverage for poor families…

Poor Phonemic Discrimination Does Not Underlie Poor Verbal Short-Term Memory in Down Syndrome

ERIC Educational Resources Information Center

Purser, Harry R. M.; Jarrold, Christopher

2013-01-01

Individuals with Down syndrome tend to have a marked impairment of verbal short-term memory. The chief aim of this study was to investigate whether phonemic discrimination contributes to this deficit. The secondary aim was to investigate whether phonological representations are degraded in verbal short-term memory in people with Down syndrome…

Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer

NASA Astrophysics Data System (ADS)

Nilsson, Roland; Jain, Mohit; Madhusudhan, Nikhil; Sheppard, Nina Gustafsson; Strittmatter, Laura; Kampf, Caroline; Huang, Jenny; Asplund, Anna; Mootha, Vamsi K.

2014-01-01

Metabolic remodeling is now widely regarded as a hallmark of cancer, but it is not clear whether individual metabolic strategies are frequently exploited by many tumours. Here we compare messenger RNA profiles of 1,454 metabolic enzymes across 1,981 tumours spanning 19 cancer types to identify enzymes that are consistently differentially expressed. Our meta-analysis recovers established targets of some of the most widely used chemotherapeutics, including dihydrofolate reductase, thymidylate synthase and ribonucleotide reductase, while also spotlighting new enzymes, such as the mitochondrial proline biosynthetic enzyme PYCR1. The highest scoring pathway is mitochondrial one-carbon metabolism and is centred on MTHFD2. MTHFD2 RNA and protein are markedly elevated in many cancers and correlated with poor survival in breast cancer. MTHFD2 is expressed in the developing embryo, but is absent in most healthy adult tissues, even those that are proliferating. Our study highlights the importance of mitochondrial compartmentalization of one-carbon metabolism in cancer and raises important therapeutic hypotheses.

Transcriptional and Cell Cycle Alterations Mark Aging of Primary Human Adipose-Derived Stem Cells.

PubMed

Shan, Xiaoyin; Roberts, Cleresa; Kim, Eun Ji; Brenner, Ariana; Grant, Gregory; Percec, Ivona

2017-05-01

Adult stem cells play a critical role in the maintenance of tissue homeostasis and prevention of aging. While the regenerative potential of stem cells with low cellular turnover, such as adipose-derived stem cells (ASCs), is increasingly recognized, the study of chronological aging in ASCs is technically difficult and remains poorly understood. Here, we use our model of chronological aging in primary human ASCs to examine genome-wide transcriptional networks. We demonstrate first that the transcriptome of aging ASCs is distinctly more stable than that of age-matched fibroblasts, and further, that age-dependent modifications in cell cycle progression and translation initiation specifically characterize aging ASCs in conjunction with increased nascent protein synthesis and a distinctly shortened G1 phase. Our results reveal novel chronological aging mechanisms in ASCs that are inherently different from differentiated cells and that may reflect an organismal attempt to meet the increased demands of tissue and organ homeostasis during aging. Stem Cells 2017;35:1392-1401. © 2017 AlphaMed Press.

A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells.

PubMed

Cook, Peter C; Owen, Heather; Deaton, Aimée M; Borger, Jessica G; Brown, Sheila L; Clouaire, Thomas; Jones, Gareth-Rhys; Jones, Lucy H; Lundie, Rachel J; Marley, Angela K; Morrison, Vicky L; Phythian-Adams, Alexander T; Wachter, Elisabeth; Webb, Lauren M; Sutherland, Tara E; Thomas, Graham D; Grainger, John R; Selfridge, Jim; McKenzie, Andrew N J; Allen, Judith E; Fagerholm, Susanna C; Maizels, Rick M; Ivens, Alasdair C; Bird, Adrian; MacDonald, Andrew S

2015-04-24

Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation.

Fructose 2,6-bisphosphate and the climacteric in bananas.

PubMed

Ball, K L; ap Rees, T

1988-11-15

This work was done to test the view that there is a marked rise in the content of fructose 2,6-bisphosphate during the climacteric of the fruit of banana (Musa cavendishii Lamb ex. Paxton). Bananas were ripened in the dark in a continuous stream of air in the absence of exogenous ethylene. CO2 production and the contents of fructose 2,6-bisphosphate and sucrose were monitored over a 15-day period. A range of extraction procedures for fructose 2,6-bisphosphate were compared. Recovery of fructose 2,6-bisphosphate added to samples of unripe fruit varied from poor to unmeasurable. Recoveries from samples of ripe fruit were high. It is argued that this differential recovery of fructose 2,6-bisphosphate undermines claims that the amount of this compound increases at the climacteric. When recoveries are taken into account, our data suggest that there is no major change in fructose 2,6-bisphosphate content during the onset of the climacteric in bananas.

The microprotein Minion controls cell fusion and muscle formation

PubMed Central

Zhang, Qiao; Vashisht, Ajay A.; O'Rourke, Jason; Corbel, Stéphane Y; Moran, Rita; Romero, Angelica; Miraglia, Loren; Zhang, Jia; Durrant, Eric; Schmedt, Christian; Sampath, Srinath C.; Sampath, Srihari C.

2017-01-01

Although recent evidence has pointed to the existence of small open reading frame (smORF)-encoded microproteins in mammals, their function remains to be determined. Skeletal muscle development requires fusion of mononuclear progenitors to form multinucleated myotubes, a critical but poorly understood process. Here we report the identification of Minion (microprotein inducer of fusion), a smORF encoding an essential skeletal muscle specific microprotein. Myogenic progenitors lacking Minion differentiate normally but fail to form syncytial myotubes, and Minion-deficient mice die perinatally and demonstrate a marked reduction in fused muscle fibres. The fusogenic activity of Minion is conserved in the human orthologue, and co-expression of Minion and the transmembrane protein Myomaker is sufficient to induce cellular fusion accompanied by rapid cytoskeletal rearrangement, even in non-muscle cells. These findings establish Minion as a novel microprotein required for muscle development, and define a two-component programme for the induction of mammalian cell fusion. Moreover, these data also significantly expand the known functions of smORF-encoded microproteins. PMID:28569745

Congenital hand anomalies in Upper Egypt

PubMed Central

Abulezz, Tarek; Talaat, Mohamed; Elsani, Asem; Allam, Karam

2016-01-01

Background: Congenital hand anomalies are numerous and markedly variant. Their significance is attributed to the frequent occurrence and their serious social, psychological and functional impacts on patient's life. Patients and Methods: This is a follow-up study of 64 patients with hand anomalies of variable severity. All patients were presented to Plastic Surgery Department of Sohag University Hospital in a period of 24 months. Results: This study revealed that failure of differentiation and duplication deformities were the most frequent, with polydactyly was the most common anomaly encountered. The mean age of presentation was 6 years and female to male ratio was 1.46:1. Hand anomalies were either isolated, associated with other anomalies or part of a syndrome. Conclusion: Incidence of congenital hand anomalies in Upper Egypt is difficult to be estimated due to social and cultural concepts, lack of education, poor registration and deficient medical survey. Management of hand anomalies should be individualised, carefully planned and started as early as possible to achieve the best outcome. PMID:27833283

Fungal Mimicry of a Mammalian Aminopeptidase Disables Innate Immunity and Promotes Pathogenicity.

PubMed

Sterkel, Alana K; Lorenzini, Jenna L; Fites, J Scott; Subramanian Vignesh, Kavitha; Sullivan, Thomas D; Wuthrich, Marcel; Brandhorst, Tristan; Hernandez-Santos, Nydiaris; Deepe, George S; Klein, Bruce S

2016-03-09

Systemic fungal infections trigger marked immune-regulatory disturbances, but the mechanisms are poorly understood. We report that the pathogenic yeast of Blastomyces dermatitidis elaborates dipeptidyl-peptidase IVA (DppIVA), a close mimic of the mammalian ectopeptidase CD26, which modulates critical aspects of hematopoiesis. We show that, like the mammalian enzyme, fungal DppIVA cleaved C-C chemokines and GM-CSF. Yeast producing DppIVA crippled the recruitment and differentiation of monocytes and prevented phagocyte activation and ROS production. Silencing fungal DppIVA gene expression curtailed virulence and restored recruitment of CCR2(+) monocytes, generation of TipDC, and phagocyte killing of yeast. Pharmacological blockade of DppIVA restored leukocyte effector functions and stemmed infection, while addition of recombinant DppIVA to gene-silenced yeast enabled them to evade leukocyte defense. Thus, fungal DppIVA mediates immune-regulatory disturbances that underlie invasive fungal disease. These findings reveal a form of molecular piracy by a broadly conserved aminopeptidase during disease pathogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

Genome-Wide Reprogramming of Transcript Architecture by Temperature Specifies the Developmental States of the Human Pathogen Histoplasma

PubMed Central

Gilmore, Sarah A.; Voorhies, Mark; Gebhart, Dana; Sil, Anita

2015-01-01

Eukaryotic cells integrate layers of gene regulation to coordinate complex cellular processes; however, mechanisms of post-transcriptional gene regulation remain poorly studied. The human fungal pathogen Histoplasma capsulatum (Hc) responds to environmental or host temperature by initiating unique transcriptional programs to specify multicellular (hyphae) or unicellular (yeast) developmental states that function in infectivity or pathogenesis, respectively. Here we used recent advances in next-generation sequencing to uncover a novel re-programming of transcript length between Hc developmental cell types. We found that ~2% percent of Hc transcripts exhibit 5’ leader sequences that differ markedly in length between morphogenetic states. Ribosome density and mRNA abundance measurements of differential leader transcripts revealed nuanced transcriptional and translational regulation. One such class of regulated longer leader transcripts exhibited tight transcriptional and translational repression. Further examination of these dually repressed genes revealed that some control Hc morphology and that their strict regulation is necessary for the pathogen to make appropriate developmental decisions in response to temperature. PMID:26177267

Genome-Wide Reprogramming of Transcript Architecture by Temperature Specifies the Developmental States of the Human Pathogen Histoplasma.

PubMed

Gilmore, Sarah A; Voorhies, Mark; Gebhart, Dana; Sil, Anita

2015-07-01

Eukaryotic cells integrate layers of gene regulation to coordinate complex cellular processes; however, mechanisms of post-transcriptional gene regulation remain poorly studied. The human fungal pathogen Histoplasma capsulatum (Hc) responds to environmental or host temperature by initiating unique transcriptional programs to specify multicellular (hyphae) or unicellular (yeast) developmental states that function in infectivity or pathogenesis, respectively. Here we used recent advances in next-generation sequencing to uncover a novel re-programming of transcript length between Hc developmental cell types. We found that ~2% percent of Hc transcripts exhibit 5' leader sequences that differ markedly in length between morphogenetic states. Ribosome density and mRNA abundance measurements of differential leader transcripts revealed nuanced transcriptional and translational regulation. One such class of regulated longer leader transcripts exhibited tight transcriptional and translational repression. Further examination of these dually repressed genes revealed that some control Hc morphology and that their strict regulation is necessary for the pathogen to make appropriate developmental decisions in response to temperature.

Social Determinants of Health in the United States: Addressing Major Health Inequality Trends for the Nation, 1935-2016.

PubMed

Singh, Gopal K; Daus, Gem P; Allender, Michelle; Ramey, Christine T; Martin, Elijah K; Perry, Chrisp; Reyes, Andrew A De Los; Vedamuthu, Ivy P

2017-01-01

This study describes key population health concepts and examines major empirical trends in US health and healthcare inequalities from 1935 to 2016 according to important social determinants such as race/ethnicity, education, income, poverty, area deprivation, unemployment, housing, rural-urban residence, and geographic location. Long-term trend data from the National Vital Statistics System, National Health Interview Survey, National Survey of Children's Health, American Community Survey, and Behavioral Risk Factor Surveillance System were used to examine racial/ethnic, socioeconomic, rural-urban, and geographic inequalities in health and health care. Life tables, age-adjusted rates, prevalence, and risk ratios were used to examine health differentials, which were tested for statistical significance at the 0.05 level. Life expectancy of Americans increased from 69.7 years in 1950 to 78.8 years in 2015. However, despite the overall improvement, substantial gender and racial/ethnic disparities remained. In 2015, life expectancy was highest for Asian/Pacific Islanders (87.7 years) and lowest for African-Americans (75.7 years). Life expectancy was lower in rural areas and varied from 74.5 years for men in rural areas to 82.4 years for women in large metro areas, with rural-urban disparities increasing during the 1990-2014 time period. Infant mortality rates declined dramatically during the past eight decades. However, racial disparities widened over time; in 2015, black infants had 2.3 times higher mortality than white infants (11.4 vs. 4.9 per 1,000 live births). Infant and child mortality was markedly higher in rural areas and poor communities. Black infants and children in poor, rural communities had nearly three times higher mortality rate compared to those in affluent, rural areas. Racial/ethnic, socioeconomic, and geographic disparities were particularly marked in mortality and/or morbidity from cardiovascular disease, cancer, diabetes, COPD, HIV/AIDS, homicide, psychological distress, hypertension, smoking, obesity, and access to quality health care. Despite the overall health improvement, significant social disparities remain in a number of health indicators, most notably in life expectancy and infant mortality. Marked disparities in various health outcomes indicate the underlying significance of social determinants in disease prevention and health promotion and necessitate systematic and continued monitoring of health inequalities according to social factors. A multi-sectoral approach is needed to tackle persistent and widening health inequalities among Americans.

[Poorly differentiated thyroid carcinomas: new therapeutic considerations].

PubMed

Graf, Hans

2005-10-01

For most differentiated thyroid carcinomas, as papillary and follicular carcinomas, following total thyroidectomy and 131I therapy for thyroid remnant ablation, treatment with thyroid hormones to suppress TSH levels will reduce the growth of any remaining thyroid cancer cells, and thyroid cell-specific radiation therapy will either cure or control the disease. Thyroid carcinomas are considered poorly differentiated when they start to lose such functions as iodine uptake and thyrotropin-dependence for growth and production of thyroid proteins like NIS, thyroglobulin and desiodases. One of the greatest challenges in the management of patients with follicular cell-derived thyroid cancer is the treatment of tumors that progressed despite surgery, (131)I and T4 suppression of TSH. With the better knowledge of the abnormal molecular signaling in thyroid cancer cells, actually known targeted cancer therapies, directed against molecules involved in neoplastic transformation, are being used. As the critical molecular requirements for tumor initiation, maintenance and progression are identified, combination therapies with targeted agents acting on each of them will improve the treatment of poorly differentiated thyroid carcinoma.

Clinical Signatures of Mucinous and Poorly Differentiated Subtypes of Colorectal Adenocarcinomas by a Propensity Score Analysis of an Independent Patient Database from Three Phase III Trials.

PubMed

Kanda, Mitsuro; Oba, Koji; Aoyama, Toru; Kashiwabara, Kosuke; Mayanagi, Shuhei; Maeda, Hiromichi; Honda, Michitaka; Hamada, Chikuma; Sadahiro, Sotaro; Sakamoto, Junichi; Saji, Shigetoyo; Yoshikawa, Takaki

2018-04-01

Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. Independent patient data analysis of a pooled database from 3 phase III trials was performed. An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. The treatment regimens of postoperative chemotherapy are now somewhat outdated. Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype require special attention during follow-up, even for stage II disease, because of the risk of peritoneal or local recurrence. See Video Abstract at http://links.lww.com/DCR/A531.

Germ layer differentiation during early hindgut and cloaca formation in rabbit and pig embryos

PubMed Central

Hassoun, Romia; Schwartz, Peter; Rath, Detlef; Viebahn, Christoph; Männer, Jörg

2010-01-01

Relative to recent advances in understanding molecular requirements for endoderm differentiation, the dynamics of germ layer morphology and the topographical distribution of molecular factors involved in endoderm formation at the caudal pole of the embryonic disc are still poorly defined. To discover common principles of mammalian germ layer development, pig and rabbit embryos at late gastrulation and early neurulation stages were analysed as species with a human-like embryonic disc morphology, using correlative light and electron microscopy. Close intercellular contact but no direct structural evidence of endoderm formation such as mesenchymal–epithelial transition between posterior primitive streak mesoderm and the emerging posterior endoderm were found. However, a two-step process closely related to posterior germ layer differentiation emerged for the formation of the cloacal membrane: (i) a continuous mesoderm layer and numerous patches of electron-dense flocculent extracellular matrix mark the prospective region of cloacal membrane formation; and (ii) mesoderm cells and all extracellular matrix including the basement membrane are lost locally and close intercellular contact between the endoderm and ectoderm is established. The latter process involves single cells at first and then gradually spreads to form a longitudinally oriented seam-like cloacal membrane. These gradual changes were found from gastrulation to early somite stages in the pig, whereas they were found from early somite to mid-somite stages in the rabbit; in both species cloacal membrane formation is complete prior to secondary neurulation. The results highlight the structural requirements for endoderm formation during development of the hindgut and suggest new mechanisms for the pathogenesis of common urogenital and anorectal malformations. PMID:20874819

[Study on relationship between blood supply from pulmonary artery and pathological characteristics of patients with primary bronchogenic carcinoma].

PubMed

Zhang, Yongkui; Le, Hanbo; Chen, Zhijun; Wang, Chaoye; Zhang, Binjie

2006-01-01

At present, it has been known that the bronchogenic artery participates in the blood supply of primary bronchogenic carcinoma, but there is controversy about the blood supply from pulmonary artery in primary bronchogenic carcinoma. The aim of this study is to assess the relationship between the blood supply from pulmonary artery and pathological characteristis of patients with primary bronchogenic carcinoma. The pulmonary arteries in 43 surgical samples of bronchogenic carcinoma were marked, then the iopromide was used to selective pulmonary arteriography in digital subtraction angiography (DSA). The relationship between tumor with blood supply from pulmonary artery and the pathologic characteristics was observed. There were 34 samples with blood supply from pulmonary artery ( 79.07%) , and 9 samples without blood supply from pulmonary artery (20.93%). The development rate of peripheral lung cancer (100.00%) was significantly higher than that of central lung cancer (64.00%) (P < 0.01) . The development rate of squamous cell carcinoma (91.30%) was remarkably higher than that of adenocarcinoma (61.11%) (P < 0.05). The development rate of poorly differentiated lung cancer (95.00%) was remarkably higher than that of well and moderately differentiated lung cancer (65.22%) (P < 0.05). There was a positive relationship between the tumor size and the development rate (P < 0.05). In primary bronchogenic carcinoma, the pulmonary artery blood supply exists in most of tumors. There is relationship between the blood supply from pulmonary artery and general type, histopathology, cell differentiation and tumor size of lung cancer. The blood supply from pulmonary artery doesn't relate to tumor stage.

Do olfactory behaviour and marking responses of Konik polski stallions to faeces from conspecifics of either sex differ?

PubMed

Jezierski, Tadeusz; Jaworski, Zbigniew; Sobczyńska, Magdalena; Ensminger, John; Górecka-Bruzda, Aleksandra

2017-09-27

The aim of the study was to assess whether adult stallions differentiate their olfactory and marking behaviour towards the excreta of their potential male rivals and mares. Four Konik polski stallions were individually exposed simultaneously to their own and each others' faeces as well as faeces of mares in oestrus vs. dioestrus. Five series of 30min observation sessions were conducted in a round pen each on two consecutive days from March to July, totaling in 5h observation per stallion. Stallions sniffed and displayed flehmen reaction towards mares' faeces significantly longer (P<0.01) than towards stallions' faeces. No significant differences were found in marking by defecations upon stallions' vs. mares' faeces. The stallions urinated exclusively on mares' faeces. Sniffing, flehmen, defecations and urinations performed towards faeces of mares in oestrus vs. dioestrus did not differ significantly. The results showed that stallions differentiate their olfactory behaviour towards excreta of conspecifics of different sex but perhaps not towards faeces of females in different reproductive status. This for the first time establishes that stallions exhibit different marking behaviour upon stallions' vs. mares' faeces. It is hypothesized that marking of other stallions' faeces by defecation may advertise presence of the stallion, whereas marking of mares' faeces by urination may serve to mask the presence of a mare to prevent potential rivals from locating the mare in an area where mares' faeces are found. Copyright © 2017 Elsevier B.V. All rights reserved.

Contribution of Socio-Emotional Development Game to Social Integration of Young Children from Disadvantaged Backgrounds

ERIC Educational Resources Information Center

Cuc, Maria Claudia; Macarie, Simona

2012-01-01

In Romania postmodern education system is built on a new philosophy of education, which promotes a new concept, as the social fact and reference value in building human capital. Integration effects, of globalization, poor management and poor government policy, have brought out another aspect of Romania, poverty, which leaves its mark on the…

Social Capital and Poor Communities. A Volume in the Ford Foundation Series on Asset Building.

ERIC Educational Resources Information Center

Saegert, Susan, Ed.; Thompson, J. Phillip, Ed.; Warren, Mark R., Ed.

This collection of papers shows the significant achievements that can be made through collective strategies that empower the poor to become active partners in revitalizing their neighborhoods. The 12 chapters are: (1) "The Role of Social Capital in Combating Poverty" (Mark R. Warren, J. Phillip Thompson, and Susan Saegert); (2) "Social Capital and…

Correlation between Standardized Uptake Value of 68Ga-DOTA-NOC Positron Emission Tomography/Computed Tomography and Pathological Classification of Neuroendocrine Tumors.

PubMed

Kaewput, Chalermrat; Suppiah, Subapriya; Vinjamuri, Sobhan

2018-01-01

The aim of our study was to correlate tumor uptake of 68 Ga-DOTA-NOC positron emission tomography/computed tomography (PET/CT) with the pathological grade of neuroendocrine tumors (NETs). 68 Ga-DOTA-NOC PET/CT examinations in 41 patients with histopathologically proven NETs were included in the study. Maximum standardized uptake value (SUV max ) and averaged SUV SUV mean of "main tumor lesions" were calculated for quantitative analyses after background subtraction. Uptake on main tumor lesions was compared and correlated with the tumor histological grade based on Ki-67 index and pathological differentiation. Classification was performed into three grades according to Ki-67 levels; low grade: Ki-67 <2, intermediate grade: Ki-67 3-20, and high grade: Ki-67 >20. Pathological differentiation was graded into well- and poorly differentiated groups. The values were compared and evaluated for correlation and agreement between the two parameters was performed. Our study revealed negatively fair agreement between SUV max of tumor and Ki-67 index ( r = -0.241) and negatively poor agreement between SUV mean of tumor and Ki-67 index ( r = -0.094). SUV max of low-grade, intermediate-grade, and high-grade Ki-67 index is 26.18 ± 14.56, 30.71 ± 24.44, and 6.60 ± 4.59, respectively. Meanwhile, SUV mean of low-grade, intermediate-grade, and high-grade Ki-67 is 8.92 ± 7.15, 9.09 ± 5.18, and 3.00 ± 1.38, respectively. As expected, there was statistically significant decreased SUV max and SUV mean in high-grade tumors (poorly differentiated NETs) as compared with low- and intermediate-grade tumors (well-differentiated NETs). SUV of 68 Ga-DOTA-NOC PET/CT is not correlated with histological grade of NETs. However, there was statistically significant decreased tumor uptake of 68 Ga-DOTA-NOC in poorly differentiated NETs as compared with the well-differentiated group. As a result of this pilot study, we confirm that the lower tumor uptake of 68 Ga-DOTA-NOC may be associated with aggressive behavior and may, therefore, result in poor prognosis.

Comparative study of ROR2 and WNT5a expression in squamous/adenosquamous carcinoma and adenocarcinoma of the gallbladder

PubMed Central

Wu, Zheng-Chun; Xiong, Li; Wang, Ling-Xiang; Miao, Xiong-Ying; Liu, Zi-Ru; Li, Dai-Qiang; Zou, Qiong; Liu, Kui-Jie; Zhao, Hua; Yang, Zhu-Lin

2017-01-01

AIM To investigate the expression and clinical pathological significance of ROR2 and WNT5a in gallbladder squamous/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC). METHODS EnVision immunohistochemistry was used to stain for ROR2 and WNT5a in 46 SC/ASC patients and 80 AC patients. RESULTS Poorly differentiated AC among AC patients aged > 45 years were significantly more frequent compared with SC/ASC patients, while tumors with a maximal diameter > 3 cm in the SC/ASC group were significantly more frequent compared with the AC group. Positive ROR2 and WNT5a expression was significantly lower in SC/ASC or AC with a maximal mass diameter ≤ 3 cm, a TNM stage of I + II, no lymph node metastasis, no surrounding invasion, and radical resection than in patients with a maximal mass diameter > 3 cm, TNM stage IV, lymph node metastasis, surrounding invasion, and no resection. Positive ROR2 expression in patients with highly differentiated SC/ASC was significantly lower than in patients with poorly differentiated SC/ASC. Positive ROR2 and WNT5a expression levels in highly differentiated AC were significantly lower than in poorly differentiated AC. Kaplan-Meier survival analysis showed that differentiation degree, maximal mass diameter, TNM stage, lymph node metastasis, surrounding invasion, surgical procedure and the ROR2 and WNT5a expression levels were closely related to average survival of SC/ASC or AC. The survival of SC/ASC or AC patients with positive expression of ROR2 and WNT5a was significantly shorter than that of patients with negative expression results. Cox multivariate analysis revealed that poor differentiation, a maximal diameter of the mass ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, unresected surgery and positive ROR2 or WNT5a expression in the SC/ASC or AC patients were negatively correlated with the postoperative survival rate and positively correlated with mortality, which are risk factors and independent prognostic predictors. CONCLUSION SC/ASC or AC patients with positive ROR2 or WNT5a expression generally have a poor prognosis. PMID:28465645

Chloroplast membrane alterations in triazine-resistant Amaranthus retroflexus biotypes

PubMed Central

Arntzen, Charles J.; Ditto, Cathy L.; Brewer, Philip E.

1979-01-01

The effectiveness of diuron, atrazine, procyazine, and cyanazine were compared in controlling growth of redroot pigweed (Amaranthus retroflexus L.) in hydroponic culture. A very marked differential inhibition response was observed for atrazine between resistant and susceptible biotypes. Procyazine and cyanazine exhibited less dramatic differential responses, whereas diuron was equally effective in controlling growth in both biotypes. Photosystem II activity of chloroplasts from both triazine-resistant and triazine-susceptible biotypes was inhibited by diuron but only the chloroplasts from triazine-susceptible biotypes were inhibited significantly by atrazine. The photochemical activity of chloroplasts from triazine-resistant biotypes was partially resistant to procyazine or cyanazine inhibition. The parallel lack of diuron differential effects, partial procyazine and cyanazine differential response, and very marked atrazine differential response in both whole plant and chloroplast assays indicates that the chloroplast is the site of selective herbicide tolerance in these triazine-resistant redroot pigweed biotypes. Photosystem II photochemical properties were characterized by analysis of chlorophyll fluorescence transients in the presence or absence of herbicides. Data with susceptible chloroplasts indicated that both diuron and atrazine inhibit electron flow very near the primary electron acceptor of photosystem II. Only diuron altered the fluorescence transient in resistant chloroplasts. In untreated preparations there were marked differences in the fast phases of the fluorescence increase in resistant vs. susceptible chloroplasts; these data are interpreted as showing that the resistant plastids have an alteration in the rate of reoxidation of the primary photosystem II electron acceptor. Electrophoretic analysis of chloroplast membrane proteins of the two biotypes showed small changes in the electrophoretic mobilities of two polypeptide species. The data provide evidence for the following herbicide resistance mechanism: genetically controlled modification of the herbicide target site. Images PMID:16592608

Earth fissures and localized differential subsidence

USGS Publications Warehouse

Holzer, Thomas L.; Pampeyan, Earl Haig

1979-01-01

Long tension cracks caused by declines of ground-water level at four sites in Arizona, California, and Nevada occur at points of maximum, convex-upward curvature in subsidence profiles based on relevelings of closely-spaced bench marks aligned perpendicular to the cracks. We conclude the cracks are caused by horizontal strains associated with the differential subsidence.

Differential Effects of Reinforcement on the Self-Monitoring of On-Task Behavior

ERIC Educational Resources Information Center

Otero, Tiffany L.; Haut, Jillian M.

2016-01-01

In the current study, the differential effects of reinforcement on a self-monitoring intervention were evaluated. Three students nominated by their teachers for having a marked difficultly maintaining on-task behaviors participated in the study. Using an alternating treatments single-case design to assess self-monitoring with and without…

Current Direction and Velocity Measurements Using GPS Receivers Mounted on Floats at Tom Bevill Lock and Dam

DTIC Science & Technology

2002-12-01

radio and batteries. The procedures outlined in this CHETN will concentrate on the Magellan GPS ProMARK X-CP receiver as it was used to collect...The Magellan GPS ProMARK X-CP is a small robust light receiver that can log 9 hr of both pseudorange and carrier phase satellite data for post...post- processing software, pseudorange GPS data recorded by the ProMARK X-CP can be post-processed differential to achieve 1-3 m (3.3-9.8 ft) horizontal

Differential Regulation of Protein- and Polysaccharide-Specific Ig Isotype Production In Vivo in Response to Intact Streptococcus pneumoniae

DTIC Science & Technology

2006-01-01

IL-4-/- mice. A marked enhancement in the induction of pro-inflammatory cytokines was observed in the absence of IL- 10, relative to controls. IgG...that it was phenol-extractable. Immunization of wild-type mice with phenol-extracted PPS14 also resulted in a marked reduction in the IgG, although not...Thus, CBA/N (xid) mice [124], which have a loss-of-function point mutation in the Btk gene [125, 126] exhibit a marked reduction in peritoneal B-1a

A Poised Chromatin Platform for TGF-[beta] Access to Master Regulators

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

Xi, Qiaoran; Wang, Zhanxin; Zaromytidou, Alexia-Ileana

2012-02-07

Specific chromatin marks keep master regulators of differentiation silent yet poised for activation by extracellular signals. We report that nodal TGF-{beta} signals use the poised histone mark H3K9me3 to trigger differentiation of mammalian embryonic stem cells. Nodal receptors induce the formation of companion Smad4-Smad2/3 and TRIM33-Smad2/3 complexes. The PHD-Bromo cassette of TRIM33 facilitates binding of TRIM33-Smad2/3 to H3K9me3 and H3K18ac on the promoters of mesendoderm regulators Gsc and Mixl1. The crystal structure of this cassette, bound to histone H3 peptides, illustrates that PHD recognizes K9me3, and Bromo binds an adjacent K18ac. The interaction between TRIM33-Smad2/3 and H3K9me3 displaces the chromatin-compactingmore » factor HP1, making nodal response elements accessible to Smad4-Smad2/3 for Pol II recruitment. In turn, Smad4 increases K18 acetylation to augment TRIM33-Smad2/3 binding. Thus, nodal effectors use the H3K9me3 mark as a platform to switch master regulators of stem cell differentiation from the poised to the active state.« less

Regulation of cAMP and GSK3 signaling pathways contributes to the neuronal conversion of glioma

PubMed Central

Kim, Yongbo; Che, Lihua; Kim, Jeong Beom; Chang, Gyeong Eon; Cheong, Eunji; Kang, Seok-Gu; Ha, Yoon

2017-01-01

Glioma is the most malignant type of primary central nervous system tumors, and has an extremely poor prognosis. One potential therapeutic approach is to induce the terminal differentiation of glioma through the forced expression of pro-neural factors. Our goal is to show the proof of concept of the neuronal conversion of C6 glioma through the combined action of small molecules. We investigated the various changes in gene expression, cell-specific marker expression, signaling pathways, physiological characteristics, and morphology in glioma after combination treatment with two small molecules (CHIR99021, a glycogen synthase kinase 3 [GSK3] inhibitor and forskolin, a cyclic adenosine monophosphate [cAMP] activator). Here, we show that the combined action of CHIR99021 and forskolin converted malignant glioma into fully differentiated neurons with no malignant characteristics; inhibited the proliferation of malignant glioma; and significantly down-regulated gene ontology and gene expression profiles related to cell division, gliogenesis, and angiogenesis in small molecule–induced neurons. In vivo, the combined action of CHIR99021 and forskolin markedly delayed neurological deficits and significantly reduced the tumor volume. We suggest that reprogramming technology may be a potential treatment strategy replacing the therapeutic paradigm of traditional treatment of malignant glioma, and a combination molecule comprising a GSK3 inhibitor and a cAMP inducer could be the next generation of anticancer drugs. PMID:29161257

Sonographic features of thyroid nodules that may help distinguish clinically atypical subacute thyroiditis from thyroid malignancy.

PubMed

Pan, Fu-shun; Wang, Wei; Wang, Yan; Xu, Ming; Liang, Jin-yu; Zheng, Yan-ling; Xie, Xiao-yan; Li, Xiao-xi

2015-04-01

The purpose of this study was to evaluate sonographic features for distinguishing clinically atypical subacute thyroiditis from malignant thyroid nodules. A total of 165 hypoechoic thyroid nodules without calcification in 135 patients with histologic diagnosis were included in this study. These nodules were classified into 2 groups: a thyroiditis group (55 nodules in 36 patients) and a malignancy group (110 nodules in 99 patients). The sonographic features of the groups were retrospectively reviewed. No significant differences were detected for the variables of marked echogenicity, a taller-than-wide shape, and mixed vascularity. However, a poorly defined margin was detected more frequently in the thyroiditis group than the malignancy group (P < .05); it yielded a high capability for differential diagnosis of atypical subacute thyroiditis, with sensitivity and specificity of 87.3% and 80.9%, respectively. Centripetal reduction echogenicity was observed exclusively in the thyroiditis group, with high specificity (100%) but low sensitivity (21.8%) for atypical subacute thyroiditis diagnosis. All of the thyroiditis nodules with a positive color signal showed noninternal vascularity (negative predictive value, 100%). There is a considerable overlap between the sonographic features of atypical subacute thyroiditis and thyroid malignancy. However, the margin, echogenicity, and vascularity type are helpful indicators for differential diagnosis of atypical subacute thyroiditis. © 2015 by the American Institute of Ultrasound in Medicine.

Injectable self-gelling composites for bone tissue engineering based on gellan gum hydrogel enriched with different bioglasses.

PubMed

Douglas, Timothy E L; Piwowarczyk, Wojciech; Pamula, Elzbieta; Liskova, Jana; Schaubroeck, David; Leeuwenburgh, Sander C G; Brackman, Gilles; Balcaen, Lieve; Detsch, Rainer; Declercq, Heidi; Cholewa-Kowalska, Katarzyna; Dokupil, Agnieszka; Cuijpers, Vincent M J I; Vanhaecke, Frank; Cornelissen, Ria; Coenye, Tom; Boccaccini, Aldo R; Dubruel, Peter

2014-08-01

Hydrogels of biocompatible calcium-crosslinkable polysaccharide gellan gum (GG) were enriched with bioglass particles to enhance (i) mineralization with calcium phosphate (CaP); (ii) antibacterial properties and (iii) growth of bone-forming cells for future bone regeneration applications. Three bioglasses were compared, namely one calcium-rich and one calcium-poor preparation both produced by a sol-gel technique (hereafter referred to as A2 and S2, respectively) and one preparation of composition close to that of the commonly used 45S5 type (hereafter referred to as NBG). Incubation in SBF for 7 d, 14 d and 21 d caused apatite formation in bioglass-containing but not in bioglass-free samples, as confirmed by FTIR, XRD, SEM, ICP-OES, and measurements of dry mass, i.e. mass attributable to polymer and mineral and not water. Mechanical testing revealed an increase in compressive modulus in samples containing S2 and NBG but not A2. Antibacterial testing using biofilm-forming meticillin-resistant staphylococcus aureus (MRSA) showed markedly higher antibacterial activity of samples containing A2 and S2 than samples containing NBG and bioglass-free samples. Cell biological characterization using rat mesenchymal stem cells (rMSCs) revealed a stimulatory effect of NBG on rMSC differentiation. The addition of bioglass thus promotes GG mineralizability and, depending on bioglass type, antibacterial properties and rMSC differentiation.

Core-binding factor beta interacts with Runx2 and is required for skeletal development.

PubMed

Yoshida, Carolina A; Furuichi, Tatsuya; Fujita, Takashi; Fukuyama, Ryo; Kanatani, Naoko; Kobayashi, Shinji; Satake, Masanobu; Takada, Kenji; Komori, Toshihisa

2002-12-01

Core-binding factor beta (CBFbeta, also called polyomavirus enhancer binding protein 2beta (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans. CBFbeta forms a heterodimer with RUNX1 (runt-related transcription factor 1), which has a DNA binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFbeta are essential for hematopoiesis. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. Mice deficient in Cbfb (Cbfb(-/-)) die at midgestation, so the function of Cbfbeta in skeletal development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb(-/-) mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb(-/-) mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfbeta was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfbeta is required for the function of Runx2 in skeletal development.

Generality of vertebrate developmental patterns: evidence for a dermomyotome in fish

PubMed Central

Devoto, S.H.

2012-01-01

Summary The somitic compartment that gives rise to trunk muscle and dermis in amniotes is an epithelial sheet on the external surface of the somite, and is known as the dermomyotome. However, despite its central role in the development of the trunk and limbs, the evolutionary history of the dermomyotome and its role in non-amniotes is poorly understood. We have tested whether a tissue with the morphological and molecular characteristics of a dermomyotome exists in non-amniotes. We show that representatives of the agnathans and of all major clades of gnathostomes each have a layer of cells on the surface of the somite, external to the embryonic myotome. These external cells do not show any signs of terminal myogenic or dermogenic differentiation. Moreover, in the embryos of bony fishes as diverse as sturgeons (Chondrostei) and zebrafish (Teleostei) this layer of cells expresses the pax 3 and 7 genes that mark myogenic precursors. Some of the pax7-expressing cells also express the differentiation-promoting myogenic regulatory factor Myogenin and appear to enter into the myotome. We therefore suggest that the dermomyotome is an ancient and conserved structure that evolved prior to the last common ancestor of all vertebrates. The identification of a dermomyotome in fish makes it possible to apply the powerful cellular and genetic approaches available in zebrafish to the understanding of this key developmental structure. PMID:16409387

Rich-Poor Income Gap Hits 40-Year High As Poverty Rate Stalls.

ERIC Educational Resources Information Center

Center on Budget and Policy Priorities, Washington, DC.

On September 26, 1990, the Census Bureau released its 1989 figures on poverty and income which showed that no significant progress was made in reducing poverty in 1989, and that gaps between rich and poor and between the wealthy and the middle class hit their widest points in more than 40 years. Although 1989 marked the seventh year of economic…

Markedly severe dystonia in Japanese encephalitis.

PubMed

Kalita, J; Misra, U K

2000-11-01

Encephalitis has been reported to be a rare cause of severe dystonia. We describe five patients with markedly severe dystonia from Japanese encephalitis. These patients with markedly severe dystonia were seen during the past 8 years as a subgroup of 50 patients with Japanese encephalitis. The diagnosis of markedly severe dystonia was based on increasingly frequent episodes of generalized dystonia with bulbar, respiratory, or metabolic derangement or leading to exhaustion or pain. The diagnosis of JE was based on clinicoradiologic features and a fourfold increase of hemagglutination-inhibiting antibody titers in paired serum. The outcome of the patients was defined as a good, partial, or poor recovery on the basis of 1-year clinical status. All the patients were males, and their ages ranged from 6 to 19 years. Movement disorders appeared 1 to 3 weeks after the illness as the level of consciousness started improving. During the next 1 to 4 weeks, patients began to experience markedly severe dystonia. It was associated with marked axial dystonia resulting in opisthotonus and retrocollis in five patients, jaw-opening dystonia in two patients, teeth clenching in one patient, and oculogyric crisis and neck deviation in another patient. The attacks of markedly severe dystonia lasted for 2 to 30 minutes and occurred as many as 20 to 30 times daily. Other developments included fixed limb dystonia in one patient, severe spasticity and rigidity in five patients, and focal muscle wasting in one patient. These patients had only a modest improvement after treatment. Markedly severe dystonia abated by 2 to 6 months in all the patients who were followed up. Cranial magnetic resonance imaging showed bilateral thalamic involvement in all patients, brainstem involvement in three patients, and basal ganglia involvement in two patients. At the 3-month follow-up, all patients had a poor outcome. At 1 year, one patient had a complete recovery; one had a partial recovery; and two were bedridden. It can be concluded that markedly severe dystonia is an important and serious sequela of Japanese encephalitis and may occur as the result of thalamus, midbrain, or basal ganglia involvement in various combinations.

Distinguishing between Poor/Dysfunctional Parenting and Child Emotional Maltreatment

ERIC Educational Resources Information Center

Wolfe, David A.; McIsaac, Caroline

2011-01-01

Objective: This paper was intended to distinguish between poor parenting and child emotional maltreatment (CEM), to inform child welfare and public health policymakers of the need for differentiated responses. Methods: Scientific literature was integrated with current practice and assumptions relating to poor/dysfunctional parenting and child…

Radical operation for hilar cholangiocarcinoma in comparable Eastern and Western centers: Outcome analysis and prognostic factors.

PubMed

Kimura, Norihisa; Young, Alastair L; Toyoki, Yoshikazu; Wyatt, Judith I; Toogood, Giles J; Hidalgo, Ernest; Prasad, K Rajendra; Kudo, Daisuke; Ishido, Keinosuke; Hakamada, Kenichi; Lodge, J Peter A

2017-09-01

Extensive resection for hilar cholangiocarcinoma is the most effective treatment, but high morbidity and poor prognosis remain concerns. Previous data have shown marked differences in outcomes between comparable Eastern and Western centers. We compared the outcomes of the management for hilar cholangiocarcinoma at one Japanese and one British institution with comparable experience. Of 298 consecutive patients with hilar cholangiocarcinoma evaluated at Hirosaki University Hospital, Japan and St. James's University Hospital, Leeds, UK, 183 underwent radical resection. Clinicopathologic variables and postoperative outcomes were compared. Significant differences were not observed between the Hirosaki and Leeds cohorts in overall outcomes despite several differences in the patient characteristics. Although there was a difference in 90-day mortality (2.5% vs 13.6%, respectively), disease-specific 5-year survival rates were 32.8% and 31.9%, respectively (P = .767). Multivariate analysis identified trisectionectomy (odds ratio = 2.32; P = .010), combined pancreatoduodenectomy (odds ratio = 7.88; P = .010), and perioperative blood transfusion (odds ratio = 1.88; P = .045) were associated with postoperative major complications, while preoperative biliary drainage associated with postoperative major complications, while preoperative biliary drainage (risk ratio = 2.21; P = .018), perioperative blood transfusion (risk ratio = 1.58; P = .029), lymph node metastasis (risk ratio = 2.00; P = .002), moderate/poorly differentiated tumor (risk ratio = 1.72; P = .029), microvascular invasion (risk ratio = 1.63; P = .046), and R1 resection (risk ratio = 1.90; P = .005) were risk factors for poor survival. Disease-specific survival and prognostic factors were similar in both centers. Meticulous operative technique to avoid perioperative blood transfusion may improve long-term survival. Copyright © 2017 Elsevier Inc. All rights reserved.

Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel.

PubMed

Galeazzi, Roberta; Olivieri, Fabiola; Spazzafumo, Liana; Rose, Giuseppina; Montesanto, Alberto; Giovagnetti, Simona; Cecchini, Sara; Malatesta, Gelsomina; Di Pillo, Raffaele; Antonicelli, Roberto

2018-06-23

The clinical efficacy of clopidogrel in secondary prevention of vascular events is hampered by marked inter-patient variability in drug response, which partially depends on genetic make-up. The aim of this pilot prospective study was to evaluate 12-month cardiovascular outcomes in elderly patients with acute coronary syndrome (ACS) receiving dual antiplatelet therapy (aspirin and clopidogrel) according to the clustering of CYP2C19 and ABCB1 genetic variants. Participants were 100 consecutive ACS patients who were genotyped for CYP2C19 (G681A and C-806T) and ABCB1 (C3435T) polymorphisms, which affect clopidogrel metabolism and bioavailability, using PCR-restriction fragment length polymorphism. They were then grouped as poor, extensive and ultra-rapid metabolisers based on the combination of CYP2C19 loss-of-function (CYP2C19*2) and gain-of-function (CYP2C19*17) alleles and ABCB1 alleles. The predictive value of each phenotype for acute vascular events was estimated based on 12-month cardiovascular outcomes. The poor metabolisers were at an increased risk of thrombotic events (OR 1.26; 95% CI 1.099-1.45; χ 2  = 5.676; p = 0.027), whereas the ultra-rapid metabolisers had a 1.31-fold increased risk of bleeding events compared with the poor and extensive metabolisers (OR 1.31; 95% CI 1.033-1.67; χ 2  = 5.676; p = 0.048). Logistic regression model, including age, sex, BMI and smoking habit, confirmed the differential risk of major events in low and ultra-rapid metabolisers. Our findings suggest that ACS patients classified as 'poor or ultra-rapid' metabolisers based on CYP2C19 and ABCB1 genotypes should receive alternative antiplatelet therapies to clopidogrel.

In vitro chemoresistance testing in well differentiated carcinoid tumors.

USDA-ARS?s Scientific Manuscript database

Well-differentiated, “typical” carcinoid tumors traditionally have a very poor response to chemotherapy. We hypothesized that tumor specimens from well differentiated carcinoid tumors would be highly resistant to the effects of chemotherapy when tested against a variety of antineoplastic agents in v...

Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia

PubMed Central

Boutzen, Héléna; Saland, Estelle; Larrue, Clément; de Toni, Fabienne; Gales, Lara; Castelli, Florence A.; Cathebas, Mathilde; Zaghdoudi, Sonia; Stuani, Lucille; Kaoma, Tony; Riscal, Romain; Yang, Guangli; Hirsch, Pierre; David, Marion; De Mas-Mansat, Véronique; Delabesse, Eric; Vallar, Laurent; Delhommeau, François; Jouanin, Isabelle; Ouerfelli, Ouathek; Le Cam, Laurent; Linares, Laetitia K.; Junot, Christophe; Portais, Jean-Charles; Vergez, François; Récher, Christian

2016-01-01

Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD–Scid–IL2rγnull mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies. PMID:26951332

[Lymph node and distant metastases of thyroid gland cancer. Metastases in the thyroid glands].

PubMed

Schmid, K W

2015-11-01

The different biological features of the various major entities of thyroid cancer, e.g. papillary, follicular, poorly differentiated, anaplastic and medullary, depend to a large extent on their different metastatic spread. Papillary thyroid cancer (PTC) has a propensity for cervical lymphatic spread that occurs in 20-50 % of patients whereas distant metastasis occurs in < 5 % of cases. Cervical lymphadenopathy may be the first symptom particularly of (micro) PTC. In contrast follicular thyroid cancer (FTC) has a marked propensity for vascular but not lymphatic invasion and 10-20 % of FTC develop distant metastases. At the time of diagnosis approximately one third of medullary thyroid cancer (MTC) cases show lymph node metastases, in 10-15 % distant metastases and 25 % develop metastases during the course of the disease. Poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) spread via both lymphatic and vascular invasion. Thus distant metastases are relatively uncommon in DTC and when they occur, long-term stable disease is the typical clinical course. The major sites of distant metastases are the lungs and bone. Metastases to the brain, breasts, liver, kidneys, muscle and skin are relatively rare or even rare. The thyroid gland itself can be a site of metastases from a variety of other tumors. In autopsy series of patients with disseminated cancer disease, metastases to the thyroid gland were found in up to 10 % of cases. Metastases from other primary tumors to the thyroid gland have been reported in 1.4-3 % of patients who have surgery for suspected cancer of the thyroid gland. The most common primary cancers that metastasize to the thyroid gland are renal cell (48.1 %), colorectal (10.4 %), lung (8.3 %) and breast cancer (7.8 %) and surprisingly often sarcomas (4.0 %).

AgNORs in hyperplasia, papilloma and oral squamous cell carcinoma.

PubMed

Fonseca, L M; do Carmo, M A

2000-01-01

Ten inflammatory fibrous hyperplasias, ten papillomas, and nineteen oral squamous cell carcinomas were analyzed by the AgNOR technique to determine if different disturbances of oral epithelia presented different AgNOR counts. The papilloma group showed higher mean AgNOR counts (3.15 +/- 0.58) than the hyperplasia group (1.98 +/- 0.24) and smaller than the well-differentiated oral squamous cell carcinoma group (6.56 +/- 1.25) and poorly differentiated oral squamous cell carcinoma group (7.07 +/- 1.60). The differences among the groups of lesions were statistically significant (P < 0.05) except between the well differentiated oral squamous cell carcinoma group and the poorly differentiated oral squamous cell carcinoma group. Our findings suggest that the cellular proliferation ratio in papillomas is greater than hyperplasias and smaller than carcinomas.

Poor phonemic discrimination does not underlie poor verbal short-term memory in Down syndrome.

PubMed

Purser, Harry R M; Jarrold, Christopher

2013-05-01

Individuals with Down syndrome tend to have a marked impairment of verbal short-term memory. The chief aim of this study was to investigate whether phonemic discrimination contributes to this deficit. The secondary aim was to investigate whether phonological representations are degraded in verbal short-term memory in people with Down syndrome relative to control participants. To answer these questions, two tasks were used: a discrimination task, in which memory load was as low as possible, and a short-term recognition task that used the same stimulus items. Individuals with Down syndrome were found to perform significantly better than a nonverbal-matched typically developing group on the discrimination task, but they performed significantly more poorly than that group on the recognition task. The Down syndrome group was outperformed by an additional vocabulary-matched control group on the discrimination task but was outperformed to a markedly greater extent on the recognition task. Taken together, the results strongly indicate that phonemic discrimination ability is not central to the verbal short-term memory deficit associated with Down syndrome. Copyright © 2013 Elsevier Inc. All rights reserved.

Midwifery students experience of teamwork projects involving mark-related peer feedback.

PubMed

Hastie, Carolyn R; Fahy, Kathleen M; Parratt, Jenny A; Grace, Sandra

2016-06-01

Lack of teamwork skills among health care professionals endangers patients and enables workplace bullying. Individual teamwork skills are increasingly being assessed in the undergraduate health courses but rarely defined, made explicit or taught. To remedy these deficiencies we introduced a longitudinal educational strategy across all three years of the Bachelor of Midwifery program. To report on students' experiences of engaging in team based assignments which involved mark-related peer feedback. Stories of midwifery students' experiences were collected from 17 participants across the three years of the degree. These were transcribed and analysed thematically and interpreted using feminist collaborative conversations. Most participants reported being in well-functioning teams and enjoyed the experience; they spoke of 'we' and said 'Everyone was on Board'. Students in poorly functioning teams spoke of 'I' and 'they'. These students complained about the poor performance of others but they didn't speak up because they 'didn't want to make waves' and they didn't have the skills to be able to confidently manage conflict. All participants agreed 'Peer-related marks cause mayhem'. Teamwork skills should be specifically taught and assessed. These skills take time to develop. Students, therefore, should be engaged in a teamwork assignment in each semester of the entire program. Peer feedback should be moderated by the teacher and not directly related to marks. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

High contrast laser marking of alumina

NASA Astrophysics Data System (ADS)

Penide, J.; Quintero, F.; Riveiro, A.; Fernández, A.; del Val, J.; Comesaña, R.; Lusquiños, F.; Pou, J.

2015-05-01

Alumina serves as raw material for a broad range of advanced ceramic products. These elements should usually be identified by some characters or symbols printed directly on them. In this sense, laser marking is an efficient, reliable and widely implemented process in industry. However, laser marking of alumina still leads to poor results since the process is not able to produce a dark mark, yielding bad contrast. In this paper, we present an experimental study on the process of marking alumina by three different lasers working in two wavelengths: 1064 nm (Near-infrared) and 532 nm (visible, green radiation). A colorimetric analysis has been carried out in order to compare the resulting marks and its contrast. The most suitable laser operating conditions were also defined and are reported here. Moreover, the physical process of marking by NIR lasers is discussed in detail. Field Emission Scanning Electron Microscopy, High Resolution Transmission Electron Microscopy and X-ray Photoelectron Spectroscopy were also employed to analyze the results. Finally, we propose an explanation for the differences of the coloration induced under different atmospheres and laser parameters. We concluded that the atmosphere is the key parameter, being the inert one the best choice to produce the darkest marks.

Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini*

PubMed Central

Vuorenpää, Anne; Jørgensen, Trine N.; Newman, Amy H.; Madsen, Kenneth L.; Scheinin, Mika

2016-01-01

The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we use the fluorescent cocaine analogue JHC 1-64, as well as several other approaches, to investigate the trafficking itinerary of NET in live noradrenergic neurons. Confocal imaging revealed extensive constitutive internalization of JHC 1-64-labeled NET in the neuronal somata, proximal extensions and presynaptic boutons. Phorbol 12-myristate 13-acetate increased intracellular accumulation of JHC 1-64-labeled NET and caused a parallel reduction in uptake capacity. Internalized NET strongly colocalized with the “long loop” recycling marker Rab11, whereas less overlap was seen with the “short loop” recycling marker Rab4 and the late endosomal marker Rab7. Moreover, mitigating Rab11 function by overexpression of dominant negative Rab11 impaired NET function. Sorting of NET to the Rab11 recycling compartment was further supported by confocal imaging and reversible biotinylation experiments in transfected differentiated CATH.a cells. In contrast to NET, the dopamine transporter displayed markedly less constitutive internalization and limited sorting to the Rab11 recycling compartment in the differentiated CATH.a cells. Exchange of domains between the two homologous transporters revealed that this difference was determined by non-conserved structural elements in the intracellular N terminus. We conclude that NET displays a distinct trafficking itinerary characterized by continuous shuffling between the plasma membrane and the Rab11 recycling compartment and that the functional integrity of the Rab11 compartment is critical for maintaining proper presynaptic NET function. PMID:26786096

Axed MUC4 (MUC4/X) aggravates pancreatic malignant phenotype by activating integrin-β1/FAK/ERK pathway.

PubMed

Jahan, Rahat; Macha, Muzafar A; Rachagani, Satyanarayana; Das, Srustidhar; Smith, Lynette M; Kaur, Sukhwinder; Batra, Surinder K

2018-08-01

Alternative splicing is evolving as an eminent player of oncogenic signaling for tumor development and progression. Mucin 4 (MUC4), a type I membrane-bound mucin, is differentially expressed in pancreatic cancer (PC) and plays a critical role in its progression and metastasis. However, the molecular implications of MUC4 splice variants during disease pathogenesis remain obscure. The present study delineates the pathological and molecular significance of a unique splice variant of MUC4, MUC4/X, which lacks the largest exon 2, along with exon 3. Exon 2 encodes for the highly glycosylated tandem repeat (TR) domain of MUC4 and its absence creates MUC4/X, which is devoid of TR. Expression analysis from PC clinical samples revealed significant upregulation of MUC4/X in PC tissues with most differential expression in poorly differentiated tumors. In vitro studies suggest that overexpression of MUC4/X in wild-type-MUC4 (WT-MUC4) null PC cell lines markedly enhanced PC cell proliferation, invasion, and adhesion to extracellular matrix (ECM) proteins. Furthermore, MUC4/X overexpression leads to an increase in the tumorigenic potential of PC cells in orthotopic transplantation studies. In line with these findings, doxycycline-induced expression of MUC4/X in an endogenous WT-MUC4 expressing PC cell line (Capan-1) also displayed enhanced cell proliferation, invasion, and adhesion to ECM, compared to WT-MUC4 alone, emphasizing its direct involvement in the aggressive behavior of PC cells. Investigation into the molecular mechanism suggested that MUC4/X facilitated PC tumorigenesis via integrin-β1/FAK/ERK signaling pathway. Overall, these findings revealed the novel role of MUC4/X in promoting and sustaining the oncogenic features of PC. Copyright © 2018 Elsevier B.V. All rights reserved.

Modeling Noisy Data with Differential Equations Using Observed and Expected Matrices

ERIC Educational Resources Information Center

Deboeck, Pascal R.; Boker, Steven M.

