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1

The antitumor efficacy of calcitriol: preclinical studies.  

PubMed

Studies in our laboratory demonstrate that vitamin D (1,25 dihydroxycholecalciferol or calcitriol) has significant antitumor activity in vitro and in vivo in murine and human squamous cell, prostate, lung, pancreatic and myeloma model systems. Calcitriol induces G0/G1 arrest, modulates p27 and p21, the cyclin-dependent kinase (cdk) inhibitors implicated in G1 arrest, and induces cleavage of caspase 3, PARP and the mitogen-activated protein kinase (MEK) in a caspase-dependent manner. Calcitriol also decreases phospho-Erk (P-Erk) and phospho-Akt (P-Akt), kinases that regulate cell survival pathways and up-regulate the pro-apoptotic signaling molecule, MEKK-1. Glucocorticoids enhance calcitriol-mediated activities pre-clinically in vitro and in vivo. Dexamethasone (dex) significantly potentiated the antitumor effect of calcitriol and decreased calcitriol-induced hypercalcemia. Both in vitro and in vivo, dex increased vitamin D receptor (VDR) ligand binding in the tumor while decreasing binding in intestinal mucosa, the site of calcium absorption. These studies demonstrated that calcitriol has significant antiproliferative activity in a number of pre-clinical model systems and form the groundwork for on-going clinical studies investigating calcitriol as an anticancer agent. PMID:16886662

Johnson, Candace S; Muindi, Josephia R; Hershberger, Pamela A; Trump, Donald L

2006-01-01

2

Nonindustry-Sponsored Preclinical Studies on Statins Yield Greater Efficacy Estimates Than Industry-Sponsored Studies: A Meta-Analysis  

PubMed Central

Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966–April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I2 statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (?1.99; 95% CI ?2.68, ?1.31) versus studies sponsored by industry (?0.73; 95% CI ?1.00, ?0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study. PMID:24465178

Krauth, David; Anglemyer, Andrew; Philipps, Rose; Bero, Lisa

2014-01-01

3

Nubac Disc Arthroplasty: Preclinical Studies and Preliminary Safety and Efficacy Evaluations  

PubMed Central

Background Disc arthroplasty is gaining popularity for treatment of low-back pain caused by degenerative disc disease (DDD). It can involve total disc replacement or partial disc or nucleus replacement (or augmentation). Compared with total disc replacement, nucleus replacement is less invasive, has less surgical risk, has faster postoperative recovery, and doesn't “burn bridges” should further surgery be required. However, nucleus replacement has a high risk of implant expulsion because the device is not fixed to the vertebrae. Nubac is the first polyetheretherketone (PEEK)-on-PEEK articulated disc arthroplasty device designed to optimally restore the lumbar anatomy and biomechanics. Methods ISO 10993 standards were used to evaluate the biocompatibility of the PEEK material. Chemical and thermal–mechanical tests and in vivo study assessed PEEK's biostability after exposure to high g irradiation and harsh oxidative conditions. Biomechanical tests to evaluate kinematic properties and anatomical restoration of the implanted lumbar motion segments and implant expulsion risk assessments were performed with a human cadaveric model. Because of the novelty of PEEK-on-PEEK as a self-mating articulating material, extensive wear tests were conducted with unidirectional and coupled motions. Static and fatigue strength also were tested. Animal study with a baboon model was conducted with gross, radiographic, biomechanical, and histological evaluations at 6 and 12 months postoperatively. Preliminary clinical data were collected through a prospective multicenter cohort study. Results PEEK demonstrated exceptional biocompatibility and biodurability. Nubac restored disc height and motion segment range of motion. The unique articulating design of the Nubac demonstrated low risk of implant expulsion in a human cadaveric model. Wear tests showed that the Nubac has minimal wear and compares favorably to other disc arthroplasty materials. The Nubac also had excellent static and fatigue properties for the intended application. The animal study showed that the Nubac caused no adverse local or systematic tissue reaction and there was no detectable wear debris. The preliminary clinical data showed no major intraoperative vascular and neurological complications. There was significant Visual Analog Scale and Oswestry Disability Index score improvement. Conclusions The preclinical data supported the design rationale, and the preliminary clinical data (level II evidence) on safety and efficacy were encouraging. Clinical Relevance The Nubac could be a viable first surgical option for patients with back pain caused by DDD.