2010-01-01

Complex intraindividual variability observed in psychology may be well described using differential equations. It is difficult, however, to apply differential equation models in psychological contexts, as time series are frequently short, poorly sampled, and have large proportions of measurement and dynamic error. Furthermore, current methods for…

Epigenetic programming during monocyte to macrophage differentiation and trained innate immunity

PubMed Central

Saeed, Sadia; Quintin, Jessica; Kerstens, Hindrik H.D.; Rao, Nagesha A; Aghajanirefah, Ali; Matarese, Filomena; Cheng, Shih-Chin; Ratter, Jacqueline; Berentsen, Kim; van der Ent, Martijn A.; Sharifi, Nilofar; Janssen-Megens, Eva M.; Huurne, Menno Ter; Mandoli, Amit; van Schaik, Tom; Ng, Aylwin; Burden, Frances; Downes, Kate; Frontini, Mattia; Kumar, Vinod; Giamarellos-Bourboulis, Evangelos J; Ouwehand, Willem H; van der Meer, Jos W.M.; Joosten, Leo A.B.; Wijmenga, Cisca; Martens, Joost H.A.; Xavier, Ramnik J.; Logie, Colin; Netea, Mihai G.; Stunnenberg, Hendrik G.

2014-01-01

Structured Abstract Introduction Monocytes circulate in the bloodstream for up to 3–5 days. Concomitantly, immunological imprinting of either tolerance (immunosuppression) or trained immunity (innate immune memory) determines the functional fate of monocytes and monocyte-derived macrophages, as observed after infection or vaccination. Methods Purified circulating monocytes from healthy volunteers were differentiated under the homeostatic M-CSF concentrations present in human serum. During the first 24 hours, trained immunity was induced by β-glucan (BG) priming, while post-sepsis immunoparalysis was mimicked by exposure to LPS, generating endotoxin-induced tolerance. Epigenomic profiling of the histone marks H3K4me1, H3K4me3 and H3K27ac, DNase I accessibility and RNA sequencing were performed at both the start of the experiment (ex vivo monocytes) and at the end of the six days of in vitro culture (macrophages). Results Compared to monocytes (Mo), naïve macrophages (Mf) display a remodeled metabolic enzyme repertoire and attenuated innate inflammatory pathways; most likely necessary to generate functional tissue macrophages. Epigenetic profiling uncovered ~8000 dynamic regions associated with ~11000 DNase I hypersensitive sites. Changes in histone acetylation identified most dynamic events. Furthermore, these regions of differential histone marks displayed some degree of DNase I accessibility that was already present in monocytes. H3K4me1 mark increased in parallel with de novo H3K27ac deposition at distal regulatory regions; H3K4me1 mark remained even after the loss of H3K27ac, marking decommissioned regulatory elements. β-glucan priming specifically induced ~3000 distal regulatory elements, whereas LPS-tolerization uniquely induced H3K27ac at ~500 distal regulatory regions. At the transcriptional level, we identified co-regulated gene modules during monocyte to macrophage differentiation, as well as discordant modules between trained and tolerized cells. These indicate that training likely involves an increased expression of modules expressed in naïve macrophages, including genes that code for metabolic enzymes. On the other hand, endotoxin tolerance involves gene modules that are more active in monocytes than in naïve macrophages. About 12% of known human transcription factors display variation in expression during macrophage differentiation, training and tolerance. We also observed transcription factor motifs in DNase I hypersensitive sites at condition-specific dynamic epigenomic regions, implying that specific transcription factors are required for trained and tolerized macrophage epigenetic and transcriptional programs. Finally, our analyses and functional validation indicate that the inhibition of cAMP generation blocked trained immunity in vitro and during an in vivo model of lethal C. albicans infection, abolishing the protective effects of trained immunity. Discussion We documented the importance of epigenetic regulation of the immunological pathways underlying monocyte-to-macrophage differentiation and trained immunity. These dynamic epigenetic elements may inform on potential pharmacological targets that modulate innate immunity. Altogether, we uncovered the epigenetic and transcriptional programs of monocyte differentiation to macrophages that distinguish tolerant and trained macrophage phenotypes, providing a resource to further understand and manipulate immune-mediated responses. PMID:25258085

Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy

PubMed Central

Shimomura, Iichiro; Hammer, Robert E.; Richardson, James A.; Ikemoto, Shinji; Bashmakov, Yuriy; Goldstein, Joseph L.; Brown, Michael S.

1998-01-01

Overexpression of the nuclear form of sterol regulatory element-binding protein-1c (nSREBP-1c/ADD1) in cultured 3T3-L1 preadipocytes was shown previously to promote adipocyte differentiation. Here, we produced transgenic mice that overexpress nSREBP-1c in adipose tissue under the control of the adipocyte-specific aP2 enhancer/promoter. A syndrome with the following features was observed: (1) Disordered differentiation of adipose tissue. White fat failed to differentiate fully, and the size of white fat depots was markedly decreased. Brown fat was hypertrophic and contained fat-laden cells resembling immature white fat. Levels of mRNA encoding adipocyte differentiation markers (C/EBPα, PPARγ, adipsin, leptin, UCP1) were reduced, but levels of Pref-1 and TNFα were increased. (2) Marked insulin resistance with 60-fold elevation in plasma insulin. (3) Diabetes mellitus with elevated blood glucose (>300 mg/dl) that failed to decline when insulin was injected. (4) Fatty liver from birth and elevated plasma triglyceride levels later in life. These mice exhibit many of the features of congenital generalized lipodystrophy (CGL), an autosomal recessive disorder in humans. PMID:9784493

DNA Methylation Program in Developing Hippocampus and Its Alteration by Alcohol

PubMed Central

Chen, Yuanyuan; Ozturk, Nail Can; Zhou, Feng C.

2013-01-01

During hippocampal development, the Cornus Ammonis (CA) and the dentate gyrus (DG) undergo waves of neurogenesis and neuronal migration and maturation independently. This stage is widely known to be vulnerable to environmental stresses, but its underlying mechanism is unclear. Alcohol exposure has been shown to alter the expression of genes that regulate the fate, survival, migration and differentiation of pyramidal and granule cells. Undermining this process might compromise hippocampal development underlying the learning and memory deficits known in Fetal Alcohol Spectrum Disorders (FASD). We have previously demonstrated that DNA methylation was programmed along with neural tube development. Here, we demonstrated that DNA methylation program (DMP) proceeded along with hippocampal neuronal differentiation and maturation, and how this DMP was affected by fetal alcohol exposure. C57BL/6 mice were treated with 4% v/v ethanol through a liquid diet along with pair-fed and chow-fed controls from gestation day (E) 7 to E16. We found that a characteristic DMP, including 5-methylcytidine (5mC), 5-hydroxylmethylcytidine (5hmC) and their binding proteins, led the hippocampal neuronal differentiation and maturation spatiotemporally as indicated by their phenotypic marks in the CA and DG pre- and post-natally. Alcohol hindered the acquisition and progression of methylation marks, and altered the chromatin translocation of these marks in the nucleus, which was correlated with developmental retardation. PMID:23544149

[The impact of socioeconomic factors on the gender differences of disability and subjective health among elderly Koreans].

PubMed

Jeon, Gyeong Suk; Jang, Soong Nang; Rhee, Seon Ja

2009-05-01

Research on the gender differences of health among older Korean people has been limited compared with the research for other stages of life. This study first examined the patterns and magnitude of the gender differences of health in later life. Second, we examined the gender differences in the health of older men and women that were attributable to differing socioeconomic conditions. Using the nationally representative 2005 Korean National Health and Nutrition Examination Survey, the gender differences in disability and subjective poor health were assessed by calculating the age adjusted and gender-specific prevalence. Logistic regression analyses were used to assess if the differences between the men and women for health could be explained by differential exposure to socioeconomic factors and/or the differential vulnerability of men and women to these socioeconomic factors. Our results indicated that older women were more likely than the men to report disability and poor subjective health. The health disadvantage of older women was diminished by differential experiences with socioeconomic factors, and especially education. The differences shrink as much as 43.7% in the case of disability and 35.4% in the case of poor subjective health by the differential exposure to educational attainment. Any differential vulnerability to socioeconomic factors was not found between the men and women, which means that socioeconomic factors may have similar effect on health in both genders. Differential socioeconomic experience and exposure between the men and women might cause gender difference in health in old age Koreans.

The Number of Pathologically Positive Lymph Nodes and Pathological Tumor Depth Predicts Prognosis in Patients With Poorly Differentiated Squamous Cell Carcinoma of the Oral Cavity

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

Kang, Chung-Jan; Head and Neck Oncology Group, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Lin, Chien-Yu

2011-11-15

Purpose: The objective of this retrospective study was twofold: (1) to investigate prognostic factors for clinical outcomes in patients with poorly differentiated oral cavity squamous cell carcinoma and (2) to identify specific prognostic subgroups that may help to guide treatment decisions. Methods and Materials: We examined 102 patients with poorly differentiated oral cavity squamous cell carcinoma. All patients were followed for at least 24 months after surgery or until death. The 5-year rates of local control, neck control, distant metastasis, disease-free, disease-specific, and overall survival served as main outcome measures. Results: The 5-year rates were as follows: local control (79%),more » neck control (64%), distant metastases (27%), disease-free survival (48%), disease-specific survival (52%), and overall survival (42%). Multivariable analysis showed that the number of pathologically positive nodes ({>=}4 vs. {<=}3) was a significant predictor of neck control, distant metastasis, and disease-free, disease-specific, and overall survival rates. In addition, the presence of tumor depth of {>=}11 mm (vs. <11 mm) was a significant predictor of distant metastasis, disease-specific survival, and overall survival rates. The combination of the two predictors (26.5%, 27/102) was independently associated with poorer neck control (p = 0.0319), distant metastasis (p < 0.0001), and disease-free (p < 0.0001), disease-specific (p < 0.0001), and overall survival (p < 0.0001) rates. Conclusions: In patients with poorly differentiated oral cavity squamous cell carcinoma, the presence of at least 4 pathologically positive lymph nodes and of a pathological tumor depth {>=}11 mm identifies a subset of subjects with poor clinical outcomes. Patients carrying both risk factors are suitable candidates for the development of novel therapeutic approaches.« less

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

PubMed Central

Zha, Weibin; Edin, Matthew L.; Vendrov, Kimberly C.; Schuck, Robert N.; Lih, Fred B.; Jat, Jawahar Lal; Bradbury, J. Alyce; DeGraff, Laura M.; Hua, Kunjie; Tomer, Kenneth B.; Falck, John R.; Zeldin, Darryl C.; Lee, Craig R.

2014-01-01

Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences. PMID:25114171

Analysis of the ontogeny of the murine humoral response to Neisseria meningitidis B capsular polysaccharide reveals levels of complexity relevant to vaccine development.

PubMed

Colino, J; Outschoorn, I

2001-12-15

Although purified capsular polysaccharide of Neisseria meningitidis group B (CpsB) is not immunogenic at any age, CpsB on the bacterial surface elicits antibody responses late in ontogeny. Therefore, a detailed analysis of the ontogeny of the murine anti-CpsB response to N. meningitidis could determine key parameters regarding the poor immunogenicity of CpsB. The effects of bacterial dose, hyperimmunization, age, and sex on the induction of primary and secondary anti-CpsB immunoglobulin isotype profiles were studied. It was demonstrated that the timing and repetition of immunization and of the bacterial dose have a marked differential effect on the primary induction of anti-CpsB immunoglobulin isotypes and on the ability to induce anti-CpsB antibody responses after subsequent rechallenge. It is noteworthy that the ontogeny of the response is related to the appearance of natural anti-CpsB antibodies, but this is not associated with the presence of CpsB cross-reactive antigens in the microflora.

Age-Related Decline in Primary CD8+ T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8+ T Cells.

PubMed

Quinn, Kylie M; Fox, Annette; Harland, Kim L; Russ, Brendan E; Li, Jasmine; Nguyen, Thi H O; Loh, Liyen; Olshanksy, Moshe; Naeem, Haroon; Tsyganov, Kirill; Wiede, Florian; Webster, Rosela; Blyth, Chantelle; Sng, Xavier Y X; Tiganis, Tony; Powell, David; Doherty, Peter C; Turner, Stephen J; Kedzierska, Katherine; La Gruta, Nicole L

2018-06-19

Age-associated decreases in primary CD8 + T cell responses occur, in part, due to direct effects on naive CD8 + T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated "virtual memory" (T VM ) cells, but their contribution to age-related functional decline is unclear. Here, we show that T VM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (T N cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged T VM cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Hemorrhagic Stroke in an Adolescent Female with HIV-Associated Thrombotic Thrombocytopenic Purpura

PubMed Central

Rakhmanina, Natella; Wong, Edward CC; Davis, Jeremiah C; Ray, Patricio E

2014-01-01

HIV-1 infection can trigger acute episodes of Idiopathic Thrombocytoponic Purpura (ITP), and Thrombotic Thrombocytopenic Purpura (TTP), particularly in populations with advanced disease and poor adherence to antiretroviral therapy (ART). These diseases should be distinguished because they respond to different treatments. Previous studies done in adults with HIV-TTP have recommended the prompt initiation or re-initiation of ART in parallel with plasma exchange therapy to improve the clinical outcome of these patients. Here, we describe a case of HIV-TTP resulting in an acute hemorrhagic stroke in a 16 year old female with perinatally acquired HIV infection and non-adherence to ART, who presented with severe thrombocytopenia, microangiopathic hemolytic anemia, and a past medical history of HIV-ITP. Both differential diagnosis and treatments for HIV-ITP and HIV-TTP were considered simultaneously. A decrease in plasma ADAMTS13 activity (<5%) without detectable inhibitory antibodies confirmed the diagnosis of HIV-TTP. Re-initiation of ART and plasma exchange resulted in a marked decrease in the HIV-RNA viral load, recovery of the platelet count, and complete recovery was achieved with sustained virologic suppression. PMID:25429351

Transcriptional Profiling Reveals a Common Metabolic Program for Tumorigenicity in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells

PubMed Central

Liu, Mengling; Xia, Yingfeng; Ding, Jane; Ye, Bingwei; Zhao, Erhu; Choi, Jeong-Hyeon; Alptekin, Ahmet; Yan, Chunhong; Dong, Zheng; Huang, Shuang; Yang, Liqun; Cui, Hongjuan; Zha, Yunhong; Ding, Han-Fei

2017-01-01

Summary High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of TH-MYCN mice, an animal model of high-risk neuroblastoma with MYCN amplification. Transcriptional profiling reveals that mouse neuroblastoma sphere-forming cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element-binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Genetic and pharmacological inhibition of the metabolic program markedly decreases the growth and tumorigenicity of both mouse neuroblastoma sphere-forming cells and human neuroblastoma cell lines. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma. PMID:27705805

Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells.

PubMed

Liu, Mengling; Xia, Yingfeng; Ding, Jane; Ye, Bingwei; Zhao, Erhu; Choi, Jeong-Hyeon; Alptekin, Ahmet; Yan, Chunhong; Dong, Zheng; Huang, Shuang; Yang, Liqun; Cui, Hongjuan; Zha, Yunhong; Ding, Han-Fei

2016-10-04

High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here, we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of the TH-MYCN mouse, an animal model of high-risk neuroblastoma with MYCN amplification. Transcriptional profiling reveals that mouse neuroblastoma sphere-forming cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Genetic and pharmacological inhibition of the metabolic program markedly decreases the growth and tumorigenicity of both mouse neuroblastoma sphere-forming cells and human neuroblastoma cell lines. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Genetics, evolution and conservation of Bromeliaceae

PubMed Central

Zanella, Camila M.; Janke, Aline; Palma-Silva, Clarisse; Kaltchuk-Santos, Eliane; Pinheiro, Felipe G.; Paggi, Gecele M.; Soares, Luis E.S.; Goetze, Márcia; Büttow, Miriam V.; Bered, Fernanda

2012-01-01

Bromeliaceae is a morphologically distinctive and ecologically diverse family originating in the New World. Three centers of diversity, 58 genera, and about 3,140 bromeliad species are currently recognized. We compiled all of the studies related to the reproductive biology, genetic diversity, and population structure of the Bromeliaceae, and discuss the evolution and conservation of this family. Bromeliads are preferentially pollinated by vertebrates and show marked variation in breeding systems, from predominant inbreeding to predominant outcrossing, as well as constancy in chromosome number (2n = 2x = 50). Autogamous or mixed mating system bromeliads have a high inbreeding coefficient (FIS), while outcrossing species show low FIS. The degree of differentiation among populations (FST)of species ranges from 0.043 to 0.961, which can be influenced by pollen and seed dispersal effects, clonal growth, gene flow rates, and connectivity among populations. The evolutionary history of the Bromeliaceae is poorly known, although some studies have indicated that the family arose in the Guayana Shield roughly 100 Mya. We believe that genetic, cytogenetic, and reproductive data will be essential for diagnosing species status and for assisting conservation programs. PMID:23412953

Spectral analysis of tissues from patients with cancer using a portable spectroscopic diagnostic ratiometer unit

NASA Astrophysics Data System (ADS)

Sordillo, Laura A.; Pu, Yang; Sordillo, Peter P.; Budansky, Yury; Alfano, R. R.

2014-05-01

Spectral profiles of tissues from patients with breast carcinoma, malignant carcinoid and non-small cell lung carcinoma were acquired using native fluorescence spectroscopy. A novel spectroscopic ratiometer device (S3-LED) with selective excitation wavelengths at 280 nm and 335 nm was used to produce the emission spectra of the key biomolecules, tryptophan and NADH, in the tissue samples. In each of the samples, analysis of emission intensity peaks from biomolecules showed increased 340 nm/440 nm and 340 nm/460 nm ratios in the malignant samples compared to their paired normal samples. This most likely represented increased tryptophan to NADH ratios in the malignant tissue samples compared to their paired normal samples. Among the non-small cell lung carcinoma and breast carcinomas, it appeared that tumors of very large size or poor differentiation had an even greater increase in the 340 nm/440 nm and 340 nm/460 nm ratios. In the samples of malignant carcinoid, which is known to be a highly metabolically active tumor, a marked increase in these ratios was also seen.

Preparation, characterization and in vitro evaluation of solid dispersions containing docetaxel.

PubMed

Chen, Jie; Qiu, Liyan; Hu, Minxin; Jin, Yi; Han, Jieru

2008-06-01

Solid dispersions using water-soluble carriers were studied for improving the dissolution of docetaxel, a poorly soluble compound. In order to obtain the most optimized formulation, we prepared many solid dispersions with different carriers, different solvents, or at a series of drug-to-carrier ratios, and compared their dissolution. The accumulative dissolution of docetaxel from poloxamer 188 was more excellent than that from PVP(k30) and glyceryl monostearate, and the dissolution of docetaxel from solid dispersion was markedly higher than that of pure docetaxel; meanwhile the increased dissolution was partly dependent on the ratios of docetaxel and poloxamer 188. The ethanol used to prepare solid dispersion is of more significant effect on the dissolution of docetaxel than that of acetone. The docetaxel/poloxamer 188 system was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and environmental scanning electron microscope (ESEM). The results of DSC, XRD, and ESEM analyses of docetaxel/poloxamer 188 system showed that there are intermolecular interactions between docetaxel and poloxamer, and the crystallinity of docetaxel disappeared. These results show that solid dispersion is a promising approach of developing docetaxel drug formulates.

The single-nucleotide polymorphisms in CHD5 affect the prognosis of patients with hepatocellular carcinoma

PubMed Central

Zhu, Xiao; Kong, Qingming; Xie, Liwei; Chen, Zhihong; Li, Hongmei; Zhu, Zhu; Huang, Yongmei; Lan, Feifei; Luo, Haiqing; Zhan, Jingting; Ding, Hongrong; Lei, Jinli; Xiao, Qin; Fu, Weiming; Fan, Wenguo; Zhang, Jinfang; Luo, Hui

2018-01-01

Previous studies showed that the low expressions of chromodomain-helicase-DNA-binding protein 5 (CHD5) were intensively associated with deteriorative biologic and clinical characteristics as well as outcomes in many tumors. The aim of this study is to determine whether CHD5 single nucleotide polymorphisms (SNPs) contribute to the prognosis of hepatocellular carcima (HCC). The SNPs were selected according to their linkage disequilibrium (LD) in the targeted next-generation sequencing (NGS) and then genotyped with TaqMan probers. We revealed a rare haplotype AG in CHD5 (SNPs: rs12564469-rs9434711) was markedly associated with HCC prognosis. The univariate and multivariate regression analyses revealed the patients with worse overall survival time were those with tumor metastasis and haplotype AG, as well as cirrhosis, poor differentiation and IV-TNM stage. Based on the available public databases, we discovered the significant association between haplotype AG and CHD5 mRNA expressions only existed in Chinese. These data proposed that the potentially genetic haplotype might functionally contribute to HCC prognosis and CHD5 mRNA expressions. PMID:29568352

Quinacrine pretreatment reduces microwave-induced neuronal damage by stabilizing the cell membrane

PubMed Central

Ding, Xue-feng; Wu, Yan; Qu, Wen-rui; Fan, Ming; Zhao, Yong-qi

2018-01-01

Quinacrine, widely used to treat parasitic diseases, binds to cell membranes. We previously found that quinacrine pretreatment reduced microwave radiation damage in rat hippocampal neurons, but the molecular mechanism remains poorly understood. Considering the thermal effects of microwave radiation and the protective effects of quinacrine on heat damage in cells, we hypothesized that quinacrine would prevent microwave radiation damage to cells in a mechanism associated with cell membrane stability. To test this, we used retinoic acid to induce PC12 cells to differentiate into neuron-like cells. We then pretreated the neurons with quinacrine (20 and 40 mM) and irradiated them with 50 mW/cm2 microwaves for 3 or 6 hours. Flow cytometry, atomic force microscopy and western blot assays revealed that irradiated cells pretreated with quinacrine showed markedly less apoptosis, necrosis, and membrane damage, and greater expression of heat shock protein 70, than cells exposed to microwave irradiation alone. These results suggest that quinacrine stabilizes the neuronal membrane structure by upregulating the expression of heat shock protein 70, thus reducing neuronal injury caused by microwave radiation. PMID:29623929

A method for phenomenological analysis of ecological data.

NASA Technical Reports Server (NTRS)

Huang, H.-W.; Morowitz, H. J.

1972-01-01

The experimental meaning of the phenomenological differential equations for a competing population is reviewed. It is concluded that it is virtually impossible to construct the differential equations precise enough for studying stability. We consider instead a method of phenomenological analysis which can be applied to a set of population curves. We suggest an ecological index calculated from the population curves, which indicates a group property of the entire system. As a function of time, the index is presumably insensitive to Volterra type fluctuations. A marked increase of the index's value however indicates a marked change of the environmental conditions. It is not easy to deduce the group property from the population curves alone, because a change in population is in general due to the superposition of external disturbances and Volterra fluctuations.

Social Determinants of Health in the United States: Addressing Major Health Inequality Trends for the Nation, 1935-2016

PubMed Central

Singh, Gopal K.; Daus, Gem P.; Allender, Michelle; Ramey, Christine T.; Martin, Elijah K.; Perry, Chrisp; Reyes, Andrew A. De Los; Vedamuthu, Ivy P.

2017-01-01

Objectives: This study describes key population health concepts and examines major empirical trends in US health and healthcare inequalities from 1935 to 2016 according to important social determinants such as race/ethnicity, education, income, poverty, area deprivation, unemployment, housing, rural-urban residence, and geographic location. Methods: Long-term trend data from the National Vital Statistics System, National Health Interview Survey, National Survey of Children’s Health, American Community Survey, and Behavioral Risk Factor Surveillance System were used to examine racial/ethnic, socioeconomic, rural-urban, and geographic inequalities in health and health care. Life tables, age-adjusted rates, prevalence, and risk ratios were used to examine health differentials, which were tested for statistical significance at the 0.05 level. Results: Life expectancy of Americans increased from 69.7 years in 1950 to 78.8 years in 2015. However, despite the overall improvement, substantial gender and racial/ethnic disparities remained. In 2015, life expectancy was highest for Asian/Pacific Islanders (87.7 years) and lowest for African-Americans (75.7 years). Life expectancy was lower in rural areas and varied from 74.5 years for men in rural areas to 82.4 years for women in large metro areas, with rural-urban disparities increasing during the 1990-2014 time period. Infant mortality rates declined dramatically during the past eight decades. However, racial disparities widened over time; in 2015, black infants had 2.3 times higher mortality than white infants (11.4 vs. 4.9 per 1,000 live births). Infant and child mortality was markedly higher in rural areas and poor communities. Black infants and children in poor, rural communities had nearly three times higher mortality rate compared to those in affluent, rural areas. Racial/ethnic, socioeconomic, and geographic disparities were particularly marked in mortality and/or morbidity from cardiovascular disease, cancer, diabetes, COPD, HIV/AIDS, homicide, psychological distress, hypertension, smoking, obesity, and access to quality health care. Conclusions and Global Health Implications: Despite the overall health improvement, significant social disparities remain in a number of health indicators, most notably in life expectancy and infant mortality. Marked disparities in various health outcomes indicate the underlying significance of social determinants in disease prevention and health promotion and necessitate systematic and continued monitoring of health inequalities according to social factors. A multi-sectoral approach is needed to tackle persistent and widening health inequalities among Americans. PMID:29367890

Unperturbed vs. post-transplantation hematopoiesis: both in vivo but different.

PubMed

Busch, Katrin; Rodewald, Hans-Reimer

2016-07-01

Hematopoietic stem cell (HSC) transplantation has yielded tremendous information on experimental properties of HSCs. Yet, it remains unclear whether transplantation reflects the physiology of hematopoiesis. A limitation is the difficulty in accessing HSC functions without isolation, in-vitro manipulation and readout for potential. New genetic fate mapping and clonal marking techniques now shed light on hematopoiesis under physiological conditions. Transposon-based genetic marks were introduced across the entire hematopoietic system to follow the clonal dynamics of these tags over time. A polyclonal source downstream from stem cells was found responsible for the production of at least granulocytes. In independent experiments, HSCs were genetically marked in adult mice, and the kinetics of label emergence throughout the system was followed over time. These experiments uncovered that during physiological steady-state hematopoiesis large numbers of HSCs yield differentiated progeny. Individual HSCs were active only rarely, indicating their very slow periodicity of differentiation rather than quiescence. Noninvasive genetic experiments in mice have identified a major role of stem and progenitor cells downstream from HSCs as drivers of adult hematopoiesis, and revealed that post-transplantation hematopoiesis differs quantitatively from normal steady-state hematopoiesis.

Ultrafast lasers for precise and corrosion free marking on chirurgical steels

NASA Astrophysics Data System (ADS)

Neugebauer, Christoph; Aalderink, Dennis; Maurer, Erich; Faisst, Birgit; Budnicki, Aleksander

2017-02-01

The unique properties of ultrashort laser pulses and the decrease of invest pave the way to numerous novel applications. Even in the very price sensitive field of laser marking, ultrashort laser can compete due to a new cost structure and remarkable properties of the marking results. In this study we concentrated on industrial marking of medical equipment by using IR ultrashort lasers and compared the results with common marking laser systems. We demonstrate the benefits of ultrashort lasers marking on chirurgical devices, observing the influence of pulse energy, pulse duration, scanning velocity in respect to the visibility, corrosion resistance and long term durability under clinical conditions. Nowadays many parts and products are marked for the purpose of identification and traceability. One kind of laser marking is the well known annealing of stainless steel by nanosecond marking lasers. When annealing occurs a colored oxide layer grows due to the local heating of the material surface. Compared to the raw material, the annealed marking shows increased corrosion sensitivity. Regarding the traceability, the poor durability of the ns marking resulting in contrast reduction and the corrosion susceptibility are a huge problem. Therefore three different laser sources with ns-psfs pulse duration were observed. The focus rests on the realization of parameter studies (various lasers) and their effect on the corrosion and passivation behavior. Furthermore analysis of the oxide layers by use of EDX and XRD were performed to obtain further information on the composition and structure of the markings.

Recognition in context: Implications for trade mark law.

PubMed

Humphreys, Michael S; McFarlane, Kimberley A; Burt, Jennifer S; Kelly, Sarah J; Weatherall, Kimberlee G; Burrell, Robert G

2017-10-01

Context effects in recognition have played a major role in evaluating theories of recognition. Understanding how context impacts recognition is also important for making sound trade mark law. Consumers attempting to discriminate between the brand they are looking for and a look-alike product often have to differentiate products which share a great deal of common context: positioning on the supermarket shelf, the type of store, aspects of the packaging, or brand claims. Trade mark and related laws aim to protect brands and reduce consumer confusion, but courts assessing allegations of trade mark infringement often lack careful empirical evidence concerning the impact of brand and context similarity, and, in the absence of such evidence, make assumptions about how consumers respond to brands that downplay the importance of context and focus on the similarity of registered marks. The experiments reported in this paper aimed to test certain common assumptions in trade mark law, providing evidence that shared context can cause mistakes even where brand similarity is low.

CD5+ true SLL/CLL with plasmacytic differentiation and an unusual 1p36 translocation: case report and review of the literature.

PubMed

Evans, H L; Polski, J M; Deshpande, V; Dunphy, C H

2000-11-01

Lymphoplasmacytic lymphoma (LPL) and small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL)are distinct clinicopathologic entities. Although some cases of SLL/CLL may show plasmacytic differentiation and be associated with monoclonal immunoglobulin in serum, such cases appear to be very rare, and if plasma cell differentiation were marked, differentiation of SLL/CLL from LPL could be difficult. We report a rare case of true CD5-positive small lymphocytic lymphoma/chronic lymphocytic leukemia with unequivocal plasmacytic differentiation. This case also showed an abnormality of chromosome 1p36 not previously described in small lymphocytic lymphoma/chronic lymphocytic leukemia.

Estimating the hatchery fraction of a natural population: a Bayesian approach

USGS Publications Warehouse

Barber, Jarrett J.; Gerow, Kenneth G.; Connolly, Patrick J.; Singh, Sarabdeep

2011-01-01

There is strong and growing interest in estimating the proportion of hatchery fish that are in a natural population (the hatchery fraction). In a sample of fish from the relevant population, some are observed to be marked, indicating their origin as hatchery fish. The observed proportion of marked fish is usually less than the actual hatchery fraction, since the observed proportion is determined by the proportion originally marked, differential survival (usually lower) of marked fish relative to unmarked hatchery fish, and rates of mark retention and detection. Bayesian methods can work well in a setting such as this, in which empirical data are limited but for which there may be considerable expert judgment regarding these values. We explored a Bayesian estimation of the hatchery fraction using Monte Carlo–Markov chain methods. Based on our findings, we created an interactive Excel tool to implement the algorithm, which we have made available for free.

Cyclin-dependent kinase 11p110 (CDK11p110) is crucial for human breast cancer cell proliferation and growth

PubMed Central

Zhou, Yubing; Han, Chao; Li, Duolu; Yu, Zujiang; Li, Fengmei; Li, Feng; An, Qi; Bai, Huili; Zhang, Xiaojian; Duan, Zhenfeng; Kan, Quancheng

2015-01-01

Cyclin-dependent kinases (CDKs) play important roles in the development of many types of cancers by binding with their paired cyclins. However, the function of CDK11 larger protein isomer, CDK11p110, in the tumorigenesis of human breast cancer remains unclear. In the present study, we explored the effects and molecular mechanisms of CDK11p110 in the proliferation and growth of breast cancer cells by determining the expression of CDK11p110 in breast tumor tissues and examining the phenotypic changes of breast cancer cells after CDK11p110 knockdown. We found that CDK11p110 was highly expressed in breast tumor tissues and cell lines. Tissue microarray analysis showed that elevated CDK11p110 expression in breast cancer tissues significantly correlated with poor differentiation, and was also associated with advanced TNM stage and poor clinical prognosis for breast cancer patients. In vitro knockdown of CDK11p110 by siRNA significantly inhibited cell growth and migration, and dramatically induced apoptosis in breast cancer cells. Flow cytometry demonstrated that cells were markedly arrested in G1 phase of the cell cycle after CDK11p110 downregulation. These findings suggest that CDK11p110 is critical for the proliferation and growth of breast cancer cells, which highlights CDK11p110 may be a promising therapeutic target for the treatment of breast cancer. PMID:25990212

Evaluation of contemporary prostate and urothelial lineage biomarkers in a consecutive cohort of poorly differentiated bladder neck carcinomas.

PubMed

Mohanty, Sambit K; Smith, Steven C; Chang, Elena; Luthringer, Daniel J; Gown, Allen M; Aron, Manju; Amin, Mahul B

2014-08-01

New immunohistochemical (IHC) markers of urothelial carcinoma (UCa) and prostatic adenocarcinoma (PCa) have emerged in recent years, yet comparative studies to establish markers remain lacking. We aimed to identify an effective but parsimonious approach for poorly differentiated bladder neck lesions, to establish a best practice panel approach in a setting simulating prospective use. We tested the performance of a panel of IHC markers on whole sections of a consecutive cohort of transurethral resection specimens of poorly differentiated, challenging bladder neck resections (n=36). In the setting of poorly differentiated bladder neck carcinomas, biomarker sensitivities for UCa were as follows: GATA3, 100%; S100P, 88%; p63, 75%; and cytokeratin (CK) 5/6, 56%; specificities of each were 100%. CK7 and CK20 showed sensitivities of 75% and 63%, though these were only 85% and 80% specific. For PCa markers, NKX3.1, p501S, prostate-specific membrane antigen, and androgen receptor (AR) each showed 100% sensitivity, outperforming ERG (35%) and prostate-specific antigen (PSA; 25%). All the prostate histogenesis markers were 100% specific, except for AR, which was positive in 13% of the UCa cases. Novel IHC markers show improved diagnostic performance that enables positive and negative support for identifying histogenesis with the use of as few as two markers for this critical therapeutic distinction. PSA underperforms newer markers. Copyright© by the American Society for Clinical Pathology.

Rural-urban migration and child survival in urban Bangladesh: are the urban migrants and poor disadvantaged?

PubMed

Islam, M Mazharul; Azad, Kazi Md Abul Kalam

2008-01-01

This paper analyses the levels and trends of childhood mortality in urban Bangladesh, and examines whether children's survival chances are poorer among the urban migrants and urban poor. It also examines the determinants of child survival in urban Bangladesh. Data come from the 1999-2000 Bangladesh Demographic and Health Survey. The results indicate that, although the indices of infant and child mortality are consistently better in urban areas, the urban-rural differentials in childhood mortality have diminished in recent years. The study identifies two distinct child morality regimes in urban Bangladesh: one for urban natives and one for rural-urban migrants. Under-five mortality is higher among children born to urban migrants compared with children born to life-long urban natives (102 and 62 per 1000 live births, respectively). The migrant-native mortality differentials more-or-less correspond with the differences in socioeconomic status. Like childhood mortality rates, rural-urban migrants seem to be moderately disadvantaged by economic status compared with their urban native counterparts. Within the urban areas, the child survival status is even worse among the migrant poor than among the average urban poor, especially recent migrants. This poor-non-poor differential in childhood mortality is higher in urban areas than in rural areas. The study findings indicate that rapid growth of the urban population in recent years due to rural-to-urban migration, coupled with higher risk of mortality among migrant's children, may be considered as one of the major explanations for slower decline in under-five mortality in urban Bangladesh, thus diminishing urban-rural differentials in childhood mortality in Bangladesh. The study demonstrates that housing conditions and access to safe drinking water and hygienic toilet facilities are the most critical determinants of child survival in urban areas, even after controlling for migration status. The findings of the study may have important policy implications for urban planning, highlighting the need to target migrant groups and the urban poor within urban areas in the provision of health care services.

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

Adachi, Atsuo; Takahashi, Tomosaburo, E-mail: ttaka@koto.kpu-m.ac.jp; Ogata, Takehiro

Highlights: Black-Right-Pointing-Pointer NFAT5 protein expression is downregulated during cardiomyogenesis. Black-Right-Pointing-Pointer Inhibition of NFAT5 function suppresses canonical Wnt signaling. Black-Right-Pointing-Pointer Inhibition of NFAT5 function attenuates mesodermal induction. Black-Right-Pointing-Pointer NFAT5 function is required for cardiomyogenesis. -- Abstract: While nuclear factor of activated T cells 5 (NFAT5), a transcription factor implicated in osmotic stress response, is suggested to be involved in other processes such as migration and proliferation, its role in cardiomyogenesis is largely unknown. Here, we examined the role of NFAT5 in cardiac differentiation of P19CL6 cells, and observed that it was abundantly expressed in undifferentiated P19CL6 cells, and its protein expressionmore » was significantly downregulated by enhanced proteasomal degradation during DMSO-induced cardiomyogenesis. Expression of a dominant negative mutant of NFAT5 markedly attenuated cardiomyogenesis, which was associated with the inhibition of mesodermal differentiation. TOPflash reporter assay revealed that the transcriptional activity of canonical Wnt signaling was activated prior to mesodermal differentiation, and this activation was markedly attenuated by NFAT5 inhibition. Pharmacological activation of canonical Wnt signaling by [2 Prime Z, 3 Prime E]-6-bromoindirubin-3 Prime -oxime (BIO) restored Brachyury expression in NFAT5DN-expressing cells. Inhibition of NFAT5 markedly attenuated Wnt3 and Wnt3a induction. Expression of Dkk1 and Cerberus1, which are secreted Wnt antagonists, was also inhibited by NFAT5 inhibition. Thus, endogenous NFAT5 regulates the coordinated expression of Wnt ligands and antagonists, which are essential for cardiomyogenesis through the canonical Wnt pathway. These results demonstrated a novel role of NFAT5 in cardiac differentiation of stem cells.« less

Epigenetic Marks Define the Lineage and Differentiation Potential of Two Distinct Neural Crest-Derived Intermediate Odontogenic Progenitor Populations

PubMed Central

Gopinathan, Gokul; Kolokythas, Antonia

2013-01-01

Epigenetic mechanisms, such as histone modifications, play an active role in the differentiation and lineage commitment of mesenchymal stem cells. In the present study, epigenetic states and differentiation profiles of two odontogenic neural crest-derived intermediate progenitor populations were compared: dental pulp (DP) and dental follicle (DF). ChIP on chip assays revealed substantial H3K27me3-mediated repression of odontoblast lineage genes DSPP and dentin matrix protein 1 (DMP1) in DF cells, but not in DP cells. Mineralization inductive conditions caused steep increases of mineralization and patterning gene expression levels in DP cells when compared to DF cells. In contrast, mineralization induction resulted in a highly dynamic histone modification response in DF cells, while there was only a subdued effect in DP cells. Both DF and DP progenitors featured H3K4me3-active marks on the promoters of early mineralization genes RUNX2, MSX2, and DLX5, while OSX, IBSP, and BGLAP promoters were enriched for H3K9me3 or H3K27me3. Compared to DF cells, DP cells expressed higher levels of three pluripotency-associated genes, OCT4, NANOG, and SOX2. Finally, gene ontology comparison of bivalent marks unique for DP and DF cells highlighted cell–cell attachment genes in DP cells and neurogenesis genes in DF cells. In conclusion, the present study indicates that the DF intermediate odontogenic neural crest lineage is distinguished from its DP counterpart by epigenetic repression of DSPP and DMP1 genes and through dynamic histone enrichment responses to mineralization induction. Findings presented here highlight the crucial role of epigenetic regulatory mechanisms in the terminal differentiation of odontogenic neural crest lineages. PMID:23379639

Hepatocytic differentiation of mesenchymal stem cells in cocultures with fetal liver cells.

PubMed

Lange, Claudia; Bruns, Helge; Kluth, Dietrich; Zander, Axel-R; Fiegel, Henning-C

2006-04-21

To investigate the hepatocytic differentiation of mesenchymal stem cells (MSCs) in co-cultures with fetal liver cells (FLC) and the possibility to expand differentiated hepatocytic cells. MSCs were marked with green fluorescent protein (GFP) by retroviral gene transduction. Clonal marked MSCs were either cultured under liver stimulating conditions using fibronectin-coated culture dishes and medium supplemented with stem cell factor (SCF), hepatocyte growth factor (HGF), epidermal growth factor (EGF), and fibroblast growth factor 4 (FGF-4) alone, or in presence of freshly isolated FLC. Cells in co-cultures were harvested, and GFP+ or GFP- cells were separated using fluorescence activated cell sorting. Reverse transcription-polymerase chain reaction (RT-PCR) for the liver specific markers cytokeratin-18 (CK-18), albumin, and alpha-fetoprotein (AFP) was performed in different cell populations. Under the specified culture conditions, rat MSCs co-cultured with FLC expressed albumin, CK-18, and AFP-RNA over two weeks. At wk 3, MSCs lost hepatocytic gene expression, probably due to overgrowth of the cocultured FLC. FLC also showed a stable liver specific gene expression in the co-cultures and a very high growth potential. The rat MSCs from bone marrow can differentiate hepatocytic cells in the presence of FLC in vitro and the presence of MSCs in co-cultures also provides a beneficial environment for expansion and differentiation of FLC.

Increased phospho-AKT is associated with loss of the androgen receptor during the progression of N-methyl-N-nitrosourea-induced prostate carcinogenesis in rats.

PubMed

Liao, Zhiming; Wang, Shihua; Boileau, Thomas W-M; Erdman, John W; Clinton, Steven K

2005-07-01

Characterization of molecular events during N-methyl-N-nitrosourea (MNU)-induced rat prostate carcinogenesis enhances the utility of this model for the preclinical assessment of preventive strategies. Androgen independence is typical of advanced human prostate cancer and may occur through multiple mechanisms including the loss of androgen receptor (AR) expression and the activation of alternative signaling pathways. We examined the interrelationships between AR and p-AKT expression by immunohistochemical staining during MNU-androgen-induced prostate carcinogenesis in male Wistar-Unilever rats. Histone nuclear staining and image analysis was employed to assess parallel changes in chromatin and nuclear structure. The percentage of AR positive nuclei decreased (P < 0.01) as carcinogenesis progressed: hyperplasia (92%), atypical hyperplasia (92%), well-differentiated adenocarcinoma (57%), moderately-differentiated adenocarcinoma (19%), and poorly-differentiated adenocarcinoma (10%). Conversely, p-AKT staining increased significantly during carcinogenesis. Sparse staining was observed in normal tissues (0.2% of epithelial area) and hyperplastic lesions (0.1%), while expression increased significantly (P < 0.001) in atypical hyperplasia (7.6%), well-differentiated adenocarcinoma (16.7%), moderately-differentiated adenocarcinoma (19.6%), and poorly-differentiated adenocarcinoma (17.4%). In parallel, nuclear morphometry revealed increased nuclear size, greater irregularity, and lower DNA compactness as cancers became more poorly differentiated. In the MNU model, the progressive evolution of dominant tumor cell populations showing an increase in p-AKT in parallel with a decline in AR staining suggests that activation of AKT signaling may be one of several mechanisms contributing to androgen insensitivity during prostate cancer progression. Our observations mimic findings suggested by human studies and support the relevance of the MNU model in preclinical studies of preventive strategies. (c) 2005 Wiley-Liss, Inc.

[Observation of curative effect of herpes zoster treated with acupuncture based on syndrome differentiation combined with pricking and cupping].

PubMed

Pan, Hua

2011-10-01

To compare the differences of curative effects of herpes zoster treated with acupuncture based on syndrome differentiation combined with pricking and cupping and simple pricking and cupping. Eighty-six cases were randomly divided into an observation group (43 cases) and a control group (43 cases). In observation group, acupoints selection based on syndrome differentiation i.e. Quchi (LI 11), Zusanli (ST 36), Sanyinjiao (SP 6), etc. were selected and pricking and cupping at affected parts were applied, and the cases were classified into damp heat in liver and gallbladder, damp retention and spleen deficiency, and qi deficiency and blood stasis. In control group, all the cases were simplely treated with pricking and cupping at affected parts. The treatment was given once a day, and seven days were made one session. The curative effect was evaluated after 2 courses, and the follow-up was carried on after 1 month. The cured and markedly effective rate was 93.0% (40/43) in observation group, superior to that of 67.4% (29/43) in control group (P < 0.01). Postherpetic neuralgia: there was 2.3% (1/43) in observation group, inferior to that of 14.0% (6/43) in control group. Comparison in 3 types: the cured and markedly effective rate of damp heat in liver and gallbladder: 94.7% (18/19) in observation group, and 85.7% (18/21) in control group, showing no significant difference between groups (P > 0.05). The cured and markedly effective rate of damp retention and spleen deficiency: 93.8% (15/16) in observation group, superior to that of 60.0% (9/15) in control group (P < 0. 05). The cured and markedly effective rate of qi deficiency and blood stasis: 87.5% (7/8) in observation group, superior to that of 28.6% (2/7) in control group (P < 0.05). For herpes zoster, acupoints selection based on syndrome differentiation combined with pricking and cupping therapy is high pertinent and effective, the postherpetic neuralgia can be reduced significantly and the curative effect is superior to that of simple pricking and cupping.

Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration.

PubMed

Lee, Sang Goo; Huang, Mingqian; Obholzer, Nikolaus D; Sun, Shan; Li, Wenyan; Petrillo, Marco; Dai, Pu; Zhou, Yi; Cotanche, Douglas A; Megason, Sean G; Li, Huawei; Chen, Zheng-Yi

2016-01-01

Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration.

Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration

PubMed Central

Obholzer, Nikolaus D.; Sun, Shan; Li, Wenyan; Petrillo, Marco; Dai, Pu; Zhou, Yi; Cotanche, Douglas A.; Megason, Sean G.; Li, Huawei; Chen, Zheng-Yi

2016-01-01

Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration. PMID:27351484

Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells

PubMed Central

Ali, Dalia; Hamam, Rimi; Alfayez, Musaed; Kassem, Moustapha; Aldahmash, Abdullah

2016-01-01

The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchymal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still not fully understood. Herein, we performed an epigenetic library functional screen and identified several novel compounds, including abexinostat, which promoted adipocytic and osteoblastic differentiation of hMSCs. Using gene expression microarrays, chromatin immunoprecipitation for H3K9Ac combined with high-throughput DNA sequencing (ChIP-seq), and bioinformatics, we identified several key genes involved in regulating stem cell proliferation and differentiation that were targeted by abexinostat. Concordantly, ChIP-quantitative polymerase chain reaction revealed marked increase in H3K9Ac epigenetic mark on the promoter region of AdipoQ, FABP4, PPARγ, KLF15, CEBPA, SP7, and ALPL in abexinostat-treated hMSCs. Pharmacological inhibition of focal adhesion kinase (PF-573228) or insulin-like growth factor-1R/insulin receptor (NVP-AEW51) signaling exhibited significant inhibition of abexinostat-mediated adipocytic differentiation, whereas inhibition of WNT (XAV939) or transforming growth factor-β (SB505124) signaling abrogated abexinostat-mediated osteogenic differentiation of hMSCs. Our findings provide insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways governing adipocyte and osteoblast differentiation. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies and tissue engineering. Significance This unbiased epigenetic library functional screen identified several novel compounds, including abexinostat, that promoted adipocytic and osteoblastic differentiation of human skeletal (mesenchymal or stromal) stem cells (hMSCs). These data provide new insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways controlling adipocyte and osteoblast differentiation of hMSCs. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies for tissue engineering, bone disease, obesity, and metabolic-disorders. PMID:27194745

Silencing PRDM14 expression by an innovative RNAi therapy inhibits stemness, tumorigenicity, and metastasis of breast cancer

PubMed Central

Taniguchi, Hiroaki; Hoshino, Daisuke; Moriya, Chiharu; Zembutsu, Hitoshi; Nishiyama, Nobuhiro; Yamamoto, Hiroyuki; Kataoka, Kazunori; Imai, Kohzoh

2017-01-01

PR domain zinc finger protein 14 (PRDM14) maintains stemness in embryonic stem cells via epigenetic mechanisms. Although PRDM14 is elevated in several cancers, it is unclear if and how PRDM14 confers stem cell-like properties and epigenetic changes to cancer cells. Here, we examined the phenotypic characteristics and epigenetic and gene expression profiles of cancer cells that differentially express PRDM14, and assessed the potential of PRDM14-targeted cancer therapy. PRDM14 expression was markedly increased in many different cancer types and correlated with poor survival of breast cancer patients. PRDM14 conferred stem cell-like phenotypes to cancer cells and regulated the expression of genes involved in cancer stemness, metastasis, and chemoresistance. PRDM14 also reduced the methylation of proto-oncogene and stemness gene promoters and PRDM14-binding regions were primarily occupied by histone H3 Lys-4 trimethylation (H3K4me3), both of which are positively correlated with gene expression. Moreover, strong PRDM14 binding sites coincided with promoters containing both H3K4me3 and H3K27me3 histone marks. Using calcium phosphate hybrid micelles as an RNAi delivery system, silencing of PRDM14 expression by chimera RNAi reduced tumor size and metastasis in vivo without causing adverse effects. Conditional loss of PRDM14 function also improved survival of MMTV-Wnt-1 transgenic mice, a spontaneous model of murine breast cancer. Our findings suggest that PRDM14 inhibition may be an effective and novel therapy for cancer stem cells. PMID:28423353

The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy

PubMed Central

Aronsen, Jan Magnus; Ferrini, Arianna; Brien, Patrick; Alkass, Kanar; Tomasso, Antonio; Agrawal, Asmita; Bergmann, Olaf; Reik, Wolf; Roderick, Hywel Llewelyn

2016-01-01

Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function and is often a precursor to heart failure. In contrast, physiologically induced hypertrophy is adaptive, resulting in improved cardiac function. The processes that selectively induce these hypertrophic states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 and H3K27me3, which are involved in stable cellular differentiation, specifically in cardiomyocytes from physiologically and pathologically hypertrophied rat hearts, and correlated these marks with their associated transcriptomes. This analysis revealed the pervasive loss of euchromatic H3K9me2 as a conserved feature of pathological hypertrophy that was associated with reexpression of fetal genes. In hypertrophy, H3K9me2 was reduced following a miR-217–mediated decrease in expression of the H3K9 dimethyltransferases EHMT1 and EHMT2 (EHMT1/2). miR-217–mediated, genetic, or pharmacological inactivation of EHMT1/2 was sufficient to promote pathological hypertrophy and fetal gene reexpression, while suppression of this pathway protected against pathological hypertrophy both in vitro and in mice. Thus, we have established a conserved mechanism involving a departure of the cardiomyocyte epigenome from its adult cellular identity to a reprogrammed state that is accompanied by reexpression of fetal genes and pathological hypertrophy. These results suggest that targeting miR-217 and EHMT1/2 to prevent H3K9 methylation loss is a viable therapeutic approach for the treatment of heart disease. PMID:27893464

Unpacking Trauma Exposure Risk Factors and Differential Pathways of Influence: Predicting Postwar Mental Distress in Bosnian Adolescents

ERIC Educational Resources Information Center

Layne, Christopher M.; Olsen, Joseph A.; Baker, Aaron; Legerski, John-Paul; Isakson, Brian; Pasalic, Alma; Durakovic-Belko, Elvira; Dapo, Nermin; Campara, Nihada; Arslanagic, Berina; Saltzman, William R.; Pynoos, Robert S.

2010-01-01

Methods are needed for quantifying the potency and differential effects of risk factors to identify at-risk groups for theory building and intervention. Traditional methods for constructing war exposure measures are poorly suited to "unpack" differential relations between specific types of exposure and specific outcomes. This study of…

Development of measures to improve field performance of retroreflective raised pavement markers.

DOT National Transportation Integrated Search

2009-02-01

Retroreflective raised pavement markers (RRPMs) are routinely used in Texas to supplement highway : pavement markings. In recent years, problems of marker failure such as poor retention on pavements, : physical damage, and loss of retroreflectivity a...

Asthma and Respiratory Allergic Disease

EPA Science Inventory

The pathogenesis of non-communicable diseases such as allergy is complex and poorly understood. The causes of chronic allergic diseases including asthma involve to a large extent, immunomodulation of the adaptive and particularly the innate immune systems and are markedly influen...

Evaluation and differential diagnosis of marked, persistent eosinophilia

PubMed Central

Mejia, Rojelio; Nutman, Thomas B.

2012-01-01

High grade eosinophilia in patients can be a diagnostic dilemma, as the etiologies are extensive and varied. Hypereosinophilic syndromes (HES) are a group of heterogeneous disorders, many of which remain ill-defined. By definition, HES must be distinguished from other disorders with persistently elevated eosinophilia with a defined cause. Although marked eosinophilia worldwide is most commonly caused by helminth (worm) infections, non-infectious causes must be sought including drug reactions, malignancies, and immunologic, inflammatory and allergic diseases. PMID:22449625

Color Preference Shifts in Preschool Children by Differential Sensory Conditioning

ERIC Educational Resources Information Center

Brick, Robert H.; Walls, Richard T.

1973-01-01

Ratings over five repeated measures and a two week follow-up indicated that color preferences shifted markedly, yielding the expected interaction. The racial implications of these findings are discussed. (Authors)

Epigenetics of the antibody response

PubMed Central

Li, Guideng; Zan, Hong; Xu, Zhenming; Casali, Paolo

2013-01-01

Epigenetic marks, such as DNA methylation, histone posttranslational modifications and microRNAs, are induced in B cells by the same stimuli that drive the antibody response. They play major roles in regulating somatic hypermutation (SHM), class switch DNA recombination (CSR) and differentiation to plasma cells or long-lived memory B cells. Histone modifications target the CSR and, possibly, SHM machinery to the immunoglobulin locus; they together with DNA methylation and microRNAs modulate the expression of critical elements of that machinery, such as AID, as well as factors central to plasma cell differentiation, such as Blimp-1. These inducible B cell-intrinsic epigenetic marks instruct the maturation of antibody responses. Their dysregulation plays an important role in aberrant antibody responses to foreign antigens, such as those of microbial pathogens, and self-antigens, such those targeted in autoimmunity, and B cell neoplasias. PMID:23643790

Species-Specific 5 mC and 5 hmC Genomic Landscapes Indicate Epigenetic Contribution to Human Brain Evolution

PubMed Central

Madrid, Andy; Chopra, Pankaj; Alisch, Reid S.

2018-01-01

Human evolution from non-human primates has seen substantial change in the central nervous system, with the molecular mechanisms underlying human brain evolution remaining largely unknown. Methylation of cytosine at the fifth carbon (5-methylcytosine; 5 mC) is an essential epigenetic mark linked to neurodevelopment, as well as neurological disease. The emergence of another modified form of cytosine (5-hydroxymethylcytosine; 5 hmC) that is enriched in the brain further substantiates a role for these epigenetic marks in neurodevelopment, yet little is known about the evolutionary importance of these marks in brain development. Here, human and monkey brain tissue were profiled, identifying 5,516 and 4,070 loci that were differentially methylated and hydroxymethylated, respectively, between the species. Annotation of these loci to the human genome revealed genes critical for the development of the nervous system and that are associated with intelligence and higher cognitive functioning, such as RELN and GNAS. Moreover, ontological analyses of these differentially methylated and hydroxymethylated genes revealed a significant enrichment of neuronal/immunological–related processes, including neurogenesis and axon development. Finally, the sequences flanking the differentially methylated/hydroxymethylated loci contained a significant enrichment of binding sites for neurodevelopmentally important transcription factors (e.g., OTX1 and PITX1), suggesting that DNA methylation may regulate gene expression by mediating transcription factor binding on these transcripts. Together, these data support dynamic species-specific epigenetic contributions in the evolution and development of the human brain from non-human primates. PMID:29491831

Differentiation of indirect self-destructiveness due to sex (gender) in individuals after suicide attempts.

PubMed

Tsirigotis, Konstantinos-; Gruszczyński, Wojciech; Tsirigotis-Maniecka, Marta Afrodyta

2015-01-01

The aim of this study was to examine the sex (gender) differentiation of indirect self-destructiveness as a generalised behavioural tendency and its manifestations in individuals who attempted suicides. 147 individuals (114 females and 33 males) after suicide attempts were studied; the reference group consisted of 558 individuals (399 females and 159 males). Indirect self-destructiveness was examined by means of the Polish version of the Chronic Self-Destructiveness Scale (CS-DS) including Transgression and Risk (A1), Poor Health Maintenance (A2), Personal and Social Neglects (A3), Lack of Planfulness (A4) and Helplessness, Passiveness in the Face of Problems/Difficulties (A5). Sex (gender) and suicide attempt significantly differentiate scores of the subjects on all indices/scales of indirect self-destructiveness. Scores of individuals after suicide attempts are considerably higher on almost all scales. In that group, significant differences between females and males occurred on the A2-Poor Health Maintenance, A3-Personal and Social Neglects, A4-Lack of Planfulness and A5-Helplessness scales. It was only on the A2-Poor Health Maintenance scale that females achieved higher scores. The intensity of indirect self-destructiveness in females who attempted suicides achieved the level observed in males who attempted suicides. Poor health maintenance was also more intense in them than in the group of males. Males after suicide attempts displayed the lowest poor health maintenance. Results of this study may have preventive and therapeutic implications.

Remodelling of three-dimensional organization of the nucleus during terminal keratinocyte differentiation in the epidermis

PubMed Central

Gdula, Michal R.; Poterlowicz, Krzysztof; Mardaryev, Andrei N.; Sharov, Andrey A.; Peng, Y.; Fessing, Michael Y.; Botchkarev, Vladimir A.

2014-01-01

The nucleus of epidermal keratinocytes is a complex and highly compartmentalized organelle, whose structure is markedly changed during terminal differentiation and transition of the genome from a transcriptionally active state seen in the basal and spinous epidermal cells to a fully inactive state in the keratinized cells of the cornified layer. Here, using multi-color confocal microscopy, followed by computational image analysis and mathematical modelling, we demonstrate that in normal mouse foot-pad epidermis transition of keratinocytes from basal epidermal layer to the granular layer is accompanied by marked differences in nuclear architecture and micro-environment including: i) decrease of the nuclear volume, ii) decrease in expression of the markers of transcriptionally-active chromatin; iii) internalization and decrease in the number of nucleoli; iv) increase in the number of pericentromeric heterochromatic clusters; v) increase in the frequency of associations between pericentromeric clusters, chromosomal territory 3, and nucleoli. These data suggest a role for nucleoli and pericentromeric heterochromatin clusters as organizers of nuclear micro-environment required for proper execution of gene expression programs in differentiating keratinocytes and provide important background information for further analyses of alterations in the topological genome organization seen in pathological skin conditions including disorders of epidermal differentiation and epidermal tumors. PMID:23407401

SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation.

PubMed

Kidder, Benjamin L; Hu, Gangqing; Cui, Kairong; Zhao, Keji

2017-01-01

Epigenetic regulation of chromatin states is thought to control the self-renewal and differentiation of embryonic stem (ES) cells. However, the roles of repressive histone modifications such as trimethylated histone 4 lysine 20 (H4K20me3) in pluripotency and development are largely unknown. Here, we show that the histone lysine methyltransferase SMYD5 mediates H4K20me3 at heterochromatin regions. Depletion of SMYD5 leads to compromised self-renewal, including dysregulated expression of OCT4 targets, and perturbed differentiation. SMYD5-bound regions are enriched with repetitive DNA elements. Knockdown of SMYD5 results in a global decrease of H4K20me3 levels, a redistribution of heterochromatin constituents including H3K9me3/2, G9a, and HP1α, and de-repression of endogenous retroelements. A loss of SMYD5-dependent silencing of heterochromatin nearby genic regions leads to upregulated expression of lineage-specific genes, thus contributing to the decreased self-renewal and perturbed differentiation of SMYD5-depleted ES cells. Altogether, these findings implicate a role for SMYD5 in regulating ES cell self-renewal and H4K20me3-marked heterochromatin.

CD147 promotes the formation of functional osteoclasts through NFATc1 signalling

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

Nishioku, Tsuyoshi, E-mail: nishiokut@niu.ac.jp; Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180; Terasawa, Mariko

CD147, a membrane glycoprotein of the immunoglobulin superfamily, is highly upregulated during dynamic cellular events including tissue remodelling. Elevated CD147 expression is present in the joint of rheumatoid arthritis patients. However, the role of CD147 in bone destruction remains unclear. To determine whether CD147 is involved in osteoclastogenesis, we studied its expression in mouse osteoclasts and its role in osteoclast differentiation and function. CD147 expression was markedly upregulated during osteoclast differentiation. To investigate the role of CD147 in receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption activity, osteoclast precursor cells were transfected with CD147 siRNA. Decreasedmore » CD147 expression inhibited osteoclast formation and bone resorption, inhibited RANKL-induced nuclear translocation of the nuclear factor of activated T cells (NFAT) c1 and decreased the expression of the d2 isoform of vacuolar ATPase Vo domain and cathepsin K. Therefore, CD147 plays a critical role in the differentiation and function of osteoclasts by upregulating NFATc1 through the autoamplification of its expression in osteoclastogenesis. - Highlights: • CD147 expression was markedly upregulated during osteoclast differentiation. • Downregulation of CD147 expression inhibited osteoclastgenesis and bone resorption. • Decreased CD147 expression inhibited RANKL-induced nuclear translocation of NFATc1.« less

Genetic Profile of Adenoid Cystic Carcinomas (ACC) with High-Grade Transformation versus Solid Type

PubMed Central

Costa, Ana Flávia; Altemani, Albina; Vékony, Hedy; Bloemena, Elisabeth; Fresno, Florentino; Suárez, Carlos; Llorente, José Luis; Hermsen, Mario

2010-01-01

Background: ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features and to compare results to solid ACC. Methods: Genome-wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, 4 with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), 5 solid ACC. In addition, Ki-67 index and p53 immunopositivity was assessed. Results: ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component. Conclusion: ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC. PMID:20978318

Genetic profile of adenoid cystic carcinomas (ACC) with high-grade transformation versus solid type.

PubMed

Costa, Ana Flávia; Altemani, Albina; Vékony, Hedy; Bloemena, Elisabeth; Fresno, Florentino; Suárez, Carlos; Llorente, José Luis; Hermsen, Mario

2010-01-01

ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features and to compare results to solid ACC. genome-wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, 4 with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), 5 solid ACC. In addition, Ki-67 index and p53 immunopositivity was assessed. ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component. ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC.

Genetic profile of adenoid cystic carcinomas (ACC) with high-grade transformation versus solid type.

PubMed

Costa, Ana Flávia; Altemani, Albina; Vékony, Hedy; Bloemena, Elisabeth; Fresno, Florentino; Suárez, Carlos; Llorente, José Luis; Hermsen, Mario

2011-08-01

ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features, and to compare results to solid ACC. Genome wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, four with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), and five solid ACC. In addition, Ki67 index and p53 immunopositivity was assessed. ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component. ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC.

Involvements of Estrogen Receptor, Proliferating Cell Nuclear Antigen and p53 in Endometrial Adenocarcinoma Development in Donryu Rats

PubMed Central

Yoshida, Midori; Katsuda, Shin-ichi; Maekawa, Akihiko

2012-01-01

Involvements of estrogen receptor (ER)α, proliferating cell nuclear antigen (PCNA) and p53 in the uterine carcinogenesis process in Donryu rats, a high yield strain of the uterine cancer were investigated immunohistochemically. ERα was expressed in atypical endometrial hyperplasia, accepted as a precancerous lesion of the uterine tumors, as well as well- and in moderately-differentiated endometrial adenocarcinomas, and the intensities of expression were similar to those in the luminal epithelial cells of the atrophic uterus at 15 months of age. The expression, however, was negative in the tumor cells of poorly differentiated type. Good growth of implanted grafts of the poorly-differentiated adenocarcinomas in both sexes with or without gonadectomy supported the estrogen independency of tumor progression to malignancy. PCNA labeling indices were increased with tumor development from atypical hyperplasia to adenocarcinoma. The tumor cells in poorly-differentiated adenocarcinomas were positive for p53 positive but negative for p21 expression, suggesting accumulation of mutated p53. These results indicate that the consistent ERα expression is involved in initiation and promotion steps of uterine carcinogenesis, but not progression. In addition, PCNA is related to tumor development and the expression of mutated p53 might be a late event during endometrial carcinogenesis. PMID:23345926

The marked tree site : evaluation of basal reinforcement of flexible pavements with geosynthetics.

DOT National Transportation Integrated Search

2011-12-01

This document presents findings from a three-year, full-scale, field research project : aimed at determining the benefits of using geosynthetic reinforcements to improve the : performance of flexible pavements constructed over poor subgrade soils. Th...

Experimental Constraints on the Chemical Differentiation of Mercurys Mantle

NASA Technical Reports Server (NTRS)

Boujibar, A.; Righter, K.; Pando, K.; Danielson, L.

2015-01-01

Mercury is known as being the most reduced terrestrial planet with the highest core/mantle ratio. Results from MESSENGER spacecraft have shown that its surface is FeO-poor (2-4 wt%) and S-rich (up to 6-7 wt%), which confirms the reducing nature of its silicate mantle. In addition several features suggest important melting stages of the Mercurian mantle: widespread volcanic deposits on its surface, a high crustal thickness (approximately 10% of the planet's volume) and chemical compositions of its surface suggesting several stages of differentiation and remelting processes. Therefore it is likely that igneous processes like magma ocean crystallization and continuous melting have induced chemical and mineralogical heterogeneities in the Mercurian mantle. The extent and nature of compositional variations produced by partial melting remains poorly constrained for the particular compositions of Mercury (very reducing conditions, low FeO-contents and high sulfur-contents). Melting experiments with bulk Mercury-analogue compositions are scarce and with poorly con-trolled starting compositions. Therefore additional experimental data are needed to better understand the differentiation processes that lead to the observed chemical compositions of Mercury's surface.

The Differential Vector Phase-Locked Loop for Global Navigation Satellite System Signal Tracking

DTIC Science & Technology

2014-06-01

DAF Approved: //signed// John F. Raquet, PhD (Chairman) //signed// Mark E. Oxley, PhD (Member) //signed// Maj Marshall E. Haker , PhD (Member) 16 May...busy as you keep yourself. Dr. Mark Oxley and Dr. Marshall Haker for your sage guidance as members of my committee. Dr. Ken Fisher for making Kalman...Raquet, Dr. Marshall Haker , and Mr. Ben Downing at AFIT, following notes for Dr. Raquet’s Advanced GPS Receiver Design class. The second type was RINEX

Evaluation of desmin as a diagnostic and prognostic marker of childhood rhabdomyosarcomas and embryonal sarcomas.

PubMed Central

Dias, P.; Kumar, P.; Marsden, H. B.; Morris-Jones, P. H.; Birch, J.; Swindell, R.; Kumar, S.

1987-01-01

The diagnostic and prognostic relevance of desmin expression in 80 rhabdomyosarcomas (RMS) and 5 embryonal sarcomas (ES) was examined using a peroxidase anti-peroxidase staining procedure. Fifty-nine RMS but only one ES stained for desmin (P less than 0.05). The maximum percentage of desmin containing cells was 49 in RMS compared with only 1% in ES. Desmin positivity correlated inversely with survival (P less than 0.02) in that RMS with high proportions of desmin positive cells were associated with poorer prognoses than those containing fewer desmin positive cells. If the degree of expression of desmin is related to myogenic differentiation, then our results indicate that poorly differentiated RMS tend to have a better prognosis than the well differentiated tumours. One possible explanation is that the poorly differentiated RMS respond better to chemotherapy than to well differentiated RMS. A multivariant analysis incorporating desmin staining, treatment, histology, age and gender revealed that the two most significant independent prognostic factors were treatment and histology. Images Figure 1 PMID:3311112

Unperturbed vs. post-transplantation hematopoiesis: both in vivo but different

PubMed Central

Busch, Katrin; Rodewald, Hans-Reimer

2016-01-01

Purpose of review Hematopoietic stem cell (HSC) transplantation has yielded tremendous information on experimental properties of HSCs. Yet, it remains unclear whether transplantation reflects the physiology of hematopoiesis. A limitation is the difficulty in accessing HSC functions without isolation, in-vitro manipulation and readout for potential. New genetic fate mapping and clonal marking techniques now shed light on hematopoiesis under physiological conditions. Recent findings Transposon-based genetic marks were introduced across the entire hematopoietic system to follow the clonal dynamics of these tags over time. A polyclonal source downstream from stem cells was found responsible for the production of at least granulocytes. In independent experiments, HSCs were genetically marked in adult mice, and the kinetics of label emergence throughout the system was followed over time. These experiments uncovered that during physiological steady-state hematopoiesis large numbers of HSCs yield differentiated progeny. Individual HSCs were active only rarely, indicating their very slow periodicity of differentiation rather than quiescence. Summary Noninvasive genetic experiments in mice have identified a major role of stem and progenitor cells downstream from HSCs as drivers of adult hematopoiesis, and revealed that post-transplantation hematopoiesis differs quantitatively from normal steady-state hematopoiesis. PMID:27213498

Hardiness commitment, gender, and age differentiate university academic performance.

PubMed

Sheard, Michael

2009-03-01

The increasing diversity of students, particularly in age, attending university has seen a concomitant interest in factors predicting academic success. This 2-year correlational study examined whether age, gender (demographic variables), and hardiness (cognitive/emotional variable) differentiate and predict university final degree grade point average (GPA) and final-year dissertation mark. Data are reported from a total of 134 university undergraduate students. Participants provided baseline data in questionnaires administered during the first week of their second year of undergraduate study and gave consent for their academic progress to be tracked. Final degree GPA and dissertation mark were the academic performance criteria. Mature-age students achieved higher final degree GPA compared to young undergraduates. Female students significantly outperformed their male counterparts in each measured academic assessment criteria. Female students also reported a significantly higher mean score on hardiness commitment compared to male students. commitment was the most significant positive correlate of academic achievement. Final degree GPA and dissertation mark were significantly predicted by commitment, and commitment and gender, respectively. The findings have implications for universities targeting academic support services to maximize student scholastic potential. Future research should incorporate hardiness, gender, and age with other variables known to predict academic success.

The Advertising Strategies of Early E-cigarette Brand Leaders in the United States.

PubMed

Haardörfer, Regine; Cahn, Zachary; Lewis, Michael; Kothari, Shreya; Sarmah, Raina; Getachew, Betelihem; Berg, Carla J

2017-04-01

We examined differential advertising strategies used by 4 major United States e-cigarette companies with differential affiliations with the traditional tobacco industry (ie, Njoy - independent, Blu - acquired, Vuse and MarkTen - launched by cigarette companies) over time. We conducted a mixed-methods study regarding e-cigarette adspend, adspend per media channel (eg, TV, print), and advertising messaging strategies among these 4 top e-cigarette brands from January 2013 through December 2015. E-cigarette adspend increased from $59 million in 2013 to $91 million in 2014, followed by a sharp decline to $37 million in 2015. These companies showed distinct spending trajectories overall and across media channels, with Njoy and Vuse spending a higher proportion of their dollars on TV and Blu and MarkTen spending more on print. Marketing messages were also different by company. Key themes included switching from cigarettes (particularly by Njoy and Blu), circumventing smoke-free policies (particularly by Blu), and technological advancement (particularly by Vuse and MarkTen). These e-cigarette brands have shifted their adspend, use of media channels, and advertising messaging strategies over time. Some differing strategies may reflect the different affiliations of each brand to the traditional cigarette industry.

Comparison of reading and listening-reading techniques for administration of PIAT Reading Comprehension subtest: justification for the bypass approach.

PubMed

Weinberg, W A; McLean, A; Brumback, R A

1988-04-01

The Peabody Individual Achievement Test (PIAT) Reading Comprehension subtest was administered to a group of 23 learning disabled children in Grades 5 through 7 who had been classified by the clinical Lexical Paradigm as good readers or poor readers. Using standardized test administration, 14 poor readers scored substantially below the 9 good readers; however, when the child was allowed to listen and read silently while the test item was read aloud, poor readers showed marked improvement in performance compared to only moderate improvement shown by the good readers. This difference in improvement between the groups was significant and resulted in poor readers achieving performance similar to that of the good readers administered the test in the standard manner.

Live cell imaging reveals marked variability in myoblast proliferation and fate

PubMed Central

2013-01-01

Background During the process of muscle regeneration, activated stem cells termed satellite cells proliferate, and then differentiate to form new myofibers that restore the injured area. Yet not all satellite cells contribute to muscle repair. Some continue to proliferate, others die, and others become quiescent and are available for regeneration following subsequent injury. The mechanisms that regulate the adoption of different cell fates in a muscle cell precursor population remain unclear. Methods We have used live cell imaging and lineage tracing to study cell fate in the C2 myoblast line. Results Analyzing the behavior of individual myoblasts revealed marked variability in both cell cycle duration and viability, but similarities between cells derived from the same parental lineage. As a consequence, lineage sizes and outcomes differed dramatically, and individual lineages made uneven contributions toward the terminally differentiated population. Thus, the cohort of myoblasts undergoing differentiation at the end of an experiment differed dramatically from the lineages present at the beginning. Treatment with IGF-I increased myoblast number by maintaining viability and by stimulating a fraction of cells to complete one additional cell cycle in differentiation medium, and as a consequence reduced the variability of the terminal population compared with controls. Conclusion Our results reveal that heterogeneity of responses to external cues is an intrinsic property of cultured myoblasts that may be explained in part by parental lineage, and demonstrate the power of live cell imaging for understanding how muscle differentiation is regulated. PMID:23638706

Expression of E-cadherin and β-catenin in basaloid and conventional squamous cell carcinoma of the oral cavity: are potential prognostic markers?

PubMed Central

2014-01-01

Background Basaloid squamous cell carcinoma presents with a preference for the head and neck region, and shows a distinct aggressive behavior, with frequent local recurrences, regional and distant metastasis. The alterations in the cadherin-catenin complex are fundamental requirements for the metastasis process, and this is the first study to evaluate the immunostaining of E-cadherin and β-catenin in oral basaloid squamous cell carcinoma. Methods Seventeen cases of this tumor located exclusively in the mouth were compared to 26 cases of poorly differentiated squamous cell carcinoma and 28 cases of well to moderately differentiated squamous cell carcinoma matched by stage and tumor site. The immunostaining of E-cadherin and β-catenin were evaluated in the three groups and compared to their clinicopathological features and prognosis. Results For groups poorly differentiated squamous cell carcinoma and basaloid squamous cell carcinoma, reduction or absence of E-cadherin staining was observed in more than 80.0% of carcinomas, and it was statistically significant compared to well to moderately differentiated squamous cell carcinoma (p = .019). A strong expression of β-catenin was observed in 26.9% and 20.8% of well to moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma, respectively, and in 41.2% of basaloid squamous cell carcinoma. The 5-year and 10-year overall and disease-free survival rates demonstrated no significant differences among all three groups. Conclusions The clinical and biological behavior of three groups of the oral cavity tumors evaluated are similar. E-cadherin and β-catenin immunostaining showed no prognostic value for basaloid and conventional squamous cell carcinomas. PMID:24893577

Expression of E-cadherin and β-catenin in basaloid and conventional squamous cell carcinoma of the oral cavity: are potential prognostic markers?

PubMed

Hanemann, João Adolfo Costa; Oliveira, Denise Tostes; Nonogaki, Suely; Nishimoto, Inês Nobuko; de Carli, Marina Lara; Landman, Gilles; Kowalski, Luiz Paulo

2014-06-03

Basaloid squamous cell carcinoma presents with a preference for the head and neck region, and shows a distinct aggressive behavior, with frequent local recurrences, regional and distant metastasis. The alterations in the cadherin-catenin complex are fundamental requirements for the metastasis process, and this is the first study to evaluate the immunostaining of E-cadherin and β-catenin in oral basaloid squamous cell carcinoma. Seventeen cases of this tumor located exclusively in the mouth were compared to 26 cases of poorly differentiated squamous cell carcinoma and 28 cases of well to moderately differentiated squamous cell carcinoma matched by stage and tumor site. The immunostaining of E-cadherin and β-catenin were evaluated in the three groups and compared to their clinicopathological features and prognosis. For groups poorly differentiated squamous cell carcinoma and basaloid squamous cell carcinoma, reduction or absence of E-cadherin staining was observed in more than 80.0% of carcinomas, and it was statistically significant compared to well to moderately differentiated squamous cell carcinoma (p = .019). A strong expression of β-catenin was observed in 26.9% and 20.8% of well to moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma, respectively, and in 41.2% of basaloid squamous cell carcinoma. The 5-year and 10-year overall and disease-free survival rates demonstrated no significant differences among all three groups. The clinical and biological behavior of three groups of the oral cavity tumors evaluated are similar. E-cadherin and β-catenin immunostaining showed no prognostic value for basaloid and conventional squamous cell carcinomas.

Oncologic Phenotype of Peripheral Neuroblastic Tumors Associated With PHOX2B Non-Polyalanine Repeat Expansion Mutations.

PubMed

Heide, Solveig; Masliah-Planchon, Julien; Isidor, Bertrand; Guimier, Anne; Bodet, Damien; Coze, Carole; Deville, Anne; Thebault, Estelle; Pasquier, Corinne Jeanne; Cassagnau, Elisabeth; Pierron, Gaelle; Clément, Nathalie; Schleiermacher, Gudrun; Amiel, Jeanne; Delattre, Olivier; Peuchmaur, Michel; Bourdeaut, Franck

2016-01-01

Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail. We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM. Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array-comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow-up of 5 years. Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling. © 2015 Wiley Periodicals, Inc.

Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors.

PubMed

Yachida, Shinichi; Vakiani, Efsevia; White, Catherine M; Zhong, Yi; Saunders, Tyler; Morgan, Richard; de Wilde, Roeland F; Maitra, Anirban; Hicks, Jessica; Demarzo, Angelo M; Shi, Chanjuan; Sharma, Rajni; Laheru, Daniel; Edil, Barish H; Wolfgang, Christopher L; Schulick, Richard D; Hruban, Ralph H; Tang, Laura H; Klimstra, David S; Iacobuzio-Donahue, Christine A

2012-02-01

Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.

BMP8B Is a Tumor Suppressor Gene Regulated by Histone Acetylation in Gastric Cancer.

PubMed

Wisnieski, Fernanda; Leal, Mariana Ferreira; Calcagno, Danielle Queiroz; Santos, Leonardo Caires; Gigek, Carolina Oliveira; Chen, Elizabeth Suchi; Artigiani, Ricardo; Demachki, Sâmia; Assumpção, Paulo Pimentel; Lourenço, Laércio Gomes; Burbano, Rommel Rodríguez; Smith, Marília Cardoso

2017-04-01

Different from genetic alterations, the reversible nature of epigenetic modifications provides an interesting opportunity for the development of clinically relevant therapeutics in different tumors. In this study, we aimed to screen and validate candidate genes regulated by the epigenetic marker associated with transcriptional activation, histone acetylation, in gastric cancer (GC). We first compared gene expression profile of trichostatin A-treated and control GC cell lines using microarray assay. Among the 55 differentially expressed genes identified in this analysis, we chose the up-regulated genes BMP8B and BAMBI for further analyses, that included mRNA and histone acetylation quantification in paired GC and nontumor tissue samples. BMP8B expression was reduced in GC compared to nontumor samples (P < 0.01). In addition, reduced BMP8B expression was associated with poorly differentiated GC (P = 0.02). No differences or histopathological associations were identified concerning BAMBI expression. Furthermore, acetylated H3K9 and H4K16 levels at BMP8B were increased in GC compared to nontumors (P < 0.05). However, reduced levels of acetylated H3K9 and H4K16 were associated with poorly differentiated GC (P < 0.05). Reduced levels of acetylated H3K9 was also associated with diffuse-type histological GC (P < 0.05). Notably, reduced BMP8B mRNA and acetylated H4K16 levels were positively correlated in poorly differentiated GC (P < 0.05). Our study demonstrated that BMP8B seems to be a tumor suppressor gene regulated by H4K16 acetylation in poorly differentiated GC. Therefore, BMP8B may be a potential target for TSA-based therapies in this GC sample subset. J. Cell. Biochem. 118: 869-877, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The neurotoxicant, cuprizone, retards the differentiation of oligodendrocytes in vitro.

PubMed

Cammer, W

1999-10-15

The effects of oxalyldihydrazone (cuprizone) on weanling rodents provided an early protocol for toxic demyelination in vivo, in which degeneration of oligodendrocytes preceded disruption of the myelin sheath, and in which remyelination could take place. We administered cuprizone to oligodendrocyte-enriched glial-cell cultures and to mixed glial-cell cultures from neonatal rat brains. The cultures were treated with cuprizone for 1 h and allowed to continue differentiating on subsequent days. Treated cultures and respective control cultures were fixed with 4% paraformaldehyde (w/v) and immunostained with double immunofluorescence. MAbO4 was used to mark precursors and mature oligodendrocytes, and anti-myelin basic protein (MBP) to mark mature oligodendrocytes (O4+/MBP+), as distinguished from precursors, which were O4+/MBP-. Cell counts suggested that cuprizone inhibited the maturation of oligodendrocytes without diminishing the numbers of precursors, and appeared to affect the mitochondria in those cells.

The transcriptional landscape of αβ T cell differentiation

PubMed Central

Mingueneau, Michael; Kreslavsky, Taras; Gray, Daniel; Heng, Tracy; Cruse, Richard; Ericson, Jeffrey; Bendall, Sean; Spitzer, Matt; Nolan, Garry; Kobayashi, Koichi; von Boehmer, Harald; Mathis, Diane; Benoist, Christophe

2013-01-01

αβT cell differentiation from thymic precursors is a complex process, explored here with the breadth of ImmGen expression datasets, analyzing how differentiation of thymic precursors gives rise to transcriptomes. After surprisingly gradual changes though early T commitment, transit through the CD4+CD8+ stage involves a shutdown or rare breadth, and correlating tightly with MYC. MHC-driven selection promotes a large-scale transcriptional reactivation. We identify distinct signatures that mark cells destined for positive selection versus apoptotic deletion. Differential expression of surprisingly few genes accompany CD4 or CD8 commitment, a similarity that carries through to peripheral T cells and their activation, revealed by mass cytometry phosphoproteomics. The novel transcripts identified as candidate mediators of key transitions help define the “known unknown” of thymocyte differentiation. PMID:23644507

Camouflage effects of various colour-marking morphs against different microhabitat backgrounds in a polymorphic pygmy grasshopper Tetrix japonica.

PubMed

Tsurui, Kaori; Honma, Atsushi; Nishida, Takayoshi

2010-07-06

Colour-marking polymorphism is widely distributed among cryptic species. To account for the adaptive significance of such polymorphisms, several hypotheses have been proposed to date. Although these hypotheses argue over the degree of camouflage effects of marking morphs (and the interactions between morphs and their microhabitat backgrounds), as far as we know, most empirical evidence has been provided under unnatural conditions (i.e., using artificial prey). Tetrix japonica, a pygmy grasshopper, is highly polymorphic in colour-markings and occurs in both sand and grass microhabitats. Even within a microhabitat, T. japonica is highly polymorphic. Using humans as dummy predators and printed photographs in which various morphs of grasshoppers were placed against different backgrounds, we addressed three questions to test the neutral, background heterogeneity, and differential crypsis hypotheses in four marking-type morphs: 1) do the morphs differ in the degree of crypsis in each microhabitat, 2) are different morphs most cryptic in specific backgrounds of the microhabitats, and 3) does the morph frequency reflect the degree of crypsis? The degree of camouflage differed among the four morphs; therefore, the neutral hypothesis was rejected. Furthermore, the order of camouflage advantage among morphs differed depending on the two types of backgrounds (sand and grass), although the grass background consistently provided greater camouflage effects. Thus, based on our results, we could not reject the background heterogeneity hypothesis. Under field conditions, the more cryptic morphs comprised a minority of the population. Overall, our results demonstrate that the different morphs were not equivalent in the degree of crypsis, but the degree of camouflage of the morphs was not consistent with the morph frequency. These findings suggest that trade-offs exist between the camouflage benefit of body colouration and other fitness components, providing a better understanding of the adaptive significance of colour-markings and presumably supporting the differential crypsis hypothesis.

Abnormal Epigenetic Regulation of Immune System during Aging.

PubMed

Jasiulionis, Miriam G

2018-01-01

Epigenetics refers to the study of mechanisms controlling the chromatin structure, which has fundamental role in the regulation of gene expression and genome stability. Epigenetic marks, such as DNA methylation and histone modifications, are established during embryonic development and epigenetic profiles are stably inherited during mitosis, ensuring cell differentiation and fate. Under the effect of intrinsic and extrinsic factors, such as metabolic profile, hormones, nutrition, drugs, smoke, and stress, epigenetic marks are actively modulated. In this sense, the lifestyle may affect significantly the epigenome, and as a result, the gene expression profile and cell function. Epigenetic alterations are a hallmark of aging and diseases, such as cancer. Among biological systems compromised with aging is the decline of immune response. Different regulators of immune response have their promoters and enhancers susceptible to the modulation by epigenetic marks, which is fundamental to the differentiation and function of immune cells. Consistent evidence has showed the regulation of innate immune cells, and T and B lymphocytes by epigenetic mechanisms. Therefore, age-dependent alterations in epigenetic marks may result in the decline of immune function and this might contribute to the increased incidence of diseases in old people. In order to maintain health, we need to better understand how to avoid epigenetic alterations related to immune aging. In this review, the contribution of epigenetic mechanisms to the loss of immune function during aging will be discussed, and the promise of new means of disease prevention and management will be pointed.

Granulated colloidal silicon dioxide-based self-microemulsifying tablets, as a versatile approach in enhancement of solubility and therapeutic potential of anti-diabetic agent: formulation design and in vitro/in vivo evaluation.

PubMed

Pandey, Vikas; Gilhotra, Ritu M; Kohli, Seema

2017-06-01

The current research work was executed with an aim to explore and promote the potential of self-microemusifying drug delivery systems (SMEDDS) in the form of tablets, in order to enhance solubility and oral bioavailability of poorly aqueous soluble drug Repaglinide (RPG). RPG-loaded liquid SMEDDS were developed consisting Labrafil M 1944CS, Kolliphor EL and Propylene glycol, which were then characterized on various parameters. After characterization and optimization, liquid SMEDDS were converted into solid form by adsorbing on Aeroperl® 300 pharma and polyplasdone TM XL. Further, selection of suitable excipients was done and mixed with prepared solidified SMEDDS powder followed by the preparation of self-microemulsifying tablets (SMET's) wet granulation-compression method. SMET's were subjected to differential scanning calorimetry (DSC) and particle X-ray diffraction (RXRD) studies, results of which indicated transformation of crystalline structure of RPG because of dispersion of RPG at molecular level in liquid SMEDDS. This was further assured by micrographs obtained from scanning electron microscope. SMET's shown more than 85% (30 min) of in vitro drug release in contrast to conventional marketed tablets (13.2%) and pure RPG drug (3.2%). Results of in vivo studies furnished that SMET's had shown marked decrease in the blood glucose level and prolonged duration of action (up to 8 h) in comparison with conventional marketed tablets and pure RPG drug. In conclusion, SMET's serves as a promising tool for successful oral delivery of poorly aqueous soluble drug(s) such as RPG.

[A case of glioblastoma multiforme which indicated the early stage on brain MRI].

PubMed

Ono, K; Tohma, Y; Yoshida, M; Takamori, M

2000-04-01

A 57-year-old male was urgently carried to our hospital because of sudden loss of consciousness, lasting about 10 minutes. He had resumed consciousness before he arrived at our hospital. Neurologically, he had mild muscle weakness of the right arm. Deep tendon reflexes in the right upper extremity were reduced. In high level functions, speech disturbance, dysgraphia (disturbed ability to write Hiragana), and constructive apraxia were noted. A brain MRI upon admission showed a poorly demarcated, high signal intensity area in the cortical and subcortical layers of the left temporal and parietal lobes. This was visible on T 2 weighted images(T 2 WI), although no abnormalities were visible on T 1 weighted images(T 1 WI). No contrast enhancement was effected by Gd-DTPA. The patient was therefore suspected of having a tumor or degenerative disease and was monitored closely. About 4 months later after onset, his symptoms became aggravated, and brain MRI disclosed a marked low signal intensity area on T 1 WI and a heterogeneous high signal intensity area on T 2 WI. The abnormal signal intensity area was surrounded by extensive edema and mass effect. Ring-shaped, irregular, contrast enhanced areas were also visible. Cerebral angiography revealed a poorly demarcated tumor stain in the area supplied by the middle cerebral artery. The tumor was removed surgically and was histopathologically rated as glioblastoma multiforme(GBM). Because this case represents a valuable example of early stage of GBM, it will be discussed in this paper, along with differential diagnoses.

Minnesota Multiphasic Personality Inventory Differences between Terminators and Continuers in Youth Counseling

ERIC Educational Resources Information Center

Horton, Margaret; Kriauciunas, Romualdas

1970-01-01

Thirty-two terminators and 28 continuers in personal counseling were compared on three measures derived from precounseling Minnesota Multiphasic Personality Inventory (MMPI) data. It was concluded that poor adolescent prospects for counseling are those characterized by marked rebellion toward authority. (Author)

Formative Evaluation of a Neuroanatomy Course

ERIC Educational Resources Information Center

Sterret, Patrick R.; Littlefield, John H.

1976-01-01

Student cognitive performance data and affective reactions provided the basis for a formative evaluation of this neuroanatomy curriculum for freshmen medical students. The cerebral hempispheres topic area was marked by poor cognitive performance and low ratings in lecture quality. Videotapes designed to augment neurophysiology also received low…

Involvement of PSMD10, CDK4, and Tumor Suppressors in Development of Intrahepatic Cholangiocarcinoma of Syrian Golden Hamsters Induced by Clonorchis sinensis and N-Nitrosodimethylamine

PubMed Central

Uddin, Md. Hafiz; Choi, Min-Ho; Kim, Woo Ho; Jang, Ja-June; Hong, Sung-Tae

2015-01-01

Background Clonorchis sinensis is a group-I bio-carcinogen for cholangiocarcinoma (CCA). Although the epidemiological evidence links clonorchiasis and CCA, the underlying molecular mechanism involved in this process is poorly understood. In the present study, we investigated expression of oncogenes and tumor suppressors, including PSMD10, CDK4, p53 and RB in C. sinensis induced hamster CCA model. Methods Different histochemical/immunohistochemical techniques were performed to detect CCA in 4 groups of hamsters: uninfected control (Ctrl.), infected with C. sinensis (Cs), ingested N-nitrosodimethylamine (NDMA), and both Cs infected and NDMA introduced (Cs+NDMA). The liver tissues from all groups were analyzed for gene/protein expressions by quantitative PCR (qPCR) and western blotting. Principal Findings CCA was observed in all hamsters of Cs+NDMA group with well, moderate, and poorly differentiated types measured in 21.8% ± 1.5%, 13.3% ± 1.3%, and 10.8% ± 1.3% of total tissue section areas respectively. All CCA differentiations progressed in a time dependent manner, starting from the 8th week of infection. CCA stroma was characterized with increased collagen type I, mucin, and proliferative cell nuclear antigen (PCNA). The qPCR analysis showed PSMD10, CDK4 and p16INK4 were over-expressed, whereas p53 was under-expressed in the Cs+NDMA group. We observed no change in RB1 at mRNA level but found significant down-regulation of RB protein. The apoptosis related genes, BAX and caspase 9 were found downregulated in the CCA tissue. Gene/protein expressions were matched well with the pathological changes of different groups except the NDMA group. Though the hamsters in the NDMA group showed no marked pathological lesions, we observed over-expression of Akt/PKB and p53 genes proposing molecular interplay in this group which might be related to the CCA initiation in this animal model. Conclusions/Significance The present findings suggest that oncogenes, PSMD10 and CDK4, and tumor suppressors, p53 and RB, are involved in the carcinogenesis process of C. sinensis induced CCA in hamsters. PMID:26313366

Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti-PD-1/PD-L1 therapy.

PubMed

Roberts, Jordan A; Gonzalez, Raul S; Das, Satya; Berlin, Jordan; Shi, Chanjuan

2017-12-01

Poorly differentiated neuroendocrine carcinoma of the digestive system has a dismal prognosis with limited treatment options. This study aimed to investigate expression of the PD-1/PD-L1 pathway in these tumors. Thirty-seven patients with a poorly differentiated neuroendocrine carcinoma of the digestive system were identified. Their electronic medical records, pathology reports, and pathology slides were reviewed for demographics, clinical history, and pathologic features. Tumor sections were immunohistochemically labeled for PD-1 and PD-L1, and expression of PD-1 and PD-L1 on tumor and tumor-associated immune cells was analyzed and compared between small cell and large cell neuroendocrine carcinomas. The mean age of patients was 61 years old with 18 men and 19 women. The colorectum (n=20) was the most common primary site; other primary sites included the pancreaticobiliary system, esophagus, stomach, duodenum, and ampulla. Expression of PD-1 was detected on tumor cells (n=6, 16%) as well as on tumor-associated immune cells (n=23, 63%). The 6 cases with PD-1 expression on tumor cells also had the expression on immune cells. Expression of PD-L1 was visualized on tumor cells in 5 cases (14%) and on tumor-associated immune cells in 10 cases (27%). There was no difference in PD-1 and PD-L1 expression between small cell and large cell neuroendocrine carcinomas. In conclusion, PD-1/PD-L1 expression is a frequent occurrence in poorly differentiated neuroendocrine carcinomas of the digestive system. Checkpoint blockade targeting the PD-1/PD-L1 pathway may have a potential role in treating patients with this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of Morphological Awareness in Young Chinese Readers: Comparing Poor Comprehenders and Good Comprehenders

ERIC Educational Resources Information Center

Zhang, Haomin

2017-01-01

The present study explored the relationship between reading comprehension skill and morphological awareness among young Chinese readers. The objectives were to investigate whether morphological awareness is a critical cognitive and linguistic ability to differentiate poor comprehenders and good comprehenders and to further scrutinize the…

Expression of thymidylate synthase and glutathione-s-transferase pi in patients with esophageal squamous cell carcinoma.

PubMed

Huang, Jun-Xing; Li, Feng-Yue; Xiao, Wei; Song, Zheng-Xiang; Qian, Rong-Yu; Chen, Ping; Salminen, Eeva

2009-09-14

To investigate the expression of thymidylate synthase (TS) and glutathione-s-transferase pi (GST-pi) in esophageal squamous cell carcinoma and their association with the clinicopathologic characteristics. Immunohistochemical methods were used to detect the expression of TS and GST-pi in surgically resected formalin-fixed, paraffin-embedded esophageal squamous cell carcinoma (ESCC) tissue sections from 102 patients (median age, 58 years) and in 28 normal esophageal mucosa (NEM) samples. The relationship between TS and GST-pi expression and clinicopathologic factors was examined. The expression of TS and GST-pi was not statistically significantly associated with age of the patients, tumor size, lymph node metastasis, depth of invasion or tumor stage. TS staining was positive in 17.86% of normal esophageal mucosa and in 42.16% of ESCC samples (P < 0.05). The expression level of TS was not only significantly lower in well-differentiated (21.88%) than in poorly-differentiated carcinomas (51.43%, P < 0.05), but was also significantly higher in samples from male patients (46.51%) than from female patients (18.75%, P < 0.05). GST-pi was positively stained in 78.57% of normal esophageal mucosa and in 53.92% of ESCC samples (P < 0.05). The expression level of GST-pi was also significantly higher in well-differentiated carcinomas (65.63%) than in poorly-differentiated carcinomas (35.00%, P < 0.05). The expression of TS and of GST-pi may be used as molecular markers for the characterization of ESCC. Poorly-differentiated cells showed increased expression of TS and reduced expression of GST-pi.

Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression.

PubMed

Costa, Ana F; Altemani, Albina; García-Inclán, Cristina; Fresno, Florentino; Suárez, Carlos; Llorente, José L; Hermsen, Mario

2014-06-01

Adenoid cystic carcinomas can occasionally undergo dedifferentiation, a phenomenon also referred to as high-grade transformation. However, cases of adenoid cystic carcinomas have been described showing transformation to adenocarcinomas that are not poorly differentiated, indicating that high-grade transformation may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form, which may encompass a wide spectrum of carcinomas in terms of aggressiveness. The aim of this study was to gain more insight in the biology of this pathological phenomenon by means of genetic profiling of both histological components. Using microarray comparative genomic hybridization, we compared the genome-wide DNA copy-number changes of the conventional and transformed area of eight adenoid cystic carcinomas with high-grade transformation, comprising four with transformation into moderately differentiated adenocarcinomas and four into poorly differentiated carcinomas. In general, the poorly differentiated carcinoma cases showed a higher total number of copy-number changes than the moderately differentiated adenocarcinoma cases, and this correlated with a worse clinical course. Special attention was given to chromosomal translocation and protein expression of MYB, recently being considered to be an early and major oncogenic event in adenoid cystic carcinomas. Our data showed that the process of high-grade transformation is not always accompanied by an accumulation of genetic alterations; both conventional and transformed components harbored unique genetic alterations, which indicate a parallel progression. Our data further demonstrated that the MYB/NFIB translocation is not necessarily an early event or fundamental for the progression to adenoid cystic carcinoma with high-grade transformation.

Ascl1 (Mash1) Knockout Perturbs Differentiation of Nonneuronal Cells in Olfactory Epithelium

PubMed Central

Jang, Woochan; Wildner, Hendrik; Schwob, James E.

2012-01-01

The embryonic olfactory epithelium (OE) generates only a very few olfactory sensory neurons when the basic helix-loop-helix transcription factor, ASCL1 (previously known as MASH1) is eliminated by gene mutation. We have closely examined the structure and composition of the OE of knockout mice and found that the absence of neurons dramatically affects the differentiation of multiple other epithelial cell types as well. The most prominent effect is observed within the two known populations of stem and progenitor cells of the epithelium. The emergence of horizontal basal cells, a multipotent progenitor population in the adult epithelium, is anomalous in the Ascl1 knockout mice. The differentiation of globose basal cells, another multipotent progenitor population in the adult OE, is also aberrant. All of the persisting globose basal cells are marked by SOX2 expression, suggesting a prominent role for SOX2 in progenitors upstream of Ascl1. However, NOTCH1-expressing basal cells are absent from the knockout; since NOTCH1 signaling normally acts to suppress Ascl1 via HES1 and drives sustentacular (Sus) cell differentiation during adult epithelial regeneration, its absence suggests reciprocity between neurogenesis and the differentiation of Sus cells. Indeed, the Sus cells of the mutant mice express a markedly lower level of HES1, strengthening that notion of reciprocity. Duct/gland development appears normal. Finally, the expression of cKIT by basal cells is also undetectable, except in those small patches where neurogenesis escapes the effects of Ascl1 knockout and neurons are born. Thus, persistent neurogenic failure distorts the differentiation of multiple other cell types in the olfactory epithelium. PMID:23284756

Reconstructing human pancreatic differentiation by mapping specific cell populations during development.

PubMed

Ramond, Cyrille; Glaser, Nicolas; Berthault, Claire; Ameri, Jacqueline; Kirkegaard, Jeannette Schlichting; Hansson, Mattias; Honoré, Christian; Semb, Henrik; Scharfmann, Raphaël

2017-07-21

Information remains scarce on human development compared to animal models. Here, we reconstructed human fetal pancreatic differentiation using cell surface markers. We demonstrate that at 7weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate into the acinar, ductal or endocrine lineages. Development towards the acinar lineage is paralleled by an increase in GP2 expression. Conversely, a subset of the GP2 + population undergoes endocrine differentiation by down-regulating GP2 and CD142 and turning on NEUROG3 , a marker of endocrine differentiation. Endocrine maturation progresses by up-regulating SUSD2 and lowering ECAD levels. Finally, in vitro differentiation of pancreatic endocrine cells derived from human pluripotent stem cells mimics key in vivo events. Our work paves the way to extend our understanding of the origin of mature human pancreatic cell types and how such lineage decisions are regulated.

[Differentiated physiotherapy of lumbar pain].

PubMed

Chernyshova, L P; Galimova, E S

2011-01-01

The results of the present study confirm the efficacy of combined differential treatment of pain sensation in the lower back with the use of the up-to-date physiotherapeutic methods. The choice of a concrete method depended on the mechanism of development of the vertebral syndrome (compression, disfixation, disgenia or aseptic inflammation). The treatment resulted in the improvement of major integral characteristics of the pathological process, marked reduction in the duration of therapy, and significant prolongation of the remission period.

Temporal Stability of Genetic Variability and Differentiation in the Three-Spined Stickleback (Gasterosteus aculeatus)

PubMed Central

DeFaveri, Jacquelin; Merilä, Juha

2015-01-01

Temporal variation in allele frequencies, whether caused by deterministic or stochastic forces, can inform us about interesting demographic and evolutionary phenomena occurring in wild populations. In spite of the continued surge of interest in the genetics of three-spined stickleback (Gasterosteus aculeatus) populations, little attention has been paid towards the temporal stability of allele frequency distributions, and whether there are consistent differences in effective size (Ne) of local populations. We investigated temporal stability of genetic variability and differentiation in 15 microsatellite loci within and among eight collection sites of varying habitat type, surveyed twice over a six-year time period. In addition, Nes were estimated with the expectation that they would be lowest in isolated ponds, intermediate in larger lakes and largest in open marine sites. In spite of the marked differences in genetic variability and differentiation among the study sites, the temporal differences in allele frequencies, as well as measures of genetic diversity and differentiation, were negligible. Accordingly, the Ne estimates were temporally stable, but tended to be lower in ponds than in lake or marine habitats. Hence, we conclude that allele frequencies in putatively neutral markers in three-spined sticklebacks seem to be temporally stable – at least over periods of few generations – across a wide range of habitat types differing markedly in levels of genetic variability, effective population size and gene flow. PMID:25853707

Temporal stability of genetic variability and differentiation in the three-spined stickleback (Gasterosteus aculeatus).

PubMed

DeFaveri, Jacquelin; Merilä, Juha

2015-01-01

Temporal variation in allele frequencies, whether caused by deterministic or stochastic forces, can inform us about interesting demographic and evolutionary phenomena occurring in wild populations. In spite of the continued surge of interest in the genetics of three-spined stickleback (Gasterosteus aculeatus) populations, little attention has been paid towards the temporal stability of allele frequency distributions, and whether there are consistent differences in effective size (Ne) of local populations. We investigated temporal stability of genetic variability and differentiation in 15 microsatellite loci within and among eight collection sites of varying habitat type, surveyed twice over a six-year time period. In addition, Nes were estimated with the expectation that they would be lowest in isolated ponds, intermediate in larger lakes and largest in open marine sites. In spite of the marked differences in genetic variability and differentiation among the study sites, the temporal differences in allele frequencies, as well as measures of genetic diversity and differentiation, were negligible. Accordingly, the Ne estimates were temporally stable, but tended to be lower in ponds than in lake or marine habitats. Hence, we conclude that allele frequencies in putatively neutral markers in three-spined sticklebacks seem to be temporally stable - at least over periods of few generations - across a wide range of habitat types differing markedly in levels of genetic variability, effective population size and gene flow.

Genome-wide map of quantified epigenetic changes during in vitro chondrogenic differentiation of primary human mesenchymal stem cells.

PubMed

Herlofsen, Sarah R; Bryne, Jan Christian; Høiby, Torill; Wang, Li; Issner, Robbyn; Zhang, Xiaolan; Coyne, Michael J; Boyle, Patrick; Gu, Hongcang; Meza-Zepeda, Leonardo A; Collas, Philippe; Mikkelsen, Tarjei S; Brinchmann, Jan E

2013-02-15

For safe clinical application of engineered cartilage made from mesenchymal stem cells (MSCs), molecular mechanisms for chondrogenic differentiation must be known in detail. Changes in gene expression and extracellular matrix synthesis have been extensively studied, but the epigenomic modifications underlying these changes have not been described. To this end we performed whole-genome chromatin immunoprecipitation and deep sequencing to quantify six histone modifications, reduced representation bisulphite sequencing to quantify DNA methylation and mRNA microarrays to quantify gene expression before and after 7 days of chondrogenic differentiation of MSCs in an alginate scaffold. To add to the clinical relevance of our observations, the study is based on primary bone marrow-derived MSCs from four donors, allowing us to investigate inter-individual variations. We see two levels of relationship between epigenetic marking and gene expression. First, a large number of genes ontogenetically linked to MSC properties and the musculoskeletal system are epigenetically prepatterned by moderate changes in H3K4me3 and H3K9ac near transcription start sites. Most of these genes remain transcriptionally unaltered. Second, transcriptionally upregulated genes, more closely associated with chondrogenesis, are marked by H3K36me3 in gene bodies, highly increased H3K4me3 and H3K9ac on promoters and 5' end of genes, and increased H3K27ac and H3K4me1 marking in at least one enhancer region per upregulated gene. Within the 7-day time frame, changes in promoter DNA methylation do not correlate significantly with changes in gene expression. Inter-donor variability analysis shows high level of similarity between the donors for this data set. Histone modifications, rather than DNA methylation, provide the primary epigenetic control of early differentiation of MSCs towards the chondrogenic lineage.

Medical management of children with epilepsy.

PubMed

Ackermann, S; Wilmshurst, J M

2015-02-01

Epilepsy is a common neurological condition presenting to the pediatrician. There are many seizure mimics and the differential diagnosis of paroxysmal events is wide which may make a definitive diagnosis challenging. Epilepsy is a heterogeneous condition with marked variability in presentation, underlying etiologies, associated comorbidities and outcomes. The reorganization of epilepsies in 2010 reflects an increasing understanding of the neuropathological and etiological mechanisms as a result of rapid technological advances in neuroimaging techniques and molecular genetics in particular. An increasing number of treatment options are available although high quality evidence, applicable to children, is lacking. Choices should be tailored to the individual patient applying knowledge of adverse drug effects, including the potential for seizure exacerbation in certain syndromes. Neurobehavioral and psychiatric comorbidities occur in up to 80% of children and frequently remain unrecognized. Screening for these conditions should form part of holistic management, along with awareness of the psychosocial and educational needs of the child from the time of initial diagnosis. The management of individual children with epilepsy therefore presents a myriad challenges. Early referral to a specialist with expertise in the management of pediatric epilepsy should be sought whenever there is diagnostic uncertainty or a poor response to therapy.

Personality traits predict treatment outcome with an antidepressant in patients with functional gastrointestinal disorder.

PubMed

Tanum, L; Malt, U F

2000-09-01

We investigated the relationship between personality traits and response to treatment with the tetracyclic antidepressant mianserin or placebo in patients with functional gastrointestinal disorder (FGD) without psychopathology. Forty-eight patients completed the Buss-Durkee Hostility Inventory, Neuroticism Extroversion Openness -Personality Inventory (NEO-PI), and Eysenck Personality Questionnaire (EPQ), neuroticism + lie subscales, before they were consecutively allocated to a 7-week double-blind treatment study with mianserin or placebo. Treatment response to pain and target symptoms were recorded daily with the Visual Analogue Scale and Clinical Global Improvement Scale at every visit. A low level of neuroticism and little concealed aggressiveness predicted treatment outcome with the antidepressant drug mianserin in non-psychiatric patients with FGD. Inversely, moderate to high neuroticism and marked concealed aggressiveness predicted poor response to treatment. These findings were most prominent in women. Personality traits were better predictors of treatment outcome than serotonergic sensitivity assessed with the fenfluramine test. Assessment of the personality traits negativism, irritability, aggression, and neuroticism may predict response to drug treatment of FGD even when serotonergic sensitivity is controlled for. If confirmed in future studies, the findings point towards a more differential psychopharmacologic treatment of FGD.

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity.

PubMed

Zha, Weibin; Edin, Matthew L; Vendrov, Kimberly C; Schuck, Robert N; Lih, Fred B; Jat, Jawahar Lal; Bradbury, J Alyce; DeGraff, Laura M; Hua, Kunjie; Tomer, Kenneth B; Falck, John R; Zeldin, Darryl C; Lee, Craig R

2014-10-01

Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

The first investigation of Wilms' tumour atomic structure-nitrogen and carbon isotopic composition as a novel biomarker for the most individual approach in cancer disease

PubMed Central

Taran, Katarzyna; Frączek, Tomasz; Sikora-Szubert, Anita; Sitkiewicz, Anna; Młynarski, Wojciech; Kobos, Józef; Paneth, Piotr

2016-01-01

The paper describes a novel approach to investigating Wilms' tumour (nephroblastoma) biology at the atomic level. Isotope Ratio Mass Spectrometry (IRMS) was used to directly assess the isotope ratios of nitrogen and carbon in 84 Wilms' tumour tissue samples from 28 cases representing the histological spectrum of nephroblastoma. Marked differences in nitrogen and carbon isotope ratios were found between nephroblastoma histological types and along the course of cancer disease, with a breakout in isotope ratio of the examined elements in tumour tissue found between stages 2 and 3. Different isotopic compositions with regard to nitrogen and carbon content were observed in blastemal Wilms' tumour, with and without focal anaplasia, and in poorly- and well-differentiated epithelial nephroblastoma. This first assessment of nitrogen and carbon isotope ratio reveals the previously unknown part of Wilms' tumour biology and represents a potential novel biomarker, allowing for a highly individual approach to treating cancer. Furthermore, this method of estimating isotopic composition appears to be the most sensitive tool yet for cancer tissue evaluation, and a valuable complement to established cancer study methods with prospective clinical impact. PMID:27732932

Long-term differences in extinction risk among the seven forms of rarity

PubMed Central

Harnik, Paul G.; Simpson, Carl; Payne, Jonathan L.

2012-01-01

Rarity is widely used to predict the vulnerability of species to extinction. Species can be rare in markedly different ways, but the relative impacts of these different forms of rarity on extinction risk are poorly known and cannot be determined through observations of species that are not yet extinct. The fossil record provides a valuable archive with which we can directly determine which aspects of rarity lead to the greatest risk. Previous palaeontological analyses confirm that rarity is associated with extinction risk, but the relative contributions of different types of rarity to extinction risk remain unknown because their impacts have never been examined simultaneously. Here, we analyse a global database of fossil marine animals spanning the past 500 million years, examining differential extinction with respect to multiple rarity types within each geological stage. We observe systematic differences in extinction risk over time among marine genera classified according to their rarity. Geographic range played a primary role in determining extinction, and habitat breadth a secondary role, whereas local abundance had little effect. These results suggest that current reductions in geographic range size will lead to pronounced increases in long-term extinction risk even if local populations are relatively large at present. PMID:23097507

Long-term differences in extinction risk among the seven forms of rarity.

PubMed

Harnik, Paul G; Simpson, Carl; Payne, Jonathan L

2012-12-22

Rarity is widely used to predict the vulnerability of species to extinction. Species can be rare in markedly different ways, but the relative impacts of these different forms of rarity on extinction risk are poorly known and cannot be determined through observations of species that are not yet extinct. The fossil record provides a valuable archive with which we can directly determine which aspects of rarity lead to the greatest risk. Previous palaeontological analyses confirm that rarity is associated with extinction risk, but the relative contributions of different types of rarity to extinction risk remain unknown because their impacts have never been examined simultaneously. Here, we analyse a global database of fossil marine animals spanning the past 500 million years, examining differential extinction with respect to multiple rarity types within each geological stage. We observe systematic differences in extinction risk over time among marine genera classified according to their rarity. Geographic range played a primary role in determining extinction, and habitat breadth a secondary role, whereas local abundance had little effect. These results suggest that current reductions in geographic range size will lead to pronounced increases in long-term extinction risk even if local populations are relatively large at present.

RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure.