Songer, Matthew; Pimenta, Luis; Werner, Dieter; Reyes-Sanchez, Alejandro; Balsano, Massimo; Agrillo, Umberto; Coric, Domagoj; Davenport, Kenneth; Yuan, Hansen

2007-01-01

4

Pasteurization of bone for tumour eradication prior to reimplantation – An in vitro & pre-clinical efficacy study  

PubMed Central

Background & objectives: In current era of limb-salvage therapy, pasteurization of bone sarcomas is receiving growing attention as a potential extracorporeal treatment and cost-effective alternative to allografts and radiation before surgical reimplantation. Detailed in vitro and in vivo pre-clinical study to evaluate efficacy of pasteurization to eradicate malignant cells has not been reported yet. The present study was carried out to assess the efficacy of pasteurization to kill tumour cells both in vitro and in vivo. Methods: Surgically resected specimens of osteosarcomas (n=4) were cut into equal halves and one section was pasteurized by heating at 60°C to 65°C for 40 min. Paired samples before and after pasteurization were studied in vitro for DNA ploidy, evaluation of histological change and elimination of mitotic activity. These tissues were transplanted in immune-deficient NOD-SCID mice to evaluate effect on tumour-generating ability, presence of human nuclei, osteopontin and cytokine/chemokines released in tumour-transplanted mice. Results: Non-pasteurized tumour samples had viable tumour cells which exhibited significant growth in culture, increased proliferative ability and clonogenic potential while respective pasteurized tumour tissues did not grow in culture and did not exhibit clonogenicity. Flow cytometry revealed that propidium iodide positive dead cells increased significantly (P< 0.01) post pasteurization. Seven of 12 non-pasteurized tumour transplanted mice demonstrated tumour-forming ability as against 0 of 12 in pasteurized tumour transplanted mice. Solid tumour xenografts exhibited strong expression of anti-human nuclei and osteopontin by immunohistochemistry as well as secretary human interluekin-6 (IL-6) while pasteurized mice failed to express these markers. Interpretation & conclusions: This study has provided a basis to establish pasteurization as being efficacious in ensuring tumour eradication from resected bone tumour specimens. Pasteurized tumour bearing bone can thus safely be used to reconstruct large defects after tumour resection. PMID:24927346

Kode, Jyoti; Taur, Prasad; Gulia, Ashish; Jambhekar, Nirmala; Agarwal, Manish; Puri, Ajay

2014-01-01

5

Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study  

PubMed Central

Purpose To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. Methods Seven normally-sighted feline subjects were implanted for 96–143 days with a suprachoroidal electrode array and six were chronically stimulated for 70–105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. Results All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11–15 k? during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. Conclusions Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents. PMID:24853376

Nayagam, David A. X.; Williams, Richard A.; Allen, Penelope J.; Shivdasani, Mohit N.; Luu, Chi D.; Salinas-LaRosa, Cesar M.; Finch, Sue; Ayton, Lauren N.; Saunders, Alexia L.; McPhedran, Michelle; McGowan, Ceara; Villalobos, Joel; Fallon, James B.; Wise, Andrew K.; Yeoh, Jonathan; Xu, Jin; Feng, Helen; Millard, Rodney; McWade, Melanie; Thien, Patrick C.; Williams, Chris E.; Shepherd, Robert K.

2014-01-01

6

An Independent Study of the Preclinical Efficacy of C2-8 in the R6/2 Transgenic Mouse Model of Huntington's Disease  