PubMed

Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung; Qiu, Jinsong; Chapski, Douglas J; Rau, Christoph D; Zhou, Yu; Abdellatif, Maha; Nakano, Astushi; Vondriska, Thomas M; Xiao, Xinshu; Fu, Xiang-Dong; Chen, Jau-Nian; Wang, Yibin

2016-01-01

RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload-induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease.

RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure

PubMed Central

Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung; Qiu, Jinsong; Chapski, Douglas J.; Rau, Christoph D.; Zhou, Yu; Abdellatif, Maha; Nakano, Astushi; Vondriska, Thomas M.; Xiao, Xinshu; Fu, Xiang-Dong; Chen, Jau-Nian; Wang, Yibin

2015-01-01

RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload–induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease. PMID:26619120

Oxidative stress damages rRNA inside the ribosome and differentially affects the catalytic center

PubMed Central

Willi, Jessica; Küpfer, Pascal; Evéquoz, Damien; Fernandez, Guillermo; Polacek, Norbert

2018-01-01

Abstract Intracellular levels of reactive oxygen species (ROS) increase as a consequence of oxidative stress and represent a major source of damage to biomolecules. Due to its high cellular abundance RNA is more frequently the target for oxidative damage than DNA. Nevertheless the functional consequences of damage on stable RNA are poorly understood. Using a genome-wide approach, based on 8-oxo-guanosine immunoprecipitation, we present evidence that the most abundant non-coding RNA in a cell, the ribosomal RNA (rRNA), is target for oxidative nucleobase damage by ROS. Subjecting ribosomes to oxidative stress, we demonstrate that oxidized 23S rRNA inhibits the ribosome during protein biosynthesis. Placing single oxidized nucleobases at specific position within the ribosome's catalytic center by atomic mutagenesis resulted in markedly different functional outcomes. While some active site nucleobases tolerated oxidative damage well, oxidation at others had detrimental effects on protein synthesis by inhibiting different sub-steps of the ribosomal elongation cycle. Our data provide molecular insight into the biological consequences of RNA oxidation in one of the most central cellular enzymes and reveal mechanistic insight on the role of individual active site nucleobases during translation. PMID:29309687

Focal myositis: A review.

PubMed

Devic, P; Gallay, L; Streichenberger, N; Petiot, P

2016-11-01

Amongst the heterogeneous group of inflammatory myopathies, focal myositis stands as a rare and benign dysimmune disease. Although it can be associated with root and/or nerve lesions, traumatic muscle lesions and autoimmune diseases, its triggering factors remain poorly understood. Defined as an isolated inflammatory pseudotumour usually restricted to one skeletal muscle, clinical presentation of focal myositis is that of a rapidly growing solitary mass within a single muscle, usually in the lower limbs. Electromyography shows spontaneous activity associated with a myopathic pattern. MRI reveals a contrast enhanced enlarged muscle appearing hyper-intense on FAT-SAT T2 weighted images. Adjacent structures are spared and there are no calcifications. Serum creatine kinase (CK) levels are usually moderately augmented and biological markers of systemic inflammation are absent in most cases. Pathological histological features include marked variation in fibre size, inflammatory infiltrates mostly composed of T CD4+ lymphocytes and macrophages, degenerating/regenerating fibres and interstitial fibrosis. Differential diagnoses are numerous and include myositis of other origin with focal onset. Steroid treatment should be reserved for patients who present with major pain, nerve lesions, associated autoimmune disease, or elevated C reactive protein or CK. Copyright © 2016 Elsevier B.V. All rights reserved.

Clinical characteristics and computed tomography findings of pulmonary toxoplasmosis after hematopoietic stem cell transplantation.

PubMed

Sumi, Masahiko; Norose, Kazumi; Hikosaka, Kenji; Kaiume, Hiroko; Takeda, Wataru; Kirihara, Takehiko; Kurihara, Taro; Sato, Keijiro; Ueki, Toshimitsu; Hiroshima, Yuki; Kuraishi, Hiroshi; Watanabe, Masahide; Kobayashi, Hikaru

2016-12-01

The prognosis of pulmonary toxoplasmosis, including disseminated toxoplasmosis involving the lungs, following hematopoietic stem cell transplantation (HSCT) is extremely poor due to the difficulties associated with early diagnosis and the rapidly progressive deterioration of multiorgan function. In our institution, we identified nine cases of toxoplasmosis, representing incidences of 2.2 and 19.6 % among all HSCT recipients and seropositive HSCT recipients, respectively. Of the patients with toxoplasmosis, six had pulmonary toxoplasmosis. Chest computed tomography (CT) findings revealed centrilobular, patchy ground-glass opacities (n = 3), diffuse ground-glass opacities (n = 2), ground-glass opacities with septal thickening (n = 1), and marked pleural effusion (n = 1). All cases died, except for one with suspected pulmonary toxoplasmosis who was diagnosed by a polymerase chain reaction assay 2 days after the onset of symptoms. In pulmonary toxoplasmosis, CT findings are non-specific and may mimic pulmonary congestion, atypical pneumonia, viral pneumonitis, and bronchopneumonia. Early diagnosis and treatment is crucial for overcoming this serious infectious complication. Pulmonary toxoplasmosis should be considered during differential diagnosis in a recipient with otherwise unexplained signs of infection and CT findings with ground-glass opacities, regardless of the distribution.

Alteration of Gene Expression, DNA Methylation, and Histone Methylation in Free Radical Scavenging Networks in Adult Mouse Hippocampus following Fetal Alcohol Exposure.

PubMed

Chater-Diehl, Eric J; Laufer, Benjamin I; Castellani, Christina A; Alberry, Bonnie L; Singh, Shiva M

2016-01-01

The molecular basis of Fetal Alcohol Spectrum Disorders (FASD) is poorly understood; however, epigenetic and gene expression changes have been implicated. We have developed a mouse model of FASD characterized by learning and memory impairment and persistent gene expression changes. Epigenetic marks may maintain expression changes over a mouse's lifetime, an area few have explored. Here, mice were injected with saline or ethanol on postnatal days four and seven. At 70 days of age gene expression microarray, methylated DNA immunoprecipitation microarray, H3K4me3 and H3K27me3 chromatin immunoprecipitation microarray were performed. Following extensive pathway analysis of the affected genes, we identified the top affected gene expression pathway as "Free radical scavenging". We confirmed six of these changes by droplet digital PCR including the caspase Casp3 and Wnt transcription factor Tcf7l2. The top pathway for all methylation-affected genes was "Peroxisome biogenesis"; we confirmed differential DNA methylation in the Acca1 thiolase promoter. Altered methylation and gene expression in oxidative stress pathways in the adult hippocampus suggests a novel interface between epigenetic and oxidative stress mechanisms in FASD.

Functional and unmodified MWNTs for delivery of the water-insoluble drug Carvedilol - A drug-loading mechanism

NASA Astrophysics Data System (ADS)

Li, Yuting; Wang, Tianyi; Wang, Jing; Jiang, Tongying; Cheng, Gang; Wang, Siling

2011-04-01

The purpose of this study was to develop carboxyl multi-wall carbon nanotubes (MWNTs) and unmodified MWNTs loaded with a poorly water-soluble drug, intended to improve the drug loading capacity, dissolubility and study the drug-loading mechanism. MWNTs were modified with a carboxyl group through the acid treatment. MWNTs as well as the resulting functionalized MWNTs were investigated as scaffold for loading the model drug, Carvedilol (CAR), using three different methods (the fusion method, the incipient wetness impregnation method, and the solvent method). The effects of different pore size, specific surface area and physical state were systematically studied using scanning electron microscopy (SEM), thermogravimetric analysis (TGA), Fourier transformation infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), nitrogen adsorption, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The functional MWNTs allowed a higher drug loading than the unmodified preparations. The methods used to load the drug had a marked effect on the drug-loading, dissolution, and physical state of the drug as well as its distribution. In addition, the solubility of the drug was increased when carried by both MWNTs and functional MWNTs, and this might help to improve the bioavailability.

A comparative study between xerographic, computer-assisted overlay generation and animated-superimposition methods in bite mark analyses.

PubMed

Tai, Meng Wei; Chong, Zhen Feng; Asif, Muhammad Khan; Rahmat, Rabiah A; Nambiar, Phrabhakaran

2016-09-01

This study was to compare the suitability and precision of xerographic and computer-assisted methods for bite mark investigations. Eleven subjects were asked to bite on their forearm and the bite marks were photographically recorded. Alginate impressions of the subjects' dentition were taken and their casts were made using dental stone. The overlays generated by xerographic method were obtained by photocopying the subjects' casts and the incisal edge outlines were then transferred on a transparent sheet. The bite mark images were imported into Adobe Photoshop® software and printed to life-size. The bite mark analyses using xerographically generated overlays were done by comparing an overlay to the corresponding printed bite mark images manually. In computer-assisted method, the subjects' casts were scanned into Adobe Photoshop®. The bite mark analyses using computer-assisted overlay generation were done by matching an overlay and the corresponding bite mark images digitally using Adobe Photoshop®. Another comparison method was superimposing the cast images with corresponding bite mark images employing the Adobe Photoshop® CS6 and GIF-Animator©. A score with a range of 0-3 was given during analysis to each precision-determining criterion and the score was increased with better matching. The Kruskal Wallis H test showed significant difference between the three sets of data (H=18.761, p<0.05). In conclusion, bite mark analysis using the computer-assisted animated-superimposition method was the most accurate, followed by the computer-assisted overlay generation and lastly the xerographic method. The superior precision contributed by digital method is discernible despite the human skin being a poor recording medium of bite marks. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Differentiation- and apoptosis-inducing activities by pentacyclic triterpenes on a mouse melanoma cell line.

PubMed

Hata, Keishi; Hori, Kazuyuki; Takahashi, Saori

2002-05-01

In a study to investigate the relationship between the chemical structure and the differentiation-inducing activity of pentacyclic triterpenes, several lupane, oleanane, and ursane triterpenes were prepared and their effects on B16 2F2 melanoma cell differentiation and growth were examined. Eleven lupane triterpenes used in this study acted on the melanoma cells as a melanogen, but no induction of melanogenesis of B16 2F2 cells by oleanane and ursane was detected. The differences at C-17 of the lupane series and acetylation of the OH group at C-3 did not markedly influence their activities. However, the ED(50) value for up-regulation of melanin biosynthesis was markedly decreased by the oxidation of the OH group at C-3 of lupeol (1). Betulinic acid (11), its methyl ester (12), lup-28-al-20(29)-ene-3beta-ol (9), and lup-28-al-20(29)-en-3-one (10) inhibited B16 2F2 cell proliferation by induction of apoptosis. These findings suggested that the carbonyl group at C-17 might be essential for the apoptotic effects of these compounds on B16 2F2 cells.

Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts

PubMed Central

Doi, Akiko; Park, In-Hyun; Wen, Bo; Murakami, Peter; Aryee, Martin J; Irizarry, Rafael; Herb, Brian; Ladd-Acosta, Christine; Rho, Junsung; Loewer, Sabine; Miller, Justine; Schlaeger, Thorsten; Daley, George Q; Feinberg, Andrew P

2010-01-01

Induced pluripotent stem (iPS) cells are derived by epigenetic reprogramming, but their DNA methylation patterns have not yet been analyzed on a genome-wide scale. Here, we find substantial hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts. The differentially methylated regions (DMRs) in the reprogrammed cells (denoted R-DMRs) were significantly enriched in tissue-specific (T-DMRs; 2.6-fold, P < 10−4) and cancer-specific DMRs (C-DMRs; 3.6-fold, P < 10−4). Notably, even though the iPS cells are derived from fibroblasts, their R-DMRs can distinguish between normal brain, liver and spleen cells and between colon cancer and normal colon cells. Thus, many DMRs are broadly involved in tissue differentiation, epigenetic reprogramming and cancer. We observed colocalization of hypomethylated R-DMRs with hypermethylated C-DMRs and bivalent chromatin marks, and colocalization of hypermethylated R-DMRs with hypomethylated C-DMRs and the absence of bivalent marks, suggesting two mechanisms for epigenetic reprogramming in iPS cells and cancer. PMID:19881528

Electrodermal reactivity and its association to substance use disorders.

PubMed

Taylor, Jeanette

2004-11-01

Poor electrodermal response modulation is associated with substance use disorders, but the specificity of the relationship has not been tested. To test this, 112 college students were assessed for psychiatric symptoms using structured interviews and for ability to modulate skin conductance responses to 2-s 92- or 110-dB white noise blasts that varied in temporal predictability. Twenty-eight good and 28 poor modulators were compared on symptoms of alcohol and illicit drug use disorders, personality disorders (antisocial, borderline, histrionic, and narcissistic), social and specific phobia, and depression. As expected, poor modulators had significantly more symptoms of substance use disorders than good modulators. Groups did not differ in symptoms of anxiety disorder, depression, or personality disorders marked by disinhibition. Poor electrodermal response modulation may reflect a biological risk factor for substance use disorders in particular.

Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival.

PubMed

Laws, Mary J; Taylor, Robert N; Sidell, Neil; DeMayo, Francesco J; Lydon, John P; Gutstein, David E; Bagchi, Milan K; Bagchi, Indrani C

2008-08-01

In the uterus, the formation of new maternal blood vessels in the stromal compartment at the time of embryonic implantation is critical for the establishment and maintenance of pregnancy. Although uterine angiogenesis is known to be influenced by the steroid hormones estrogen (E) and progesterone (P), the underlying molecular pathways remain poorly understood. Here, we report that the expression of connexin 43 (Cx43), a major gap junction protein, is markedly enhanced in response to E in uterine stromal cells surrounding the implanted embryo during the early phases of pregnancy. Conditional deletion of the Cx43 gene in these stromal cells and the consequent disruption of their gap junctions led to a striking impairment in the development of new blood vessels within the stromal compartment, resulting in the arrest of embryo growth and early pregnancy loss. Further analysis of this phenotypical defect revealed that loss of Cx43 expression resulted in aberrant differentiation of uterine stromal cells and impaired production of several key angiogenic factors, including the vascular endothelial growth factor (Vegf). Ablation of CX43 expression in human endometrial stromal cells in vitro led to similar findings. Collectively, these results uncovered a unique link between steroid hormone-regulated cell-cell communication within the pregnant uterus and the development of an elaborate vascular network that supports embryonic growth. Our study presents the first evidence that Cx43-type gap junctions play a critical and conserved role in modulating stromal differentiation, and regulate the consequent production of crucial paracrine signals that control uterine neovascularization during implantation.

Pulmonary FGF-18 gene expression is downregulated during the canalicular-saccular stages in nitrofen-induced hypoplastic lungs.

PubMed

Takahashi, Hiromizu; Friedmacher, Florian; Fujiwara, Naho; Hofmann, Alejandro; Kutasy, Balazs; Gosemann, Jan-Hendrik; Puri, Prem

2013-11-01

Pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH) represents one of the major challenges in neonatal intensive care. However, the molecular pathogenesis of PH is still poorly understood. In developing fetal lungs, fibroblast growth factor 18 (FGF-18) plays a crucial role in distal airway maturation. FGF-18 knockouts show smaller lung sizes with reduced alveolar spaces and thicker interstitial mesenchymal compartments, highlighting its important function for fetal lung growth and differentiation. We hypothesized that pulmonary FGF-18 gene expression is downregulated during late gestation in nitrofen-induced hypoplastic lungs. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetuses were harvested on D18 and D21, and lungs were divided into three groups: controls, hypoplastic lungs without CDH [CDH(-)], and hypoplastic lungs with CDH [CDH(+)] (n = 24 at each time-point). Pulmonary FGF-18 gene expression levels were analyzed by qRT-PCR. Immunohistochemistry was performed to investigate FGF-18 protein expression/distribution. Relative mRNA levels of pulmonary FGF-18 gene expression were significantly decreased in CDH(-) and CDH(+) on D18 and D21 compared to controls (p < 0.05 and p < 0.01, respectively). Immunoreactivity of FGF-18 was markedly diminished in mesenchymal cells surrounding the airway epithelium on D18 and D21 compared to controls. Downregulation of FGF-18 gene expression in nitrofen-induced hypoplastic lungs suggests that decreased FGF-18 expression during the canalicular-saccular stages may interfere with saccular-alveolar differentiation and distal airway maturation resulting in PH.

Computerized microscopic image analysis of follicular lymphoma

NASA Astrophysics Data System (ADS)

Sertel, Olcay; Kong, Jun; Lozanski, Gerard; Catalyurek, Umit; Saltz, Joel H.; Gurcan, Metin N.

2008-03-01

Follicular Lymphoma (FL) is a cancer arising from the lymphatic system. Originating from follicle center B cells, FL is mainly comprised of centrocytes (usually middle-to-small sized cells) and centroblasts (relatively large malignant cells). According to the World Health Organization's recommendations, there are three histological grades of FL characterized by the number of centroblasts per high-power field (hpf) of area 0.159 mm2. In current practice, these cells are manually counted from ten representative fields of follicles after visual examination of hematoxylin and eosin (H&E) stained slides by pathologists. Several studies clearly demonstrate the poor reproducibility of this grading system with very low inter-reader agreement. In this study, we are developing a computerized system to assist pathologists with this process. A hybrid approach that combines information from several slides with different stains has been developed. Thus, follicles are first detected from digitized microscopy images with immunohistochemistry (IHC) stains, (i.e., CD10 and CD20). The average sensitivity and specificity of the follicle detection tested on 30 images at 2×, 4× and 8× magnifications are 85.5+/-9.8% and 92.5+/-4.0%, respectively. Since the centroblasts detection is carried out in the H&E-stained slides, the follicles in the IHC-stained images are mapped to H&E-stained counterparts. To evaluate the centroblast differentiation capabilities of the system, 11 hpf images have been marked by an experienced pathologist who identified 41 centroblast cells and 53 non-centroblast cells. A non-supervised clustering process differentiates the centroblast cells from noncentroblast cells, resulting in 92.68% sensitivity and 90.57% specificity.

Insights into population ecology and sexual selection in snakes through the application of DNA-based genetic markers.

PubMed

Gibbs, H L; Weatherhead, P J

2001-01-01

Hypervariable genetic markers have revolutionized studies of kinship, behavioral ecology, and population biology in vertebrate groups such as birds, but their use in snakes remains limited. To illustrate the value of such markers in snakes, we review studies that have used microsatellite DNA loci to analyze local population differentiation and parentage in snakes. Four ecologically distinct species of snakes all show evidence for differentiation at small spatial scales (2-15 km), but with substantial differences among species. This result highlights how genetic analysis can reveal hidden aspects of the natural history of difficult-to-observe taxa, and it raises important questions about the ecological factors that may contribute to restricted gene flow. A 3-year study of genetic parentage in marked populations of the northern water snake showed that (1) participation in mating aggregations was a poor predictor of genetic-based measures of reproductive success; (2) multiple paternity was high, yet there was no detectable fitness advantage to multiple mating by females; and (3) the opportunity for selection was far higher in males than in females due to a larger variance in male reproductive success, and yet this resulted in no detectable selection on morphological variation in males. Thus genetic markers have provided accurate measures of individual reproductive success in this species, an important step toward resolving the adaptive significance of key features including multiple paternity and reversed sexual size dimorphism. Overall these studies illustrate how genetic analyses of snakes provide previously unobtainable information of long-standing interest to behavioral ecologists.

Platelet-Poor and Platelet-Rich Plasma Stimulate Bone Lineage Differentiation in Periodontal Ligament Stem Cells.

PubMed

Martínez, Constanza E; González, Sergio A; Palma, Verónica; Smith, Patricio C

2016-02-01

Plasma-derived fractions have been used as an autologous source of growth factors; however, limited knowledge concerning their biologic effects has hampered their clinical application. In this study, the authors analyze the content and specific effect of both platelet-rich plasma (PRP) and platelet-poor plasma (PPP) on osteoblastic differentiation using primary cultures of human periodontal ligament stem cells (HPLSCs). The authors evaluated the growth factor content of PRP and PPP using a proteome profiler array and enzyme-linked immunosorbent assay. HPLSCs were characterized by flow cytometry and differentiation assays. The effect of PRP and PPP on HPLSC bone differentiation was analyzed by quantifying calcium deposition after 14 and 21 days of treatment. Albeit at different concentrations, the two fractions had similar profiles of growth factors, the most representative being platelet-derived growth factor (PDGF) isoforms (PDGF-AA, -BB, and -AB), insulin-like growth factor binding protein (IGFBP)-2, and IGFBP-6. Both formulations exerted a comparable stimulus on osteoblastic differentiation even at low doses (2.5%), increasing calcium deposits in HPLSCs. PRP and PPP showed a similar protein profile and exerted comparable effects on bone differentiation. Further studies are needed to characterize and compare the effects of PPP and PRP on bone healing in vivo.

Competing Visions of Education in Timor-Leste's Curriculum Reform

ERIC Educational Resources Information Center

Ogden, Laura

2017-01-01

Timor-Leste's independence in 2002 marked the end of centuries of foreign control. Early post-independence education reforms successfully increased school enrolments and rebuilt education infrastructure, however, teacher qualifications and student outcomes have remained poor. The current Curriculum Reform, initiated in 2013, aims to improve…

Developing a Curriculum to Enhance Self-Concept.

ERIC Educational Resources Information Center

Helm, Estelle Bailey

1980-01-01

Good self-esteem and self-concept have a bearing on a child's performance in school. The article describes ways to recognize poor self-image in a child and suggests strategies for building self-concept. Activities listed include positive marking of papers, bibliotherapy, improvisational drama, and values clarification. (DS)

Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat

PubMed Central

Lopez, David Fernandez; Faustino, Joel; Daneman, Richard; Zhou, Lu; Lee, Sarah; Derugin, Nikita; Wendland, Michael F.; Vexler, Zinaida S

2012-01-01

The immaturity of the CNS at birth greatly affects injury after stroke but the contribution of the blood-brain barrier (BBB) to the differential response to stroke in adults and neonates is poorly understood. We asked if the structure and function of the BBB is disrupted differently in neonatal and adult rats by transient middle cerebral artery occlusion. In adult rats, albumin leakage into injured regions was markedly increased during 2–24 h reperfusion but leakage remained low in the neonates. Functional assays employing intravascular tracers in the neonates showed that BBB permeability to both large (70-kDa dextran) and small (3-kDa dextran, Gd-DTPA) tracers remained largely undisturbed 24h after reperfusion. The profoundly different functional integrity of the BBB was associated with the largely nonoverlapping patterns of regulated genes in endothelial cells purified from injured and uninjured adult and neonatal brain at 24h (endothelial transcriptome, 31,042 total probe sets). Within significantly regulated 1,266 probe sets in injured adults and 361 probe sets in neonates, changes in the gene expression of the basal lamina components, adhesion molecules, the tight junction protein occludin, and MMP-9 were among the key differences. The protein expression of collagen-IV, laminin, claudin-5, occludin and ZO-1 was also better preserved in neonatal rats. Neutrophil infiltration remained low in acutely injured neonates but neutralization of CINC-1 in the systemic circulation enhanced neutrophil infiltration, BBB permeability and injury. The markedly more integrant BBB in neonatal brain than in adult brain after acute stroke may have major implications for the treatment of neonatal stroke. PMID:22787045

Age-associated increase in heterochromatic marks in murine and primate tissues

PubMed Central

Kreiling, Jill A.; Tamamori-Adachi, Mimi; Sexton, Alec N.; Jeyapalan, Jessie C.; Munoz-Najar, Ursula; Peterson, Abigail L.; Manivannan, Jayameenakshi; Rogers, Elizabeth S.; Pchelintsev, Nikolay A.; Adams, Peter D.; Sedivy, John M.

2011-01-01

Summary Chromatin is highly dynamic and subject to extensive remodeling under many physiological conditions. Changes in chromatin that occur during the aging process are poorly documented and understood in higher organisms, such as mammals. We developed an immunofluorescence assay to quantitatively detect, at the single cell level, changes in the nuclear content of chromatin-associated proteins. We find increased levels of the heterochromatin-associated proteins histone macro H2A (mH2A) and heterochromatin protein 1 beta (HP1β) in human fibroblasts during replicative senescence in culture, and for the first time, an age-associated increase in these heterochromatin marks in several tissues of mice and primates. Mouse lung was characterized by monophasic mH2A expression histograms at both ages, and an increase in mean staining intensity at old age. In the mouse liver we observed increased age-associated localization of mH2A to regions of pericentromeric heterochromatin. In skeletal muscle we found two populations of cells with either low or high mH2A levels. This pattern of expression was similar in mouse and baboon, and showed a clear increase in the proportion of nuclei with high mH2A levels in older animals. The frequencies of cells displaying evidence of increased heterochromatinization are too high to be readily accounted for by replicative or oncogene-induced cellular senescence, and are prominently found in terminally differentiated, post mitotic tissues that are not conventionally thought to be susceptible to senescence. Our findings distinguish specific chromatin states in individual cells of mammalian tissues, and provide a foundation to further investigate the progressive epigenetic changes that occur during aging. PMID:21176091

Age-associated increase in heterochromatic marks in murine and primate tissues.

PubMed

Kreiling, Jill A; Tamamori-Adachi, Mimi; Sexton, Alec N; Jeyapalan, Jessie C; Munoz-Najar, Ursula; Peterson, Abigail L; Manivannan, Jayameenakshi; Rogers, Elizabeth S; Pchelintsev, Nikolay A; Adams, Peter D; Sedivy, John M

2011-04-01

Chromatin is highly dynamic and subject to extensive remodeling under many physiologic conditions. Changes in chromatin that occur during the aging process are poorly documented and understood in higher organisms, such as mammals. We developed an immunofluorescence assay to quantitatively detect, at the single cell level, changes in the nuclear content of chromatin-associated proteins. We found increased levels of the heterochromatin-associated proteins histone macro H2A (mH2A) and heterochromatin protein 1 beta (HP1β) in human fibroblasts during replicative senescence in culture, and for the first time, an age-associated increase in these heterochromatin marks in several tissues of mice and primates. Mouse lung was characterized by monophasic mH2A expression histograms at both ages, and an increase in mean staining intensity at old age. In the mouse liver, we observed increased age-associated localization of mH2A to regions of pericentromeric heterochromatin. In the skeletal muscle, we found two populations of cells with either low or high mH2A levels. This pattern of expression was similar in mouse and baboon, and showed a clear increase in the proportion of nuclei with high mH2A levels in older animals. The frequencies of cells displaying evidence of increased heterochromatinization are too high to be readily accounted for by replicative or oncogene-induced cellular senescence, and are prominently found in terminally differentiated, postmitotic tissues that are not conventionally thought to be susceptible to senescence. Our findings distinguish specific chromatin states in individual cells of mammalian tissues, and provide a foundation to investigate further the progressive epigenetic changes that occur during aging. © 2010 The Authors. Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Comparing population size estimators for plethodontid salamanders

USGS Publications Warehouse

Bailey, L.L.; Simons, T.R.; Pollock, K.H.

2004-01-01

Despite concern over amphibian declines, few studies estimate absolute abundances because of logistic and economic constraints and previously poor estimator performance. Two estimation approaches recommended for amphibian studies are mark-recapture and depletion (or removal) sampling. We compared abundance estimation via various mark-recapture and depletion methods, using data from a three-year study of terrestrial salamanders in Great Smoky Mountains National Park. Our results indicate that short-term closed-population, robust design, and depletion methods estimate surface population of salamanders (i.e., those near the surface and available for capture during a given sampling occasion). In longer duration studies, temporary emigration violates assumptions of both open- and closed-population mark-recapture estimation models. However, if the temporary emigration is completely random, these models should yield unbiased estimates of the total population (superpopulation) of salamanders in the sampled area. We recommend using Pollock's robust design in mark-recapture studies because of its flexibility to incorporate variation in capture probabilities and to estimate temporary emigration probabilities.

Diffraction-based overlay measurement on dedicated mark using rigorous modeling method

NASA Astrophysics Data System (ADS)

Lu, Hailiang; Wang, Fan; Zhang, Qingyun; Chen, Yonghui; Zhou, Chang

2012-03-01

Diffraction Based Overlay (DBO) is widely evaluated by numerous authors, results show DBO can provide better performance than Imaging Based Overlay (IBO). However, DBO has its own problems. As well known, Modeling based DBO (mDBO) faces challenges of low measurement sensitivity and crosstalk between various structure parameters, which may result in poor accuracy and precision. Meanwhile, main obstacle encountered by empirical DBO (eDBO) is that a few pads must be employed to gain sufficient information on overlay-induced diffraction signature variations, which consumes more wafer space and costs more measuring time. Also, eDBO may suffer from mark profile asymmetry caused by processes. In this paper, we propose an alternative DBO technology that employs a dedicated overlay mark and takes a rigorous modeling approach. This technology needs only two or three pads for each direction, which is economic and time saving. While overlay measurement error induced by mark profile asymmetry being reduced, this technology is expected to be as accurate and precise as scatterometry technologies.

Using Differentiated Instruction to Increase Mathematics Achievement in Elementary Students

ERIC Educational Resources Information Center

Faulkner, Jennifer H.

2013-01-01

As evidenced by the poor mathematics performance in American schools, specifically in the school district in the current study, providing identical educational opportunities for diverse students does not necessarily increase academic achievement for everyone. Differentiation is an instructional method that has been found to be successful in…

The value of histological grading of biopsy and resection specimens in early stage oral squamous cell carcinomas.

PubMed

Dik, Eric A; Ipenburg, Norbertus A; Kessler, Peter A; van Es, Robert J J; Willems, Stefan M

2018-04-05

In oral squamous cell carcinoma (OSCC) the differentiation grade of the tumor is determined on the biopsy and the resection specimen. The relation between tumor grade, nodal metastasis and survival is debatable. The aims of this study were to determine the correlation between differentiation grade of the biopsy and the resection specimen. Furthermore, we wanted to correlate tumor differentiation grade with nodal stage and survival. One-hundred and forty-five patients with OSCC staged as T1-2, N0 of the tongue, floor of mouth or cheek with primary resection of the tumor were examined. Biopsy and resection specimen were histologically re-assessed with regard to differentiation grade, as well as infiltrative, peri-neural and vascular invasive growth. This study showed a poor correlation between differentiation grade in the incisional biopsy and the resection specimen of the same tumor. No significant relation between differentiation grade of the resection specimen and nodal involvement, as well as overall and disease-specific survival was found. In early OSCC the differentiation grade determined by biopsy is of little predictive value for the grading of the resection specimen. Poor differentiation grade could not be related to the presence of nodal metastasis or survival and seems not to have any prognostic value concerning outcome. Treatment planning must be related to these findings. Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Esophageal Cancer: Associations With (pN+) Lymph Node Metastases.

PubMed

Rice, Thomas W; Ishwaran, Hemant; Hofstetter, Wayne L; Schipper, Paul H; Kesler, Kenneth A; Law, Simon; Lerut, E M R; Denlinger, Chadrick E; Salo, Jarmo A; Scott, Walter J; Watson, Thomas J; Allen, Mark S; Chen, Long-Qi; Rusch, Valerie W; Cerfolio, Robert J; Luketich, James D; Duranceau, Andre; Darling, Gail E; Pera, Manuel; Apperson-Hansen, Carolyn; Blackstone, Eugene H

2017-01-01

To identify the associations of lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer. Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics. Data on 5806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration were analyzed by Random Forest machine learning techniques. pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones. In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well-differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status.

Treatment Response and Outcomes of Grade 3 Pancreatic Neuroendocrine Neoplasms Based on Morphology: Well Differentiated Versus Poorly Differentiated.

PubMed

Raj, Nitya; Valentino, Emily; Capanu, Marinela; Tang, Laura H; Basturk, Olca; Untch, Brian R; Allen, Peter J; Klimstra, David S; Reidy-Lagunes, Diane

2017-03-01

Emerging data suggest that not all grade 3 (G3) pancreatic neuroendocrine neoplasms (panNENs) behave the same; tumor differentiation may predict outcome. Patients with G3 panNENs treated at our institution between 1999 and 2014 were identified. Demographics, response to therapy, and overall survival were determined. Forty-five patients were identified, 16 with G3 well differentiated pancreatic neuroendocrine tumors (WD-panNETs) and 29 with poorly differentiated neuroendocrine carcinomas (PDNEC). Median overall survival in G3 WD-panNET patients was 52.2 months (95% confidence interval, 19.3-86.9 months) compared with 10.1 months (95% confidence interval, 6.9-12.4 months) in PDNEC patients (P = 0.0009). Response rate to platinum agents was 10% in G3 WD-panNETs and 37% in PDNEC. Response rate to alkylating agents was 50% in G3 WD-panNETs and 50% in PDNEC. Both G3 WD-panNETs and PDNEC responded to platinum and alkylating agents. Overall survival was significantly greater in G3 WD-panNETs compared with PDNEC. These findings challenge current classification and suggest that G3 panNENs should be classified by morphology.

Limited Awareness of the Essences of Certification or Compliance Markings on Medical Devices.

PubMed

Foo, Jong Yong Abdiel; Tan, Xin Ji Alan

2017-06-01

Medical devices have been long used for odiagnostic, therapeutic or rehabilitation purposes. Currently, they can range from a low-cost portable device that is often used for personal health monitoring to high-end sophisticated equipment that can only be operated by trained professionals. Depending on the functional purposes, there are different certification or compliance markings on the device when it is sold. One common certification marking is the Conformité Européenne affixation but this has a range of certification mark numbering for a variety of functional purposes. While the regulators and medical device manufacturers understand the associated significance and clinical implications, these may not be apparent to the professionals (using or maintaining the device) and the general public. With portable healthcare devices and mobile applications gaining popularity, better awareness of certification marking will be needed. Particularly, there are differences in the allowed functional purposes and the associated cost derivations of devices with a seemingly similar nature. A preferred approach such as an easy-to-understand notation next to any certification marking on a device can aid in differentiation without the need to digest mountainous regulatory details.

Analytical methods for chemical and sensory characterization of scent-markings in large wild mammals: a review.

PubMed

Soso, Simone B; Koziel, Jacek A; Johnson, Anna; Lee, Young Jin; Fairbanks, W Sue

2014-03-05

In conjoining the disciplines of "ethology" and "chemistry" the field of "Ethochemistry" has been instituted. Ethochemistry is an effective tool in conservation efforts of endangered species and the understanding of behavioral patterns across all species. Chemical constituents of scent-markings have an important, yet poorly understood function in territoriality, reproduction, dominance, and impact on evolutionary biology, especially in large mammals. Particular attention has recently been focused on scent-marking analysis of great cats (Kalahari leopards (Panthera pardus), puma (Puma concolor) snow leopard (Panthera uncia), African lions (Panthera leo), cheetahs (Acinonyx jubatus), and tigers (Panthera tigris)) for the purpose of conservation. Sensory analyses of scent-markings could address knowledge gaps in ethochemistry. The objective of this review is to summarize the current state-of-the art of both the chemical and sensory analyses of scent-markings in wild mammals. Specific focus is placed on sampling and sample preparation, chemical analysis, sensory analysis, and simultaneous chemical and sensory analyses. Constituents of exocrine and endocrine secretions have been most commonly studied with chromatography-based analytical separations. Odor analysis of scent-markings provides an insight into the animal's sensory perception. A limited number of articles have been published in the area of sensory characterization of scent marks. Simultaneous chemical and sensory analyses with chromatography-olfactometry hyphenation could potentially aid conservation efforts by linking perceived odor, compounds responsible for odor, and resulting behavior.

Estimating avian population size using Bowden's estimator

USGS Publications Warehouse

Diefenbach, D.R.

2009-01-01

Avian researchers often uniquely mark birds, and multiple estimators could be used to estimate population size using individually identified birds. However, most estimators of population size require that all sightings of marked birds be uniquely identified, and many assume homogeneous detection probabilities. Bowden's estimator can incorporate sightings of marked birds that are not uniquely identified and relax assumptions required of other estimators. I used computer simulation to evaluate the performance of Bowden's estimator for situations likely to be encountered in bird studies. When the assumptions of the estimator were met, abundance and variance estimates and confidence-interval coverage were accurate. However, precision was poor for small population sizes (N < 50) unless a large percentage of the population was marked (>75%) and multiple (≥8) sighting surveys were conducted. If additional birds are marked after sighting surveys begin, it is important to initially mark a large proportion of the population (pm ≥ 0.5 if N ≤ 100 or pm > 0.1 if N ≥ 250) and minimize sightings in which birds are not uniquely identified; otherwise, most population estimates will be overestimated by >10%. Bowden's estimator can be useful for avian studies because birds can be resighted multiple times during a single survey, not all sightings of marked birds have to uniquely identify individuals, detection probabilities among birds can vary, and the complete study area does not have to be surveyed. I provide computer code for use with pilot data to design mark-resight surveys to meet desired precision for abundance estimates.

Genome‑wide identification of long noncoding RNAs in CCl4‑induced liver fibrosis via RNA sequencing.

PubMed

Gong, Zhenghua; Tang, Jialin; Xiang, Tianxin; Lin, Jiayu; Deng, Chaowen; Peng, Yanzhong; Zheng, Jie; Hu, Guoxin

2018-05-07

Liver fibrosis occurs as a result of chronic liver lesions, which may subsequently develop into liver cirrhosis and hepatocellular carcinoma. The involvement of long noncoding RNAs (lncRNAs) in liver fibrosis is being increasingly recognized. However, the exact mechanisms and functions of the majority of lncRNAs are poorly characterized. In the present study, the hepatotoxic substance carbon tetrachloride (CCl4) was employed to induce liver fibrosis in an animal model and agenome‑wide identification of lncRNAs in fibrotic liver tissues compared with CCl4 untreated liver tissues was performed using RNA sequencing. Sprague‑Dawley rats were treated with CCl4 for 8 weeks. Histopathogical alterations were observed in liver tissues, and serum levels of alanine aminotransferase, aspartate aminotransferase, transforming growth factor‑β1 and tumor necrosis factor‑α were significantly higher, in the CCl4‑treated group compared with the CCl4 untreated group. RNA sequencing of liver tissues demonstrated that 231 lncRNAs and 1,036 mRNAs were differentially expressed between the two groups. Furthermore, bioinformatics analysis demonstrated that the differentially expressed mRNAs were predominantly enriched in 'ECM‑receptor interaction', 'PI3K‑Akt signaling pathway' and 'focal adhesion' pathways, all of which are essential for liver fibrosis development. Validation of 12 significantly aberrant lncRNAs by reverse transcription‑quantitative polymerase chain reaction indicated that the expression patterns of 11 lncRNAs were consistent with the sequencing data. Furthermore, overexpression of lncRNA NR_002155.1, which was markedly downregulated in CCl4‑treated liver tissues, was demonstrated to inhibit HSC‑T6 cell proliferation in vitro. In conclusion, the present study determined the expression patterns of mRNAs and lncRNAs in fibrotic liver tissue induced by CCl4. The identified differentially expressed lncRNAs may serve as novel diagnostic biomarkers and therapeutic targets for liver fibrosis.

Growth differentiation factor‑5 induces tenomodulin expression via phosphorylation of p38 and promotes viability of murine mesenchymal stem cells from compact bone.

PubMed

Qu, Yanlong; Zhou, Li; Lv, Bing; Wang, Chunlei; Li, Pengwei

2018-03-01

Growth differentiation factor (GDF)‑5 serves a role in tissue development and tenomodulin serves an important role in the development of tendons. The effects of GDF‑5 on mesenchymal stem cells (MSCs), particularly with regards to tendon bioengineering, are poorly understood. The present study aimed to investigate the effects of GDF‑5 on cell viability and tenomodulin expression in MSCs from murine compact bone. MSCs were isolated from murine compact bones and confirmed by flow cytometric analysis. In addition, the adipogenic, osteoblastic and chondrocyte differentiation capabilities of the MSCs were determined. MSCs were treated with GDF‑5 and the effects of GDF‑5 on MSC viability were determined. The mRNA and protein expression levels of tenomodulin were detected by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. MSCs from murine compact bone were successfully isolated. GDF‑5 had optimal effects on cell viability at 100 ng/ml (+36.9% of control group without GDF‑5 treatment, P<0.01) and its effects peaked after 6 days of treatment (+56.6% of control group, P<0.001). Compared with the control group, treatment with 100 ng/ml GDF‑5 for 4 days enhanced the mRNA expression levels of tenomodulin (3.56±0.94 vs. 1.02±0.25; P<0.05). In addition, p38 was activated by GDF‑5, as determined by enhanced expression levels of phosphorylated p38 (p‑p38). The GDF‑5‑induced protein expression levels of p‑p38 and tenomodulin were markedly inhibited following treatment with SB203580, an inhibitor of p38 mitogen‑activated protein kinase. These results suggested that GDF‑5 treatment may increase tenomodulin protein expression via phosphorylation of p38 in MSCs from murine compact bone. These findings may aid the future development of tendon bioengineering.

ATP synthase promotes germ cell differentiation independent of oxidative phosphorylation

PubMed Central

Teixeira, Felipe K.; Sanchez, Carlos G.; Hurd, Thomas R.; Seifert, Jessica R. K.; Czech, Benjamin; Preall, Jonathan B.; Hannon, Gregory J.; Lehmann, Ruth

2015-01-01

The differentiation of stem cells is a tightly regulated process essential for animal development and tissue homeostasis. Through this process, attainment of new identity and function is achieved by marked changes in cellular properties. Intrinsic cellular mechanisms governing stem cell differentiation remain largely unknown, in part because systematic forward genetic approaches to the problem have not been widely used1,2. Analysing genes required for germline stem cell differentiation in the Drosophila ovary, we find that the mitochondrial ATP synthase plays a critical role in this process. Unexpectedly, the ATP synthesizing function of this complex was not necessary for differentiation, as knockdown of other members of the oxidative phosphorylation system did not disrupt the process. Instead, the ATP synthase acted to promote the maturation of mitochondrial cristae during differentiation through dimerization and specific upregulation of the ATP synthase complex. Taken together, our results suggest that ATP synthase-dependent crista maturation is a key developmental process required for differentiation independent of oxidative phosphorylation. PMID:25915123

Proteomic analysis of human follicular fluid in poor ovarian responders during in vitro fertilization.

PubMed

Oh, Jae Won; Kim, Seul Ki; Cho, Kyung-Cho; Kim, Min-Sik; Suh, Chang Suk; Lee, Jung Ryeol; Kim, Kwang Pyo

2017-03-01

Poor ovarian response (POR) in controlled ovarian stimulation is often observed during in vitro fertilization and embryo transfer cycles and it is a major problem. A POR has been found to be related to several factors, including advanced age, high body mass index, and history of ovarian or pelvic surgery. However, it is difficult to predict POR, as there are no specific biomarkers known. In this study, we used quantitative proteomic analyses to investigate potential biomarkers that can predict poor response during in vitro fertilization based on follicular fluid samples. A total of 1079 proteins were identified using a high-resolution orbitrap mass spectrometer coupled online to a nanoflow-LC system. It is notable that 65 upregulated and 66 downregulated proteins were found to be functionally enriched in poor responders. We also validated these differentially expressed proteins using a triple-quadrupole mass spectrometer for quantification of targeted proteins. Of the differentially expressed proteins, three proteins (pregnancy zone protein, renin, and sushi repeat-containing protein SRPX) were regarded as statistically significant (p < 0.05). © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Interactive contributions of self-regulation deficits and social motivation to psychopathology: Unraveling divergent pathways to aggressive behavior and depressive symptoms

PubMed Central

RUDOLPH, KAREN D.; TROOP-GORDON, WENDY; LLEWELLYN, NICOLE

2015-01-01

Poor self-regulation has been implicated as a significant risk factor for the development of multiple forms of psychopathology. This research examined the proposition that self-regulation deficits differentially predict aggressive behavior and depressive symptoms, depending on children’s social approach versus avoidance motivation. A prospective, multiple-informant approach was used to test this hypothesis in 419 children (M age = 8.92, SD = 0.36). Parents rated children’s inhibitory control. Children completed measures of social approach–avoidance motivation and depressive symptoms. Teachers rated children’s aggressive behavior. As anticipated, poor inhibitory control predicted aggressive behavior in boys with high but not low approach motivation and low but not high avoidance motivation, whereas poor inhibitory control predicted depressive symptoms in girls with high but not low avoidance motivation. This research supports several complementary theoretical models of psychopathology and provides insight into the differential contributions of poor self-regulation to maladaptive developmental outcomes. The findings suggest the need for targeted intervention programs that consider heterogeneity among children with self-regulatory deficits. PMID:23627953

Marking cell layers with spectinomycin provides a new tool for monitoring cell fate during leaf development.

PubMed

Pyke, K; Zubko, M K; Day, A

2000-10-01

Spectinomycin, an inhibitor of plastid protein synthesis, can be used to mark specific cell layers in the shoot meristem of Brassica napus. Pale yellow-green (YG) plants resulting from spectinomycin-treatment can be propagated indefinitely in vitro. Microscopic examination showed that YG-plants result from inactivation of plastids in the L2 and L3 layers and are composed of a pale green epidermis covering a white mesophyll layer. Epidermal cells of YG and normal green plants are similar and contain 10-20 small pale green plastids. YG plants are equivalent to periclinal chimeras with the important distinction that there is no genotypic difference between the white and green cell layers. Periclinal divisions of epidermal cells take place at all stages of leaf development to produce invaginations of green mesophyll located in sectors of widely varying sizes. A periclinal division rate of 1 in 3000-4000 anticlinal divisions for the adaxial epidermis, was 2-3-fold higher than that estimated for the abaxial epidermis. Analysis of white and green mesophyll showed that chloroplasts are essential for palisade cell differentiation and this requirement is cell-autonomous. Stable marking of cell lineages with spectinomycin is simple, rapid and reveals the requirement for functional plastids in cellular differentiation.

The Advertising Strategies of Early E-cigarette Brand Leaders in the United States

PubMed Central

Haardörfer, Regine; Cahn, Zachary; Lewis, Michael; Kothari, Shreya; Sarmah, Raina; Getachew, Betelihem; Berg, Carla J.

2017-01-01

Objectives We examined differential advertising strategies used by 4 major United States e-cigarette companies with differential affiliations with the traditional tobacco industry (ie, Njoy - independent, Blu – acquired, Vuse and MarkTen – launched by cigarette companies) over time. Methods We conducted a mixed-methods study regarding e-cigarette adspend, adspend per media channel (eg, TV, print), and advertising messaging strategies among these 4 top e-cigarette brands from January 2013 through December 2015. Results E-cigarette adspend increased from $59 million in 2013 to $91 million in 2014, followed by a sharp decline to $37 million in 2015. These companies showed distinct spending trajectories overall and across media channels, with Njoy and Vuse spending a higher proportion of their dollars on TV and Blu and MarkTen spending more on print. Marketing messages were also different by company. Key themes included switching from cigarettes (particularly by Njoy and Blu), circumventing smoke-free policies (particularly by Blu), and technological advancement (particularly by Vuse and MarkTen). Conclusions These e-cigarette brands have shifted their adspend, use of media channels, and advertising messaging strategies over time. Some differing strategies may reflect the different affiliations of each brand to the traditional cigarette industry. PMID:29392167

Share One Way Resilience Can Make A Difference In Your City

EPA Science Inventory

The Proctor Creek neighborhood in Atlanta is a poor, mostly African American community plagued by flooding, derelict housing, mold, and pathogens in the creek. Tires found in the creek bear the mark of municipal service vehicles. The area is prey to extreme heat and environmenta...

Death of Meritocracy Reconsidered

ERIC Educational Resources Information Center

Fisher, Trevor

2011-01-01

Poor social mobility has become controversial, with the stranglehold of the independent schools over elite universities intensifying during the New Labour period. The author identifies the failure of New Labour's Mark 2 A level reforms to deal with the situation, particularly the introduction of the A star at A level, which has given the…

Subitizing and Counting in Typical and Atypical Development

ERIC Educational Resources Information Center

Schleifer, Patrick; Landerl, Karin

2011-01-01

Enumeration performance in standard dot counting paradigms was investigated for different age groups with typical and atypically poor development of arithmetic skills. Experiment 1 showed a high correspondence between response times and saccadic frequencies for four age groups with typical development. Age differences were more marked for the…

The Employment Mismatch

ERIC Educational Resources Information Center

Fischer, Karin

2013-01-01

Employers value a four-year college degree, many of them more than ever. Yet half of those surveyed recently by "The Chronicle" and American Public Media's "Marketplace" said they had trouble finding recent graduates qualified to fill positions at their company or organization. Nearly a third gave colleges just fair to poor marks for producing…

Variations in Cognitive Maps: Understanding Individual Differences in Navigation

ERIC Educational Resources Information Center

Weisberg, Steven M.; Schinazi, Victor R.; Newcombe, Nora S.; Shipley, Thomas F.; Epstein, Russell A.

2014-01-01

There are marked individual differences in the formation of cognitive maps both in the real world and in virtual environments (VE; e.g., Blajenkova, Motes, & Kozhevnikov, 2005; Chai & Jacobs, 2010; Ishikawa & Montello, 2006; Wen, Ishikawa, & Sato, 2011). These differences, however, are poorly understood and can be difficult to…

Cytological diagnosis of metastatic glioblastoma in the pleural effusion of a lung transplant patient.

PubMed

Nauen, David W; Li, Qing Kay

2014-07-01

The extracranial metastasis of glioblastoma is a rare event. We report the case of a patient who developed metastatic glioblastoma in pleural effusion 15 months after lung transplant, with emphasis on differential diagnosis based on cytological material. In our case, tumor cells had pleomorphic nuclei, prominent nucleoli, and fine vesicular chromatin. Some were arranged in a poorly formed pseudo-glandular architecture, mimicking a poorly differentiated adenocarcinoma. The cytological diagnosis of metastatic glioblastoma is difficult and depends critically on clinical history and suspicion, particularly in the transplant setting. Review of the literature indicates that transmission/metastasis of intracranial malignancy occurs rarely following organ transplantation, with some debate on the suitability for transplant of organs from affected donors. Although the situation is uncommon, this report of the cytological findings of extracranial glioblastoma may extend our current knowledge and provide additional differential diagnostic information for this entity. © 2013 Wiley Periodicals, Inc.

Retinoic acid-induced differentiation of retrovirus-infected HL-60 cells is associated with enhanced transcription from the viral long terminal repeat

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

Collins, S.J.

1988-11-01

The author infected different human leukemic cell lines with an amphotropic retrovirus vector (designated PA317/N2) which confers G418 resistance and contains the Moloney murine leukemia virus long terminal repeat. In retrovirus-infected G418-resistant HL-60 cells, induction of granulocyte differentiation by retinoic acid was invariably accompanied by a marked increase (5- to 10-fold) in the transcriptional activity of the integrated retroviral long terminal repeat.

In-vivo RGB marking and multicolour single-cell tracking in the adult brain

PubMed Central

Gomez-Nicola, Diego; Riecken, Kristoffer; Fehse, Boris; Perry, V. Hugh

2014-01-01

In neuroscience it is a technical challenge to identify and follow the temporal and spatial distribution of cells as they differentiate. We hypothesised that RGB marking, the tagging of individual cells with unique hues resulting from simultaneous expression of the three basic colours red, green and blue, provides a convenient toolbox for the study of the CNS anatomy at the single-cell level. Using γ-retroviral and lentiviral vector sets we describe for the first time the in-vivo multicolour RGB marking of neurons in the adult brain. RGB marking also enabled us to track the spatial and temporal fate of neural stem cells in the adult brain. The application of different viral envelopes and promoters provided a useful approach to track the generation of neurons vs. glial cells at the neurogenic niche, allowing the identification of the prominent generation of new astrocytes to the striatum. Multicolour RGB marking could serve as a universal and reproducible method to study and manipulate the CNS at the single-cell level, in both health and disease. PMID:25531807

Fucoidan promotes early step of cardiac differentiation from human embryonic stem cells and long-term maintenance of beating areas.

PubMed

Hamidi, Sofiane; Letourneur, Didier; Aid-Launais, Rachida; Di Stefano, Antonio; Vainchenker, William; Norol, Françoise; Le Visage, Catherine

2014-04-01

Somatic stem cells require specific niches and three-dimensional scaffolds provide ways to mimic this microenvironment. Here, we studied a scaffold based on Fucoidan, a sulfated polysaccharide known to influence morphogen gradients during embryonic development, to support human embryonic stem cells (hESCs) differentiation toward the cardiac lineage. A macroporous (pore 200 μm) Fucoidan scaffold was selected to support hESCs attachment and proliferation. Using a protocol based on the cardiogenic morphogen bone morphogenic protein 2 (BMP2) and transforming growth factor (TGFβ) followed by tumor necrosis factor (TNFα), an effector of cardiopoietic priming, we examined the cardiac differentiation in the scaffold compared to culture dishes and embryoid bodies (EBs). At day 8, Fucoidan scaffolds supported a significantly higher expression of the 3 genes encoding for transcription factors marking the early step of embryonic cardiac differentiation NKX2.5 (p<0.05), MEF2C (p<0.01), and GATA4 (p<0.01), confirmed by flow cytometry analysis for MEF2C and NKX2.5. The ability of Fucoidan scaffolds to locally concentrate and slowly release TGFβ and TNFα was confirmed by Luminex technology. We also found that Fucoidan scaffolds supported the late stage of embryonic cardiac differentiation marked by a significantly higher atrial natriuretic factor (ANF) expression (p<0.001), although only rare beating areas were observed. We postulated that absence of mechanical stress in the soft hydrogel impaired sarcomere formation, as confirmed by molecular analysis of the cardiac muscle myosin MYH6 and immunohistological staining of sarcomeric α-actinin. Nevertheless, Fucoidan scaffolds contributed to the development of thin filaments connecting beating areas through promotion of smooth muscle cells, thus enabling maintenance of beating areas for up to 6 months. In conclusion, Fucoidan scaffolds appear as a very promising biomaterial to control cardiac differentiation from hESCs that could be further combined with mechanical stress to promote sarcomere formation at terminal stages of differentiation.

Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

PubMed

Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

2015-08-15

Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

Making (mis) sense of asymptomatic marked hypercalcemia in pregnancy.

PubMed

Maltese, Giuseppe; Izatt, Louise; McGowan, Barbara M; Hafeez, Kashif; Hubbard, Johnathan G; Carroll, Paul V

2017-10-01

We describe a rare case of homozygous inactivating calcium-sensing receptor mutation detected during pregnancy and mimicking primary hyperparathyroidism. In pregnancy, the differential diagnosis of hypercalcaemia requires a cautious approach as physiological changes in calcium homeostasis may mask rare genetic conditions.

Use of heart rate variability differentiates between physical and psychological states

USDA-ARS?s Scientific Manuscript database

The major goal of animal welfare scientists is to determine when animals are experiencing a state of good welfare or poor welfare. The goal of this research was to determine if measures of heart rate variability can be used to differentiate whether animals are experiencing differing states of physi...

The Populus homeobox gene ARBORKNOX2 regulates cell differentiation during secondary growth

Treesearch

Juan Du; Shawn D. Mansfield; Andrew T. Groover

2009-01-01

The stem cells of the vascular cambium divide to produce daughter cells, which in turn divide before undergoing differentiation during the radial growth of woody stems. The genetic regulation of these developmental events is poorly understood, however. We report here the cloning and functional characterization of a Populus class-I KNOX...

Anti-Neoplastic Activity of Two Flavone Isomers Derived from Gnaphalium elegans and Achyrocline bogotensis

PubMed Central

Pendleton, Morgan H.; Torrenegra, Ruben D.; Rodriguez, Oscar E.; Harirforoosh, Sam; Ballester, Maria; Lightner, Janet; Krishnan, Koyamangalath; Ramsauer, Victoria P.

2012-01-01

Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae, genera Gnaphalium and Achyrocline reputed to have anti-cancer properties. Our studies indicate that 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays potent activity against more differentiated carcinomas of the colon (Caco-2), and pancreas (Panc28), whereas 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) cytototoxic action is observed on poorly differentiated carcinomas of the colon (HCT116), pancreas (Mia PaCa), and breast (SK-BR3). Both flavones induced cell death (>50%) as proven by MTT cell viability assay in these cancer cell lines, all of which are regarded as highly tumorigenic. At the concentrations studied (5–80 µM), neither flavone demonstrated activity against the less tumorigenic cell lines, breast cancer MCF-7 cells, androgen-responsive LNCaP human prostate cancer line, and androgen-unresponsive PC3 prostate cancer cells. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays activity against more differentiated carcinomas of the colon and pancreas, but minimal cytotoxicity on poorly differentiated carcinomas of these organs. On the contrary, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) is highly cytotoxic to poorly differentiated carcinomas of the colon, pancreas, and breast with minimal activity against more differentiated carcinomas of the same organs. These differential effects suggest activation of distinct apoptotic pathways. In conclusion, the specific chemical properties of these two flavone isomers dictate mechanistic properties which may be relevant when evaluating biological responses to flavones. PMID:22768128

Primary dedifferentiated liposarcoma of the axilla arising in a mixed, well-differentiated and myxoid liposarcoma.

PubMed

Campbell, Garth S; Lawrence, Thomas J; Porter, Scott E; Rezeanu, Luminita

2012-01-01

We describe a case of mixed liposarcoma of the axilla presenting as a high grade undifferentiated sarcoma with areas of well-differentiated and myxoid liposarcoma. MRI demonstrated a lobulated, septated intermuscular mass with marked heterogeneous gadolinium enhancement. A small focus of the tumor demonstrated fat suppressed signal more characteristic of well-differentiated liposarcoma. Pathologic analysis following wide local excision revealed a large, high grade sarcomatous component with highly pleomorphic cells with a thin rim of well-differentiated and myxoid liposarcoma on histologic examination. Dedifferentiated liposarcomas arising outside of the retroperitoneum are very rare, as are dedifferentiated liposarcomas arising from a histologically mixed liposarcoma. In this regard, this case illustrates an unusual combination of tumor location and histology which, to our knowledge, has not previously been reported.

Primary Dedifferentiated Liposarcoma of the Axilla Arising in a Mixed, Well-differentiated and Myxoid Liposarcoma

PubMed Central

Campbell, Garth S.; Lawrence, Thomas J.; Porter, Scott E.; Rezeanu, Luminita

2012-01-01

We describe a case of mixed liposarcoma of the axilla presenting as a high grade undifferentiated sarcoma with areas of well-differentiated and myxoid liposarcoma. MRI demonstrated a lobulated, septated intermuscular mass with marked heterogeneous gadolinium enhancement. A small focus of the tumor demonstrated fat suppressed signal more characteristic of well-differentiated liposarcoma. Pathologic analysis following wide local excision revealed a large, high grade sarcomatous component with highly pleomorphic cells with a thin rim of well-differentiated and myxoid liposarcoma on histologic examination. Dedifferentiated liposarcomas arising outside of the retroperitoneum are very rare, as are dedifferentiated liposarcomas arising from a histologically mixed liposarcoma. In this regard, this case illustrates an unusual combination of tumor location and histology which, to our knowledge, has not previously been reported. PMID:22690275

Enhanced reactive oxygen species overexpression by CuO nanoparticles in poorly differentiated hepatocellular carcinoma cells

NASA Astrophysics Data System (ADS)

Kung, Mei-Lang; Hsieh, Shu-Ling; Wu, Chih-Chung; Chu, Tian-Huei; Lin, Yu-Chun; Yeh, Bi-Wen; Hsieh, Shuchen

2015-01-01

Copper oxide nanoparticles (CuO NPs) are known to exhibit toxic effects on a variety of cell types and organs. To determine the oxidative impact of CuO NPs on hepatocellular carcinoma (HCC) cells, well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) cells were exposed to CuO NPs. Cell viability assay showed that the median inhibition concentration (IC50) for SK-Hep-1 and HepG2 cells was 25 μg ml-1 and 85 μg ml-1, respectively. Cellular fluorescence intensity using DCFH-DA staining analysis revealed significant intracellular reactive oxygen species (ROS) generation of up to 242% in SK-Hep-1 cells, compared with 86% in HepG2 cells. HPLC analysis demonstrated that a CuO NP treatment caused cellular GSH depletion of 58% and a GSH/GSSG ratio decrease to ~0.1 in SK-Hep-1 cells. The oxidative stress caused by enhanced superoxide anion production was observed in both HepG2 (146%) and SK-Hep-1 (192%) cells. The Griess assay verified that CuO NPs induced NO production (170%) in SK-Hep-1 cells. Comet assay and western blot further demonstrated that CuO NPs induced severe DNA strand breakage (70%) in SK-Hep-1 cells and caused DNA damage via increased γ-H2AX levels. These results suggest that well-differentiated HepG2 cells possess a robust antioxidant defense system against CuO NP-induced ROS stress and exhibit more tolerance to oxidative stress. Conversely, poorly differentiated SK-Hep-1 cells exhibited a deregulated antioxidant defense system that allowed accumulation of CuO NP-induced ROS and resulted in severe cytotoxicity.Copper oxide nanoparticles (CuO NPs) are known to exhibit toxic effects on a variety of cell types and organs. To determine the oxidative impact of CuO NPs on hepatocellular carcinoma (HCC) cells, well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) cells were exposed to CuO NPs. Cell viability assay showed that the median inhibition concentration (IC50) for SK-Hep-1 and HepG2 cells was 25 μg ml-1 and 85 μg ml-1, respectively. Cellular fluorescence intensity using DCFH-DA staining analysis revealed significant intracellular reactive oxygen species (ROS) generation of up to 242% in SK-Hep-1 cells, compared with 86% in HepG2 cells. HPLC analysis demonstrated that a CuO NP treatment caused cellular GSH depletion of 58% and a GSH/GSSG ratio decrease to ~0.1 in SK-Hep-1 cells. The oxidative stress caused by enhanced superoxide anion production was observed in both HepG2 (146%) and SK-Hep-1 (192%) cells. The Griess assay verified that CuO NPs induced NO production (170%) in SK-Hep-1 cells. Comet assay and western blot further demonstrated that CuO NPs induced severe DNA strand breakage (70%) in SK-Hep-1 cells and caused DNA damage via increased γ-H2AX levels. These results suggest that well-differentiated HepG2 cells possess a robust antioxidant defense system against CuO NP-induced ROS stress and exhibit more tolerance to oxidative stress. Conversely, poorly differentiated SK-Hep-1 cells exhibited a deregulated antioxidant defense system that allowed accumulation of CuO NP-induced ROS and resulted in severe cytotoxicity. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr05843g

Amniotic-Fluid Stem Cells: Growth Dynamics and Differentiation Potential after a CD-117-Based Selection Procedure

PubMed Central

Arnhold, S.; Glüer, S.; Hartmann, K.; Raabe, O.; Addicks, K.; Wenisch, S.; Hoopmann, M.

2011-01-01

Amniotic fluid (AF) has become an interesting source of fetal stem cells. However, AF contains heterogeneous and multiple, partially differentiated cell types. After isolation from the amniotic fluid, cells were characterized regarding their morphology and growth dynamics. They were sorted by magnetic associated cell sorting using the surface marker CD 117. In order to show stem cell characteristics such as pluripotency and to evaluate a possible therapeutic application of these cells, AF fluid-derived stem cells were differentiated along the adipogenic, osteogenic, and chondrogenic as well as the neuronal lineage under hypoxic conditions. Our findings reveal that magnetic associated cell sorting (MACS) does not markedly influence growth characteristics as demonstrated by the generation doubling time. There was, however, an effect regarding an altered adipogenic, osteogenic, and chondrogenic differentiation capacity in the selected cell fraction. In contrast, in the unselected cell population neuronal differentiation is enhanced. PMID:21437196

Computer-aided diagnosis of focal liver lesions by use of physicians' subjective classification of echogenic patterns in baseline and contrast-enhanced ultrasonography.

PubMed

Sugimoto, Katsutoshi; Shiraishi, Junji; Moriyasu, Fuminori; Doi, Kunio

2009-04-01

To develop a computer-aided diagnostic (CAD) scheme for classifying focal liver lesions (FLLs) by use of physicians' subjective classification of echogenic patterns of FLLs on baseline and contrast-enhanced ultrasonography (US). A total of 137 hepatic lesions in 137 patients were evaluated with B-mode and NC100100 (Sonazoid)-enhanced pulse-inversion US; lesions included 74 hepatocellular carcinomas (HCCs) (23: well-differentiated, 36: moderately differentiated, 15: poorly differentiated HCCs), 33 liver metastases, and 30 liver hemangiomas. Three physicians evaluated single images at B-mode and arterial phases with a cine mode. Physicians were asked to classify each lesion into one of eight B-mode and one of eight enhancement patterns, but did not make a diagnosis. To classify five types of FLLs, we employed a decision tree model with four decision nodes and four artificial neural networks (ANNs). The results of the physicians' pattern classifications were used successively for four different ANNs in making decisions at each of the decision nodes in the decision tree model. The classification accuracies for the 137 FLLs were 84.8% for metastasis, 93.3% for hemangioma, and 98.6% for all HCCs. In addition, the classification accuracies for histological differentiation types of HCCs were 65.2% for well-differentiated HCC, 41.7% for moderately differentiated HCC, and 80.0% for poorly differentiated HCC. This CAD scheme has the potential to improve the diagnostic accuracy of liver lesions. However, the accuracy in the histologic differential diagnosis of HCC based on baseline and contrast-enhanced US is still limited.

Lin28 sustains early renal progenitors and induces Wilms tumor

PubMed Central

Urbach, Achia; Yermalovich, Alena; Zhang, Jin; Spina, Catherine S.; Zhu, Hao; Perez-Atayde, Antonio R.; Shukrun, Rachel; Charlton, Jocelyn; Sebire, Neil; Mifsud, William; Dekel, Benjamin; Pritchard-Jones, Kathy; Daley, George Q.

2014-01-01

Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis. PMID:24732380

A cell cycle-independent, conditional gene inactivation strategy for differentially tagging wild-type and mutant cells.

PubMed

Nagarkar-Jaiswal, Sonal; Manivannan, Sathiya N; Zuo, Zhongyuan; Bellen, Hugo J

2017-05-31

Here, we describe a novel method based on intronic MiMIC insertions described in Nagarkar-Jaiswal et al. (2015) to perform conditional gene inactivation in Drosophila . Mosaic analysis in Drosophila cannot be easily performed in post-mitotic cells. We therefore, therefore, developed Flip-Flop, a flippase -dependent in vivo cassette-inversion method that marks wild-type cells with the endogenous EGFP-tagged protein, whereas mutant cells are marked with mCherry upon inversion. We document the ease and usefulness of this strategy in differential tagging of wild-type and mutant cells in mosaics. We use this approach to phenotypically characterize the loss of SNF4Aγ , encoding the γ subunit of the AMP Kinase complex. The Flip-Flop method is efficient and reliable, and permits conditional gene inactivation based on both spatial and temporal cues, in a cell cycle-, and developmental stage-independent fashion, creating a platform for systematic screens of gene function in developing and adult flies with unprecedented detail.

JMJD3 aids in reprogramming of bone marrow progenitor cells to hepatic phenotype through epigenetic activation of hepatic transcription factors

PubMed Central

Kochat, Veena; Equbal, Zaffar; Baligar, Prakash; Kumar, Vikash; Srivastava, Madhulika; Mukhopadhyay, Asok

2017-01-01

The strictly regulated unidirectional differentiation program in some somatic stem/progenitor cells has been found to be modified in the ectopic site (tissue) undergoing regeneration. In these cases, the lineage barrier is crossed by either heterotypic cell fusion or direct differentiation. Though studies have shown the role of coordinated genetic and epigenetic mechanisms in cellular development and differentiation, how the lineage fate of adult bone marrow progenitor cells (BMPCs) is reprogrammed during liver regeneration and whether this lineage switch is stably maintained are not clearly understood. In the present study, we wanted to decipher genetic and epigenetic mechanisms that involve in lineage reprogramming of BMPCs into hepatocyte-like cells. Here we report dynamic transcriptional change during cellular reprogramming of BMPCs to hepatocytes and dissect the epigenetic switch mechanism of BM cell-mediated liver regeneration after acute injury. Genome-wide gene expression analysis in BM-derived hepatocytes, isolated after 1 month and 5 months of transplantation, showed induction of hepatic transcriptional program and diminishing of donor signatures over the time. The transcriptional reprogramming of BM-derived cells was found to be the result of enrichment of activating marks (H3K4me3 and H3K9Ac) and loss of repressive marks (H3K27me3 and H3K9me3) at the promoters of hepatic transcription factors (HTFs). Further analyses showed that BMPCs possess bivalent histone marks (H3K4me3 and H3K27me3) at the promoters of crucial HTFs. H3K27 methylation dynamics at the HTFs was antagonistically regulated by EZH2 and JMJD3. Preliminary evidence suggests a role of JMJD3 in removal of H3K27me3 mark from promoters of HTFs, thus activating epigenetically poised hepatic genes in BMPCs prior to partial nuclear reprogramming. The importance of JMJD3 in reprogramming of BMPCs to hepatic phenotype was confirmed by inhibiting catalytic function of the enzyme using small molecule GSK-J4. Our results propose a potential role of JMJD3 in lineage conversion of BM cells into hepatic lineage. PMID:28328977

Iron differentially modulates the CD4-lck and CD8-lck complexes in resting peripheral blood T-lymphocytes.

PubMed

Arosa, F A; de Sousa, M

1995-03-01

Clinical and experimental studies performed in situations of iron overload have demonstrated that iron impairs several T-cell functions. We have examined the effect of iron in the form of ferric citrate on the CD4-lck and CD8-lck complexes in view of the key role played by the tyrosine kinase p56lck in regulating T-cell functions. Ferric citrate was seen to differentially modulate the CD4-lck and CD8-lck complexes in resting peripheral blood T-lymphocytes (PBLs) cultured in the presence of this metal salt for periods of 20 to 24 hr. Thus, whereas ferric citrate invariably induced a marked decrease in the in vitro activity of the CD4-associated lck by three- to fourfold at 100 microM (P < 3 x 10(-5)), it did not affect significantly the in vitro activity of the CD8-associated lck, although modest decreases were observed in some experiments. Immunoprecipitation and subsequent lck-immunoblotting revealed that the marked decrease in CD4-lck activity induced by 100 microM of ferric citrate was due to a decrease in the amount of p56lck on CD4 immunoprecipitates. Furthermore, flow cytometry analysis showed a decrease in the surface expression of the CD4 molecule in iron-treated PBLs, as judged by a decrease in the mean fluorescence intensity (MFI), that was accompanied by a decrease in the percentage of CD4+ T-lymphocytes. In marked contrast, whereas the surface expression of the CD8 molecule was slightly decreased, the percentage of CD8+ T-lymphocytes remained constant. This differential effect of ferric citrate on the CD4+ and CD8+ T-cell subsets led to a marked decrease in the CD4/CD8 ratios in iron-treated PBLs after the 20- to 24-hr period (P < 0.001). The present results indicate that iron in the form of ferric citrate can modulate key molecules involved in the process of T-cell activation and therefore influence T-cell-mediated functions.

Can Business Students Forecast Their Own Grade?

ERIC Educational Resources Information Center

Hossain, Belayet; Tsigaris, Panagiotis

2013-01-01

This study examines grade expectations of two groups of business students for their final course mark. We separate students that are on average "better" forecasters on the basis of them not making significant forecast errors during the semester from those students that are poor forecasters of their final grade. We find that the better…

Winter variation in physiological status of cold stored and freshly lifted semi-evergreen quercus nigra seedlings

Treesearch

Rosa C. Goodman; Douglass F. Jacobs; Kent G. Apostol; Barrett C. Wilson; Emile S. Gardiner

2009-01-01

Water oak (Quercus nigra L.) is a tardily deciduous species commonly planted in afforestation projects in the Lower Mississippi River Alluvial Valley, USA. Field performance is often marked by low survival rates and top dieback, which may be associated with poor physiological quality of planting stock.

The Crisis in Black and Black.

ERIC Educational Resources Information Center

Hutchinson, Earl Ofari

These essays explore why the historic conflict between blacks and whites in the United States has become a crisis that divides many African Americans. The changing racial dynamic is not marked by conflicts. between the black middle class and the poor, black men and women, the black intellectual elite and rappers, black politicians and the urban…

How to Distinguish Normal from Disordered Children with Poor Language or Motor Skills

ERIC Educational Resources Information Center

Dyck, Murray; Piek, Jan

2010-01-01

Background & Aims: We tested the Diagnostic and Statistical Manual of Mental Disorders (DSM) hypothesis that so-called specific developmental disorders are marked by a pattern of specific discrepant achievement, and an alternative hypothesis that children with these disorders show a pattern of relatively pervasive low achievement. Methods…

One Nation, Divided: Culture, Civic Institutions, and the Marriage Divide

ERIC Educational Resources Information Center

Wilcox, W. Bradford; Wolfinger, Nicholas H.; Stokes, Charles E.

2015-01-01

Since the 1960s, the United States has witnessed a dramatic retreat from marriage, marked by divorce, cohabitation, single parenthood, and lower overall marriage rates. Marriage is now less likely to anchor adults' lives or provide a stable framework for childrearing, especially among poor and working-class Americans. Much research on the retreat…

Leukocytosis due to markedly elevated granulocyte-colony stimulating factor levels in a patient with endometrial cancer: Case report and literature review.

PubMed

Clark, Leslie H; Moll, Stephan; Houghton, Damon; O'Connor, Siohban; Soper, John T

2017-05-01

•Granulocyte-colony stimulating factor (GCSF) secretion by gynecologic tumors is rare.•Elevations in serum GCSF can be seen in the absence of tumor GSCF secretion.•Extreme leukocytosis is associated with autocrine tumor growth and poor prognosis.

Charles Dickens, Social Worker in His Time

ERIC Educational Resources Information Center

Andrews, Arlene Bowers

2012-01-01

As the world marks the 200th anniversary of Charles Dickens's birth, social workers may take note of the contributions Dickens made to 19th century social reform. Ever the advocate for people who were poor and oppressed, Dickens, in his timeless fictional narratives, continues to have relevance for contemporary social justice advocacy. This…

Reconstructing human pancreatic differentiation by mapping specific cell populations during development

PubMed Central

Ramond, Cyrille; Glaser, Nicolas; Berthault, Claire; Ameri, Jacqueline; Kirkegaard, Jeannette Schlichting; Hansson, Mattias; Honoré, Christian; Semb, Henrik; Scharfmann, Raphaël

2017-01-01

Information remains scarce on human development compared to animal models. Here, we reconstructed human fetal pancreatic differentiation using cell surface markers. We demonstrate that at 7weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate into the acinar, ductal or endocrine lineages. Development towards the acinar lineage is paralleled by an increase in GP2 expression. Conversely, a subset of the GP2+ population undergoes endocrine differentiation by down-regulating GP2 and CD142 and turning on NEUROG3, a marker of endocrine differentiation. Endocrine maturation progresses by up-regulating SUSD2 and lowering ECAD levels. Finally, in vitro differentiation of pancreatic endocrine cells derived from human pluripotent stem cells mimics key in vivo events. Our work paves the way to extend our understanding of the origin of mature human pancreatic cell types and how such lineage decisions are regulated. DOI: http://dx.doi.org/10.7554/eLife.27564.001 PMID:28731406

In vitro development of Strongylus edentatus to the fourth larval stage with notes on Strongylus vulgaris and Strongylus equinus.

PubMed

Farrar, R G; Klei, T R

1985-08-01

Strongylus edentatus was successfully cultured in vitro to the fourth larval stage (L4). Some growth continued for periods of 40-50 days at which time reductions in viability were observed in some of the culture systems tested. Various combinations of media, sera, buffers and organ explant cultures were tested. All cultures were incubated at 37 C in an atmosphere of 95% air and 5% CO2. Larvae underwent growth and differentiation to the L4 in all medium-serum combinations with and without organ explant cultures. Development and growth did occur but viability was reduced to insignificant levels in media without serum or cells. Optimal growth, differentiation, and longevity were observed in bicarbonate buffered RPMI-1640 containing 10% fetal calf serum and gerbil (Meriones unguiculatus) cecum explant cultures. Observations indicated that Strongylus vulgaris and Strongylus equinus also developed to the L4 stage using similar techniques. However, viability of S. vulgaris L4 was markedly limited. Specific morphological changes marked phases of development of S. edentatus, categorized as early, middle and late third stage, third molt and early fourth stage. Strongylus equinus appeared to follow the same developmental pattern in vitro as S. edentatus. Distinct differences in morphological features during differentiation were observed between S. edentatus and S. vulgaris.

Extremely High Expression of Antisense RNA for Wilms' Tumor 1 in Active Osteoclasts: Suppression of Wilms' Tumor 1 Protein Expression during Osteoclastogenesis.

PubMed

Li, Yin-Ji; Kukita, Akiko; Kyumoto-Nakamura, Yukari; Kukita, Toshio

2016-09-01

Wilms' tumor 1 (WT1), a zinc-finger transcription regulator of the early growth response family, identified as the product of a tumor suppressor gene of Wilms' tumors, bears potential ability to induce macrophage differentiation in blood cell differentiation. Herein, we examined the involvement of WT1 in the regulation of osteoclastogenesis. We detected a high level of WT1 protein expression in osteoclast precursors; however, WT1 expression was markedly suppressed during osteoclastogenesis. We examined expression of WT1 transcripts in bone tissue by RNA in situ hybridization. We found a high level of antisense transcripts in osteoclasts actively resorbing bone in mandible of newborn rats. Expression of antisense WT1 RNA in mandible was also confirmed by Northern blot analysis and strand-specific RT-PCR. Overexpression of antisense WT1 RNA in RAW-D cells, an osteoclast precursor cell line, resulted in a marked enhancement of osteoclastogenesis, suggesting that antisense WT1 RNA functions to suppress expression of WT1 protein in osteoclastogenesis. High level expression of antisense WT1 RNA may contribute to commitment to osteoclastogenesis, and may allow osteoclasts to maintain or stabilize their differentiation state. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Fluorescence microscopy study on the cytoskeletal displacements during sperm differentiation in the bush-cricket Tylopsis liliifolia (Fabricius) (Orthoptera: Tettigoniidae).

PubMed

Viscuso, Renata; Federico, Concetta; Saccone, Salvatore; Bonaccorsi, Bianca; Vitale, Danilo G M

2016-02-01

A study by fluorescence microscopy has been carried out on male gametes from testicular follicles, seminal vesicles, spermatophores, and seminal receptacles of the bush-cricket Tylopsis liliifolia, focusing the attention on localization and movements of F-actin and α-tubulin during sperm differentiation, since data in this respect are lacking in the Orthoptera. F-actin and α-tubulin positivity was detected in the testicular follicles, in particular at the bridges connecting spermatids of a same clone and around their nucleus, during the first differentiation stages. During the following differentiation stages in the testes, F-actin was found at one of the spermatid poles and then, during nucleus elongation, at the whole acrosomal region. A peculiar F-actin-positivity was found at the flagellum, more markedly immediately posterior to the nucleus, at the basal body region of the gametes from the testicular follicles and from the other examined districts. Other interesting data from our investigations concerns the α-tubulin displacements during the differentiation stages of the spermatid and a constant absence of α-tubulin-positivity where the centrioles are located. No positivity was also found for both α-tubulin and nuclear markers at the anterior region of the gamete, where the acrosomal wings are localized. Our results, compared with what is so far known in literature for the insects, lead us to assert that microfilaments and microtubules undergo gradual displacements, markedly in the testicular follicles, during the morphogenesis of the male gamete of T. liliifolia aimed to its organization and motility and probably also to its interaction with the female gamete. © 2015 Wiley Periodicals, Inc.

Three members of the iodothyronine deiodinase family, dio1, dio2 and dio3, are expressed in spatially and temporally specific patterns during metamorphosis of the flounder, Paralichthys olivaceus.

PubMed

Itoh, Kae; Watanabe, Kohei; Wu, Xiaoming; Suzuki, Tohru

2010-07-01

Flounder metamorphosis, marked by eye migration, lateralized pigmentation, and tissue differentiation in the stomach and skeletal muscle, is stimulated by thyroid hormone (TH). It is known that tri-iodothyronine (T3) produced by iodothyronine deiodinase type-1 (Dio1) from thyroxine (T4) enters the blood, whereas T3 produced by Dio2 penetrates into the nucleus of the Dio2-expressing cells, and then Dio3 inactivates both T4 and T3. To better understand the distinct functions of these three deiodinases in T3 regulation during flounder metamorphosis, we examined the tissue expression patterns of dio1, dio2, and dio3 in larvae of the Japanese flounder, Paralichthys olivaceus, by section in situ hybridization (SISH). We found that each deiodinase is expressed in a spatially and temporally specific pattern. dio1 is expressed in liver parenchymal cells from pro-metamorphosis to early climax, while dio2 is expressed in limited regions of the eyes, tectum, and skeletal muscles from pro-metamorphosis to post-climax. Considering these findings together with reports on other vertebrates, we predict that the liver cells expressing dio1 supply T3 to the blood, and that this systemic T3 synchronizes metamorphosis of differentiating tissues throughout the larval body, whereas the eyes, tectum, and skeletal muscles autonomously produce additional T3 for local tissue differentiation. Finally, dio3 expression is detected in skeletal muscle and gastric gland blastemas, which both undergo marked tissue differentiation at metamorphic climax. We hypothesize that dio3 expression protects these tissues from basal T3 levels early in metamorphosis, ensuring, together with the T3 surge from the liver, the synchronization of tissue differentiation at metamorphic climax.

Annexin A1 Down-Regulation in Head and Neck Cancer Is Associated with Epithelial Differentiation Status

PubMed Central

Pedrero, Juana Maria Garcia; Fernandez, M. Pilar; Morgan, Reginald O.; Zapatero, Agustin Herrero; Gonzalez, Maria Victoria; Nieto, Carlos Suarez; Rodrigo, Juan Pablo

2004-01-01

Annexin A1 (ANXA1) protein expression was evaluated by Western blot in a series of 32 head and neck squamous cell carcinomas (HNSCCs) in a search for molecular alterations that could serve as useful diagnostic/prognostic markers. ANXA1 down-regulation was observed in 24 cases (75%) compared with patient-matched normal epithelium. In relation to clinicopathological variables, ANXA1 down-regulation was significantly associated with advanced T stages (P = 0.029), locoregional lymph node metastases (P = 0.038), advanced disease stage (P = 0.006), hypopharyngeal localization (P = 0.038), and poor histological differentiation (P = 0.005). ANXA1 expression was also analyzed by immunohistochemistry in paraffin-embedded sections from 22 of 32 HNSCCs and 8 premalignant lesions. All dysplastic tissues showed significantly reduced ANXA1 expression compared to a strong positive signal observed in adjacent normal epithelia (except basal and suprabasal cells). A close association was observed between ANXA1 expression and the histological grade in HNSCC. Well-differentiated tumors presented a positive ANXA1 signal in highly keratinized areas whereas moderately and poorly differentiated tumors exhibited very weak or negative staining. Our findings clearly identify ANXA1 as an effective differentiation marker for the histopathological grading of HNSCCs and for the detection of epithelial dysplasia. PMID:14695321

Esophageal Cancer: Associations with pN+

PubMed Central

Rice, Thomas W.; Ishwaran, Hemant; Hofstetter, Wayne L.; Schipper, Paul H.; Kesler, Kenneth A.; Law, Simon; Lerut, Toni E.M.R.; Denlinger, Chadrick E.; Salo, Jarmo A.; Scott, Walter J.; Watson, Thomas J.; Allen, Mark S.; Chen, Long-Qi; Rusch, Valerie W.; Cerfolio, Robert J.; Luketich, James D.; Duranceau, Andre; Darling, Gail E.; Pera, Manuel; Apperson-Hansen, Carolyn; Blackstone, Eugene H.

2017-01-01

Objectives 1) To identify the association of positive lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and 2) to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer. Summary Background Data Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics. Methods Data on 5,806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration (WECC) were analyzed by Random Forest machine learning techniques. Results pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones. Conclusions In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well-differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status. PMID:28009736

Effects of different concentrations of Platelet-rich Plasma and Platelet-Poor Plasma on vitality and differentiation of autologous Adipose tissue-derived stem cells.

PubMed

Felthaus, Oliver; Prantl, Lukas; Skaff-Schwarze, Mona; Klein, Silvan; Anker, Alexandra; Ranieri, Marco; Kuehlmann, Britta

2017-01-01

Autologous fat grafts and adipose-derived stem cells (ASCs) can be used to treat soft tissue defects. However, the results are inconsistent and sometimes comprise tissue resorption and necrosis. This might be due to insufficient vascularization. Platelet-rich plasma (PRP) is a source of concentrated autologous platelets. The growth factors and cytokines released by platelets can facilitate angiogenesis. The simultaneous use of PRP might improve the regeneration potential of fat grafts. The optimal ratio has yet to be elucidated. A byproduct of PRP preparation is platelet-poor plasma (PPP). In this study we investigated the influence of different concentrations of PRP on the vitality and differentiation of ASCs. We processed whole blood with the Arthrex Angel centrifuge and isolated ASCs from the same donor. We tested the effects of different PRP and PPP concentrations on the vitality using resazurin assays and the differentiation of ASCs using oil-red staining. Both cell vitality and adipogenic differentiation increase to a concentration of 10% to 20% PRP. With a PRP concentration of 30% cell vitality and differentiation decrease. Both PRP and PPP can be used to expand ASCs without xenogeneic additives in cell culture. A PRP concentration above 20% has inhibitory effects.

A volatile topic: Parsing out the details of Earth's formation through experimental metal-silicate partitioning of volatile and moderately volatile elements

NASA Astrophysics Data System (ADS)

Mahan, B. M.; Siebert, J.; Blanchard, I.; Badro, J.; Sossi, P.; Moynier, F.

2017-12-01

Volatile and moderately volatile elements display different volatilities and siderophilities, as well as varying sensitivity to thermodynamic controls (X, P, T, fO2) during metal-silicate differentiation. The experimental determination of the metal-silicate partitioning of these elements permits us to evaluate processes controlling the distribution of these elements in Earth. In this work, we have combined metal-silicate partitioning data and results for S, Sn, Zn and Cu, and input these characterizations into Earth formation models. Model parameters such as source material, timing of volatile delivery, fO2 path, and degree of impactor equilibration were varied to encompass an array of possible formation scenarios. These models were then assessed to discern plausible sets of conditions that can produce current observed element-to-element ratios (e.g. S/Zn) in the Earth's present-day mantle, while also satisfying current estimates on the S content of the core, at no more than 2 wt%. The results of our models indicate two modes of accretion that can maintain chondritic element-to-element ratios for the bulk Earth and can arrive at present-day mantle abundances of these elements. The first mode requires the late addition of Earth's entire inventory of these elements (assuming a CI-chondritic composition) and late-stage accretion that is marked by partial equilibration of large impactors. The second, possibly more intuitive mode, requires that Earth accreted - at least initially - from volatile poor material preferentially depleted in S relative to Sn, Zn, and Cu. From a chemical standpoint, this source material is most similar to type I chondrule rich (and S poor) materials (Hewins and Herzberg, 1996; Mahan et al., 2017; Amsellem et al., 2017), such as the metal-bearing carbonaceous chondrites.

Increased expression of hepatocyte nuclear factor 4 alpha transcribed by promoter 2 indicates a poor prognosis in hepatocellular carcinoma.

PubMed

Cai, Shao-Hang; Lu, Shi-Xun; Liu, Li-Li; Zhang, Chris Zhiyi; Yun, Jing-Ping

2017-10-01

Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan-Meier analysis was conducted to assess the prognostic value of P2-HNF4α. The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression ( p  = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC ( p = 0.002) and vascular invasion ( p = 0.017). Kaplan-Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group ( p = 0.01), validation group ( p = 0.034), and overall group of patients with HCC ( p < 0.001). Our data show that the role of HNF4α in cancer development needs to be further refined. P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

Long non-coding RNA NRON is downregulated in HCC and suppresses tumour cell proliferation and metastasis.

PubMed

Yao, Zhicheng; Xiong, Zhiyong; Li, Ruixi; Liang, Hao; Jia, Changchang; Deng, Meihai

2018-05-14

Dysregulation of long non-coding RNAs is a newly identified mechanism for tumour progression. Previous studies have suggested that the nuclear factor of activated T cells (NFAT) gene plays a very important role in cancer growth and metastasis. However, lncNRON is a newly identified repressor of NFAT, and its function is largely unknown, especially in hepatocellular carcinoma (HCC). Therefore, the expression levels of lncNRON in 215 pairs of HCC tissue were evaluated by qRT-PCR, and its relationship to clinicopathological parameters, recurrence, and survival was analysed. Furthermore, stably overexpressing lncNRON cell lines were constructed and evaluated for cell phenotype. Finally, we detected epithelial-to-mesenchymal transition (EMT) proteins to determine the underlying mechanism involved in lncNRON function. We observed that lncNRON was downregulated in HCC tumour tissues; low lncNRON expression was associated with poor tumour differentiation and the presence of vascular tumour thrombus, which tended to result in poor clinical outcomes, as demonstrated by the recurrence rate and survival curves. Functional analysis showed that lncNRON overexpression impaired colony formation and cell viability and inhibited cell migration and invasion. A study using tumour-bearing mice showed that lncNRON markedly limited tumour growth and lung metastasis in vivo. Importantly, western blot analysis revealed that the expression of the EMT-related epithelial marker, E-cadherin, increased, whereas the expression of mesenchymal markers N-cadherin, snail, and vimentin was attenuated by lncNRON overexpression in HCC cells. Therefore, lower lncNRON expression indicates a poorer clinical outcome in HCC. LncNRON overexpression can suppress HCC growth and metastasis via inhibiting the EMT, and lncNRON may function as a new HCC prognostic marker. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Emerging disease burdens and the poor in cities of the developing world.

PubMed

Campbell, Tim; Campbell, Alana

2007-05-01

Patterns of future urban growth, combined with advances in the treatment of traditional scourges of communicable diseases, will cause a shift in the burden of disease toward category 2 (noncommunicable) and 3 (injury) conditions over the next 30 years. Communicable diseases, particularly HIV/AIDs, will continue to be the most important killers among the poor. However, new risks will emerge for several reasons. First, the marked sprawl of cities in the developing world will make access to care more difficult. Second, increasing motor vehicles and the likelihood of inadequate infrastructure will make air pollution and accidents in road traffic more common than in the past. Third, impoverished urban populations have already shown a propensity toward undernourishment, and its obverse, obesity, is already emerging as a major risk. Also, the large projected increase in slums suggests that violence and homicide will become a more important burden of health, and very large hazards will be created by fire-prone, insubstantial dwellings that will house nearly two billion people by 2030. In addition, decentralized governance will exacerbate the tensions and discontinuities that have plagued the management of health issues on the urban fringe over the past decade. Accordingly, public health agencies will need to adjust to the regional and country-specific factors to address the changing profile of risk. This analysis suggests that four factors--levels of poverty, speed of city growth, sprawl in cities, and degree of decentralization--will have importance in shaping health strategies. These factors vary in pace and intensity by region, suggesting that health care strategies for Category II and III conditions will need to be differentiated by region of the world. Also, interventions will have to rely increasingly on actors outside the ranks of public health specialists.

Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population.

PubMed

Trabelsi, Saoussen; Chabchoub, Imen; Ksira, Iadh; Karmeni, Nadhir; Mama, Nadia; Kanoun, Samia; Burford, Anna; Jury, Alexa; Mackay, Alan; Popov, Sergey; Bouaouina, Noureddine; Ben Ahmed, Slim; Mokni, Moncef; Tlili, Kalthoum; Krifa, Hedi; Yacoubi, Mohamed Tahar; Jones, Chris; Saad, Ali; H'mida Ben Brahim, Dorra

2017-05-01

It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co-deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation.

Analytical Methods for Chemical and Sensory Characterization of Scent-Markings in Large Wild Mammals: A Review

PubMed Central

Soso, Simone B.; Koziel, Jacek A.; Johnson, Anna; Lee, Young Jin; Fairbanks, W. Sue

2014-01-01

In conjoining the disciplines of “ethology” and “chemistry” the field of “Ethochemistry” has been instituted. Ethochemistry is an effective tool in conservation efforts of endangered species and the understanding of behavioral patterns across all species. Chemical constituents of scent-markings have an important, yet poorly understood function in territoriality, reproduction, dominance, and impact on evolutionary biology, especially in large mammals. Particular attention has recently been focused on scent-marking analysis of great cats (Kalahari leopards (Panthera pardus), puma (Puma concolor) snow leopard (Panthera uncia), African lions (Panthera leo), cheetahs (Acinonyx jubatus), and tigers (Panthera tigris)) for the purpose of conservation. Sensory analyses of scent-markings could address knowledge gaps in ethochemistry. The objective of this review is to summarize the current state-of-the art of both the chemical and sensory analyses of scent-markings in wild mammals. Specific focus is placed on sampling and sample preparation, chemical analysis, sensory analysis, and simultaneous chemical and sensory analyses. Constituents of exocrine and endocrine secretions have been most commonly studied with chromatography-based analytical separations. Odor analysis of scent-markings provides an insight into the animal's sensory perception. A limited number of articles have been published in the area of sensory characterization of scent marks. Simultaneous chemical and sensory analyses with chromatography-olfactometry hyphenation could potentially aid conservation efforts by linking perceived odor, compounds responsible for odor, and resulting behavior. PMID:24603639

The Use of Heart Rate Variability as a Novel Method to Differentiate between Affective States

USDA-ARS?s Scientific Manuscript database

The major goal of animal welfare scientists is to determine when animals are experiencing a state of good welfare or poor welfare. The goal of this research was to determine if measures of heart rate variability can be used to differentiate whether animals are experiencing ‘unpleasant’ versus ‘pleas...

Use of a Differential Observing Response to Expand Restricted Stimulus Control

ERIC Educational Resources Information Center

Walpole, Carrie Wallace; Roscoe, Eileen M.; Dube, William V.

2007-01-01

This study extends previous work on the use of differential observing responses (DOR) to remediate atypically restricted stimulus control. A participant with autism had high matching-to-sample accuracy scores with printed words that had no letters in common (e.g., "cat," "lid," "bug") but poor accuracy with words that had two letters in common…

Differentiating Approaches to Diabetes Self-Management of Multi-Ethnic Rural Older Adults at the Extremes of Glycemic Control

ERIC Educational Resources Information Center

Brewer-Lowry, Aleshia Nichol; Arcury, Thomas A.; Bell, Ronny A.; Quandt, Sara A.

2010-01-01

Purpose of the Study: This study identified approaches to diabetes self-management that differentiate persons with well-controlled from poorly controlled diabetes. Previous research has focused largely on persons participating in self-management interventions. Design and Methods: In-depth qualitative interviews were conducted with 48 adults, drawn…

Good phonetic errors in poor spellers are associated with right-handedness and possible weak utilisation of visuospatial abilities.

PubMed

Eglinton, Elizabeth; Annett, Marian

2008-06-01

Poor spellers in normal schools, who were not poor readers, were studied for handedness, visuospatial and other cognitive abilities in order to explore contrasts between poor spellers with and without good phonology. It was predicted by the right shift (RS) theory of handedness and cerebral dominance that those with good phonology would have strong bias to dextrality and relative weakness of the right hemisphere, while those without good phonology would have reduced bias to dextrality and relative weakness of the left hemisphere. Poor spellers with good phonetic equivalent spelling errors (GFEs) included fewer left-handers (2.4%) than poor spellers without GFEs (24.4%). Differences for hand skill were as predicted. Tests of visuospatial processing found no differences between the groups in levels of ability, but there was a marked difference in pattern of correlations between visuospatial test scores and homophonic word discrimination. Whereas good spellers (GS) and poor spellers without GFEs showed positive correlations between word discrimination and visuospatial ability, there were no significant correlations for poor spellers with GFEs. The differences for handedness and possibly for the utilisation of visuospatial skills suggest that surface dyslexics differ from phonological dyslexics in cerebral specialisation and perhaps in the quality of inter-hemispheric relations.

Changes in the population of perivascular cells in the bone tissue remodeling zones under microgravity

NASA Astrophysics Data System (ADS)

Katkova, Olena; Rodionova, Natalia; Shevel, Ivan

2016-07-01

Microgravity and long-term hypokinesia induce reduction both in bone mass and mineral saturation, which can lead to the development of osteoporosis and osteopenia. (Oganov, 2003). Reorganizations and adaptive remodeling processes in the skeleton bones occur in the topographical interconnection with blood capillaries and perivascular cells. Radioautographic studies with 3H- thymidine (Kimmel, Fee, 1980; Rodionova, 1989, 2006) have shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic. Hence the study of populations of perivascular stromal cells in areas of destructive changes is actual. Perivascular cells from metaphysis of the rat femoral bones under conditions of modeling microgravity were studied using electron microscopy and cytochemistry (hindlimb unloading, 28 days duration) and biosatellite «Bion-M1» (duration of flight from April 19 till May 19, 2013 on C57, black mice). It was revealed that both control and test groups populations of the perivascular cells are not homogeneous in remodeling adaptive zones. These populations comprise of adjacent to endothelium poorly differentiated forms and isolated cells with signs of differentiation (specific increased volume of rough endoplasmic reticulum in cytoplasm). Majority of the perivascular cells in the control group (modeling microgravity) reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In poorly differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of experimental animals reaction to the alkaline phosphatase is registered not in all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. Under microgravity some poorly differentiated perivascular cells reveal signs of destruction. Thus it was found that number of the alkaline phosphatase containing cells (i.e. osteogenic cells) declines in perivascular cells population. It is one of the mechanisms of the osteogenic process decrease of intensity in bones because of lessening support loading on the bone skeleton. In the adaptive remodeling zones of bone tissue (near the vascular canals) in experiments fibroblasts and fibrosis zones were found - areas filled with non-mineralized collagen fibrils on the bones surfaces. Hence it should be considered that decrease (removal) of support loading slows down osteogenic differentiation of the part of perivascular cells and stimulates differentiation of the fibroblast cells. Obtained data is considered as one of the cellular mechanisms of the adaptive reactions development in spongy bone under microgravity which could lead to the bone mass loss.

Characteristic community structure of Florida's subtropical wetlands: the Florida wetland condition index

EPA Science Inventory

Depending upon the classification scheme applied, there are between 10 and 45 different wetland types in Florida. Land use and land cover change has a marked effect on wetland condition, and different wetland types are affected differentially depending on many abiotic and biotic ...

PULMONARY AND CARDIAC GENE EXPRESSION FOLLOWING ACUTE ULTRAFINE CARBON PARTICLE INHALATION IN HYPERTENSIVE RATS

EPA Science Inventory

Inhalation of ultrafine carbon particles (ufCP) causes cardiac physiological changes without marked pulmonary injury or inflammation. We hypothesized that acute ufCP exposure of 13 months old Spontaneously Hypertensive (SH) rats will cause differential effects on the lung and hea...

Differentiation of vasoactive renal sympathetic nerve fibres.

PubMed

Dibona, G F

2000-01-01

Activation of renal sympathetic nerves produces marked changes in renal haemodynamics, tubular ion and water transport and renin secretion. This review examines information indicating that these effects are mediated by functionally specific groups of renal sympathetic nerve fibres separately innervating the renal vessels, tubules and juxtaglomerular granular cells.

College Board Response to "Harvard Educational Review" Article by Santelices and Wilson

ERIC Educational Resources Information Center

College Board, 2010

2010-01-01

This is the College Board's response to a research article by Drs. Maria Veronica Santelices and Mark Wilson in the Harvard Educational Review, entitled "Unfair Treatment? The Case of Freedle, the SAT, and the Standardization Approach to Differential Item Functioning" (see EJ930622).

The upside down world of diabetes care medical economics and what we might do to improve it.

PubMed

Harlan, David M; Hirsch, Irl B

2017-04-01

Increasingly over the past generation, the American healthcare delivery system has received consistently poor marks with regard to public health outcomes and costs. This review by two seasoned diabetes care providers is intended to shed light on the fundamental flaws we believe to underlie that poor performance, and suggest options for better outcomes and cost efficiencies. Despite major advances in diabetes management medications and tools, overall public health with regard to diabetes outcomes remains poor. Efforts focused on controlling costs appear to be exacerbating the problem. For chronic diseases like diabetes, fee-for-service care models are fundamentally flawed and predictably fail. We suggest that a major overhaul of the medical economics underlying diabetes care can improve patient outcomes and decrease costs.

Reversible inhibition of lysine specific demethylase 1 is a novel anti-tumor strategy for poorly differentiated endometrial carcinoma.

PubMed

Theisen, Emily R; Gajiwala, Snehal; Bearss, Jared; Sorna, Venkataswamy; Sharma, Sunil; Janat-Amsbury, Margit

2014-10-09

Endometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE. The effects of HCI2509 on viability, proliferation, anchorage-independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509. Both AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p=0.034). Our findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma.

Poorly Differentiated Medullary Phenotype Predicts Poor Survival in Early Lymph Node-Negative Gastro-Esophageal Adenocarcinomas.

PubMed

Treese, Christoph; Sanchez, Pedro; Grabowski, Patricia; Berg, Erika; Bläker, Hendrik; Kruschewski, Martin; Haase, Oliver; Hummel, Michael; Daum, Severin

2016-01-01

5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0). Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival. 129 patients (48 female) with a mean follow-up of 129.1 months were identified. 5-year overall survival was 83.9%, 5-year tumor related survival was 95.1%. Poorly differentiated medullary cancer subtypes (p<0.001) and positive vein invasion (p<0.001) were identified as risk factors for decreased overall-and tumor related survival. Ki-67 (p = 0.012) and TP53 mutation (p = 0.044) were the only immunohistochemical markers associated with worse overall survival but did not reach significance for decreased tumor related survival. In the presented study patients with AGE/S in stage UICC-I-N0 had a better prognosis as previously reported for Caucasian patients. Poorly differentiated medullary subtype was associated with reduced survival and should be considered when studying prognosis in these patients.

Spontaneous osteosarcoma of the femur in a non-obese diabetic mouse

PubMed Central

Hong, Sunhwa; Lee, Hyun-A; Choe, Ohmok; Chung, Youngho

2011-01-01

An abnormal swelling was identified in the distal portion of the right femur in a 1-year-old non-obese diabetic (NOD) mouse. Grossly, a large mass of the distal femur was observed in the right femur. Lesions were poorly marginated, associated with destruction of the cancellous and cortical elements of the bone, and showed ossification within the soft tissue component. Histologically, the tumor was identified as a poorly differentiated sarcoma. Histopathologic examination of the bone masses revealed invasive proliferation of poorly differentiated neoplastic mesenchymal cells forming streams, bundles, and nests, which resulted in destruction of normal bone. Neoplastic cells exhibited random variation in cellular appearance and arrangement, as well as matrix composition and abundance. Haphazard and often intermingling patterns of osteogenic, chondroblastic, lipoblastic, and angiogenic tissues were present. Larger areas of neoplastic bone and hyaline cartilage contained multiple large areas of hemorrhage and necrosis bordered by neoplastic cells. The mass was diagnosed as an osteosarcoma. To our knowledge, this is the first spontaneous osteosarcoma in an NOD mouse. PMID:21998615

Radiotherapy in poor risk patients with stage I cancer of the endometrium: results of not giving external beam radiotherapy.

PubMed

DeCruze, B; Guthrie, D

1999-01-01

Poor prognosis (poorly differentiated and/or deep myometrial invasion) Stage I endometrial cancer can have a relapse rate as high as 50%. Traditionally, most clinical oncologists treat these patients with external beam radiotherapy after surgery but there is no evidence to show that this improves survival. The retrospective study looks at the results of not giving external beam radiotherapy in 25 consecutive patients and compares the results with a group of 13 consecutive patients who did have such treatment. The two groups were comparable with regard to age, degree of differentiation and degree of invasion. Survival was comparable in the two groups. There is no evidence of any obvious decrease in survival from withholding external beam radiotherapy, but this was not a prospective randomized controlled trial. This study illustrates that it is essential that the Medical Research Council ASTEC trial should be supported because this will determine the true place of external beam radiotherapy in such patients.

Socioeconomic Correlates of Gender Differential in Poor Health Status Among Older Adults in India.

PubMed

Pandey, Anamika; Ladusingh, Laishram

2015-10-01

Assessment of the health status of the older adults can go a long way in controlling the disease burden and monitoring the path to healthy aging in India. In the absence of a population-based clinical survey to collect data on morbidities and other health conditions through biomarkers, self-rated health by nationally representative older population is used for understanding factors contributing to the gender differential in health status. Socioeconomic status is the most important factor explaining 59% of the gender gap in self-assessed health among older adults. The vulnerability of older women in terms of educational attainment, occupational status, and economic dependency is responsible for the higher level of poor self-assessed health. The gender gap in self-assessed poor health among older Indian adults, which perpetuates over the life course resulting in severe health disadvantages at old age can be reduced considerably through social empowerment and gender sensitive public policies. © The Author(s) 2013.

Shared epitope-aryl hydrocarbon receptor crosstalk underlies the mechanism of gene-environment interaction in autoimmune arthritis.

PubMed

Fu, Jiaqi; Nogueira, Sarah V; Drongelen, Vincent van; Coit, Patrick; Ling, Song; Rosloniec, Edward F; Sawalha, Amr H; Holoshitz, Joseph

2018-05-01

The susceptibility to autoimmune diseases is affected by genetic and environmental factors. In rheumatoid arthritis (RA), the shared epitope (SE), a five-amino acid sequence motif encoded by RA-associated HLA-DRB1 alleles, is the single most significant genetic risk factor. The risk conferred by the SE is increased in a multiplicative way by exposure to various environmental pollutants, such as cigarette smoke. The mechanism of this synergistic interaction is unknown. It is worth noting that the SE has recently been found to act as a signal transduction ligand that facilitates differentiation of Th17 cells and osteoclasts in vitro and in vivo. Intriguingly, the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the xenobiotic effects of many pollutants, including tobacco combustion products, has been found to activate similar biologic effects. Prompted by these similarities, we sought to determine whether the SE and AhR signaling pathways interact in autoimmune arthritis. Here we uncovered a nuclear factor kappa B-mediated synergistic interaction between the SE and AhR pathways that leads to markedly enhanced osteoclast differentiation and Th17 polarization in vitro. Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a robust increase in arthritis severity, bone destruction, overabundance of osteoclasts, and IL17-expressing cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, this study identifies a previously unrecognized mechanism of gene-environment interaction that could provide insights into the well-described but poorly understood amplification of the genetic risk for RA upon exposure to environmental pollutants. Copyright © 2018 the Author(s). Published by PNAS.

Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice*

PubMed Central

Lei, Wei; Feng, Xu-Hui; Deng, Wen-Bo; Ni, Hua; Zhang, Zhi-Rong; Jia, Bo; Yang, Xin-Ling; Wang, Tong-Song; Liu, Ji-Long; Su, Ren-Wei; Liang, Xiao-Huan; Qi, Qian-Rong; Yang, Zeng-Ming

2012-01-01

Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus. PMID:22403396

Peptidoglycan and lipoteichoic acid, components of the streptococcal cell wall, have marked and differential effects on adhesion molecule expression and the production of reactive oxygen species in human whole blood leukocytes.

PubMed

Saetre, T; Kähler, H; Foster, S J; Lyberg, T

2000-07-01

To elucidate the pathophysiology of infections with Streptococcus pyogenes we applied flow cytometric techniques to study dose-response and time-related effects of the streptococcal cell-wall-derived components lipoteichoic acid (LTA 0.005 to 50 microg/ml) and peptidoglycan (10 and 100 microg/ml) on the expression of leukocyte adhesion molecules, the CD14 receptor, and the production of leukocyte reactive oxygen species (ROS). LTA (50 microg/ml, 1-2 h) markedly increased the expression of CD11b (approximately 5-fold), CD11c (approximately 2-fold) and CD11a. Concomitantly, CD62L was downregulated (60%). Peptidoglycan alone or in combination with LTA had little effect on adhesion molecules, except for an amplification of the downregulation of CD62L to 90%. Monocyte CD14 expression was doubled by LTA. Leukocyte ROS production was 10-fold and 5-fold increased by peptidoglycan in granulocytes and monocytes, respectively. LTA alone had no effect, while the combination of peptidoglycan with LTA doubled the increase in ROS caused by peptidoglycan. LTA and peptidoglycan had marked and differential effects: LTA caused mainly adhesion molecule modulation, whereas peptidoglycan mainly increased ROS production. These changes are important in inflammatory cell activation and recruitment, intracellular microbial killing and adverse tissue injury.

Determination of tenogenic differentiation in human mesenchymal stem cells by terahertz waves for measurement of the optical property of cellular suspensions

NASA Astrophysics Data System (ADS)

Morita, Yasuyuki; Azuchi, Kosuke; Ju, Yang; Suzuki, Satoshi; Xu, Baiyao; Yamamoto, Shuhei

2014-06-01

Technology for identifying stem cell-to-tenocyte differentiation that is non-contact and non-destructive in vitro is essential in tissue engineering. It has been found that expression of various RNA and proteins produced by differentiated cells is elevated when human bone marrow mesenchymal stem cells (hBMSCs) differentiate into tenocytes. Also, such biomolecules have absorption bands in the terahertz range. Thus, we attempted to evaluate whether terahertz waves could be used to distinguish hBMSC-to-tenocyte differentiation. Terahertz time-domain spectroscopy (THz-TDS) using femtosecond laser pulses was used for terahertz measurements. HBMSCs differentiated into tenocytes with mechanical stimulation: 10% cyclical uniaxial stretching at 1 Hz for 24 or 48 h. Cellular suspensions before and after differentiation were measured with terahertz waves. Complex refractive index, consisting of a refractive index (real) and an extinction coefficient (imaginary) obtained from the transmitted terahertz signals, was evaluated before and after differentiation at 1.0 THz. As a result, the THz-TDS system enabled discrimination of hBMSC-to-tenocyte differentiation due to the marked contrast in optical parameter before and after differentiation. This is the first report of the potential of a THz-TDS system for the detection of tenogenic differentiation using a non-contact and non-destructive in vitro technique.

[Comparison of bite marks and teeth features using 2D and 3D methods].

PubMed

Lorkiewicz-Muszyńska, Dorota; Glapiński, Mariusz; Zaba, Czesław; Łabecka, Marzena

2011-01-01

The nature of bite marks is complex. They are found at the scene of crime on different materials and surfaces - not only on human body and corpse, but also on food products and material objects. Human bites on skin are sometimes difficult to interpret and to analyze because of the specific character of skin--elastic and distortable--and because different areas of human body have different surfaces and curvatures. A bite mark left at the scene of crime can be a highly helpful way to lead investigators to criminals. The study was performed to establish: 1) whether bite marks exhibit variations in the accuracy of impressions on different materials, 2) whether it is possible to use the 3D method in the process of identifying an individual based on the comparison of bite marks revealed at the scene, and 3D scans of dental casts, 3) whether application of the 3D method allows for elimination of secondary photographic distortion of bite marks. The authors carried out experiments on simulated cases. Five volunteers bit various materials with different surfaces. Experimental bite marks were collected with emphasis on differentiations of materials. Subsequently, dental impressions were taken from five volunteers in order to prepare five sets of dental casts (the maxilla and mandible. The biting edges of teeth were impressed in wax to create an imprint. The samples of dental casts, corresponding wax bite impressions and bite marks from different materials were scanned with 2D and 3D scanners and photographs were taken. All of these were examined in detail and then compared using different methods (2D and 3D). 1) Bite marks exhibit variations in accuracy of impression on different materials. The most legible reproduction of bite marks was seen on cheese. 2) In comparison of bite marks, the 3D method and 3D scans of dental casts are highly accurate. 3) The 3D method helps to eliminate secondary photographic distortion of bite marks.

Metastatic thyroid carcinoma without identifiable primary tumor within the thyroid gland: a retrospective study of a rare phenomenon.

PubMed

Xu, Bin; Scognamiglio, Theresa; Cohen, Perry R; Prasad, Manju L; Hasanovic, Adnan; Tuttle, Robert Michael; Katabi, Nora; Ghossein, Ronald A

2017-07-01

Metastatic papillary thyroid carcinoma (PTC) without an identifiable primary tumor despite extensive microscopic examination of the thyroid gland is a rare but true phenomenon.We retrieved 7 of such cases and described in detail the clinical and pathologic features of these tumors. BRAF V600E immunohistochemistry and Sequenom molecular profile were conducted in selected cases. All patients harbored metastatic disease in the central (n=3), lateral (n=3), or both neck compartments (n=1). The histotype of the metastatic disease was PTC (n=5), poorly differentiated thyroid carcinoma in association with a PTC columnar variant (n=1), and anaplastic thyroid carcinoma in association with a PTC tall cell variant (n=1). Fibrosis was present in the thyroid of 5 patients. All patients with PTC were alive without evidence of recurrence. The 76-year-old patient with poorly differentiated thyroid carcinoma did not recur and died of unknown causes. Finally, the patient with anaplastic thyroid carcinoma was alive with distant metastasis at last follow-up. The median follow-up for this cohort was 2.2years (range, 0.8-17). BRAF V600E was detected in 4 of 6 cases by immunohistochemistry. In conclusion, metastatic nodal disease without identifiable thyroid primary is a rare but real phenomenon of unknown mechanisms. Although most tumors are low grade and well differentiated, aggressive behavior due to poorly differentiated or anaplastic carcinoma can happen. Most cases are BRAF V600E -positive thyroid tumors. A papillary carcinoma phenotype is found in all reported cases. Copyright © 2017 Elsevier Inc. All rights reserved.

Wild-type phosphatase and tensin homolog deleted on chromosome 10 improved the sensitivity of cells to rapamycin through regulating phosphorylation of Akt in esophageal squamous cell carcinoma.

PubMed

Lu, Z; Wang, J; Zheng, Y; Yang, S; Liu, M; Chen, X; Wang, C; Hou, G

2017-02-01

Esophageal squamous cell carcinoma (ESCC) is one of the most frequently diagnosed cancers in China, but the etiology and mode of carcinogenesis of this disease remain poorly understood. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), as a negative regulator of Akt/mTOR pathway, frequently mutates or is inactive in many cancers. Although mTOR has been thought a promising cancer therapeutic target, the sensitivity of tumor cells to rapamycin was still to be revaluated. In this study, we measured the effects of rapamycin on cell proliferation and phosphorylation of Akt in ESCC cells with varying degrees of differentiation. And then, the relationship between PTEN status and the sensitivity of cells to rapamycin was investigated in EC9706 cells with or without wild-type PTEN in vitro and in vivo. The results demonstrated ESCC cells with poor differentiation were insensitive to rapamycin of high concentration and rapamycin obviously promoted the phosphorylation of Akt in these cells, but it had no obvious effects on p-Akt in cells with well differentiation. Also, we showed that wild-type PTEN improved the sensitivity of poor differentiation cells to rapamycin through inhibiting phosphorylation of Akt in vitro and in vivo. This study explored the possible molecular mechanism of some ESCC cells insensitive to rapamycin and provided a measure for treating ESCC patients with PTEN inactivation using mTOR inhibitors. © 2015 International Society for Diseases of the Esophagus.

Single cell and single molecule techniques for the analysis of the epigenome

NASA Astrophysics Data System (ADS)

Wallin, Christopher Benjamin

Epigenetic regulation is a critical biological process for the health and development of a cell. Epigenetic regulation is facilitated by covalent modifications to the underlying DNA and chromatin proteins. A fundamental understanding of these epigenetic modifications and their associated interactions at the molecular scale is necessary to explain phenomena including cellular identity, stem cell plasticity, and neoplastic transformation. It is widely known that abnormal epigenetic profiles have been linked to many diseases, most notably cancer. While the field of epigenetics has progressed rapidly with conventional techniques, significant advances remain to be made with respect to combinatoric analysis of epigenetic marks and single cell epigenetics. Therefore, in this dissertation, I will discuss our development of devices and methodologies to address these pertinent issues. First, we designed a preparatory polydimethylsiloxane (PDMS) microdevice for the extraction, purification, and stretching of human chromosomal DNA and chromatin from small cell populations down to a single cell. The valveless device captures cells by size exclusion within the micropillars, entraps the DNA or chromatin in the micropillars after cell lysis, purifies away the cellular debris, and fluorescently labels the DNA and/or chromatin all within a single reaction chamber. With the device, we achieve nearly 100% extraction efficiency of the DNA. The device is also used for in-channel immunostaining of chromatin followed by downstream single molecule chromatin analysis in nanochannels (SCAN). Second, using multi-color, time-correlated single molecule measurements in nanochannels, simultaneous coincidence detection of 2 epigenetic marks is demonstrated. Coincidence detection of 3 epigenetic marks is also established using a pulsed interleaved excitation scheme. With these two promising results, genome-wide quantification of epigenetic marks was pursued. Unfortunately, quantitative SCAN never materialized. Reasons for this, including poor signal to background, are explained in detail. Third, development of mobility-SCAN, an analytical technique for measuring and analyzing single molecules based on their fluorescent signature and their electrophoretic mobility in nanochannels is described. We use the technique to differentiate biomolecules from complex mixtures and derive parameters such as diffusion coefficients and effective charges. Finally, the device is used to detect binding interactions of various complexes similar to affinity capillary electrophoresis, but on a single molecule level. Fourth, we conclude by briefly discussing SCAN-sort, a technique to sort individual chromatin molecules based on their fluorescent emissions for further downstream analysis such as DNA sequencing. We demonstrate a 2-fold enrichment of chromatin from sorting and discuss possible system modifications for better performance in the future.

Aprocta cylindrica (Nematoda) infection in a European Robin (Erithacus rubecula) in Britain.

PubMed

Beckmann, Katie M; Harris, Eileen; Pocknell, Ann M; John, Shinto K; Macgregor, Shaheed K; Cunningham, Andrew A; Lawson, Becki

2014-10-01

A European Robin (Erithacus rubecula) found dead in England had marked blepharitis and periocular alopecia associated with Aprocta cylindrica (Nematoda: Aproctidae) and concurrent mixed fungal infections. Aprocta cylindrica should be considered a differential diagnosis in periocular abnormalities of robins and other insectivorous, migratory passerines in Western Europe.

A Sexuality Education Discourses Framework: Conservative, Liberal, Critical, and Postmodern

ERIC Educational Resources Information Center

Jones, Tiffany

2011-01-01

Sexuality education debates are layered with discourses based on markedly different constructions of sexuality. Rather than seeing these discourses as purely oppositional, this article frames them as complex and varied. It provides a new framework for understanding sexuality education which differentiates 28 discourses by orientation to education,…

A Sociolinguistic Study of Differential Object Marking (DOM) in Two Varieties of Contemporary Spanish

ERIC Educational Resources Information Center

Balasch Rodriguez, Sonia

2011-01-01

This sociolinguistic-variationist investigation sheds light on two little-studied issues concerning Spanish DOM, or variable use of a before animate "direct objects" (DOs), in vernacular language: the complex interaction of co-occurring linguistic (type of verb; definiteness, specificity, grammatical number, topicality, type and…

A Model of Psychopathology Based on an Integration of MMPI Actuarial Systems.

ERIC Educational Resources Information Center

Skinner, Harvey A.; Jackson, Douglas N.

1978-01-01

Evaluated relationships among Minnesota Multiphasic Personality Inventory (MMPI) code types from the Gilberstadt and Duker and the Marks, Seeman, and Haller systems. Superordinate types were identified: neurotic, psychotic and sociopathic. Data from the MMPI do not support the practice of highly differentiated classification within the three…

Intermediate filament proteins and actin isoforms as markers for soft-tissue tumor differentiation and origin. III. Hemangiopericytomas and glomus tumors.

PubMed Central

Schürch, W.; Skalli, O.; Lagacé, R.; Seemayer, T. A.; Gabbiani, G.

1990-01-01

Intermediate filament proteins and actin isoforms of a series of 12 malignant hemangiopericytomas and five glomus tumors were examined by light microscopy, transmission electron microscopy, two-dimensional gel electrophoresis (2D-GE), and by immunohistochemistry, the latter using monoclonal or affinity-purified polyclonal antibodies to desmin, vimentin, cytokeratins, alpha-smooth muscle, and alpha-sarcomeric actins. By light microscopy, all hemangiopericytomas disclosed a predominant vascular pattern with scant storiform, myxoid and spindle cell areas, and with variable degrees of perivascular fibrosis. By ultrastructure, smooth muscle differentiation was observed in each hemangiopericytoma. Immunohistochemically, neoplastic cells of hemangiopericytomas expressed vimentin as the sole intermediate filament protein and lacked alpha-smooth muscle or alpha-sarcomeric actins. 2D-GE revealed only beta and gamma actins, in proportions typical for fibroblastic tissues. Glomus tumors revealed vimentin and alpha-smooth muscle actin within glomus cells by immunohistochemical techniques and disclosed ultrastructurally distinct smooth muscle differentiation. Therefore hemangiopericytomas represent a distinct soft-tissue neoplasm with uniform morphologic, immunohistochemical, and biochemical features most likely related to glomus tumors, the former representing an aggressive and potentially malignant neoplasm of vascular smooth muscle cells and the latter a well-differentiated neoplasm of vascular smooth muscle cells. Because malignant hemangiopericytomas disclose smooth muscle differentiation by ultrastructure, but do not express alpha-smooth muscle actin, as normal pericytes and glomus cells, it is suggested that these neoplasms represent highly vascularized smooth muscle neoplasms, ie, poorly differentiated leiomyosarcomas derived from vascular smooth muscle cells or their equivalent, the pericytes, which have lost alpha-smooth muscle actin as a differentiation marker that is similar to many conventional poorly differentiated leiomyosarcomas. Images Figure 6 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:2158236

An Experimental Test of Differential Susceptibility to Parenting among Emotionally-Dysregulated Children in a Randomized Controlled Trial for Oppositional Behavior

ERIC Educational Resources Information Center

Scott, Stephen; O'Connor, Thomas G.

2012-01-01

Background: The concept of differential susceptibility has challenged the potential meaning of personal traits such as poor ability to regulate emotions. Under the traditional model of diathesis/stress, personal characteristics such as liability to angry outbursts are seen as essentially disadvantageous, emerging under duress in a way that is…

The Populus Class III HD ZIP transcription factor POPCORONA affects cell differentiation during secondary growth of woody stems

Treesearch

Juan Du; Eriko Miura; Marcel Robischon; Ciera Martinez; Andrew Groover

2011-01-01

The developmental mechanisms regulating cell differentiation and patterning during the secondary growth of woody tissues are poorly understood. Class III HD ZIP transcription factors are evolutionarily ancient and play fundamental roles in various aspects of plant development. Here we investigate the role of a Class III HD ZIP transcription factor, ...

GSK3 is a regulator of RAR-mediated differentiation

PubMed Central

Gupta, K; Gulen, F; Sun, L; Aguilera, R; Chakrabarti, A; Kiselar, J; Agarwal, MK; Wald, DN

2015-01-01

Acute myeloid leukemia (AML) is the most common form of leukemia in adults. Unfortunately, the standard therapeutic agents used for this disease have high toxicities and poor efficacy. The one exception to these poor outcomes is the use of the retinoid, all-trans retinoic acid (ATRA), for a rare subtype of AML (APL). The use of the differentiation agent, ATRA, in combination with low-dose chemotherapy leads to the long-term survival and presumed cure of 75–85% of patients. Unfortunately ATRA has not been clinically useful for other subtypes of AML. Though many non-APL leukemic cells respond to ATRA, they require significantly higher concentrations of ATRA for effective differentiation. Here we show that the combination of ATRA with glycogen synthase kinase 3 (GSK3) inhibition significantly enhances ATRA-mediated AML differentiation and growth inhibition. These studies have revealed that ATRA's receptor, the retinoic acid receptor (RAR), is a novel target of GSK3 phosphorylation and that GSK3 can impact the expression and transcriptional activity of the RAR. Overall, our studies suggest the clinical potential of ATRA and GSK3 inhibition for AML and provide a mechanistic framework to explain the promising activity of this combination regimen. PMID:22222598

Ethnic density and depressive symptoms among African Americans: threshold and differential effects across social and demographic subgroups.

PubMed

Bécares, Laia; Nazroo, James; Jackson, James

2014-12-01

We examined the association between Black ethnic density and depressive symptoms among African Americans. We sought to ascertain whether a threshold exists in the association between Black ethnic density and an important mental health outcome, and to identify differential effects of this association across social, economic, and demographic subpopulations. We analyzed the African American sample (n = 3570) from the National Survey of American Life, which we geocoded to the 2000 US Census. We determined the threshold with a multivariable regression spline model. We examined differential effects of ethnic density with random-effects multilevel linear regressions stratified by sociodemographic characteristics. The protective association between Black ethnic density and depressive symptoms changed direction, becoming a detrimental effect, when ethnic density reached 85%. Black ethnic density was protective for lower socioeconomic positions and detrimental for the better-off categories. The masking effects of area deprivation were stronger in the highest levels of Black ethnic density. Addressing racism, racial discrimination, economic deprivation, and poor services-the main drivers differentiating ethnic density from residential segregation-will help to ensure that the racial/ethnic composition of a neighborhood is not a risk factor for poor mental health.

Ethnic Density and Depressive Symptoms Among African Americans: Threshold and Differential Effects Across Social and Demographic Subgroups

PubMed Central

Nazroo, James; Jackson, James

2014-01-01

Objectives. We examined the association between Black ethnic density and depressive symptoms among African Americans. We sought to ascertain whether a threshold exists in the association between Black ethnic density and an important mental health outcome, and to identify differential effects of this association across social, economic, and demographic subpopulations. Methods. We analyzed the African American sample (n = 3570) from the National Survey of American Life, which we geocoded to the 2000 US Census. We determined the threshold with a multivariable regression spline model. We examined differential effects of ethnic density with random-effects multilevel linear regressions stratified by sociodemographic characteristics. Results. The protective association between Black ethnic density and depressive symptoms changed direction, becoming a detrimental effect, when ethnic density reached 85%. Black ethnic density was protective for lower socioeconomic positions and detrimental for the better-off categories. The masking effects of area deprivation were stronger in the highest levels of Black ethnic density. Conclusions. Addressing racism, racial discrimination, economic deprivation, and poor services—the main drivers differentiating ethnic density from residential segregation—will help to ensure that the racial/ethnic composition of a neighborhood is not a risk factor for poor mental health. PMID:25322307

Bottom-up limitation of a stream salamander in a detritus-based food web

Treesearch

Brent R. Johnson; J. Bruce Wallace

2005-01-01

The indirect effects that resources can have on higher trophic levels remain poorly understood for detritus-based ecosystems. Our objective was to examine effects of long-term terrestrial litter exclusion on a larval salamander, Eurycea wilderae, in a detritus-based stream. After 4 years of exclusion treatment, we conducted a mark-recapture study and...

Is Heterobasidion annosum Poorly Adapted to Incite Disease in Cool, Wet Environments?

Treesearch

Charles G. Shaw III

1989-01-01

An argument is advanced to suggest that infection and damage caused in coniferous forests by Heterobasidion annosum are markedly less severe, and survival of the fungus less common, under cool, wet conditions than in other climates. This premise is supported by the author's incisive insights, experience in southeastern Alaska, and data from this...

Two Perspectives on Inclusion in the United States

ERIC Educational Resources Information Center

Dudley-Marling, Curt; Burns, Mary Bridget

2014-01-01

The history of schooling for students with disabilities in the United States is marked by exclusion and, until the passage of the "Education for All Children Act" in the 1970s, a substantial number of students with disabilities were denied free public education and many more were poorly served by public schools. The requirement that all…

Alcelaphine gammaherpesvirus 1-induced malignant catarrhal fever in a Watusi (bos taurus africanus) steer in a North American game park

USDA-ARS?s Scientific Manuscript database

A 10 year-old Watusi (Bos taurus africanus) steer housed at a drive-through game park in Winston, Oregon developed severe clinical illness including: fever, marked nasal discharge, injected scleral and conjunctival membranes, plus oral hemorrhages and erosions. The animal responded poorly to support...

Teenagers: fertility control behavior and attitudes before and after abortion, childbearing or negative pregnancy test.

PubMed

Evans, J R; Selstad, G; Welcher, W H

1976-01-01

Following abortion or delivery, teenagers' knowledge and use of effective contraception improved markedly; but those who had negative pregnancy tests continued to take risks--and to get pregnant--subsequently. Most sexually active teenagers were poorly educated on the facts of reproduction, and began to have intercourse before seeking contraception.

Student Engagement in Social Justice at the "Universidad Centroamericana"

ERIC Educational Resources Information Center

Maita, Gianna

2015-01-01

Civic engagement of young people has evolved in Nicaragua as its political environment has changed. There is a marked difference between youth involvement in Nicaragua during the Sandinista Revolution from 1979 through the early 1980s, when it was a cultural norm for young people to serve in solidarity with the poor, and today, when universities…

The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis

PubMed Central

Zhang, Weiwei; Ran, Qian; Xiang, Yang; Zhong, Jiang F.; Li, Shengwen Calvin

2018-01-01

Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation. PMID:29765406

Scent marking behavior as an odorant communication in mice

PubMed Central

Arakawa, Hiroyuki; Blanchard, D. Caroline; Arakawa, Keiko; Dunlap, Christopher; Blanchard, Robert J.

2008-01-01

In rodents, where chemical signals play a particularly important role in determining intraspecies interactions including social dominance and intersexual relationships, various studies have shown that behavior is sensitive to conspecific odor cues. Mice use urinary scent marks for communication with individual conspecifics in many social contexts. Urinary scent involves genetic information about individuals such as species, sex, and individual identity as well as metabolic information such as social dominance, and reproductive and health status, which are mediated by chemical proteins in scent marks including the major histocompatibility complex and the major urinary proteins. The odor of the predator which can be considered to be a threatening signal for the prey also modulate mouse behavior in which scent marking is suppressed in response to the cat odor exposure in mice. These odorant chemicals are detected and recognized through two olfactory bulbs, the role of which in detection of chemosignals with biological relevant appears to be differential, but partly overlapped. Mice deposit scent marks toward conspecifics to maintain their social relationships, and inhibit scent marking in a context where natural predator, cat odor is contained. This suppression of scent marking is long-lasting (for at least 7 days) and context-dependent, while the odorant signaling to conspecifics tends to appear frequently (over 24 hrs but less than 7 days intervals) depending on the familiarity of each signal-recipient. It has been discussed that scent marking is a communicative behavior associated with territoriality toward conspecifics, indicating that the social signaling within species are sensitive to predator odor cues in terms of vulnerability to predation risk. PMID:18565582

Russell body gastritis with Dutcher bodies evaluated using magnification endoscopy

PubMed Central

Yorita, Kenji; Iwasaki, Takehiro; Uchita, Kunihisa; Kuroda, Naoto; Kojima, Koji; Iwamura, Shinichi; Tsutsumi, Yutaka; Ohno, Akinobu; Kataoka, Hiroaki

2017-01-01

Russell body gastritis (RBG) is an unusual type of chronic gastritis characterized by marked infiltration of Mott cells, which are plasma cells filled with spherical eosinophilic bodies referred to as Russell bodies. It was initially thought that Helicobacter pylori (H. pylori) infection was a major cause of RBG and that the infiltrating Mott cells were polyphenotypic; however, a number of cases of RBG without H. pylori infection or with monoclonal Mott cells have been reported. Thus, diagnostic difficulty exists in distinguishing RBG with monoclonal Mott cells from malignant lymphoma. Here, we report an unusual case of an 86-year-old-Japanese man with H. pylori-positive RBG. During the examination of melena, endoscopic evaluation confirmed a 13-mm whitish, flat lesion in the gastric antrum. Magnification endoscopy with narrow-band imaging suggested that the lesion was most likely a poorly differentiated adenocarcinoma. Biopsy findings were consistent with chronic gastritis with many Mott cells with intranuclear inclusions referred to as Dutcher bodies. Endoscopic submucosal dissection confirmed the diagnosis of RBG with kappa-restricted monoclonal Mott cells. Malignant lymphoma was unlikely given the paucity of cytological atypia and Ki-67 immunoreactivity of monoclonal Mott cells. This is the first reported case of RBG with endoscopic diagnosis of malignant tumor and the presence of Dutcher bodies. PMID:28874963

When cooperation begets cooperation: the role of key individuals in galvanizing support.

PubMed

McAuliffe, Katherine; Wrangham, Richard; Glowacki, Luke; Russell, Andrew F

2015-12-05

Life abounds with examples of conspecifics actively cooperating to a common end, despite conflicts of interest being expected concerning how much each individual should contribute. Mathematical models typically find that such conflict can be resolved by partial-response strategies, leading investors to contribute relatively equitably. Using a case study approach, we show that such model expectations can be contradicted in at least four disparate contexts: (i) bi-parental care; (ii) cooperative breeding; (iii) cooperative hunting; and (iv) human cooperation. We highlight that: (a) marked variation in contributions is commonplace; and (b) individuals can often respond positively rather than negatively to the contributions of others. Existing models have surprisingly limited power in explaining these phenomena. Here, we propose that, although among-individual variation in cooperative contributions will be influenced by differential costs and benefits, there is likely to be a strong genetic or epigenetic component. We then suggest that selection can maintain high investors (key individuals) when their contributions promote support by increasing the benefits and/or reducing the costs for others. Our intentions are to raise awareness in--and provide testable hypotheses of--two of the most poorly understood, yet integral, questions regarding cooperative ventures: why do individuals vary in their contributions and when does cooperation beget cooperation? © 2015 The Author(s).

Long noncoding AFAP1-antisense RNA 1 is upregulated and promotes tumorigenesis in gastric cancer.

PubMed

Ye, Fei; Gong, Yi; Chen, Xiangheng; Yu, Meiying; Zuo, Zhongkun; Pei, Dongni; Liu, Wei; Wang, Qunwei; Zhou, Jun; Duan, Lunxi; Zhang, Leiyi; Li, Xiaojing; Tang, Tenglong; Huang, Jiangsheng

2018-05-01

Long noncoding RNA serves important roles in gastric cancer (GC). However, the prognostic significance and tumorigenesis effect of AFAP1-antisense RNA 1 (AS1) in GC remain to be clarified. The present study was conducted in order to determine the expression level of AFAP1-AS1 by reverse transcription-quantitative polymerase chain reaction. It was demonstrated that AFAP1-AS1 expression level was higher in GC tissues in comparison with adjacent tissues. By analyzing 66 GC tissue specimens, AFAP1-AS1 expression level was found to be markedly associated with tumor size, clinical stage and differentiation. By performing multivariate Cox regression test, AFAP1-AS1 expression level was confirmed to be an independent factor for poor prognosis in patients with GC. Furthermore, SGC-7901 and BGC-823 cells were used for further investigation following transfection of an AFAP1-AS1 short hairpin RNA lentiviral vector. Knockdown of AFAP1-AS1 significantly inhibited GC cell proliferation, migration and invasion abilities in vitro . Finally, nude mice experiments confirmed that downregulation of AFAP1-AS1 in GC cells suppressed tumor growth in vivo . In conclusion, the results of the present study suggested that AFAP1-AS1 may serve as a valuable prognostic indicator and therapeutic target for GC.

Regulation of retinoic acid synthetic enzymes by WT1 and HDAC inhibitors in 293 cells.

PubMed

Li, Yifan; Wang, Lei; Ai, Weipeng; He, Nianhui; Zhang, Lin; Du, Jihui; Wang, Yong; Mao, Xingjian; Ren, Junqi; Xu, Dan; Zhou, Bei; Li, Rong; Mai, Liwen

2017-09-01

All-trans retinoic acid (atRA), which is mainly generated endogenously via two steps of oxidation from vitamin A (retinol), plays an indispensible role in the development of the kidney and many other organs. Enzymes that catalyze the oxidation of retinol to generate atRA, including aldehyde dehydrogenase 1 family (ALDH1)A1, ALDH1A2 and ALDH1A3, exhibit complex expression patterns at different stages of renal development. However, molecular triggers that control these differential expression levels are poorly understood. In this study, we provide in vitro evidence to demonstrate that Wilms' tumor 1 (WT1) negatively regulates the expression of the atRA synthetic enzymes, ALDH1A1, ALDH1A2 and ALDH1A3, in the 293 cell line, leading to significant blockage of atRA production. Furthermore, we demonstrate that the suppression of ALDH1A1 by WT1 can be markedly attenuated by histone deacetylase inhibitors (HDACis). Taken together, we provide evidence to indicate that WT1 and HDACs are strong regulators of endogenous retinoic acid synthetic enzymes in 293 cells, indicating that they may be involved in the regulation of atRA synthesis.

Evolution of depleted mantle: The lead perspective

NASA Astrophysics Data System (ADS)

Tilton, George R.

1983-07-01

Isotopic data have established that, compared to estimated bulk earth abundances, the sources of oceanic basaltic lavas have been depleted in large ion lithophile elements for at least several billions of years. Various data on the Tertiary-Mesozoic Gorgona komatiite and Cretaceous Oka carbonatite show that those rocks also sample depleted mantle sources. This information is used by analogy to compare Pb isotopic data from 2.6 billion year old komatiite and carbonatite from the Suomussalmi belt of eastern Finland and Munro Township, Ontario that are with associated granitic rocks and ores that should contain marked crustal components. Within experimental error no differences are detected in the isotopic composition of initial Pb in either of the rock suites. These observations agree closely with Sr and Nd data from other laboratories showing that depleted mantle could not have originated in those areas more than a few tenths of billions of years before the rocks were emplaced. On a world-wide basis the Pb isotope data are consistent with production of depleted mantle by continuous differentiation processes acting over approximately the past 3 billion years. The data show that Pb evolution is more complex than the simpler models derived from the Rb-Sr and Sm-Nd systems. The nature of the complexity is still poorly understood.

Transcriptome characterization of immune suppression from battlefield-like stress

PubMed Central

Muhie, S; Hammamieh, R; Cummings, C; Yang, D; Jett, M

2013-01-01

Transcriptome alterations of leukocytes from soldiers who underwent 8 weeks of Army Ranger training (RASP, Ranger Assessment and Selection Program) were analyzed to evaluate impacts of battlefield-like stress on the immune response. About 1400 transcripts were differentially expressed between pre- and post-RASP leukocytes. Upon functional analysis, immune response was the most enriched biological process, and most of the transcripts associated with the immune response were downregulated. Microbial pattern recognition, chemotaxis, antigen presentation and T-cell activation were among the most downregulated immune processes. Transcription factors predicted to be stress-inhibited (IRF7, RELA, NFκB1, CREB1, IRF1 and HMGB) regulated genes involved in inflammation, maturation of dendritic cells and glucocorticoid receptor signaling. Many altered transcripts were predicted to be targets of stress-regulated microRNAs. Post-RASP leukocytes exposed ex vivo to Staphylococcal enterotoxin B showed a markedly impaired immune response to this superantigen compared with pre-RASP leukocytes, consistent with the suppression of the immune response revealed by transcriptome analyses. Our results suggest that suppression of antigen presentation and lymphocyte activation pathways, in the setting of normal blood cell counts, most likely contribute to the poor vaccine response, impaired wound healing and infection susceptibility associated with chronic intense stress. PMID:23096155

Enhancement of solubility and antidiabetic effects of Repaglinide using spray drying technique in STZ-induced diabetic rats.

PubMed

Varshosaz, Jaleh; Minayian, Mohsen; Ahmadi, Mahdieh; Ghassami, Erfaneh

2017-09-01

The purpose of the study was to enhance the solubility of the poorly water-soluble drug, Repaglinide using spray drying based solid dispersion technique by different carriers including Eudragit E100, hydroxyl propyl cellulose Mw 80 000 and poly vinyl pyrollidone K30. Optimization of the best formulation was carried out according to drug solubility, release profile, particle size and angle of repose of the solid dispersions. The optimized sample was characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The morphology of the dispersions was studied by SEM. The blood glucose lowering effect of spray dried solid dispersions was studied in normal and streptozocin-induced diabetic rats. The results showed that Eudragit E100 in 1:3 ratio could enhance drug solubility by 100-fold. DSC studies indicated a marked change in melting point of the drug possibly due to strong hydrogen bonds between the drug and Eudragit, while FT-IR study did not show obvious interactions between them. According to XRPD results Repaglinide converted to an amorphous state in the spray dried dispersions. Spray dried Repaglinide reduced the blood glucose level significantly during the 8 h of obtaining blood samples in comparison with untreated drug (p < 0.05).

Differential correlation of suicide and homicide rates according to geographical areas: A study with population-level data.

PubMed

Fountoulakis, Konstantinos N; Gonda, Xenia

2017-03-01

The current study investigated the relationship of suicide and homicide rates internationally. WHO database mortality data for 82 countries concerning suicide, homicides, and cancer and traffic accidents as controls were used. The analysis included Pearson correlation and multiple linear regression analysis. Worldwide homicidal rates explained 55.42%, 43.86% and 41.7% of male and 22.0%, 22.14% and 13.25% of female suicides for 2000, 2005 and 2010 respectively. In Europe there was a positive correlation between male suicide rates and all homicide rates including homicide rates in both genders, in male victims, and in female victims. In America there is no significant correlation. In Asia there is a significant correlation of male suicidal rates only with homicide rates of female victims. We observed marked and interesting differences in the pattern of association between Europe and the Americas. Overall the current paper suggests that at least in some human populations, suicidality and homicidality share common etiopathogenetic substrates and could be triggered by the same internal or external events or might develop based on common genetic background. Empirically it has been suggested that suicide is related to higher living standards while murder is related to poor quality of life and lower living standards. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Localized zinc distribution in shark vertebrae suggests differential deposition during ontogeny and across vertebral structures.

PubMed

Raoult, Vincent; Howell, Nicholas; Zahra, David; Peddemors, Victor M; Howard, Daryl L; de Jonge, Martin D; Buchan, Benjamin L; Williamson, Jane E

2018-01-01

The development of shark vertebrae and the possible drivers of inter- and intra-specific differences in vertebral structure are poorly understood. Shark vertebrae are used to examine life-history traits related to trophic ecology, movement patterns, and the management of fisheries; a better understanding of their development would be beneficial to many fields of research that rely on these calcified structures. This study used Scanning X-ray Fluorescence Microscopy to observe zinc distribution within vertebrae of ten shark species from five different orders. Zinc was mostly localised within the intermedialis and was generally detected at levels an order of magnitude lower in the corpus calcareum. In most species, zinc concentrations were higher pre-birth mark, indicating a high rate of pre-natal zinc deposition. These results suggest there are inter-specific differences in elemental deposition within vertebrae. Since the deposition of zinc is physiologically-driven, these differences suggest that the processes of growth and deposition are potentially different in the intermedialis and corpus calcareum, and that caution should be taken when extrapolating information such as annual growth bands from one structure to the other. Together these results suggest that the high inter-specific variation in vertebral zinc deposition and associated physiologies may explain the varying effectiveness of ageing methodologies applied to elasmobranch vertebrae.

When cooperation begets cooperation: the role of key individuals in galvanizing support

PubMed Central

McAuliffe, Katherine; Wrangham, Richard; Glowacki, Luke; Russell, Andrew F.

2015-01-01

Life abounds with examples of conspecifics actively cooperating to a common end, despite conflicts of interest being expected concerning how much each individual should contribute. Mathematical models typically find that such conflict can be resolved by partial-response strategies, leading investors to contribute relatively equitably. Using a case study approach, we show that such model expectations can be contradicted in at least four disparate contexts: (i) bi-parental care; (ii) cooperative breeding; (iii) cooperative hunting; and (iv) human cooperation. We highlight that: (a) marked variation in contributions is commonplace; and (b) individuals can often respond positively rather than negatively to the contributions of others. Existing models have surprisingly limited power in explaining these phenomena. Here, we propose that, although among-individual variation in cooperative contributions will be influenced by differential costs and benefits, there is likely to be a strong genetic or epigenetic component. We then suggest that selection can maintain high investors (key individuals) when their contributions promote support by increasing the benefits and/or reducing the costs for others. Our intentions are to raise awareness in—and provide testable hypotheses of—two of the most poorly understood, yet integral, questions regarding cooperative ventures: why do individuals vary in their contributions and when does cooperation beget cooperation? PMID:26503685

ES1 is a mitochondrial enlarging factor contributing to form mega-mitochondria in zebrafish cones.

PubMed

Masuda, Takamasa; Wada, Yasutaka; Kawamura, Satoru

2016-03-01

Total mass of mitochondria increases during cell proliferation and differentiation through mitochondrial biogenesis, which includes mitochondrial proliferation and growth. During the mitochondrial growth, individual mitochondria have been considered to be enlarged independently of mitochondrial fusion. However, molecular basis for this enlarging process has been poorly understood. Cone photoreceptor cells in the retina possess large mitochondria, so-called mega-mitochondria that have been considered to arise via the enlarging process. Here we show that ES1 is a novel mitochondria-enlarging factor contributing to form mega-mitochondria in cones. ES1 is specifically expressed in cones and localized to mitochondria including mega-mitochondria. Knockdown of ES1 markedly reduced the mitochondrial size in cones. In contrast, ectopic expression of ES1 in rods significantly increased both the size of individual mitochondria and the total mass of the mitochondrial cluster without changing the number of them. RNA-seq analysis showed that ERRα and its downstream mitochondrial genes were significantly up-regulated in the ES1-expressing rods, suggesting facilitation of mitochondrial enlargement via ERRα-dependent processes. Furthermore, higher energy state was detected in the ES1-expressing rods, indicating that the enlarged mitochondria by ES1 are capable of producing high energy. ES1 is the mitochondrial protein that is first found to promote enlargement of individual mitochondria.

An in vivo model of epithelial to mesenchymal transition reveals a mitogenic switch

PubMed Central

Jahn, Stephan C.; Law, Mary E.; Corsino, Patrick E.; Parker, Nicole N.; Pham, Kien; Davis, Bradley J.; Lu, Jianrong; Law, Brian K.

2012-01-01

The epithelial to mesenchymal transition (EMT) is a process by which differentiated epithelial cells transition to a mesenchymal phenotype. EMT enables the escape of epithelial cells from the rigid structural constraints of the tissue architecture to a phenotype more amenable to cell migration and, therefore, invasion and metastasis. We characterized an in vivo model of EMT and discovered that marked changes in mitogenic signaling occurred during this process. DNA microarray analysis revealed that the expression of a number of genes varied significantly between post-EMT and pre-EMT breast cancer cells. Post-EMT cancer cells upregulated mRNA encoding c-Met and the PDGF and LPA receptors, and acquired increased responsiveness to HGF, PDGF, and LPA. This rendered the post-EMT cells responsive to the growth inhibitory effects of HGF, PDGF, and LPA receptor inhibitors/antagonists. Furthermore, post- EMT cells exhibited decreased basal Raf and Erk phosphorylation, and in comparison to pre-EMT cells, their proliferation was poorly inhibited by a MEK inhibitor. These studies suggest that therapies need to be designed to target both pre-EMT and post-EMT cancer cells and that signaling changes in post- EMT cells may allow them to take advantage of paracrine signaling from the stroma in vivo. PMID:22906417

Drawing for Traffic Marking Using Bidirectional Gradient-Based Detection with MMS LIDAR Intensity

NASA Astrophysics Data System (ADS)

Takahashi, G.; Takeda, H.; Nakamura, K.

2016-06-01

Recently, the development of autonomous cars is accelerating on the integration of highly advanced artificial intelligence, which increases demand for a digital map with high accuracy. In particular, traffic markings are required to be precisely digitized since automatic driving utilizes them for position detection. To draw traffic markings, we benefit from Mobile Mapping Systems (MMS) equipped with high-density Laser imaging Detection and Ranging (LiDAR) scanners, which produces large amount of data efficiently with XYZ coordination along with reflectance intensity. Digitizing this data, on the other hand, conventionally has been dependent on human operation, which thus suffers from human errors, subjectivity errors, and low reproductivity. We have tackled this problem by means of automatic extraction of traffic marking, which partially accomplished to draw several traffic markings (G. Takahashi et al., 2014). The key idea of the method was extracting lines using the Hough transform strategically focused on changes in local reflection intensity along scan lines. However, it failed to extract traffic markings properly in a densely marked area, especially when local changing points are close each other. In this paper, we propose a bidirectional gradient-based detection method where local changing points are labelled with plus or minus group. Given that each label corresponds to the boundary between traffic markings and background, we can identify traffic markings explicitly, meaning traffic lines are differentiated correctly by the proposed method. As such, our automated method, a highly accurate and non-human-operator-dependent method using bidirectional gradient-based algorithm, can successfully extract traffic lines composed of complex shapes such as a cross walk, resulting in minimizing cost and obtaining highly accurate results.

Focus prosody of telephone numbers in Tokyo Japanese.

PubMed

Lee, Yong-Cheol; Nambu, Satoshi; Cho, Sunghye

2018-05-01

Using production and perception experiments, this study examined whether the prosodic structure inherent to telephone numbers in Tokyo Japanese affects the realization of focus prosody as well as its perception. It was hypothesized that prosodic marking of focus differs by position within the digit groups of phone number strings. Overall, focus prosody of telephone numbers was not clearly marked, resulting in poor identification in perception. However, a difference between positions within digit groups was identified, reflecting a prosodic structure where one position is assigned an accentual peak instead of the other. The findings suggest that, conforming to a language-specific prosodic structure, focus prosody within a language can vary under the influence of a particular linguistic environment.

The role of beetle marks and flower colour on visitation by monkey beetles (hopliini) in the greater cape floral region, South Africa.

PubMed

Van Kleunen, Mark; Nänni, Ingrid; Donaldson, John S; Manning, John C

2007-12-01

A deviation from the classical beetle pollination syndrome of dull-coloured flowers with an unpleasant scent is found in the Greater Cape Floral Region of South Africa. Here, monkey beetles (Scarabaeidae) visit brightly coloured, odourless flowers with conspicuous dark spots and centres (beetle marks). The role of flower colour and markings in attracting monkey beetles is still poorly understood. Artificial model flowers with different marking patterns were used to test the effect of beetle marks on visitation by monkey beetles. To test whether monkey beetles are conditioned to the colour of the local matrix species, model flowers of different colours were placed in populations of three differently coloured species of Iridaceae. Among all three matrix species the presence of dark markings of some kind (either centres or spots) increased visitation rates but the different matrix species differed in whether the effect was due to a dark centre or to dark spots. Monkey beetles were not conditioned for the colour of the matrix species: model colour was not significant in the Hesperantha vaginata and in the Romulea monadelpha matrices, whereas yellow model flowers were preferred over orange ones in the orange-flowered Sparaxis elegans matrix. This study is the first to demonstrate that beetle marks attract pollinating monkey beetles in the Greater Cape Floral Region. In contrast to plants with the classical beetle pollination syndrome that use floral scent as the most important attractant of pollinating beetles, plants with the monkey beetle pollination syndrome rely on visual signals, and, in some areas at least, monkey beetles favour flowers with dark beetle markings over unmarked flowers.

Earth fissures and localized differential subsidence

USGS Publications Warehouse

Holzer, Thomas L.; Pampeyan, Earl H.

1981-01-01

Long linear tension cracks associated with declining groundwater levels at four sites in subsiding areas in south-central Arizona, Fremont Valley, California, and Las Vegas Valley, Nevada, occur near points of maximum convex-upward curvature in subsidence profiles oriented perpendicular to the cracks. Profiles are based on repeated precise vertical control surveys of lines of closely spaced bench marks. Association of these fissures with zones of localized differential subsidence indicates that linear earth fissures are caused by horizontal tensile strains probably resulting from localized differential compaction. Horizontal tensile strains across the fissures at the point of maximum convex-upward curvature, ranging from approximately 100 to 700 microstrains (0.01 to 0.07% per year), were indicated based on measurements with a tape or electronic distance meter.

Double dissociation of pharmacologically induced deficits in visual recognition and visual discrimination learning

PubMed Central

Turchi, Janita; Buffalari, Deanne; Mishkin, Mortimer

2008-01-01

Monkeys trained in either one-trial recognition at 8- to 10-min delays or multi-trial discrimination habits with 24-h intertrial intervals received systemic cholinergic and dopaminergic antagonists, scopolamine and haloperidol, respectively, in separate sessions. Recognition memory was impaired markedly by scopolamine but not at all by haloperidol, whereas habit formation was impaired markedly by haloperidol but only minimally by scopolamine. These differential drug effects point to differences in synaptic modification induced by the two neuromodulators that parallel the contrasting properties of the two types of learning, namely, fast acquisition but weak retention of memories versus slow acquisition but durable retention of habits. PMID:18685146

Double dissociation of pharmacologically induced deficits in visual recognition and visual discrimination learning.

PubMed

Turchi, Janita; Buffalari, Deanne; Mishkin, Mortimer

2008-08-01

Monkeys trained in either one-trial recognition at 8- to 10-min delays or multi-trial discrimination habits with 24-h intertrial intervals received systemic cholinergic and dopaminergic antagonists, scopolamine and haloperidol, respectively, in separate sessions. Recognition memory was impaired markedly by scopolamine but not at all by haloperidol, whereas habit formation was impaired markedly by haloperidol but only minimally by scopolamine. These differential drug effects point to differences in synaptic modification induced by the two neuromodulators that parallel the contrasting properties of the two types of learning, namely, fast acquisition but weak retention of memories versus slow acquisition but durable retention of habits.

Oligoclonal CD8+ T-cell expansion in patients with chronic hepatitis C is associated with liver pathology and poor response to interferon-alpha therapy.

PubMed

Manfras, Burkhard J; Weidenbach, Hans; Beckh, Karl-Heinz; Kern, Peter; Möller, Peter; Adler, Guido; Mertens, Thomas; Boehm, Bernhard O

2004-05-01

The role of CD8(+) T lymphocytes in chronic hepatitis C virus (HCV) infection and in liver injury with subsequent development of fibrosis and cirrhosis is poorly understood. To address this question, we performed a follow-up study including 27 chronically HCV-infected individuals. We determined clonality and phenotypes of circulating CD8(+) T cells employing TCRBV spectratyping. Antigen specificity was tested by rMHC-peptide tetramer staining and stimulation with recombinant HCV antigens. In addition, T-cell clonality and phenotypes were followed during the variable clinical response of interferon- (IFN) alpha treatment. We could demonstrate that CD8(+) T-cell expansions were significantly associated with liver fibrosis and cirrhosis. Likewise, increased oligoclonality of circulating CD8(+) T cells in chronic HCV infection was identified as an indicator for poor clinical response to IFN-alpha therapy. Moreover, we also found that IFN-alpha therapy enhanced the differentiation of CD8(+) T cells towards a late differentiation phenotype (CD28(-) CD57(+)). In cases of virus elimination the disappearance of expanded terminally differentiated CD8(+) cells was observed. Thus, this study identifies an association of clonal expansions of circulating CD8(+) T cells with liver pathology and provides a possible explanation for the fact that response to IFN-alpha therapy diminishes with the duration of infection.

Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation.

PubMed

Zheng, Xinde; Boyer, Leah; Jin, Mingji; Mertens, Jerome; Kim, Yongsung; Ma, Li; Ma, Li; Hamm, Michael; Gage, Fred H; Hunter, Tony

2016-06-10

How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.

A Temporal Chromatin Signature in Human Embryonic Stem Cells Identifies Regulators of Cardiac Development

PubMed Central

Paige, Sharon L.; Thomas, Sean; Stoick-Cooper, Cristi L.; Wang, Hao; Maves, Lisa; Sandstrom, Richard; Pabon, Lil; Reinecke, Hans; Pratt, Gabriel; Keller, Gordon; Moon, Randall T.; Stamatoyannopoulos, John; Murry, Charles E.

2012-01-01

Summary Directed differentiation of human embryonic stem cells (ESCs) into cardiovascular cells provides a model for studying molecular mechanisms of human cardiovascular development. Though it is known that chromatin modification patterns in ESCs differ markedly from those in lineage-committed progenitors and differentiated cells, the temporal dynamics of chromatin alterations during differentiation along a defined lineage have not been studied. We show that differentiation of human ESCs into cardiovascular cells is accompanied by programmed temporal alterations in chromatin structure that distinguish key regulators of cardiovascular development from other genes. We used this temporal chromatin signature to identify regulators of cardiac development, including the homeobox gene MEIS2. We demonstrate using the zebrafish model that MEIS2 is critical for proper heart tube formation and subsequent cardiac looping. Temporal chromatin signatures should be broadly applicable to other models of stem cell differentiation to identify regulators and provide key insights into major developmental decisions. PMID:22981225

Iatrogenic Subtotal Stenosis of the Right Subclavian Artery Treated With Percutaneous Transluminal Angioplasty

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

Smeenk, Robert M., E-mail: r.m.smeenk@asz.nl; Kock, Mark C. J. M.; Elgersma, Otto E. H.

2011-02-15

This report describes a rare vascular complication of surgical placement of a marking clip and a possible approach to problem solving. A 55-year-old patient presented with loss of sensation in the fingers and loss of peripheral pulsations in the right arm 4 days after right upper lobectomy for a pT2N1 moderately differentiated adenocarcinoma of the lung. Duplex examination and computed tomography were performed the same day and showed a subtotal stenosis of the right subclavian artery, which was caused by the surgical placement of a metal clip to mark the surgical boundary. Selective angiography was subsequently performed. Percutaneous transluminal angioplastymore » (PTA) successfully dilated the stenosis and pushed the clip off. Flow in the right subclavian artery (RSA) was completely restored as were neurology and peripheral pulses. In conclusion, arterial stenosis by a surgical (marking) clip may be feasibly treated with PTA.« less

Marking cell lineages in living tissues.

PubMed

Kurup, Smita; Runions, John; Köhler, Uwe; Laplaze, Laurent; Hodge, Sarah; Haseloff, Jim

2005-05-01

We have generated a novel genetic system to visualize cell lineages in living tissues at high resolution. Heat shock was used to trigger the excision of a specific transposon and activation of a fluorescent marker gene. A histone-YFP marker was used to allow identification of cell lineages and easy counting of cells. Constitutive expression of a green fluorescent membrane protein was used to provide a precise outline of all surrounding cells. Marked lineages can be induced from specific cells within the organism by targeted laser irradiation, and the fate of the marked cells can be followed non-invasively. We have used the system to map cell lineages originating from the initials of primary and lateral roots in Arabidopsis. The lineage marking technique enabled us to measure the differential contribution of primary root pericycle cell files to developing lateral root primordia. The majority of cells in an emerging lateral root primordium derive from the central file of pericycle founder cells while off-centre founder cells contribute only a minor proliferation of tissue near the base of the root. The system shows great promise for the detailed study of cell division during morphogenesis.

New Structural Patterns in Moribund Grammar: Case Marking in Heritage German

PubMed Central

Yager, Lisa; Hellmold, Nora; Joo, Hyoun-A; Putnam, Michael T.; Rossi, Eleonora; Stafford, Catherine; Salmons, Joseph

2015-01-01

Research treats divergences between monolingual and heritage grammars in terms of performance—‘L1 attrition,’ e.g., lexical retrieval—or competence—‘incomplete acquisition’, e.g., lack of overt tense markers (e.g., Polinsky, 1995; Sorace, 2004; Montrul, 2008; Schmid, 2010). One classic difference between monolingual and Heritage German is reduction in morphological case in the latter, especially loss of dative marking. Our evidence from several Heritage German varieties suggests that speakers have not merely lost case, but rather developed innovative structures to mark it. More specifically, Heritage German speakers produce dative forms in line with established patterns of Differential Object Marking (Bossong, 1985, 1991; Aissen, 2003), suggesting a reallocated mapping of case. We take this as evidence for innovative reanalysis in heritage grammars (Putnam and Sánchez, 2013). Following Kamp and Reyle (1993) and Wechsler (2011, 2014), the dative adopts a more indexical discourse function, forging a tighter connection between morphosyntax and semantic properties. Moribund grammars deploy linguistic resources in novel ways, a finding which can help move us beyond simple narratives of ‘attrition’ and ‘incomplete acquisition.’ PMID:26635649

ARTD1 regulates osteoclastogenesis and bone homeostasis by dampening NF-κB-dependent transcription of IL-1β

PubMed Central

Robaszkiewicz, Agnieszka; Qu, Chao; Wisnik, Ewelina; Ploszaj, Tomasz; Mirsaidi, Ali; Kunze, Friedrich A.; Richards, Peter J.; Cinelli, Paolo; Mbalaviele, Gabriel; Hottiger, Michael O.

2016-01-01

While ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1, formerly PARP1) and its enzymatic activity have been shown to be important for reprogramming and differentiation of cells, such as during adipogenesis, their role and mechanism in regulating osteoclastogenesis and bone homeostasis are largely unknown. Here, in cell culture-based RANKL-induced osteoclastogenesis models, we show that silencing of ARTD1 or inhibition of its enzymatic activity enhances osteoclast differentiation and function. As a consequence of ARTD1 silencing or inhibition, the recruitment of p65/RelA to the IL-1β promoter, which is associated with transcriptionally active histone marks, IL-1β expression and inflammasome-dependent secretion of IL-1β are enhanced. This subsequently promotes sustained induction of the transcription factor Nfatc1/A and osteoclastogenesis in an autocrine manner via the IL-1 receptor. In vivo, Artd1-deficient mice display significantly decreased bone mass as a consequence of increased osteoclast differentiation. Accordingly, the expression of osteoclast markers is enhanced in mutant compared to wild-type mice. Together, these results indicate that ARTD1 controls osteoclast development and bone remodelling via its enzymatic activity by modulating the epigenetic marks surrounding the IL-1β promoter and expression of IL-1β and subsequently also Nfatc1/A. PMID:26883084

Differentiating Adolescent Self-Injury from Adolescent Depression: Possible Implications for Borderline Personality Development

ERIC Educational Resources Information Center

Crowell, Sheila E.; Beauchaine, Theodore P.; Hsiao, Ray C.; Vasilev, Christina A.; Yaptangco, Mona; Linehan, Marsha M.; McCauley, Elizabeth

2012-01-01

Self-inflicted injury (SII) in adolescence marks heightened risk for suicide attempts, completed suicide, and adult psychopathology. Although several studies have revealed elevated rates of depression among adolescents who self injure, no one has compared adolescent self injury with adolescent depression on biological, self-, and informant-report…

The Origins of Understanding Self and Other: James Mark Baldwin's Theory.

ERIC Educational Resources Information Center

Muller, Ulrich; Runions, Kevin

2003-01-01

Offers psychologist Baldwin's theory as an approach to the development of social understanding emphasizing gradual differentiation of self and other and rooting this process in embodied activity within a social context. Argues that Baldwin's account provides a stronger starting point for conceptualizing the infant's discovery of other, self, and…

Profiling of dehydropyrrolizidine alkaloids and their N-oxides in herbarium-preserved specimens of Amsinckia species using HPLC-esi(+)MS

USDA-ARS?s Scientific Manuscript database

Species of the Amsinckia genus (Boraginaceae) are known to produce potentially hepato-, pneumo-, and/or genotoxic dehydropyrrolizidine alkaloids. However, the taxonomic differentiation of Amsinckia species can be very subtle and there seems to be marked differences in toxicity toward grazing livesto...

A SEPALLATA gene is involved in the development and ripening of strawberry (Fragaria x ananassa Duch.) fruit, a non-climacteric tissue

USDA-ARS?s Scientific Manuscript database

Climacteric and non-climacteric fruits have traditionally been viewed as representing two distinct programs of ripening associated with differential respiration and ethylene hormone effects. In climacteric fruits, such as tomato and banana, the ripening process is marked by increased respiration and...

Differentiating SLI from ADHD Using Children's Sentence Recall and Production of Past Tense Morphology

ERIC Educational Resources Information Center

Redmond, Sean M.

2005-01-01

Measures of sentence recall and past tense marking were used to examine the similarities and differences between children with Attention Deficit/Hyperactivity Disorder (ADHD), children with specific language impairment (SLI), and typically developing (TD) children. Both SLI and ADHD group means for sentence recall tasks were significantly lower…

Random-modulation differential absorption lidar based on semiconductor lasers and single photon counting for atmospheric CO2 sensing

NASA Astrophysics Data System (ADS)

Quatrevalet, M.; Ai, X.; Pérez-Serrano, A.; Adamiec, P.; Barbero, J.; Fix, A.; Rarity, J. G.; Ehret, G.; Esquivias, I.

2017-09-01

Carbon dioxide (CO2) is the major anthropogenic greenhouse gas contributing to global warming and climate change. Its concentration has recently reached the 400-ppm mark, representing a more than 40 % increase with respect to its level prior to the industrial revolution.

A new species and introgression in eastern Asian hemlocks (Pinaceae: Tusga)

Treesearch

Garth Holman; Peter Del Tredici; Nathan Havill; Nam Sook Lee; Richard Cronn; Sarah Mathews; Linda Raubeson; Christopher S. Campbell

2017-01-01

Species delimitation in Pinaceae is often challenged by limited morphological differentiation and introgression. In Tsuga (hemlocks), species delimitation has been most challenging among northeastern Asian taxa, where the species are weakly marked morphologically and range in number from three to five in previous studies. Two low-copy nuclear four-...

Selectivity in L1 Attrition: Differential Object Marking in Spanish Near-Native Speakers of English

ERIC Educational Resources Information Center

Chamorro, Gloria; Sturt, Patrick; Sorace, Antonella

2016-01-01

Previous research has shown L1 attrition to be restricted to structures at the interfaces between syntax and pragmatics, but not to occur with syntactic properties that do not involve such interfaces ("Interface Hypothesis", Sorace and Filiaci in "Anaphora resolution in near-native speakers of Italian." "Second Lang…

Direct evidence of megamammal-carnivore interaction decoded from bone marks in historical fossil collections from the Pampean region

PubMed Central

Chichkoyan, Karina Vanesa; Belinchón, Margarita; Lanata, José Luis; Moigne, Anne-Marie; Martínez-Navarro, Bienvenido

2017-01-01

Pleistocene South American megafauna has traditionally attracted the interest of scientists and the popular media alike. However, ecological interactions between the species that inhabited these ecosystems, such as predator-prey relationships or interspecific competition, are poorly known. To this regard, carnivore marks imprinted on the fossil bones of megamammal remains are very useful for deciphering biological activity and, hence, potential interspecific relationships among taxa. In this article, we study historical fossil collections housed in different European and Argentinean museums that were excavated during the 19th and early 20th centuries in the Pampean region, Argentina, in order to detect carnivore marks on bones of megamammals and provide crucial information on the ecological relationships between South American taxa during the Pleistocene. Our results indicate that the long bones of megafauna from the Pampean region (e.g., the Mylodontidae and Toxodontidae families) exhibit carnivore marks. Furthermore, long bones of medium-sized species and indeterminate bones also present punctures, pits, scores and fractures. Members of the large-carnivore guild, such as ursids, canids and even felids, are recognised as the main agents that inflicted the marks. We hypothesize that the analysed carnivore marks represent the last stages of megaherbivore carcass exploitation, suggesting full consumption of these animals by the same or multiple taxa in a hunting and/or scavenging scenario. Moreover, our observations provide novel insights that help further our understanding of the palaeoecological relationships of these unique communities of megamammals. PMID:28503369

Enhanced tenogenic differentiation and tendon-like tissue formation by CHIP overexpression in tendon-derived stem cells.

PubMed

Han, Weifeng; Chen, Lei; Liu, Junpeng; Guo, Ai

2017-04-01

The carboxyl terminus of Hsc70-interacting protein (CHIP, also known as STUB1) plays critical roles in the proliferation and differentiation of many types of cells. The potential function of CHIP in tendon-derived stem cells (TDSCs) remains largely unknown at present. Here, we investigated the effects of CHIP on tenogenic differentiation of TDSCs via lentivirus-mediated overexpression. Forced expression of CHIP induced morphological changes and significantly enhanced cell proliferation, as well as tendon differentiation in vitro. Upon stimulation with differentiation induction medium, CHIP-overexpressing TDSCs displayed significant inhibition of differentiation into osteogenic and adipogenic lineages. Subsequent implantation of TDSCs overexpressing CHIP with collagen sponges into nude mice induced a marked increase in ectopic tendon formation in vivo, compared with the control group. Our findings collectively suggest that CHIP is an important contributory factor to tenogenic tissue formation. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation

NASA Astrophysics Data System (ADS)

Kolodziej, Stephan; Kuvardina, Olga N.; Oellerich, Thomas; Herglotz, Julia; Backert, Ingo; Kohrs, Nicole; Buscató, Estel. La; Wittmann, Sandra K.; Salinas-Riester, Gabriela; Bonig, Halvard; Karas, Michael; Serve, Hubert; Proschak, Ewgenij; Lausen, Jörn

2014-05-01

The transcription factor Tal1 is a critical activator or repressor of gene expression in hematopoiesis and leukaemia. The mechanism by which Tal1 differentially influences transcription of distinct genes is not fully understood. Here we show that Tal1 interacts with the peptidylarginine deiminase IV (PADI4). We demonstrate that PADI4 can act as an epigenetic coactivator through influencing H3R2me2a. At the Tal1/PADI4 target gene IL6ST the repressive H3R2me2a mark triggered by PRMT6 is counteracted by PADI4, which augments the active H3K4me3 mark and thus increases IL6ST expression. In contrast, at the CTCF promoter PADI4 acts as a repressor. We propose that the influence of PADI4 on IL6ST transcription plays a role in the control of IL6ST expression during lineage differentiation of hematopoietic stem/progenitor cells. These results open the possibility to pharmacologically influence Tal1 in leukaemia.

Bifurcation in epigenetics: Implications in development, proliferation, and diseases

NASA Astrophysics Data System (ADS)

Jost, Daniel

2014-01-01

Cells often exhibit different and stable phenotypes from the same DNA sequence. Robustness and plasticity of such cellular states are controlled by diverse transcriptional and epigenetic mechanisms, among them the modification of biochemical marks on chromatin. Here, we develop a stochastic model that describes the dynamics of epigenetic marks along a given DNA region. Through mathematical analysis, we show the emergence of bistable and persistent epigenetic states from the cooperative recruitment of modifying enzymes. We also find that the dynamical system exhibits a critical point and displays, in the presence of asymmetries in recruitment, a bifurcation diagram with hysteresis. These results have deep implications for our understanding of epigenetic regulation. In particular, our study allows one to reconcile within the same formalism the robust maintenance of epigenetic identity observed in differentiated cells, the epigenetic plasticity of pluripotent cells during differentiation, and the effects of epigenetic misregulation in diseases. Moreover, it suggests a possible mechanism for developmental transitions where the system is shifted close to the critical point to benefit from high susceptibility to developmental cues.

Partial melting of lower oceanic crust gabbro: Constraints from poikilitic clinopyroxene primocrysts

NASA Astrophysics Data System (ADS)

Leuthold, Julien; Lissenberg, C. Johan; O'Driscoll, Brian; Karakas, Ozge; Falloon, Trevor; Klimentyeva, Dina N.; Ulmer, Peter

2018-03-01

Successive magma batches underplate, ascend, stall and erupt along spreading ridges, building the oceanic crust. It is therefore important to understand the processes and conditions under which magma differentiates at mid ocean ridges. Although fractional crystallization is considered to be the dominant mechanism for magma differentiation, open-system igneous complexes also experience Melting-Assimilation-Storage-Hybridization (MASH, Hildreth and Moorbath, 1988) processes. Here, we examine crystal-scale records of partial melting in lower crustal gabbroic cumulates from the slow-spreading Atlantic oceanic ridge (Kane Megamullion; collected with Jason ROV) and the fast-spreading East Pacific Rise (Hess Deep; IODP expedition 345). Clinopyroxene oikocrysts in these gabbros preserve marked intra-crystal geochemical variations that point to crystallization-dissolution episodes of the gabbro eutectic assemblage. Kane Megamullion and Hess Deep clinopyroxene core1 primocrysts and their plagioclase inclusions indicate crystallization from high temperature basalt (>1160 and >1200°C, respectively), close to clinopyroxene saturation temperature (<50% and <25% crystallization). Step-like compatible Cr (and co-varying Al) and incompatible Ti, Zr, Y and rare earth elements (REE) decrease from anhedral core1 to overgrown core2, while Mg# and Sr/Sr* ratios increase. We show that partial resorption textures and geochemical zoning result from partial melting of REE-poor lower oceanic crust gabbroic cumulate (protolith) following intrusion by hot primitive mantle-derived melt, and subsequent overgrowth crystallization (refertilization) from a hybrid melt. In addition, towards the outer rims of crystals, Ti, Zr, Y and the REE strongly increase and Al, Cr, Mg#, Eu/Eu* and Sr/Sr* decrease, suggesting crystallization either from late-stage percolating relatively differentiated melt or from in situ trapped melt. Intrusion of primitive hot reactive melt and percolation of interstitial differentiated melt are two distinct MASH processes in the lower oceanic crust. They are potentially fundamental mechanisms for generating the wide compositional variation observed in mid-ocean ridge basalts. We furthermore propose that such processes operate at both slow- and fast-spreading ocean ridges. Thermal numerical modelling shows that the degree of lower crustal partial melting at slow-spreading ridges can locally increase up to 50%, but the overall crustal melt volume is low (less than ca. 5% of total mantle-derived and crustal melts; ca. 20% in fast-spreading ridges).

CKIP-1 suppresses odontoblastic differentiation of dental pulp stem cells via BMP2 pathway and can interact with NRP1.

PubMed

Song, Yihua; Wang, Chenfei; Gu, Zhifeng; Cao, Peipei; Huang, Dan; Feng, Guijuan; Lian, Min; Zhang, Ye; Feng, Xingmei; Gao, Zhenran

2018-05-31

Casein kinase 2 interacting protein-1 (CKIP-1) is a recently discovered intracellular regulator of bone formation, muscle cell differentiation and tumor cell proliferation. Our study aims to identify the inhibition of BMP2-Smad1/5 signaling by CKIP-1 in odontoblastic differentiation of human dental pulp stem cells (DPSCs). DPSCs infected CKIP-1 siRNA or transfected CKIP-1 full-length plasmid were cultured in odontoblastic differentiation medium or added noggin (200 ng/mL) for 21 days. We examined the effects of CKIP-1 on odontoblastic differentiation, mineralized nodules formation and interaction by western blot, real-time polymerase chain reaction (RT-PCR), alkaline phosphatase (ALP) staining, alizarin red S staining and immunoprecipitation. Firstly, we have demonstrated that CKIP-1 expression markedly decreased time-dependently along with cell odontoblastic differentiation. Indeed, the silence of CKIP-1 up-regulated odontoblastic differentiation via BMP2-Smad1/5 signaling, while CKIP-1 over-expression had a negative effect on odontoblastic differentiation of DPSCs. Furthermore, CKIP-1 could interact with Neuropilin-1 (NRP1). This work provides data that it advocates a novel perception on odontoblastic differentiation of DPSCs. Therefore, inhibiting the expression of CKIP-1 may be of great significance to the development of dental caries.

Balancing medicine prices and business sustainability: analyses of pharmacy costs, revenues and profit shed light on retail medicine mark-ups in rural Kyrgyzstan

PubMed Central

2010-01-01

Background Numerous not-for-profit pharmacies have been created to improve access to medicines for the poor, but many have failed due to insufficient financial planning and management. These pharmacies are not well described in health services literature despite strong demand from policy makers, implementers, and researchers. Surveys reporting unaffordable medicine prices and high mark-ups have spurred efforts to reduce medicine prices, but price reduction goals are arbitrary in the absence of information on pharmacy costs, revenues, and profit structures. Health services research is needed to develop sustainable and "reasonable" medicine price goals and strategic initiatives to reach them. Methods We utilized cost accounting methods on inventory and financial information obtained from a not-for-profit rural pharmacy network in mountainous Kyrgyzstan to quantify costs, revenues, profits and medicine mark-ups during establishment and maintenance periods (October 2004-December 2007). Results Twelve pharmacies and one warehouse were established in remote Kyrgyzstan with < US $25,000 due to governmental resource-sharing. The network operated at break-even profit, leaving little room to lower medicine prices and mark-ups. Medicine mark-ups needed for sustainability were greater than originally envisioned by network administration. In 2005, 55%, 35%, and 10% of the network's top 50 products revealed mark-ups of < 50%, 50-99% and > 100%, respectively. Annual mark-ups increased dramatically each year to cover increasing recurrent costs, and by 2007, only 19% and 46% of products revealed mark-ups of < 50% and 50-99%, respectively; while 35% of products revealed mark-ups > 100%. 2007 medicine mark-ups varied substantially across these products, ranging from 32% to 244%. Mark-ups needed to sustain private pharmacies would be even higher in the absence of government subsidies. Conclusion Pharmacy networks can be established in hard-to-reach regions with little funding using public-private partnership, resource-sharing models. Medicine prices and mark-ups must be interpreted with consideration for regional costs of business. Mark-ups vary dramatically across medicines. Some mark-ups appear "excessive" but are likely necessary for pharmacy viability. Pharmacy financial data is available in remote settings and can be used towards determination of "reasonable" medicine price goals. Health systems researchers must document the positive and negative financial experiences of pharmacy initiatives to inform future projects and advance access to medicines goals. PMID:20626904

Balancing medicine prices and business sustainability: analyses of pharmacy costs, revenues and profit shed light on retail medicine mark-ups in rural Kyrgyzstan.

PubMed

Waning, Brenda; Maddix, Jason; Soucy, Lyne

2010-07-13

Numerous not-for-profit pharmacies have been created to improve access to medicines for the poor, but many have failed due to insufficient financial planning and management. These pharmacies are not well described in health services literature despite strong demand from policy makers, implementers, and researchers. Surveys reporting unaffordable medicine prices and high mark-ups have spurred efforts to reduce medicine prices, but price reduction goals are arbitrary in the absence of information on pharmacy costs, revenues, and profit structures. Health services research is needed to develop sustainable and "reasonable" medicine price goals and strategic initiatives to reach them. We utilized cost accounting methods on inventory and financial information obtained from a not-for-profit rural pharmacy network in mountainous Kyrgyzstan to quantify costs, revenues, profits and medicine mark-ups during establishment and maintenance periods (October 2004-December 2007). Twelve pharmacies and one warehouse were established in remote Kyrgyzstan with < US $25,000 due to governmental resource-sharing. The network operated at break-even profit, leaving little room to lower medicine prices and mark-ups. Medicine mark-ups needed for sustainability were greater than originally envisioned by network administration. In 2005, 55%, 35%, and 10% of the network's top 50 products revealed mark-ups of < 50%, 50-99% and > 100%, respectively. Annual mark-ups increased dramatically each year to cover increasing recurrent costs, and by 2007, only 19% and 46% of products revealed mark-ups of < 50% and 50-99%, respectively; while 35% of products revealed mark-ups > 100%. 2007 medicine mark-ups varied substantially across these products, ranging from 32% to 244%. Mark-ups needed to sustain private pharmacies would be even higher in the absence of government subsidies. Pharmacy networks can be established in hard-to-reach regions with little funding using public-private partnership, resource-sharing models. Medicine prices and mark-ups must be interpreted with consideration for regional costs of business. Mark-ups vary dramatically across medicines. Some mark-ups appear "excessive" but are likely necessary for pharmacy viability. Pharmacy financial data is available in remote settings and can be used towards determination of "reasonable" medicine price goals. Health systems researchers must document the positive and negative financial experiences of pharmacy initiatives to inform future projects and advance access to medicines goals.

High-grade poorly differentiated neuroendocrine carcinoma of the breast with low oncotype Dx recurrence score: A case report.

PubMed

Munoz-Zuluaga, Carlos A; Kotiah, Sandy; Studeman, Kimberley D

2017-01-01

Primary neuroendocrine carcinoma of the breast (NECB) is a rare malignant tumor with controversial biological behavior and a lack of data guiding treatment decisions due to its scarcity. Cancer gene-expression profiling tests provide a better indication of clinical prognosis and help determine the best clinical management versus the traditional clinical and pathological parameters. This is a report of a NECB with a genetic assay that showed a low-risk tumor despite high-grade and poorly differentiated histopathological features. Patient outcomes correlate with the low risk classification without the need for adjuvant chemotherapy despite the standard clinical-pathologic approach. Analysis of cancer related genes expression and outcomes in historical NECB may elucidate new insight of this rare disease.

Induction of suppression through human T cell interactions.

PubMed

Lydyard, P M; Hayward, A R

1980-02-01

Concanavalin A (Con A) activated T cells, devoid of cells bearing Fc receptors for IgG (T - TG) help human B lymphocytes to differentiate into plasma cells (PC) in response to pokeweed mitogen (PWM). PC differentiation is reduced when adult T cells are added to such cultures. The radiosensitivity of suppression and the radioresistance of help enabled us to show that adult T cells include a suppressor-precursor which is activated by irradiated Con A-precultured T cells. Newborn T cells which include active suppressors, are both poor stimulators of suppressor-precursors and poor helpers of B cells. Our results suggest that at least two cells may mediate Con A-induced suppression, one which suppresses directly and is radiosensitive and another which is radioresistant and stimulates suppressor-precursors in a target population of T cells.

Retinoblastoma in the adolescent. Unusual clinical and histopathology findings.

PubMed

Hernández-Ayuso, I; Ríos y Valles-Valles, D; Lome-Maldonado, C; Gómez-Leal, A; Rodríguez-Martínez, H A; Rodríguez-Reyes, A A

2016-03-01

A 17-year- old male with 2years history of an intraocular mass and progressive visual loss of the left eye. Spontaneous sclera rupture occurred during enucleation. Microscopic evaluation with H-E, PAS and immunohistochemistry (NSE, GAFP, SYN, CD99) revealed a small blue round cell malignant neoplasm with extensive necrosis and apoptosis. The optic nerve, ciliary body, choroid, anterior chamber, and sclera were infiltrated. SYN was positive and CD99 was negative in neoplastic cells, consistent with a poorly differentiated retinoblastoma. Retinoblastoma is the most frequent primary intraocular malignant tumour in childhood, but occasionally older patients can be affected. Immunohistochemistry is mandatory in poorly differentiated retinoblastomas. Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

Expression of CDX-2 and Ki-67 in different grades of colorectal adenocarcinomas.

PubMed

Sen, Anway; Mitra, Sumit; Das, Ram Narayan; Dasgupta, Shatavisha; Saha, Koushik; Chatterjee, Uttara; Mukherjee, Krishnendu; Datta, Chhanda; Chattopadhyay, Bitan K

2015-01-01

CDX2 is a caudal homeobox gene essential for intestinal differentiation and is specifically expressed in colorectal adenocarcinomas. Its role in colorectal carcinogenesis is not fully elucidated. To study the expression pattern of CDX2 and Ki-67 in different grades of colorectal adenocarcinomas and to observe the relationship of their staining patterns in various tumor stages and to look for correlation if any, between Ki-67 labeling index (Ki-67 LI) and CDX2 expression. A total of 74 cases were enrolled. Detailed clinical profile, peroperative findings, histological grading and staging were noted. Immunohistochemistry for CDX2 and Ki-67 was done, and Ki-67 LI was calculated. CDX2 staining was graded semi-quantitatively, and statistical analysis was done. Age of presentation ranged from 20 to 75 years, and the male:female ratio was 1.83:1. There were 8, 47 and 13 cases of well, moderate and poorly differentiated adenocarcinomas, respectively. The mean Ki-67 LI of well, moderate and poorly differentiated adenocarcinomas were 14.25, 31.34 and 43.08 respectively, and their difference was statistically significant, correlation was also noted with stage. CDX2 expression appeared to be stronger in poorly differentiated cases, but there was no significant difference in its expression in the different grades and stages. There was no correlation between Ki-67 LI and CDX2 immunostaining pattern. The lymph node metastasis showed CDX2 positivity in all the cases. Expression of CDX2 does not significantly change with the grade of colorectal adenocarcinomas. However, it is an important diagnostic marker in metastatic colonic lesions. The Ki-67 LI, on the other hand, showed a strong correlation with histopathological grades.

Reevaluation and reclassification of resected lung carcinomas originally diagnosed as squamous cell carcinoma using immunohistochemical analysis

PubMed Central

Kadota, Kyuichi; Nitadori, Jun-ichi; Rekhtman, Natasha; Jones, David R.; Adusumilli, Prasad S.; Travis, William D.

2015-01-01

Currently, non-small cell lung carcinomas are primarily classified by light microscopy. However, recent studies have shown that poorly-differentiated tumors are more accurately classified by immunohistochemistry. In this study, we investigated the use of immunohistochemical analysis in reclassifying lung carcinomas that were originally diagnosed as squamous cell carcinoma. Tumor slides and blocks were available for histologic evaluation, and tissue microarrays were constructed from 480 patients with resected lung carcinomas originally diagnosed as squamous cell carcinoma between 1999 and 2009. Immunohistochemistry for p40, p63, thyroid transcription factor-1 (TTF-1; clone SPT24 and 8G7G3/1), Napsin A, Chromogranin A, Synaptophysin, and CD56 were performed. Staining intensity (weak, moderate, or strong) and distribution (focal or diffuse) were also recorded. Of all, 449 (93.5%) patients were confirmed as having squamous cell carcinomas; the cases were mostly diffusely positive for p40 and negative for TTF-1 (8G7G3/1). Twenty cases (4.2%) were reclassified as adenocarcinoma since they were positive for TTF-1 (8G7G3/1 or SPT24) with either no or focal p40 expression, and all of them were poorly-differentiated with squamoid morphology. In addition, 1 case was reclassified as adenosquamous carcinoma, 4 cases as large cell carcinoma, 4 cases as large cell neuroendocrine carcinoma, and 2 cases as small cell carcinoma. In poorly-differentiated non-small cell lung carcinomas, an accurate distinction between squamous cell carcinoma and adenocarcinoma cannot be reliably determined by morphology alone and requires immunohistochemical analysis, even in resected specimens. Our findings suggest that TTF-1 8G7G3/1 may be better suited as the primary antibody in differentiating adenocarcinoma from squamous cell carcinoma. PMID:25871623

Antiangiogenic Tyrosine Kinase Inhibitors: Occurrence and Risk Factors of Hemoptysis in Refractory Thyroid Cancer.

PubMed

Lamartina, Livia; Ippolito, S; Danis, M; Bidault, F; Borget, I; Berdelou, A; Al Ghuzlan, A; Hartl, D; Blanchard, P; Terroir, M; Deandreis, D; Schlumberger, M; Baudin, E; Leboulleux, S

2016-07-01

Antiangiogenic tyrosine kinase inhibitors (TKIs) are the mainstay of advanced thyroid cancer (TC) treatment. Concern is rising about TKI-related toxicity. To determine the incidence and to investigate the risk factors of hemoptysis in TC patients during TKI treatment. We analyzed consecutive TC patients treated with TKI in our center between 2005 and 2013 and performed an independent review of computed tomography scan images for airway invasion assessment. Occurrence of grade 1-2 or grade 3-5 hemoptysis according to Common Terminology Criteria for Adverse Events version 4.03 and risk factors for hemoptysis were investigated. A total of 140 patients (89 males; median age, 52 y) with medullary (56%), differentiated (33%), and poorly differentiated (11%) TC were enrolled. Thyroidectomy±neck dissection was performed in 123 patients and neck/mediastinum external-beam radiotherapy in 41 (32% with therapeutic purpose and 68% with adjuvant purpose). Patients received from 1 to 4 lines of TKI (median 1). Median follow-up was 24 months. Airway invasion was found in 65 (46%) cases. Hemoptysis occurred in 9 patients: grade 1-2 in 7 cases (5%) and grade 3-5 in 2 (1.4%) cases (fatal in 1). Hemoptysis was associated with presence of airway invasion (P = .04), poorly differentiated pathology (P = .03), history of therapeutic external-beam radiotherapy (P = .003), and thyroidectomy without neck dissection (P = .02). Airway invasion, poorly differentiated pathology, therapeutic external-beam radiotherapy, and thyroidectomy without neck dissection are associated with and increased risk of hemoptysis in TC patients during antiangiogenic TKI treatment. Further research is needed to confirm this data and to sort out interactions between these risk factors. A careful assessment of airway invasion is mandatory before TKI introduction.

A Silvicultural Evaluation of Four Methods of Marking Second-growth Northern Hardwood Stands

Treesearch

Rodney D. Jacobs

1966-01-01

Second-growth northern hardwood stands occupy an important segment of the commercial forest land of Upper Michigan and northern Wisconsin. The size- and age-class distributions and species composition of these stands vary considerably, but under all conditions most of the trees are highly defective or poorly formed or of an undesirable species. Forest managers...

Security Cooperation Activities: Strengthening a Partner Military and its Governing Institutions

DTIC Science & Technology

2016-05-26

governments suffered from economic instability , corruption, poor rule of law, and low administration of justice. Government and economic stability ...types of programs applied. Conditions defining allied state characteristics are military structure, government polity rating, and economic stability ...regional instability . Dr. Michael Mihalka and Mr. Mark Wilcox covered the trends in liberal democracy in the South Caucasus in light of economic

Bowel obsession syndrome in a patient with ulcerative colitis.

PubMed

Porcelli, Piero; Leandro, Gioacchino

2007-01-01

Gastroenterologists are often faced with the diagnostic problem of differentiating acute symptoms of ulcerative colitis from functional intestinal disorders. Bowel obsession syndrome (BOS) is an OCD-like, functional syndrome characterized by fear of fecal incontinence and compulsive behaviors of evacuation-checking. Only sparse case studies on treatment of BOS with antidepressants have been published. This is the first study on successful psychotherapy of a male patient with ulcerative colitis overlapping functional bowel symptoms and marked symptoms of BOS. Clinical recognition of BOS may help clinicians in differential diagnosis, prevent unnecessary investigations, and give patients the most appropriate treatment.

Stabilization of computational procedures for constrained dynamical systems

NASA Technical Reports Server (NTRS)

Park, K. C.; Chiou, J. C.

1988-01-01

A new stabilization method of treating constraints in multibody dynamical systems is presented. By tailoring a penalty form of the constraint equations, the method achieves stabilization without artificial damping and yields a companion matrix differential equation for the constraint forces; hence, the constraint forces are obtained by integrating the companion differential equation for the constraint forces in time. A principal feature of the method is that the errors committed in each constraint condition decay with its corresponding characteristic time scale associated with its constraint force. Numerical experiments indicate that the method yields a marked improvement over existing techniques.

Proteomic Characterization of Annexin l (ANX1) and Heat Shock Protein 27 (HSP27) as Biomarkers for Invasive Hepatocellular Carcinoma Cells.

PubMed

Wang, Ruo-Chiau; Huang, Chien-Yu; Pan, Tai-Long; Chen, Wei-Yu; Ho, Chun-Te; Liu, Tsan-Zon; Chang, Yu-Jia

2015-01-01

To search for reliable biomarkers and drug targets for management of hepatocellular carcinoma (HCC), we performed a global proteomic analysis of a pair of HCC cell lines with distinct differentiation statuses using 2-DE coupled with MALDI-TOF MS. In total, 106 and 55 proteins were successfully identified from the total cell lysate and the cytosolic, nuclear and membrane fractions in well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) HCC clonal variants, respectively. Among these proteins, nine spots corresponding to proteins differentially expressed between HCC cell types were selected and confirmed by immunofluorescence staining and western blotting. Notably, Annexin 1 (ANX1), ANX-2, vimentin and stress-associated proteins, such as GRP78, HSP75, HSC-70, protein disulfide isomerase (PDI), and heat shock protein-27 (HSP27), were exclusively up-regulated in SK-Hep-1 cells. Elevated levels of ANX-4 and antioxidant/metabolic enzymes, such as MnSOD, peroxiredoxin, NADP-dependent isocitrate dehydrogenase, α-enolase and UDP-glucose dehydrogenase, were observed in HepG2 cells. We functionally demonstrated that ANX1 and HSP27 were abundantly overexpressed only in highly invasive types of HCC cells, such as Mahlavu and SK-Hep-1. Knockdown of ANX1 or HSP27 in HCC cells resulted in a severe reduction in cell migration. The in-vitro observations of ANX1 and HSP27 expressions in HCC sample was demonstrated by immunohistochemical stains performed on HCC tissue microarrays. Poorly differentiated HCC tended to have stronger ANX1 and HSP27 expressions than well-differentiated or moderately differentiated HCC. Collectively, our findings suggest that ANX1 and HSP27 are two novel biomarkers for predicting invasive HCC phenotypes and could serve as potential treatment targets.

Paclitaxel Impairs Adipose Stem Cell Proliferation and Differentiation

PubMed Central

Choron, Rachel L.; Chang, Shaohua; Khan, Sophia; Villalobos, Miguel A.; Zhang, Ping; Carpenter, Jeffrey P.; Tulenko, Thomas N.; Liu, Yuan

2015-01-01

BACKGROUND Cancer patients with chemotherapy-induced immunosuppression have poor surgical site wound healing. Prior literature supports the use of human adipose-derived stem cell (hASC) lipoinjection to improve wound healing. It has been established multipotent hASCs facilitate neovascularization, accelerated epithelialization, and wound closure in animal models. While hASC wound therapy may benefit surgical cancer patients, the chemotherapeutic effects on hASCs are unknown. We hypothesized Paclitaxel, a chemotherapeutic agent, impairs hASC growth, multipotency, and induces apoptosis. METHODS hASCs were isolated and harvested from consented, chemotherapy and radiation naïve patients. Growth curves, MTT, and EdU assays measured cytotoxicity and proliferation. Oil-Red-O stain, Alazarin-Red stain, Matrigel tube-formation assay, and qPCR analyzed hASC differentiation. Annexin V assay measured apoptosis. Immunostaining and Western blot determined TNF-α expression. RESULTS hASCs were selectively more sensitive to Paclitaxel (0.01μM–30μM) than fibroblasts (p<0.05). After 12 days, Paclitaxel caused hASC growth arrest whereas control hASCs proliferated (p=0.006). Paclitaxel caused an 80.6% reduction in new DNA synthesis (p<0.001). Paclitaxel severely inhibited endothelial differentiation and capillary-like tube formation. Differentiation markers LPL (adipogenic), alkaline phosphatase (osteogenic), CD31 and vWF (endothelial) were significantly decreased (all: p<0.05) confirming Paclitaxel impaired differentiation. Paclitaxel was also found to induce apoptosis and TNF-α was up-regulated in Paclitaxel-treated hASCs (p<0.001). CONCLUSION Paclitaxel is more cytotoxic to hASCs than fibroblasts. Paclitaxel inhibits hASC proliferation, differentiation, and induces apoptosis, possibly through the TNF-α pathway. Paclitaxel’s severe inhibition of endothelial differentiation indicates neovascularization disruption, possibly causing poor wound healing in cancer patients receiving chemotherapy. PMID:25891676

An Analysis of Oral Reading Errors and Its Implications for Improvement of Reading Instruction. Technical Report No. 50.

ERIC Educational Resources Information Center

Au, Kathryn H.

The oral reading errors of 15 second graders were analyzed to find out if strategies used by good and poor readers could be differentiated. Patterns of errors were identified, and it was found that good readers often used context cues, while poor readers relied heavily on visual-phonic information. It was also possible to identify good and poor…

Developmental Trajectories for Children With Dyslexia and Low IQ Poor Readers

PubMed Central

2016-01-01

Reading difficulties are found in children with both high and low IQ and it is now clear that both groups exhibit difficulties in phonological processing. Here, we apply the developmental trajectories approach, a new methodology developed for studying language and cognitive impairments in developmental disorders, to both poor reader groups. The trajectory methodology enables identification of atypical versus delayed development in datasets gathered using group matching designs. Regarding the cognitive predictors of reading, which here are phonological awareness, phonological short-term memory (PSTM) and rapid automatized naming (RAN), the method showed that trajectories for the two groups diverged markedly. Children with dyslexia showed atypical development in phonological awareness, while low IQ poor readers showed developmental delay. Low IQ poor readers showed atypical PSTM and RAN development, but children with dyslexia showed developmental delay. These divergent trajectories may have important ramifications for supporting each type of poor reader, although all poor readers showed weakness in all areas. Regarding auditory processing, the developmental trajectories were very similar for the two poor reader groups. However, children with dyslexia demonstrated developmental delay for auditory discrimination of Duration, while the low IQ children showed atypical development on this measure. The data show that, regardless of IQ, poor readers have developmental trajectories that differ from typically developing children. The trajectories approach enables differences in trajectory classification to be identified across poor reader group, as well as specifying the individual nature of these trajectories. PMID:27110928

Intensity ratio curve analysis of small renal masses on T2-weighted magnetic resonance imaging: Differentiation of fat-poor angiomyolipoma from renal cell carcinoma.

PubMed

Moriyama, Shingo; Yoshida, Soichiro; Tanaka, Hajime; Tanaka, Hiroshi; Yokoyama, Minato; Ishioka, Junichiro; Matsuoka, Yoh; Saito, Kazutaka; Kihara, Kazunori; Fujii, Yasuhisa

2018-03-25

To assess the diagnostic ability of a pixel intensity-based analysis in evaluating the magnetic resonance imaging characteristics of small renal masses, especially in differentiating fat-poor angiomyolipoma from renal cell carcinoma. T2-weighted images from 121 solid small renal masses (<4 cm) without visible fat (14 fat-poor angiomyolipomas, 92 clear cell renal cell carcinomas, six chromophobe renal cell carcinomas and nine papillary renal cell carcinomas) were retrospectively evaluated. An intensity ratio curve was plotted using intensity ratios, which were ratios of signal intensities of tumor pixels (each pixel along a linear region of interest drawn across the renal tumor on T2-weighted image) to the signal intensity of a normal renal cortex. The diagnostic ability of the intensity ratio curve analysis was evaluated. The tumors were classified into three types: intensity ratio fat-poor angiomyolipoma (n = 19) with no pseudocapsule, iso-low intensity and no heterogeneity; intensity ratio clear cell renal cell carcinoma (n = 76) with a pseudocapsule, iso-high intensity and heterogeneity; and other type of intensity ratio (n = 26), including tumors that did not fall into the above two categories. The sensitivity/specificity/accuracy of the intensity ratio curve analysis in diagnosing fat-poor angiomyolipoma was 93%/94%/94%, respectively. When the intensity ratio curve analysis was applied only to the tumor with undetermined radiological diagnosis, the sensitivity for diagnosing fat-poor angiomyolipoma compared with subjective reading alone significantly improved (93% vs 50%; P = 0.014). Our novel semiquantitative model for combined assessment of key features of fat-poor angiomyolipoma, including low intensity, homogeneity and absence of a pseudocapsule on T2-weighted image, might make diagnosis of fat-poor angiomyolipoma more accurate. © 2018 The Japanese Urological Association.

The RB-related gene Rb2/p130 in neuroblastoma differentiation and in B-myb promoter down-regulation.

PubMed

Raschellà, G; Tanno, B; Bonetto, F; Negroni, A; Claudio, P P; Baldi, A; Amendola, R; Calabretta, B; Giordano, A; Paggi, M G

1998-05-01

The retinoblastoma family of nuclear factors is composed of RB, the prototype of the tumour suppressor genes and of the strictly related genes p107 and Rb2/p130. The three genes code for proteins, namely pRb, p107 and pRb2/p130, that share similar structures and functions. These proteins are expressed, often simultaneously, in many cell types and are involved in the regulation of proliferation and differentiation. We determined the expression and the phosphorylation of the RB family gene products during the DMSO-induced differentiation of the N1E-115 murine neuroblastoma cells. In this system, pRb2/p130 was strongly up-regulated during mid-late differentiation stages, while, on the contrary, pRb and p107 resulted markedly decreased at late stages. Differentiating N1E-115 cells also showed a progressive decrease in B-myb levels, a proliferation-related protein whose constitutive expression inhibits neuronal differentiation. Transfection of each of the RB family genes in these cells was able, at different degrees, to induce neuronal differentiation, to inhibit [3H]thymidine incorporation and to down-regulate the activity of the B-myb promoter.

Cellular network entropy as the energy potential in Waddington's differentiation landscape

PubMed Central

Banerji, Christopher R. S.; Miranda-Saavedra, Diego; Severini, Simone; Widschwendter, Martin; Enver, Tariq; Zhou, Joseph X.; Teschendorff, Andrew E.

2013-01-01

Differentiation is a key cellular process in normal tissue development that is significantly altered in cancer. Although molecular signatures characterising pluripotency and multipotency exist, there is, as yet, no single quantitative mark of a cellular sample's position in the global differentiation hierarchy. Here we adopt a systems view and consider the sample's network entropy, a measure of signaling pathway promiscuity, computable from a sample's genome-wide expression profile. We demonstrate that network entropy provides a quantitative, in-silico, readout of the average undifferentiated state of the profiled cells, recapitulating the known hierarchy of pluripotent, multipotent and differentiated cell types. Network entropy further exhibits dynamic changes in time course differentiation data, and in line with a sample's differentiation stage. In disease, network entropy predicts a higher level of cellular plasticity in cancer stem cell populations compared to ordinary cancer cells. Importantly, network entropy also allows identification of key differentiation pathways. Our results are consistent with the view that pluripotency is a statistical property defined at the cellular population level, correlating with intra-sample heterogeneity, and driven by the degree of signaling promiscuity in cells. In summary, network entropy provides a quantitative measure of a cell's undifferentiated state, defining its elevation in Waddington's landscape. PMID:24154593

Changes in the regulation of heat shock gene expression in neuronal cell differentiation.

PubMed

Oza, Jay; Yang, Jingxian; Chen, Kuang Yu; Liu, Alice Y-C

2008-01-01

Neuronal differentiation of the NG108-15 neuroblastoma-glioma hybrid cells is accompanied by a marked attenuation in the heat shock induction of the Hsp70-firefly luciferase reporter gene activity. Analysis of the amount and activation of heat shock factor 1, induction of mRNA(hsp), and the synthesis and accumulation of heat shock proteins (HSPs) in the undifferentiated and differentiated cells suggest a transcriptional mechanism for this attenuation. Concomitant with a decreased induction of the 72-kDa Hsp70 protein in the differentiated cells, there is an increased abundance of the constitutive 73-kDa Hsc70, a protein known to function in vesicle trafficking. Assessment of sensitivity of the undifferentiated and differentiated cells against stress-induced cell death reveals a significantly greater vulnerability of the differentiated cells toward the cytotoxic effects of arsenite and glutamate/glycine. This study shows that changes in regulation of the HSP and HSC proteins are components of the neuronal cell differentiation program and that the attenuated induction of HSPs likely contributes to neuronal vulnerability whereas the increased expression of Hsc70 likely has a role in neural-specific functions.

Selective resistance of CD44hi T cells to p53-dependent cell death results in persistence of immunologic memory after total body irradiation.

PubMed

Yao, Zhenyu; Jones, Jennifer; Kohrt, Holbrook; Strober, Samuel

2011-10-15

Our previous studies showed that treatment of mice with total body irradiation (TBI) or total lymphoid tissue irradiation markedly changes the balance of residual T cell subsets to favor CD4(+)CD44(hi) NKT cells because of the differential resistance of the latter subset to cell death. The object of the current study was to further elucidate the changed balance and mechanisms of differential radioresistance of T cell subsets after graded doses of TBI. The experimental results showed that CD4(+) T cells were markedly more resistant than CD8(+) T cells, and CD44(hi) T cells, including NKT cells and memory T cells, were markedly more resistant than CD44(lo) (naive) T cells. The memory T cells immunized to alloantigens persisted even after myeloablative (1000 cGy) TBI and were able to prevent engraftment of bone marrow transplants. Although T cell death after 1000 cGy was prevented in p53(-/-) mice, there was progressive T cell death in p53(-/-) mice at higher doses. Although p53-dependent T cell death changed the balance of subsets, p53-independent T cell death did not. In conclusion, resistance of CD44(hi) T cells to p53-dependent cell death results in the persistence of immunological memory after TBI and can explain the immune-mediated rejection of marrow transplants in sensitized recipients.

The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes.

PubMed

Xing, Fan; Luan, Yizhao; Cai, Jing; Wu, Sihan; Mai, Jialuo; Gu, Jiayu; Zhang, Haipeng; Li, Kai; Lin, Yuan; Xiao, Xiao; Liang, Jiankai; Li, Yuan; Chen, Wenli; Tan, Yaqian; Sheng, Longxiang; Lu, Bingzheng; Lu, Wanjun; Gao, Mingshi; Qiu, Pengxin; Su, Xingwen; Yin, Wei; Hu, Jun; Chen, Zhongping; Sai, Ke; Wang, Jing; Chen, Furong; Chen, Yinsheng; Zhu, Shida; Liu, Dongbing; Cheng, Shiyuan; Xie, Zhi; Zhu, Wenbo; Yan, Guangmei

2017-01-10

Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Assessment of histological differentiation in gastric cancers using whole-volume histogram analysis of apparent diffusion coefficient maps.

PubMed

Zhang, Yujuan; Chen, Jun; Liu, Song; Shi, Hua; Guan, Wenxian; Ji, Changfeng; Guo, Tingting; Zheng, Huanhuan; Guan, Yue; Ge, Yun; He, Jian; Zhou, Zhengyang; Yang, Xiaofeng; Liu, Tian

2017-02-01

To investigate the efficacy of histogram analysis of the entire tumor volume in apparent diffusion coefficient (ADC) maps for differentiating between histological grades in gastric cancer. Seventy-eight patients with gastric cancer were enrolled in a retrospective 3.0T magnetic resonance imaging (MRI) study. ADC maps were obtained at two different b values (0 and 1000 sec/mm 2 ) for each patient. Tumors were delineated on each slice of the ADC maps, and a histogram for the entire tumor volume was subsequently generated. A series of histogram parameters (eg, skew and kurtosis) were calculated and correlated with the histological grade of the surgical specimen. The diagnostic performance of each parameter for distinguishing poorly from moderately well-differentiated gastric cancers was assessed by using the area under the receiver operating characteristic curve (AUC). There were significant differences in the 5 th , 10 th , 25 th , and 50 th percentiles, skew, and kurtosis between poorly and well-differentiated gastric cancers (P < 0.05). There were correlations between the degrees of differentiation and histogram parameters, including the 10 th percentile, skew, kurtosis, and max frequency; the correlation coefficients were 0.273, -0.361, -0.339, and -0.370, respectively. Among all the histogram parameters, the max frequency had the largest AUC value, which was 0.675. Histogram analysis of the ADC maps on the basis of the entire tumor volume can be useful in differentiating between histological grades for gastric cancer. 4 J. Magn. Reson. Imaging 2017;45:440-449. © 2016 International Society for Magnetic Resonance in Medicine.

A Differential Abundance Analysis of Very Metal-poor Stars

NASA Astrophysics Data System (ADS)

O'Malley, Erin M.; McWilliam, Andrew; Chaboyer, Brian; Thompson, Ian

2017-04-01

We have performed a differential line-by-line chemical abundance analysis, ultimately relative to the Sun, of nine very metal-poor main-sequence (MS) halo stars, near [Fe/H] = -2 dex. Our abundances range from -2.66≤slant [{Fe}/{{H}}]≤slant -1.40 dex with conservative uncertainties of 0.07 dex. We find an average [α/Fe] = 0.34 ± 0.09 dex, typical of the Milky Way. While our spectroscopic atmosphere parameters provide good agreement with Hubble Space Telescope parallaxes, there is significant disagreement with temperature and gravity parameters indicated by observed colors and theoretical isochrones. Although a systematic underestimate of the stellar temperature by a few hundred degrees could explain this difference, it is not supported by current effective temperature studies and would create large uncertainties in the abundance determinations. Both 1D and < 3{{D}}> hydrodynamical models combined with separate 1D non-LTE effects do not yet account for the atmospheres of real metal-poor MS stars, but a fully 3D non-LTE treatment may be able to explain the ionization imbalance found in this work.

Radioembolization with 90Y glass microspheres for hepatocellular carcinoma: significance of pretreatment 11C-acetate and 18F-FDG PET/CT and posttreatment 90Y PET/CT in individualized dose prescription.

PubMed

Ho, Chi Lai; Chen, Sirong; Cheung, Shing Kee; Leung, Yim Lung; Cheng, Kam Chau; Wong, Ka Nin; Wong, Yuet Hung; Leung, Thomas Wai Tong

2018-06-11

The aim of this study was to establish an algorithm for the prescription of 90 Y glass microsphere radioembolization ( 90 Y-GMRE) of HCC in individual patients based on the relationship between tumour dose (TD) and response validated by 90 Y PET/CT dosimetry and dual-tracer PET/CT metabolic parameters. The study group comprised 62 HCC patients prospectively recruited for 90 Y-GMRE who underwent pretreatment dual-tracer ( 11 C-acetate and 18 F-FDG) PET/CT as surrogate markers of HCC cellular differentiation. Pretreatment tumour-to-nontumour ratio on 99m Tc-MAA SPECT/CT (T/NT MAA ) was correlated with posttreatment 90 Y PET/CT T/NT 90Y after quantification validation. The TD-response relationship for HCC of different tracer groups was assessed on follow-up PET/CT 2 months after treatment. 90 Y PET/CT was accurate in the measurement of recovery of injected 90 Y activity (81.9-99.9%, median 94.8%). Pretreatment SPECT/CT T/NT MAA was strongly correlated with posttreatment 90 Y PET/CT T/NT 90Y (5.6 ± 3.2 versus 5.9 ± 3.5, T/NT 90Y 1.01 × T/NT MAA  + 0.161, r = 0.918, P < 0.05). The response rates were 72.4% (21/29), 70.6% (12/17) and 25% (4/16) for well, moderately and poorly differentiated HCC, respectively. The cut-off TD for a good response was significantly different between poorly differentiated and well/moderately differentiated HCC (262 Gy versus 152/174 Gy) with 89.2% sensitivity and 88% specificity. At a limiting tolerated liver dose of 70 Gy, the T/NT MAA thresholds for predicting a good response in poorly differentiated and well/moderately differentiated HCC were 3.5 and 2.0/2.3. Disregarding HCC cellular differentiation, the cut-off TD became 170 Gy, with lower sensitivity (70.3%) and specificity (76%). 90 Y PET/CT can provide accurate dosimetry for 90 Y-GMRE. Pretreatment T/NT MAA predicts posttreatment T/NT 90Y . The TD thresholds for a good response are tracer-dependent, with a strong correlation between HCC radiosensitivity and cellular differentiation and other PET-based parameters. These cytokinetic factors improve treatment efficacy while minimizing organ damage for the prescription of personalized 90 Y-GMRE.

Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis

PubMed Central

Thirdborough, Steve; Mellows, Toby; Garcia, Edwin; Woo, Jeongmin; Tod, Joanne; Frampton, Steve; Jenei, Veronika; Moutasim, Karwan A.; Kabir, Tasnuva D.; Brennan, Peter A; Venturi, Giulia; Ford, Kirsty; Herranz, Nicolas; Lim, Kue Peng; Clarke, James; Lambert, Daniel W.; Prime, Stephen S.; Underwood, Timothy J.; Vijayanand, Pandurangan; Eliceiri, Kevin W.; Woelk, Christopher; King, Emma V.; Gil, Jesus; Ottensmeier, Christian H.; Thomas, Gareth J.

2017-01-01

Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes. PMID:27992856

Uroplakin II Expression in Breast Carcinomas Showing Apocrine Differentiation: Putting Some Emphasis on Invasive Pleomorphic Lobular Carcinoma as a Potential Mimic of Urothelial Carcinoma at Metastatic Sites.

PubMed

Tajima, Shogo; Koda, Kenji

2016-01-01

Uroplakin II antibody is exclusively specific for urothelial carcinoma. Nonurothelial carcinoma has not been reported to be immunoreactive for uroplakin II. In the present study, we hypothesized that breast carcinoma showing apocrine differentiation, such as invasive pleomorphic lobular carcinoma (IPLC) and apocrine carcinoma (AC), stains positive for uroplakin II. We identified 6 cases of IPLC between 2000 and 2014 by searching a computerized pathological database. We randomly selected 10 cases of each classic invasive lobular carcinoma (cILC) and AC and five cases of apocrine metaplasia (AM) that coexisted in a surgically resected breast carcinoma specimen. Immunohistochemistry was performed for uroplakin II, GATA3, CK7, CK20, and other representative markers positive for urothelial carcinoma. All cases of IPLC, AC, and AM, except those of cILC, showed immunoreactivity for uroplakin II. Poorly differentiated urothelial carcinoma sometimes shows similar morphology to IPLC with the following immunophenotype: CK7+, CK20-, GATA3+, and uroplakin II+. In the present study, this immunophenotype was observed in all the cases of IPLC and AC. Therefore, when studying metastatic, poorly differentiated carcinoma showing the aforementioned immunophenotype, we should consider the possibility of it being IPLC in addition to metastatic urothelial carcinoma.

Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis.

PubMed

Mellone, Massimiliano; Hanley, Christopher J; Thirdborough, Steve; Mellows, Toby; Garcia, Edwin; Woo, Jeongmin; Tod, Joanne; Frampton, Steve; Jenei, Veronika; Moutasim, Karwan A; Kabir, Tasnuva D; Brennan, Peter A; Venturi, Giulia; Ford, Kirsty; Herranz, Nicolas; Lim, Kue Peng; Clarke, James; Lambert, Daniel W; Prime, Stephen S; Underwood, Timothy J; Vijayanand, Pandurangan; Eliceiri, Kevin W; Woelk, Christopher; King, Emma V; Gil, Jesus; Ottensmeier, Christian H; Thomas, Gareth J

2016-12-15

Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo , showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro , we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.

Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma

PubMed Central

Mahalingam, Kulandaivelu; Somasundaram, Kumaravel

2017-01-01

RNA binding proteins (RBPs) have been implicated in cancer development. An integrated bioinformatics analysis of RBPs (n = 1756) in various datasets (n = 11) revealed several genetic and epigenetically altered events among RBPs in glioblastoma (GBM). We identified 13 mutated and 472 differentially regulated RBPs in GBM samples. Mutations in AHNAK predicted poor prognosis. Copy number variation (CNV), DNA methylation and miRNA targeting contributed to RBP differential regulation. Two sets of differentially regulated RBPs that may be implicated in initial astrocytic transformation and glioma progression were identified. We have also identified a four RBP (NOL3, SUCLG1, HERC5 and AFF3) signature, having a unique expression pattern in glioma stem-like cells (GSCs), to be an independent poor prognostic indicator in GBM. RBP risk score derived from the signature also stratified GBM into low-risk and high-risk groups with significant survival difference. Silencing NOL3, SUCLG1 and HERC5 inhibited GSC maintenance. Gene set enrichment analysis of differentially regulated genes between high-risk and low-risk underscored the importance of inflammation, EMT and hypoxia in high-risk GBM. Thus, we provide a comprehensive overview of genetic and epigenetic regulation of RBPs in glioma development and progression. PMID:28035070

Epithelial Xbp1 Is Required for Cellular Proliferation and Differentiation during Mammary Gland Development

PubMed Central

Hasegawa, Daisuke; Calvo, Veronica; Avivar-Valderas, Alvaro; Lade, Abigale; Chou, Hsin-I; Lee, Youngmin A.; Farias, Eduardo F.; Aguirre-Ghiso, Julio A.

2015-01-01

Xbp1, a key mediator of the unfolded protein response (UPR), is activated by IRE1α-mediated splicing, which results in a frameshift to encode a protein with transcriptional activity. However, the direct function of Xbp1 in epithelial cells during mammary gland development is unknown. Here we report that the loss of Xbp1 in the mammary epithelium through targeted deletion leads to poor branching morphogenesis, impaired terminal end bud formation, and spontaneous stromal fibrosis during the adult virgin period. Additionally, epithelial Xbp1 deletion induces endoplasmic reticulum (ER) stress in the epithelium and dramatically inhibits epithelial proliferation and differentiation during lactation. The synthesis of milk and its major components, α/β-casein and whey acidic protein (WAP), is significantly reduced due to decreased prolactin receptor (Prlr) and ErbB4 expression in Xbp1-deficient mammary epithelium. Reduction of Prlr and ErbB4 expression and their diminished availability at the cell surface lead to reduced phosphorylated Stat5, an essential regulator of cell proliferation and differentiation during lactation. As a result, lactating mammary glands in these mice produce less milk protein, leading to poor pup growth and postnatal death. These findings suggest that the loss of Xbp1 induces a terminal UPR which blocks proliferation and differentiation during mammary gland development. PMID:25713103

Differences of protein expression profiles, KRAS and BRAF mutation, and prognosis in right-sided colon, left-sided colon and rectal cancer.

PubMed

Gao, Xian Hua; Yu, Guan Yu; Gong, Hai Feng; Liu, Lian Jie; Xu, Yi; Hao, Li Qiang; Liu, Peng; Liu, Zhi Hong; Bai, Chen Guang; Zhang, Wei

2017-08-11

To compare protein expression levels, gene mutation and survival among Right-Sided Colon Cancer (RSCC), Left-Sided Colon Cancer (LSCC) and rectal cancer patients, 57 cases of RSCC, 87 LSCC and 145 rectal cancer patients were included retrospectively. Our results demonstrated significant differences existed among RSCC, LSCC and rectal cancer regarding tumor diameter, differentiation, invasion depth and TNM stage. No significant difference was identified in expression levels of MLH1, MSH2, MSH6, PMS2, β-Tubulin III, P53, Ki67 and TOPIIα, and gene mutation of KRAS and BRAF among three groups. Progression Free Survival (PFS) of RSCC was significantly lower than that of LRCC and rectal cancer. In univariate analyses, RSCC, preoperative chemoradiotherapy, poor differentiation, advanced TNM stage, elevated serum CEA and CA19-9 level, tumor deposit, perineural and vascular invasion were found to be predictive factors of shorter PFS. In multivariate analyses, only differentiation and TNM stages were found to be independent predictors of PFS. In conclusion, compared with LSCC and rectal cancer, RSCC has larger tumor size, poor differentiation, advanced TNM stage and shorter survival. The shorter survival in RSCC might be attributed to the advanced tumor stage caused by its inherent position feature of proximal colon rather than genetic difference.

Mapping Human Pluripotent-to-Cardiomyocyte Differentiation: Methylomes, Transcriptomes, and Exon DNA Methylation “Memories”

PubMed Central

Tompkins, Joshua D.; Jung, Marc; Chen, Chang-yi; Lin, Ziguang; Ye, Jingjing; Godatha, Swetha; Lizhar, Elizabeth; Wu, Xiwei; Hsu, David; Couture, Larry A.; Riggs, Arthur D.

2016-01-01

The directed differentiation of human cardiomyocytes (CMs) from pluripotent cells provides an invaluable model for understanding mechanisms of cell fate determination and offers considerable promise in cardiac regenerative medicine. Here, we utilize a human embryonic stem cell suspension bank, produced according to a good manufacturing practice, to generate CMs using a fully defined and small molecule-based differentiation strategy. Primitive and cardiac mesoderm purification was used to remove non-committing and multi-lineage populations and this significantly aided the identification of key transcription factors, lncRNAs, and essential signaling pathways that define cardiomyogenesis. Global methylation profiles reflect CM development and we report on CM exon DNA methylation “memories” persisting beyond transcription repression and marking the expression history of numerous developmentally regulated genes, especially transcription factors. PMID:26981572

Properties of scattering forms and their relation to associahedra

NASA Astrophysics Data System (ADS)

de la Cruz, Leonardo; Kniss, Alexander; Weinzierl, Stefan

2018-03-01

We show that the half-integrands in the CHY representation of tree amplitudes give rise to the definition of differential forms — the scattering forms — on the moduli space of a Riemann sphere with n marked points. These differential forms have some remarkable properties. We show that all singularities are on the divisor {\\overline{M}}_{0,n}\\backslash {M}_{0,n} . Each singularity is logarithmic and the residue factorises into two differential forms of lower points. In order for this to work, we provide a threefold generalisation of the CHY polarisation factor (also known as reduced Pfaffian) towards off-shell momenta, unphysical polarisations and away from the solutions of the scattering equations. We discuss explicitly the cases of bi-adjoint scalar amplitudes, Yang-Mills amplitudes and gravity amplitudes.

The META score for differentiating metastatic from osteoporotic vertebral fractures: an independent agreement assessment.

PubMed

Besa, Pablo; Urrutia, Julio; Campos, Mauricio; Mobarec, Sebastián; Cruz, Juan Pablo; Cikutovic, Pablo; Diaz, Gonzalo

2018-04-27

Differentiating osteoporotic vertebral fractures (OVFs) from metastatic vertebral fractures (MVFs) is an important clinical challenge. A novel magnetic resonance imaging (MRI)-based score (the META score) was described, aiming to differentiate OVF from MVF. This score showed an almost perfect agreement by the group developing it, but an independent agreement evaluation is pending. We aimed to perform an independent inter- and intraobserver agreement evaluation of the META score and to test the score's capability of differentiating OVF from MVF. This is an agreement study of the META score. Sixty-four patients with confirmed OVF or MVF were assessed by six independent evaluators (three spine surgeons and three fellowship-trained radiologists) using the META score. We used the intraclass correlation coefficient (ICC) to determine the overall inter-and intraobserver agreement, and the kappa statistic (κ) to express the agreement for each individual score criterion. The score accuracy was determined by calculating the area under the receiver operating characteristic curve. Finally, we used κ to evaluate the agreement among raters to determine whether the fracture was OVF or MVF. The overall interobserver agreement was poor [ICC=0.10 (0.02-0.20)]; spine surgeons [ICC=0.75 (0.66-0.83)] had better agreement than radiologists did [ICC=0.05 (-0.08 to 0.21)]. The intraobserver agreement was poor [ICC=0.17 (0.01-0.32)]; both spine surgeons [ICC=0.21 (0.05-0.41)] and radiologists had a poor agreement [ICC=0.03 (-0.29 to 0.27)]. The agreement for each specific criterion varied from κ=0.24 to κ=0.60. The area under the receiver operating characteristic curve was 0.58 (0.64 for spine surgeons and 0.52 for radiologists, p<.01). The interobserver agreement using the META score was adequate for spine surgeons but not for other potential users (radiologists); the intraobserver agreement was poor. Further studies are thus necessary before the use of this score is recommended. Copyright © 2018 Elsevier Inc. All rights reserved.

Gene Expression Profiling of Liver Cancer Stem Cells by RNA-Sequencing

PubMed Central

Lam, Chi Tat; Ng, Michael N. P.; Yu, Wan Ching; Lau, Joyce; Wan, Timothy; Wang, Xiaoqi; Yan, Zhixiang; Liu, Hang; Fan, Sheung Tat

2012-01-01

Background Accumulating evidence supports that tumor growth and cancer relapse are driven by cancer stem cells. Our previous work has demonstrated the existence of CD90+ liver cancer stem cells (CSCs) in hepatocellular carcinoma (HCC). Nevertheless, the characteristics of these cells are still poorly understood. In this study, we employed a more sensitive RNA-sequencing (RNA-Seq) to compare the gene expression profiling of CD90+ cells sorted from tumor (CD90+CSCs) with parallel non-tumorous liver tissues (CD90+NTSCs) and elucidate the roles of putative target genes in hepatocarcinogenesis. Methodology/Principal Findings CD90+ cells were sorted respectively from tumor and adjacent non-tumorous human liver tissues using fluorescence-activated cell sorting. The amplified RNAs of CD90+ cells from 3 HCC patients were subjected to RNA-Seq analysis. A differential gene expression profile was established between CD90+CSCs and CD90+NTSCs, and validated by quantitative real-time PCR (qRT-PCR) on the same set of amplified RNAs, and further confirmed in an independent cohort of 12 HCC patients. Five hundred genes were differentially expressed (119 up-regulated and 381 down-regulated genes) between CD90+CSCs and CD90+NTSCs. Gene ontology analysis indicated that the over-expressed genes in CD90+CSCs were associated with inflammation, drug resistance and lipid metabolism. Among the differentially expressed genes, glypican-3 (GPC3), a member of glypican family, was markedly elevated in CD90+CSCs compared to CD90+NTSCs. Immunohistochemistry demonstrated that GPC3 was highly expressed in forty-two human liver tumor tissues but absent in adjacent non-tumorous liver tissues. Flow cytometry indicated that GPC3 was highly expressed in liver CD90+CSCs and mature cancer cells in liver cancer cell lines and human liver tumor tissues. Furthermore, GPC3 expression was positively correlated with the number of CD90+CSCs in liver tumor tissues. Conclusions/Significance The identified genes, such as GPC3 that are distinctly expressed in liver CD90+CSCs, may be promising gene candidates for HCC therapy without inducing damages to normal liver stem cells. PMID:22606345

Integrated Transcriptomic and Epigenomic Analysis of Primary Human Lung Epithelial Cell Differentiation

PubMed Central

Marconett, Crystal N.; Zhou, Beiyun; Rieger, Megan E.; Selamat, Suhaida A.; Dubourd, Mickael; Fang, Xiaohui; Lynch, Sean K.; Stueve, Theresa Ryan; Siegmund, Kimberly D.; Berman, Benjamin P.

2013-01-01

Elucidation of the epigenetic basis for cell-type specific gene regulation is key to gaining a full understanding of how the distinct phenotypes of differentiated cells are achieved and maintained. Here we examined how epigenetic changes are integrated with transcriptional activation to determine cell phenotype during differentiation. We performed epigenomic profiling in conjunction with transcriptomic profiling using in vitro differentiation of human primary alveolar epithelial cells (AEC). This model recapitulates an in vivo process in which AEC transition from one differentiated cell type to another during regeneration following lung injury. Interrogation of histone marks over time revealed enrichment of specific transcription factor binding motifs within regions of changing chromatin structure. Cross-referencing of these motifs with pathways showing transcriptional changes revealed known regulatory pathways of distal alveolar differentiation, such as the WNT and transforming growth factor beta (TGFB) pathways, and putative novel regulators of adult AEC differentiation including hepatocyte nuclear factor 4 alpha (HNF4A), and the retinoid X receptor (RXR) signaling pathways. Inhibition of the RXR pathway confirmed its functional relevance for alveolar differentiation. Our incorporation of epigenetic data allowed specific identification of transcription factors that are potential direct upstream regulators of the differentiation process, demonstrating the power of this approach. Integration of epigenomic data with transcriptomic profiling has broad application for the identification of regulatory pathways in other models of differentiation. PMID:23818859

Normal and cancer mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR Axis

PubMed Central

Celià-Terrassa, Toni; Liu, Daniel; Choudhury, Abrar; Hang, Xiang; Wei, Yong; Zamalloa, Jose; Alfaro-Aco, Raymundo; Chakrabarti, Rumela; Jiang, Yi-Zhou; Koh, Bong Ihn; Smith, Heath; DeCoste, Christina; Li, Jun-Jing; Shao, Zhi-Ming; Kang, Yibin

2017-01-01

Tumor-initiating cells (TICs), or cancer stem cells (CSC), possess stem cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells (MaSCs) and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER− breast tumors, functionally promotes tumor initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signaling. PMID:28530657

The Reactive–Proactive Aggression Questionnaire: Differential Correlates of Reactive and Proactive Aggression in Adolescent Boys

PubMed Central

Raine, Adrian; Dodge, Kenneth; Loeber, Rolf; Gatzke-Kopp, Lisa; Lynam, Don; Reynolds, Chandra; Stouthamer-Loeber, Magda; Liu, Jianghong

2009-01-01

This study reports the development of the Reactive–Proactive Aggression Questionnaire (RPQ), and the differential correlates of these two forms of aggression. Antisocial, psychosocial and personality measures were obtained at ages 7 and 16 years in schoolboys, while the RPQ was administered to 334 of the boys at age 16 years. Confirmatory factor analysis indicated a significant fit for a two-factor proactive–reactive model that replicated from one independent subsample to another. Proactive aggression was uniquely characterized at age 7 by initiation of fights, strong-arm tactics, delinquency, poor school motivation, poor peer relationships, single-parent status, psychosocial adversity, substance-abusing parents, and hyperactivity, and at age 16 by a psychopathic personality, blunted affect, delinquency, and serious violent offending. Reactive aggression was uniquely characterized at age 16 by impulsivity, hostility, social anxiety, lack of close friends, unusual perceptual experiences, and ideas of reference. Findings confirm and extend the differential correlates of proactive–reactive aggression, and demonstrate that this brief but reliable and valid self-report instrument can be used to assess proactive and reactive aggression in child and adolescent samples. PMID:20798781

Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest

PubMed Central

Carén, Helena; Stricker, Stefan H.; Bulstrode, Harry; Gagrica, Sladjana; Johnstone, Ewan; Bartlett, Thomas E.; Feber, Andrew; Wilson, Gareth; Teschendorff, Andrew E.; Bertone, Paul; Beck, Stephan; Pollard, Steven M.

2015-01-01

Summary Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stem cell-like cells. BMP signaling triggers cell-cycle exit and differentiation of GBM stem cells (GSCs) and, therefore, might have therapeutic value. However, the epigenetic mechanisms that accompany differentiation remain poorly defined. It is also unclear whether cell-cycle arrest is terminal. Here we find only a subset of GSC cultures exhibit astrocyte differentiation in response to BMP. Although overtly differentiated non-cycling astrocytes are generated, they remain vulnerable to cell-cycle re-entry and fail to appropriately reconfigure DNA methylation patterns. Chromatin accessibility mapping identified loci that failed to alter in response to BMP and these were enriched in SOX transcription factor-binding motifs. SOX transcription factors, therefore, may limit differentiation commitment. A similar propensity for cell-cycle re-entry and de-differentiation was observed in GSC-derived oligodendrocyte-like cells. These findings highlight significant obstacles to BMP-induced differentiation as therapy for GBM. PMID:26607953

Two Pore Channel 2 Differentially Modulates Neural Differentiation of Mouse Embryonic Stem Cells

PubMed Central

Zhang, Zhe-Hao; Lu, Ying-Ying; Yue, Jianbo

2013-01-01

Nicotinic acid adenine dinucleotide phosphate (NAADP) is an endogenous Ca2+ mobilizing nucleotide presented in various species. NAADP mobilizes Ca2+ from acidic organelles through two pore channel 2 (TPC2) in many cell types and it has been previously shown that NAADP can potently induce neuronal differentiation in PC12 cells. Here we examined the role of TPC2 signaling in the neural differentiation of mouse embryonic stem (ES) cells. We found that the expression of TPC2 was markedly decreased during the initial ES cell entry into neural progenitors, and the levels of TPC2 gradually rebounded during the late stages of neurogenesis. Correspondingly, TPC2 knockdown accelerated mouse ES cell differentiation into neural progenitors but inhibited these neural progenitors from committing to neurons. Overexpression of TPC2, on the other hand, inhibited mouse ES cell from entering the early neural lineage. Interestingly, TPC2 knockdown had no effect on the differentiation of astrocytes and oligodendrocytes of mouse ES cells. Taken together, our data indicate that TPC2 signaling plays a temporal and differential role in modulating the neural lineage entry of mouse ES cells, in that TPC2 signaling inhibits ES cell entry to early neural progenitors, but is required for late neuronal differentiation. PMID:23776607

Ca2+-dependent localization of integrin-linked kinase to cell junctions in differentiating keratinocytes.

PubMed

Vespa, Alisa; Darmon, Alison J; Turner, Christopher E; D'Souza, Sudhir J A; Dagnino, Lina

2003-03-28

Integrin complexes are necessary for proper proliferation and differentiation of epidermal keratinocytes. Differentiation of these cells is accompanied by down-regulation of integrins and focal adhesions as well as formation of intercellular adherens junctions through E-cadherin homodimerization. A central component of integrin adhesion complexes is integrin-linked kinase (ILK), which can induce loss of E-cadherin expression and epithelial-mesenchymal transformation when ectopically expressed in intestinal and mammary epithelia. In cultured primary mouse keratinocytes, we find that ILK protein levels are independent of integrin expression and signaling, since they remain constant during Ca(2+)-induced differentiation. In contrast, keratinocyte differentiation is accompanied by marked reduction in kinase activity in ILK immunoprecipitates and altered ILK subcellular distribution. Specifically, ILK distributes in close apposition to actin fibers along intercellular junctions in differentiated but not in undifferentiated keratinocytes. ILK localization to cell-cell borders occurs independently of integrin signaling and requires Ca(2+) as well as an intact actin cytoskeleton. Further, and in contrast to what is observed in other epithelial cells, ILK overexpression in differentiated keratinocytes does not promote E-cadherin down-regulation and epithelial-mesenchymal transition. Thus, novel tissue-specific mechanisms control the formation of ILK complexes associated with cell-cell junctions in differentiating murine epidermal keratinocytes.

SAA drives proinflammatory heterotypic macrophage differentiation in the lung via CSF-1R-dependent signaling

PubMed Central

Anthony, Desiree; McQualter, Jonathan L.; Bishara, Maria; Lim, Ee X.; Yatmaz, Selcuk; Seow, Huei Jiunn; Hansen, Michelle; Thompson, Michelle; Hamilton, John A.; Irving, Louis B.; Levy, Bruce D.; Vlahos, Ross; Anderson, Gary P.; Bozinovski, Steven

2014-01-01

Serum amyloid A (SAA) is expressed locally in chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD), where macrophages that do not accord with the classic M1/M2 paradigm also accumulate. In this study, the role of SAA in regulating macrophage differentiation was investigated in vitro using human blood monocytes from healthy subjects and patients with COPD and in vivo using an airway SAA challenge model in BALB/c mice. Differentiation of human monocytes with SAA stimulated the proinflammatory monokines IL-6 and IL-1β concurrently with the M2 markers CD163 and IL-10. Furthermore, SAA-differentiated macrophages stimulated with lipopolysaccharide (LPS) expressed markedly higher levels of IL-6 and IL-1β. The ALX/FPR2 antagonist WRW4 reduced IL-6 and IL-1β expression but did not significantly inhibit phagocytic and efferocytic activity. In vivo, SAA administration induced the development of a CD11chighCD11bhigh macrophage population that generated higher levels of IL-6, IL-1β, and G-CSF following ex vivo LPS challenge. Blocking CSF-1R signaling effectively reduced the number of CD11chighCD11bhigh macrophages by 71% and also markedly inhibited neutrophilic inflammation by 80%. In conclusion, our findings suggest that SAA can promote a distinct CD11chighCD11bhigh macrophage phenotype, and targeting this population may provide a novel approach to treating chronic inflammatory conditions associated with persistent SAA expression.—Anthony, D., McQualter, J. L., Bishara, M., Lim, E. X., Yatmaz, S., Seow, H. J., Hansen, M., Thompson, M., Hamilton, J. A., Irving, L. B., Levy, B. D., Vlahos, R., Anderson, G. P., Bozinovski, S. SAA drives proinflammatory heterotypic macrophage differentiation in the lung via CSF-1R-dependent signaling. PMID:24846388

Differential local tissue permissiveness influences the final fate of GPR17‐expressing oligodendrocyte precursors in two distinct models of demyelination

PubMed Central

Coppolino, Giusy T.; Marangon, Davide; Negri, Camilla; Menichetti, Gianluca; Fumagalli, Marta; Gelosa, Paolo; Dimou, Leda; Furlan, Roberto; Lecca, Davide

2018-01-01

Abstract Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17‐iCreERT2xCAG‐eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen‐induced GFP‐labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+ cells at damaged areas. However, only in the cuprizone model reacting GFP+ cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+ cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor‐1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti‐inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery. PMID:29424466

Differential local tissue permissiveness influences the final fate of GPR17-expressing oligodendrocyte precursors in two distinct models of demyelination.

PubMed

Coppolino, Giusy T; Marangon, Davide; Negri, Camilla; Menichetti, Gianluca; Fumagalli, Marta; Gelosa, Paolo; Dimou, Leda; Furlan, Roberto; Lecca, Davide; Abbracchio, Maria P

2018-05-01

Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreER T2 xCAG-eGFP mice) allowing to follow the final fate of GPR17 + cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP + cells at damaged areas. However, only in the cuprizone model reacting GFP + cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP + cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery. © 2018 The Authors GLIA Published by Wiley Periodicals, Inc.

Hyperglycemia impedes definitive endoderm differentiation of human embryonic stem cells by modulating histone methylation patterns.

PubMed

Chen, A C H; Lee, Y L; Fong, S W; Wong, C C Y; Ng, E H Y; Yeung, W S B

2017-06-01

Exposure to maternal diabetes during fetal growth is a risk factor for the development of type II diabetes (T2D) in later life. Discovery of the mechanisms involved in this association should provide valuable background for therapeutic treatments. Early embryogenesis involves epigenetic changes including histone modifications. The bivalent histone methylation marks H3K4me3 and H3K27me3 are important for regulating key developmental genes during early fetal pancreas specification. We hypothesized that maternal hyperglycemia disrupted early pancreas development through changes in histone bivalency. A human embryonic stem cell line (VAL3) was used as the cell model for studying the effects of hyperglycemia upon differentiation into definitive endoderm (DE), an early stage of the pancreatic lineage. Hyperglycemic conditions significantly down-regulated the expression levels of DE markers SOX17, FOXA2, CXCR4 and EOMES during differentiation. This was associated with retention of the repressive histone methylation mark H3K27me3 on their promoters under hyperglycemic conditions. The disruption of histone methylation patterns was observed as early as the mesendoderm stage, with Wnt/β-catenin signaling being suppressed during hyperglycemia. Treatment with Wnt/β-catenin signaling activator CHIR-99021 restored the expression levels and chromatin methylation status of DE markers, even in a hyperglycemic environment. The disruption of DE development was also found in mouse embryos at day 7.5 post coitum from diabetic mothers. Furthermore, disruption of DE differentiation in VAL3 cells led to subsequent impairment in pancreatic progenitor formation. Thus, early exposure to hyperglycemic conditions hinders DE development with a possible relationship to the later impairment of pancreas specification.

[Notch signaling pathway participates in the differentiation of hepatic progenitor cells into bile duct epithelial cells and progression of hepatic fibrosis in cholestatic liver fibrosis rat].

PubMed

Mu, Y P; Zhang, X; Xu, Y; Fan, W W; Li, X W; Chen, J M; Chen, G F; Liu, P

2017-06-08

Objective: To investigate differentiation direction of hepatic progenitor cells (HPCs) in cholestatic liver fibrosis (CLF), and the role of Notch signaling pathway in the differentiation of HPCs. Methods: A CLF rat model was established by bile duct ligation (BDL) followed by monitoring changes of Notch signal pathway and the cellular origin of proliferating cholangiocytes. After intraperitoneal injection of DAPT (a Notch signaling inhibitor) after bile duct ligation, the progress of liver fibrosis and the proliferation of cholangiocytes after inhibition of the Notch pathway were analyzed. Results: Data showed that bile duct proliferation gradually increased along with inflammatory cell infiltration and proliferating bile duct cells surrounded by abundant collagen in the BDL group. Immunostaining confirmed markedly increased expression of CK19, OV6, Sox9 and EpCAM. In addition, RT-PCR results showed that Notch signaling pathway was activated significantly. Once the Notch signaling pathway was inhibited by DAPT, bile duct proliferation markedly suppressed along with significantly decreased the mRNA expression of CK19, OV6, Sox9 and EpCAM, compared with BDL group [(10.2±0.7) vs . (22.3±0.8), (7.6±1.5) vs . (18.1±3.7), (1.4±0.4) vs . (4.1±1.1), (1.3±0.3) vs . (5.0±1.4), respectively, P <0.01]. Moreover, liver fibrosis was also reduced significantly. Conclusion: Notch signaling activation is required for HPCs differentiation into cholangiocytes in CLF and inhibition of the Notch signaling pathway may offer a therapeutic option for treating CLF.

Muscular hypertrophy of the left diaphragmatic crus: an unusual cause of a paraspinal "mass".

PubMed

Woodring, J H; Bognar, B

1998-04-01

We present a case of marked muscular hypertrophy of the muscular portion of the diaphragm and of the diaphragmatic crura in a professional opera singer. In this case the right and left crus each measured 20 mm in maximum thickness. The left crus, by nature of its vertical orientation in the sagittal plane, produced marked deviation of the inferior left paraspinal line near the diaphragm mimicking a retrocrural or paraspinal mass on the posteroanterior chest radiograph. The correct diagnosis was made by computed tomography. Muscular hypertrophy of the diaphragmatic crura should be included in the differential diagnosis of retrocrural or paraspinal masses at the level of the diaphragm.

Processing Biological Gender and Number Information during Chinese Pronoun Resolution: ERP Evidence for Functional Differentiation

ERIC Educational Resources Information Center

Xu, Xiaodong; Jiang, Xiaoming; Zhou, Xiaolin

2013-01-01

There have been a number of behavioral and neural studies on the processing of syntactic gender and number agreement information, marked by different morpho-syntactic features during sentence comprehension. By using the event-related potential (ERP) technique, the present study investigated whether the processing of semantic gender information and…

Linguistic Relativity in Japanese and English: Is Language the Primary Determinant in Object Classification?

ERIC Educational Resources Information Center

Mazuka, Reiko; Friedman, Ronald S.

2000-01-01

Tested claims by Lucy (1992a, 1992b) that differences between the number marking systems used by Yucatec Maya and English lead speakers of these languages to differentially attend to either the material composition or the shape of objects. Replicated Lucy's critical objects' classification experiments using speakers of English and Japanese.…

Ponderosa pine progenies: differential response to ultramafic and granitic soils

Treesearch

James L. Jenkinson

1974-01-01

Progenies of nine ponderosa pines native to one granitic and several ultramafic soils in the northern Sierra Nevada were grown on both soil types in a greenhouse. The progenies differed markedly in first-year growth on infertile ultramafic soils, but not on a fertile granitic soil. Growth differences between progenies were primarily related to differences in calcium...

Highlighting Text as a Study Strategy: Beyond Attentional Focusing.

ERIC Educational Resources Information Center

Lindner, Reinhard W.; And Others

Two experiments were conducted to investigate whether the strategy of differentiating main and supporting ideas with different colored highlighter pens resulted in greater use of schema building and increased recall of information by students and whether the benefits of text marking come at the time of encoding or at the time of review. Sixty-six…

Predicting Differential Item Functioning in Cross-Lingual Testing: The Case of a High Stakes Test in the Kyrgyz Republic

ERIC Educational Resources Information Center

Drummond, Todd W.

2011-01-01

Cross-lingual tests are assessment instruments created in one language and adapted for use with another language group. Practitioners and researchers use cross-lingual tests for various descriptive, analytical and selection purposes both in comparative studies across nations and within countries marked by linguistic diversity (Hambleton, 2005).…

Bedbugs: An Equal Opportunist and Cosmopolitan Creature

ERIC Educational Resources Information Center

Krause-Parello, Cheryl A.; Sciscione, Patricia

2009-01-01

Currently there is a rise in bedbugs seen in schools. The wingless, blood-sucking insects can arrive at school via student book bags, student clothing, or other personal items. If a student presents in the health office with a bite mark, the school nurse will need to differentiate between a bedbug bite and other insect bites, such as fleas,…

Differential Amygdala Response to Lower Face in Patients with Autistic Spectrum Disorders: An fMRI Study

ERIC Educational Resources Information Center

Ishitobi, Makoto; Kosaka, Hirotaka; Omori, Masao; Matsumura, Yukiko; Munesue, Toshio; Mizukami, Kimiko; Shimoyama, Tomohiro; Murata, Tetsuhito; Sadato, Norihiro; Okazawa, Hidehiko; Wada, Yuji

2011-01-01

Much functional neuroimaging evidence indicates that autistic spectrum disorders (ASD) demonstrate marked brain abnormalities in face processing. Most of these findings were obtained from studies using tasks related to whole faces. However, individuals with ASD tend to rely more on individual parts of the face for identification than on the…

Risk factors for poor work functioning of persons with schizophrenia in rural China.

PubMed

Ran, Mao-Sheng; Chen, Sheying; Chen, Elaina Y; Ran, Bo-Yu; Tang, Cui-Ping; Lin, Fu-Rong; Li, Li; Li, Si-Gan; Mao, Wen-Jun; Hu, Shi-Hui

2011-11-01

The long-term work performance of persons with schizophrenia in the community is unclear. This study examined the status of long-term work functioning and the predictors of poor work status among patients with schizophrenia in a Chinese rural area. A 10-year follow-up investigation (1994-2004) of a cohort (n = 510) of persons with schizophrenia was conducted in Xinjin County, Chengdu, China. Compared with baseline data, work functioning of patients with schizophrenia deteriorated after 10 years. The rates of not working increased significantly from 12.0% in 1994 to 23.0% in 2004. Bivariate analyses showed that the poor work functioning in 2004 was significantly associated with male gender, older age, older age of first onset, higher level of education, longer duration of illness, lower family economic status, lack of caregivers, poor work status in 1994, living in shabby or unstable house, marked symptoms, and higher score on the Social Disability Screening Schedule (SDSS). In multiple logistic regression analyses, higher score of SDSS and poor work status in 1994 were identified as unique predictors of poor work status in 2004. The status of work functioning of persons with schizophrenia decreased over the course of the illness. The risk factors for poor work functioning and specific socio-cultural environment should be considered in planning community mental health services and rehabilitation for these patients.

Factors associated with poor academic achievement among urban primary school children in Malaysia.

PubMed

Ong, L C; Chandran, V; Lim, Y Y; Chen, A H; Poh, B K

2010-03-01

The aim of this study was to identify factors associated with poor academic achievement during the early school years. This was a cross-sectional study of urban Primary Two children. Sociodemographic and medical data were obtained from questionnaires and interviews. Achievement was based on marks obtained in the core subjects of the Primary One examination. All students underwent the Raven's Standard Progressive Matrices test as a general measure of cognitive ability, audiometry and visual tests, and standardised measurements of weight and height. Out of 1,470 eligible children, 206 (14 percent) had poor academic achievement. Of the 919 children who participated in the study, 111 (12.1 percent) had poor achievement compared with 95 (17.2 percent) of the 551 non-participants. Using logistic regression analysis, the factors that were found to be independently associated with poor academic achievement were lower mean Raven scores (p-value is less than 0.001), lower mean socioeconomic status scores (p-value is less than 0.001), larger sibship size (p-value is 0.031), male gender (odds ratio [OR] 1.7; 95 percent confidence interval [CI] 1.1-2.65) and a history of prematurity (OR 14; 95 percent CI 2-97.8). Cognitive ability, gender, prematurity and social factors contribute to poor academic achievement during the early school years. The higher proportion of poor achievers among non-participants warrants further attention.

Influence of controlled encoding and retrieval facilitation on memory performance in patients with different profiles of mild cognitive impairment.

PubMed

Perri, Roberta; Monaco, Marco; Fadda, Lucia; Serra, Laura; Marra, Camillo; Caltagirone, Carlo; Bruni, Amalia C; Curcio, Sabrina; Bozzali, M; Carlesimo, Giovanni A

2015-01-01

Memory tests able to differentiate encoding and retrieval processes from the memoranda storing ones should be used to differentiate patients in a very early phase of AD. In fact, individuals with mild cognitive impairment (MCI) can be characterized by two different memory profiles: a pure amnestic one (with poor learning and retrieval and poor improvement when encoding is assisted and retrieval is facilitated) and a dysexecutive one (with inefficient encoding and/or poor retrieval strategies and improvement with assisted encoding and retrieval). The amnestic profile characterizes subjects affected by medio-temporal atrophy typical of AD. In this study, a Grober-Buschke memory procedure was used to evaluate normal controls and MCI patients with different cognitive profiles: pure amnestic (aMCIsd), amnestic plus other cognitive impairments (aMCImd) and non-amnestic (naMCI). An index of sensitivity of cueing (ISC) measured the advantage passing from free to cued recall. Results showed that both strategic and consolidation abilities were impaired in the aMCIsd and aMCImd groups and were preserved in the naMCI group. aMCImd, however, compensated the memory deficit with assisted encoding and retrieval, but aMCIsd performed very poorly. When MCI subjects were defined according to the ISC value, subjects with poor ISC were primarily in the aMCIsd group and, to a lesser extent, in the aMCImd group and the naMCI group. Finally, patients with a poor ISC showed cerebral atrophy documented in the precocious phase of AD and the retrosplenial cerebral areas seemed to be the most useful areas for identifying patients in the early phase of AD.

Ethnic differentials in parental health seeking for childhood illness in Vietnam.

PubMed

Teerawichitchainan, Bussarawan; Phillips, James F

2008-03-01

Vietnam's sustained investment in primary healthcare since the onset of socialism has lowered infant and childhood mortality rates and improved life expectancy, exceeding progress achieved in other poor countries with comparable levels of income per capita. The recent introduction of user fees for primary healthcare services has generated concern that economic policies may have adversely affected health-seeking behavior and health outcomes of the poor, particularly among impoverished families who are members of socially marginalized minority groups. This paper examines this debate by analyzing parental recall of illness and care-seeking for sick children under the age of 5 years recorded by the 2001-2002 Vietnam National Health Survey. We estimate statistical models of the determinants of parental recall of incidence and response to illness among their children. Ethnic minority parents less frequently reported their children to have been sick than Kinh and Chinese parents. When they recognize an illness episode, minority parents are less likely to seek care -- whether professional consultation or self-prescribed care -- than non-minority parents. Ethnic differentials are evident in all geographic and income levels, although adverse effects of minority status are most pronounced among poor households in remote areas. Regression estimates of the effects of ethnicity and maternal education on health decisions are pronounced even when poverty effects are controlled, suggesting that social equity may have been under-emphasized in Vietnam's early health policy deliberations. Policies extending free healthcare to poor communes affect parental decisions to seek professional care or self-prescribed care among better-off parents without affecting parental decision making among the poor. Early health initiatives for the poor may therefore have failed to offset equity problems confronting impoverished ethnic minority families.

The association between teenage motherhood and poor offspring outcomes: A national cohort study across 30 years

PubMed Central

Coyne, Claire A; Långström, Niklas; Rickert, Martin E; Lichtenstein, Paul; D’Onofrio, Brian M

2013-01-01

Teenage motherhood is associated with poor offspring outcomes but these associations may be influenced by offspring birth year because of substantial social changes in recent decades. Existing research also has not examined whether these associations are due to the specific effect of mother’s age at childbirth or factors shared by siblings in a family. We used a population-based cohort study in Sweden comprising all children born from 1960–1989 (N=3,162,239), and a subsample of siblings differentially exposed to maternal teenage childbearing (N=485,259) to address these limitations. We examined the effect of teenage childbearing on offspring violent and nonviolent criminal convictions, poor academic performance, and substance-related problems. Population-wide, teenage childbearing was associated with offspring criminal convictions, poor academic performance, and substance-related problems. The magnitude of these associations increased over time. Comparisons of differentially exposed siblings indicated no within-family association between teenage childbearing and offspring violent and nonviolent criminal convictions or poor academic performance, although offspring born to teenage mothers were more likely to experience substance-related problems than their later-born siblings. Being born to a teenage mother in Sweden has become increasingly associated with negative outcomes across time, but the nature of this association may differ by outcome. Teenage childbearing may be associated with offspring violent and nonviolent criminal convictions and poor academic performance because of shared familial risk factors but may be causally associated with offspring substance-related problems. The findings suggest that interventions to improve offspring outcomes should delay teenage childbearing and target risk factors influencing all offspring of teenage mothers. PMID:23632141

Race, Income Inequality, and Impervious Surfaces in Relation to Flooding Associated with Hurricane Harvey

NASA Astrophysics Data System (ADS)

de Sherbinin, A. M.; Mills, J.; Borkovska, O.

2017-12-01

Differential vulnerability is a concept that suggests that certain demographic groups - the poor, less educated, or minorities - are likely to be more impacted by climate extremes such as floods owing to their higher sensitivity and lower adaptive capacity. Differential exposure represents the concept that these same groups may be more highly exposed to flood events by virtue of their residing in less desirable, low-lying neighborhoods with higher percentages of impervious surface cover. This paper tests the hypothesis that poor communities of color were differentially exposed to flood risks in the aftermath of Hurricane Harvey, which struck Houston, Texas in August 2017. We explore the spatial relationship among census tracts with high percentages of low income communities of color, those with high percentages of impervious surface, and those most impacted by floods. We incorporat datasets disseminated by the NASA Socioeconomic Data and Application Center (SEDAC) - the Global Man-made Impervious Surface (GMIS) data set and the U.S. Census Grids 2010 - together with the American Community Survey (ACS) 2011-2015 and flood extent and depth data from FEMA. Preliminary analysis suggests that predominantly non-white neighborhoods have higher percentages of impervious surface cover, but that impervious surface cover is negatively correlated with flood risk. This paper will situate these findings in the context of a larger body of research exploring differential exposure to flood risks during Hurricanes Katrina and Sandy, as well as differential exposure to extreme heat in urban environments in Houston and beyond.

Overexpression of protein kinase FA/GSK-3 alpha (a proline-directed protein kinase) correlates with human hepatoma dedifferentiation/progression.

PubMed

Yang, S D; Yu, J S; Yang, C C; Lee, S C; Lee, T T; Ni, M H; Kuan, C Y; Chen, H C

1996-05-01

Computer analysis of protein phosphorylation sites sequence revealed that transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of the proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of protein kinase FA/glycogen synthase kinase-3 alpha (kinase F(A)/GSK-3 alpha) (a member of PDPK family) has been optimized for human hepatoma and used to demonstrate for the first time significantly increased (P < 0.01) activity in poorly differentiated SK-Hep-1 hepatoma (24.2 +/- 2.8 units/mg) and moderately differentiated Mahlavu hepatoma (14.5 +/- 2.2 units/mg) when compared to well differentiated Hep 3B hepatoma (8.0 +/- 2.4 units/mg). Immunoblotting analysis revealed that increased activity of kinase FA/GSK-3 alpha is due to overexpression of the protein. Elevated kinase FA/GSK-3 alpha expression in human hepatoma biopsies relative to normal liver tissue was found to be even more profound. This kinase appeared to be fivefold overexpressed in well differentiated hepatoma and 13-fold overexpressed in poorly differentiated hepatoma when compared to normal liver tissue. Taken together, the results provide initial evidence that overexpression of kinase FA/GSK-3 alpha is involved in human hepatoma dedifferentiation/progression. Since kinase FA/GSK-3 alpha is a PDPK, the results further support a potential role of this kinase in human liver tumorigenesis, especially in its dedifferentiation/progression.

Improved analysis of long-term monitoring data demonstrates marked regional declines of bat populations in the eastern United States

Treesearch

Thomas E. Ingersoll; Brent J. Sewall; Sybill K. Amelon

2013-01-01

Bats are diverse and ecologically important, but are also subject to a suite of severe threats. Evidence for localized bat mortality from these threats is well-documented in some cases, but long-term changes in regional populations of bats remain poorly understood. Bat hibernation surveys provide an opportunity to improve understanding, but analysis is complicated by...

Maintenance Operations Degradation of Airfield Pavement Markings

DTIC Science & Technology

2012-03-01

polyurea . 1.4 Research Questions To answer the problem presented, several questions need to be addressed. The first is whether or not rubber...suitable for use on airfields.  Further research is required. Cyrus and Frierson 2006 Polyurea  The material showed poor performance in...evaluating polyurea and one evaluating polyester. Both studies were undertaken to evaluate the effectiveness of polyurea or polyester as a potential

Prognostic Classifier Based on Genome-Wide DNA Methylation Profiling in Well-Differentiated Thyroid Tumors.

PubMed

Bisarro Dos Reis, Mariana; Barros-Filho, Mateus Camargo; Marchi, Fábio Albuquerque; Beltrami, Caroline Moraes; Kuasne, Hellen; Pinto, Clóvis Antônio Lopes; Ambatipudi, Srikant; Herceg, Zdenko; Kowalski, Luiz Paulo; Rogatto, Silvia Regina

2017-11-01

Even though the majority of well-differentiated thyroid carcinoma (WDTC) is indolent, a number of cases display an aggressive behavior. Cumulative evidence suggests that the deregulation of DNA methylation has the potential to point out molecular markers associated with worse prognosis. To identify a prognostic epigenetic signature in thyroid cancer. Genome-wide DNA methylation assays (450k platform, Illumina) were performed in a cohort of 50 nonneoplastic thyroid tissues (NTs), 17 benign thyroid lesions (BTLs), and 74 thyroid carcinomas (60 papillary, 8 follicular, 2 Hürthle cell, 1 poorly differentiated, and 3 anaplastic). A prognostic classifier for WDTC was developed via diagonal linear discriminant analysis. The results were compared with The Cancer Genome Atlas (TCGA) database. A specific epigenetic profile was detected according to each histological subtype. BTLs and follicular carcinomas showed a greater number of methylated CpG in comparison with NTs, whereas hypomethylation was predominant in papillary and undifferentiated carcinomas. A prognostic classifier based on 21 DNA methylation probes was able to predict poor outcome in patients with WDTC (sensitivity 63%, specificity 92% for internal data; sensitivity 64%, specificity 88% for TCGA data). High-risk score based on the classifier was considered an independent factor of poor outcome (Cox regression, P < 0.001). The methylation profile of thyroid lesions exhibited a specific signature according to the histological subtype. A meaningful algorithm composed of 21 probes was capable of predicting the recurrence in WDTC. Copyright © 2017 Endocrine Society

The EGFR signaling pathway controls gut progenitor differentiation during planarian regeneration and homeostasis.

PubMed

Barberán, Sara; Fraguas, Susanna; Cebrià, Francesc

2016-06-15

The planarian Schmidtea mediterranea maintains and regenerates all its adult tissues through the proliferation and differentiation of a single population of pluripotent adult stem cells (ASCs) called neoblasts. Despite recent advances, the mechanisms regulating ASC differentiation into mature cell types are poorly understood. Here, we show that silencing of the planarian EGF receptor egfr-1 by RNA interference (RNAi) impairs gut progenitor differentiation into mature cells, compromising gut regeneration and maintenance. We identify a new putative EGF ligand, nrg-1, the silencing of which phenocopies the defects observed in egfr-1(RNAi) animals. These findings indicate that egfr-1 and nrg-1 promote gut progenitor differentiation, and are thus essential for normal cell turnover and regeneration in the planarian gut. Our study demonstrates that the EGFR signaling pathway is an important regulator of ASC differentiation in planarians. © 2016. Published by The Company of Biologists Ltd.

Loading-related regulation of gene expression in bone in the contexts of estrogen deficiency, lack of estrogen receptor α and disuse

PubMed Central

Zaman, Gul; Saxon, Leanne K.; Sunters, Andrew; Hilton, Helen; Underhill, Peter; Williams, Debbie; Price, Joanna S.; Lanyon, Lance E.

2010-01-01

Loading-related changes in gene expression in resident cells in the tibia of female mice in the contexts of normality (WT), estrogen deficiency (WT-OVX), absence of estrogen receptor α (ERα−/−) and disuse due to sciatic neurectomy (WT-SN) were established by microarray. Total RNA was extracted from loaded and contra-lateral non-loaded tibiae at selected time points after a single, short period of dynamic loading sufficient to engender an osteogenic response. There were marked changes in the expression of many genes according to context as well as in response to loading within those contexts. In WT mice at 3, 8, 12 and 24 h after loading the expression of 642, 341, 171 and 24 genes, respectively, were differentially regulated compared with contra-lateral bones which were not loaded. Only a few of the genes differentially regulated by loading in the tibiae of WT mice have recognized roles in bone metabolism or have been linked previously to osteogenesis (Opn, Sost, Esr1, Tgfb1, Lrp1, Ostn, Timp, Mmp, Ctgf, Postn and Irs1, BMP and DLX5). The canonical pathways showing the greatest loading-related regulation were those involving pyruvate metabolism, mitochondrial dysfunction, calcium-induced apoptosis, glycolysis/gluconeogenesis, aryl hydrocarbon receptor and oxidative phosphorylation. In the tibiae from WT-OVX, ERα−/− and WT-SN mice, 440, 439 and 987 genes respectively were differentially regulated by context alone compared to WT. The early response to loading in tibiae of WT-OVX mice involved differential regulation compared to their contra-lateral non-loaded pair of fewer genes than in WT, more down-regulation than up-regulation and a later response. This was shared by WT-SN. In tibiae of ERα−/− mice, the number of genes differentially regulated by loading was markedly reduced at all time points. These data indicate that in resident bone cells, both basal and loading-related gene expression is substantially modified by context. Many of the genes differentially regulated by the earliest loading-related response were primarily involved in energy metabolism and were not specific to bone. PMID:19857613

StearoylCoA Desaturase-5: A Novel Regulator of Neuronal Cell Proliferation and Differentiation

PubMed Central

Sinner, Debora I.; Kim, Gretchun J.; Henderson, Gregory C.; Igal, R. Ariel

2012-01-01

Recent studies have demonstrated that human stearoylCoA desaturase-1 (SCD1), a Δ9-desaturase that converts saturated fatty acids (SFA) into monounsaturated fatty acids, controls the rate of lipogenesis, cell proliferation and tumorigenic capacity in cancer cells. However, the biological function of stearoylCoA desaturase-5 (SCD5), a second isoform of human SCD that is highly expressed in brain, as well as its potential role in human disease, remains unknown. In this study we report that the constitutive overexpression of human SCD5 in mouse Neuro2a cells, a widely used cell model of neuronal growth and differentiation, displayed a greater n-7 MUFA-to-SFA ratio in cell lipids compared to empty-vector transfected cells (controls). De novo synthesis of phosphatidylcholine and cholesterolesters was increased whereas phosphatidylethanolamine and triacylglycerol formation was reduced in SCD5-expressing cells with respect to their controls, suggesting a differential use of SCD5 products for lipogenic reactions. We also observed that SCD5 expression markedly accelerated the rate of cell proliferation and suppressed the induction of neurite outgrowth, a typical marker of neuronal differentiation, by retinoic acid indicating that the desaturase plays a key role in the mechanisms of cell division and differentiation. Critical signal transduction pathways that are known to modulate these processes, such epidermal growth factor receptor (EGFR)Akt/ERK and Wnt, were affected by SCD5 expression. Epidermal growth factor-induced phosphorylation of EGFR, Akt and ERK was markedly blunted in SCD5-expressing cells. Furthermore, the activity of canonical Wnt was reduced whereas the non-canonical Wnt was increased by the presence of SCD5 activity. Finally, SCD5 expression increased the secretion of recombinant Wnt5a, a non-canonical Wnt, whereas it reduced the cellular and secreted levels of canonical Wnt7b. Our data suggest that, by a coordinated modulation of key lipogenic pathways and transduction signaling cascades, SCD5 participates in the regulation of neuronal cell growth and differentiation. PMID:22745828

Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4

PubMed Central

Dhar, Shilpa S.; Lee, Sung-Hun; Kan, Pu-Yeh; Voigt, Philipp; Ma, Li; Shi, Xiaobing; Reinberg, Danny; Lee, Min Gyu

2012-01-01

Mixed-lineage leukemia 4 (MLL4; also called MLL2 and ALR) enzymatically generates trimethylated histone H3 Lys 4 (H3K4me3), a hallmark of gene activation. However, how MLL4-deposited H3K4me3 interplays with other histone marks in epigenetic processes remains largely unknown. Here, we show that MLL4 plays an essential role in differentiating NT2/D1 stem cells by activating differentiation-specific genes. A tandem plant homeodomain (PHD4–6) of MLL4 recognizes unmethylated or asymmetrically dimethylated histone H4 Arg 3 (H4R3me0 or H4R3me2a) and is required for MLL4's nucleosomal methyltransferase activity and MLL4-mediated differentiation. Kabuki syndrome mutations in PHD4–6 reduce PHD4–6's binding ability and MLL4's catalytic activity. PHD4–6's binding strength is inhibited by H4R3 symmetric dimethylation (H4R3me2s), a gene-repressive mark. The protein arginine methyltransferase 7 (PRMT7), but not PRMT5, represses MLL4 target genes by up-regulating H4R3me2s levels and antagonizes MLL4-mediated differentiation. Consistently, PRMT7 knockdown increases MLL4-catalyzed H3K4me3 levels. During differentiation, decreased H4R3me2s levels are associated with increased H3K4me3 levels at a cohort of genes, including many HOXA and HOXB genes. These findings indicate that the trans-tail inhibition of MLL4-generated H3K4me3 by PRMT7-regulated H4R3me2s may result from H4R3me2s's interference with PHD4–6's binding activity and is a novel epigenetic mechanism that underlies opposing effects of MLL4 and PRMT7 on cellular differentiation. PMID:23249737

Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4.

PubMed

Dhar, Shilpa S; Lee, Sung-Hun; Kan, Pu-Yeh; Voigt, Philipp; Ma, Li; Shi, Xiaobing; Reinberg, Danny; Lee, Min Gyu

2012-12-15

Mixed-lineage leukemia 4 (MLL4; also called MLL2 and ALR) enzymatically generates trimethylated histone H3 Lys 4 (H3K4me3), a hallmark of gene activation. However, how MLL4-deposited H3K4me3 interplays with other histone marks in epigenetic processes remains largely unknown. Here, we show that MLL4 plays an essential role in differentiating NT2/D1 stem cells by activating differentiation-specific genes. A tandem plant homeodomain (PHD(4-6)) of MLL4 recognizes unmethylated or asymmetrically dimethylated histone H4 Arg 3 (H4R3me0 or H4R3me2a) and is required for MLL4's nucleosomal methyltransferase activity and MLL4-mediated differentiation. Kabuki syndrome mutations in PHD(4-6) reduce PHD(4-6)'s binding ability and MLL4's catalytic activity. PHD(4-6)'s binding strength is inhibited by H4R3 symmetric dimethylation (H4R3me2s), a gene-repressive mark. The protein arginine methyltransferase 7 (PRMT7), but not PRMT5, represses MLL4 target genes by up-regulating H4R3me2s levels and antagonizes MLL4-mediated differentiation. Consistently, PRMT7 knockdown increases MLL4-catalyzed H3K4me3 levels. During differentiation, decreased H4R3me2s levels are associated with increased H3K4me3 levels at a cohort of genes, including many HOXA and HOXB genes. These findings indicate that the trans-tail inhibition of MLL4-generated H3K4me3 by PRMT7-regulated H4R3me2s may result from H4R3me2s's interference with PHD(4-6)'s binding activity and is a novel epigenetic mechanism that underlies opposing effects of MLL4 and PRMT7 on cellular differentiation.

Smelling fit: scent marking exposes parasitic infection status in the banded mongoose.

PubMed

Mitchell, Jessica; Cant, Michael A; Vitikainen, Emma I K; Nichols, Hazel J

2017-06-01

Preference for uninfected mates is presumed beneficial as it minimizes one's risk of contracting an infection and infecting one's offspring. In avian systems, visual ornaments are often used to indicate parasite burdens and facilitate mate choice. However, in mammals, olfactory cues have been proposed to act as a mechanism allowing potential mates to be discriminated by infection status. The effect of infection upon mammalian mate choice is mainly studied in captive rodents where experimental trials support preference for the odors of uninfected mates and some data suggest scent marking is reduced in individuals with high infection burdens. Nevertheless, whether such effects occur in nonmodel and wild systems remains poorly understood. Here, we investigate the interplay between parasite load (estimated using fecal egg counts) and scent marking behavior in a wild population of banded mongooses Mungos mungo . Focusing on a costly protozoan parasite of the genus Isospora and the nematode worm Toxocara , we first show that banded mongooses that engage in frequent, intensive scent marking have lower Isospora loads, suggesting marking behavior may be an indicator trait regarding infection status. We then use odor presentations to demonstrate that banded mongooses mark less in response to odors of opposite sexed individuals with high Isospora and Toxocara loads. As both of these parasites are known to have detrimental effects upon the health of preweaned young in other species, they would appear key targets to avoid during mate choice. Results provide support for scent as an important ornament and mechanism for advertising parasitic infection within wild mammals.

Mass imprisonment and the life course revisited: Cumulative years spent imprisoned and marked for working-age black and white men.

PubMed

Patterson, Evelyn J; Wildeman, Christopher

2015-09-01

Over the last 40 years, imprisonment has become a common stage in the life-course for low-skilled and minority men, with implications not only for inequality among adult men but also for inequality more broadly. Unfortunately, all research documenting how increases in imprisonment have transformed the life-course of poor, minority men has neglected to estimate how much time black and white men on average spend imprisoned or marked as an ex-prisoner. In this article, we fill this gap by using multistate life tables to estimate what share of their working lives (18-64) black and white men will spend imprisoned and marked as ex-prisoners. Our estimates imply that white men spend on average 0.33 years of their working lives imprisoned and 2.31 years marked, while black men spend on average 1.79 years of their working lives imprisoned and 11.14 years marked. This implies that black men spend on average one-third of their working lives either imprisoned or having been freed but marked by the penal system. For the 32.2% of black men who ever experience imprisonment (Bonczar, 2003), moreover, these estimates imply that they spend on average 5.56 years imprisoned, corresponding to 13.4% of their working lives. Taken together, these findings imply a dramatic reorientation of the life course for black men, as one-third of the black male population will spend one-seventh of their working life in prison. Copyright © 2015 Elsevier Inc. All rights reserved.

A novel application of multi-event modeling to estimate class segregation in a highly migratory oceanic vertebrate.

PubMed

Chapple, T K; Chambert, T; Kanive, P E; Jorgensen, S J; Rotella, J J; Anderson, S D; Carlisle, A B; Block, B A

2016-12-01

Spatial segregation of animals by class (i.e., maturity or sex) within a population due to differential rates of temporary emigration (TE) from study sites can be an important life history feature to consider in population assessment and management. However, such rates are poorly known; new quantitative approaches to address these knowledge gaps are needed. We present a novel application of multi-event models that takes advantage of two sources of detections to differentiate temporary emigration from apparent absence to quantify class segregation within a study population of double-marked (photo-identified and tagged with coded acoustic transmitters) white sharks (Carcharodon carcharias) in central California. We use this model to test if sex-specific patterns in TE result in disparate apparent capture probabilities (p o ) between male and female white sharks, which can affect the observed sex ratio. The best-supported model showed a contrasting pattern of Pr(TE) from coastal aggregation sites between sexes (for males Pr[TE] = 0.015 [95% CI = 0.00, 0.31] and Pr[TE]= 0.57 [0.40, 0.72] for females), but not maturity classes. Additionally, by accounting for Pr(TE) and imperfect detection, we were able to estimate class-specific values of true capture probability (p * ) for tagged and untagged sharks. The best-supported model identified differences between maturity classes but no difference between sexes or tagging impacts (tagged mature sharks p *  = 0.55 (0.46-0.63) and sub-adult sharks p*   = 0.36 (0.25, 0.50); and untagged mature sharks p *  = 0.50 (0.39-0.61) and sub-adults p *  = 0.18 (0.10, 0.31). Estimated sex-based differences in p o were linked to sex-specific differences in Pr(TE) but not in p * ; once the Pr(TE) is accounted for, the p * between sexes was not different. These results indicate that the observed sex ratio is not a consequence of unequal detectability and sex-specific values of Pr(TE) are important drivers of the observed male-dominated sex ratio. Our modeling approach reveals complex class-specific patterns in Pr(TE) and p * in a mark-recapture data set, and highlights challenges for the population modeling and conservation of white sharks in central California. The model we develop here can be used to estimate rates of temporary emigration and class segregation when two detection methods are used. © 2016 by the Ecological Society of America.

An unusual case of gastric cancer presenting with breast metastasis with pleomorphic microcalcifications.

PubMed

Luk, Yiu Shiobhon; Ka, Solomon Yig Joon; Lo, Sherwin Shing Wai; Chu, Chi Yeung; Ma, Ming Wai

2012-09-01

Breast metastasis from gastric carcinoma is rare. We present a case of right breast mass with microcalcification in which the diagnosis of poorly differentiated adenocarcinoma from the stomach was made after a biopsy. Pleomorphic microcalcification was noted in the ill-defined breast mass, which is a rare feature in breast metastasis. Since breast metastasis usually signifies advanced metastatic disease, differentiating primary breast cancer from metastasis is important for appropriate treatment.

From the inside out: a new species of armoured catfish Corydoras with the description of poorly-explored character sources (Teleostei, Siluriformes, Callichthyidae).

PubMed

Espíndola, V C; Tencatt, L F C; Pupo, F M; Villa-Verde, L; Britto, M R

2018-05-01

A new species of the armoured catfish genus Corydoras is described from the Xingu-Tapajos ecoregion, Brazilian Amazon. The new species can be distinguished from its congeners by having the following combination of features: short mesethmoid, with anterior tip poorly developed, smaller than 50% of bone length; posterior margin of pectoral spine with serrations directed towards spine tip or perpendicularly oriented; infraorbital 2 only in contact with sphenotic; ventral laminar expansion of infraorbital 1 poorly or moderately developed; flank midline covered by small dark brown or black saddles with similar size to remaining markings on body; relatively larger, scarcer and more sparsely distributed dark brown or black spots on body; absence of stripe on flank midline; caudal fin with conspicuous dark brown or black spots along its entire surface; slender body; and strongly narrow frontals. A more comprehensive description of poorly-explored internal character sources, such as the gross morphology of the brain, Weberian apparatus and swimbladder capsule elements is presented. © 2018 The Fisheries Society of the British Isles.

Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation

PubMed Central

Zheng, Xinde; Boyer, Leah; Jin, Mingji; Mertens, Jerome; Kim, Yongsung; Ma, Li; Ma, Li; Hamm, Michael; Gage, Fred H; Hunter, Tony

2016-01-01

How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size. DOI: http://dx.doi.org/10.7554/eLife.13374.001 PMID:27282387

MYB36 regulates the transition from proliferation to differentiation in the Arabidopsis root

PubMed Central

Liberman, Louisa M.; Sparks, Erin E.; Moreno-Risueno, Miguel A.; Petricka, Jalean J.; Benfey, Philip N.

2015-01-01

Stem cells are defined by their ability to self-renew and produce daughter cells that proliferate and mature. These maturing cells transition from a proliferative state to a terminal state through the process of differentiation. In the Arabidopsis thaliana root the transcription factors SCARECROW and SHORTROOT regulate specification of the bipotent stem cell that gives rise to cortical and endodermal progenitors. Subsequent progenitor proliferation and differentiation generate mature endodermis, marked by the Casparian strip, a cell-wall modification that prevents ion diffusion into and out of the vasculature. We identified a transcription factor, MYB DOMAIN PROTEIN 36 (MYB36), that regulates the transition from proliferation to differentiation in the endodermis. We show that SCARECROW directly activates MYB36 expression, and that MYB36 likely acts in a feed-forward loop to regulate essential Casparian strip formation genes. We show that myb36 mutants have delayed and defective barrier formation as well as extra divisions in the meristem. Our results demonstrate that MYB36 is a critical positive regulator of differentiation and negative regulator of cell proliferation. PMID:26371322

HIV associated eosinophilic folliculitis--differential diagnosis and management

PubMed Central

Simpson-Dent, S.; Fearfield, L. A.; Staughton, R. C.

1999-01-01

Eosinophilic folliculitis (EF) is a chronic, intensely pruritic condition of unknown pathogenesis that causes marked morbidity in those HIV patients whom it affects. There is a wide differential diagnosis of itchy skin conditions in HIV which are amenable to different treatments. It is therefore essential to take a biopsy of each suspected case and examine multiple sections of the biopsy to confirm or refute a diagnosis of EF. Treatment of EF can be difficult but we hope that by suggesting a rational approach to this and considering possible therapeutic options more patients may be helped with this troublesome dermatosis. 


 PMID:10616350

Psychiatric diagnosis and differential risks of offending following discharge.

PubMed

Coid, Jeremy W; Yang, Min; Ullrich, Simone; Hickey, Nicole; Kahtan, Nadji; Freestone, Mark

2015-01-01

Psychiatric diagnosis is not considered a risk factor for offending following discharge. However, treatment interventions and aftercare are strongly influenced by clinical primary diagnosis. We compared differential risks of reoffending of patients falling into six primary diagnostic categories following discharge from Medium Secure Units in the UK: schizophrenia/schizoaffective disorder; delusional disorder; mania/hypomania; depressive disorder; organic brain syndrome; personality disorder. We followed up 1344 patients, on average 6.2 years (SD=2.1) at risk, discharged from 7 of 14 Regional Medium Secure services in England and Wales. Outcomes were period prevalence, incidence, and cumulative probability of criminal conviction. Established demographic and criminal history predictors of reoffending were observed across different diagnostic categories. Risks of all offending were increased for personality disorder, violence/acquisitive offending for delusional disorder, sexual offending for mania/hypomania and violence/acquisitive offending for organic brain syndrome. Patterns of risk over time differed markedly between categories of mental disorder. Most patients with personality disorder who offended violently did so within 4 years of discharge. A subgroup with delusional disorder demonstrated increased risk of violent offending 5 years after discharge. Differential risks of reoffending are observed between different diagnostic groups. Clinical diagnosis should be included together with established risk measures in risk management following discharge. Close supervision of patients with personality disorder should begin immediately after discharge when risks of reoffending are greatest. For delusional disorder further investigation is needed into the marked increase in risk of violence after 5 years. Copyright © 2015 Elsevier Ltd. All rights reserved.

Interleukins-17 and 27 promote liver regeneration by sequentially inducing progenitor cell expansion and differentiation.

PubMed

Guillot, Adrien; Gasmi, Imène; Brouillet, Arthur; Ait-Ahmed, Yeni; Calderaro, Julien; Ruiz, Isaac; Gao, Bin; Lotersztajn, Sophie; Pawlotsky, Jean-Michel; Lafdil, Fouad

2018-03-01

Liver progenitor cells (LPCs)/ductular reactions (DRs) are associated with inflammation and implicated in the pathogenesis of chronic liver diseases. However, how inflammation regulates LPCs/DRs remains largely unknown. Identification of inflammatory processes that involve LPC activation and expansion represent a key step in understanding the pathogenesis of liver diseases. In the current study, we found that diverse types of chronic liver diseases are associated with elevation of infiltrated interleukin (IL)-17-positive (+) cells and cytokeratin 19 (CK19) + LPCs, and both cell types colocalized and their numbers positively correlated with each other. The role of IL-17 in the induction of LPCs was examined in a mouse model fed a choline-deficient and ethionine-supplemented (CDE) diet. Feeding of wild-type mice with the CDE diet markedly elevated CK19 + Ki67 + proliferating LPCs and hepatic inflammation. Disruption of the IL-17 gene or IL-27 receptor, alpha subunit (WSX-1) gene abolished CDE diet-induced LPC expansion and inflammation. In vitro treatment with IL-17 promoted proliferation of bipotential murine oval liver cells (a liver progenitor cell line) and markedly up-regulated IL-27 expression in macrophages. Treatment with IL-27 favored the differentiation of bipotential murine oval liver cells and freshly isolated LPCs into hepatocytes. Conclusion : The current data provide evidence for a collaborative role between IL-17 and IL-27 in promoting LPC expansion and differentiation, respectively, thereby contributing to liver regeneration. ( Hepatology Communications 2018;2:329-343).