PubMed Central

Background C2-8 is a small molecule inhibitor of polyglutamine aggregation and can reduce photoreceptor neurodegeneration in a Drosophila model of Huntington's disease (HD). Further preclinical studies have shown that oral administration of C2-8 in R6/2 HD transgenic mice can penetrate into the brain, reduce mHTT-exon1 aggregation, improve motor performance and diminish striatal neuron atrophy. Objective In this independent preclinical study, we aimed to evaluate the pharmacokinetic properties and therapeutic efficacy of C2-8 intraperitoneal (IP) delivery in the R6/2 HD mouse. Methods R6/2 mice were IP injected with low dose C2-8 (10 mg/kg), high dose C2-8 (20 mg/kg), or vehicle twice daily from 3 weeks to 3 months old. Longitudinal behavioral tests (accelerating Rotarod and wire-hang) were performed to evaluate the motor deficits, and neuropathology was measured by unbiased stereology. Results We confirmed that the compound has good blood-brain-barrier penetration after acute or sub-chronic intraperitoneal delivery. Chronic treatment with C2-8 in R6/2 mice results in a significant reduction of nuclear mHTT aggregate volume in the brains, replicating a key finding of C2-8 as a polyglutamine aggregation inhibitor in vivo. However, by comparing HD mice with C2-8 treatment to those with vehicle treatment, we were unable to demonstrate significant amelioration of motor deficits using Rotarod and wire-hang tests. Moreover, we did not observe improvement in the striatal neurodegenerative pathology, as measured by brain weight, striatal volume, and striatal neuron volume in the C2-8 treated R6/2 mice. Conclusions Our study supports the practice of independent preclinical studies for novel molecules in HD therapeutic development and suggests that the use of alternative delivery strategies and full-length HD mouse models are likely needed to further assess whether the aggregate-inhibiting properties of C2-8 can be consistently translated into a preclinical benefit in HD mice. PMID:25062731

Wang, Nan; Lu, Xiao-Hong; Sandoval, Susana V.; Yang, X. William

2014-01-01

7

Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study  

NASA Astrophysics Data System (ADS)

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

8

Preclinical studies of low back pain  

PubMed Central

Chronic low back pain is a major cause of disability and health care costs. Current treatments are inadequate for many patients. A number of preclinical models have been developed that attempt to mimic aspects of clinical conditions that contribute to low back pain. These involve application of nucleus pulposus material near the lumbar dorsal root ganglia (DRG), chronic compression of the DRG, or localized inflammation of the DRG. These models, which are primarily implemented in rats, have many common features including behavioral hypersensitivity of the hindpaw, enhanced excitability and spontaneous activity of sensory neurons, and locally elevated levels of inflammatory mediators including cytokines. Clinically, epidural injection of steroids (glucocorticoids) is commonly used when more conservative treatments fail, but clinical trials evaluating these treatments have yielded mixed results. There are relatively few preclinical studies of steroid effects in low back pain models. One preclinical study suggests that the mineralocorticoid receptor, also present in the DRG, may have pro-inflammatory effects that oppose the activation of the glucocorticoid receptor. Although the glucocorticoid receptor is the target of anti-inflammatory steroids, many clinically used steroids activate both receptors. This could be one explanation for the limited effects of epidural steroids in some patients. Additional preclinical research is needed to address other possible reasons for limited efficacy of steroids, such as central sensitization or presence of an ongoing inflammatory stimulus in some forms of low back pain. PMID:23537369

2013-01-01

9

Preclinical Studies to Predict Efficacy of Vascular Changes Induced by Combretastatin A-4 Disodium Phosphate in Patients  

SciTech Connect

Purpose: To determine how combretastatin A-4 disodium phosphate (CA4DP) dose-dependent changes in radiation response of a C3H mouse mammary carcinoma relate to measurements of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and how those mouse DCE-MRI results compare with published clinical DCE-MRI data. Methods and Materials: C3H mammary carcinomas grown in female CDF{sub 1} mice were treated when at 200 mm{sup 3} in size. Groups of mice were given graded radiation doses, either alone or followed 30 min later by an intraperitoneal injection of CA4DP, administered at doses of 10-250 mg/kg. The radiation dose producing local tumor control in 50% of treated animals at 90 days (TCD{sub 50}) was calculated for each CA4DP dose. DCE-MRI was performed before and 3 h after CA4DP administration, and parameters describing vascularity and interstitial volume were estimated. Results: TCD{sub 50} showed a dose-dependent decrease reaching significance at 25 mg/kg. At greater doses of 50 and 100 mg/kg, the TCD{sub 50} increased slightly and was not significantly different from that of controls. TCD{sub 50} significantly decreased again at 250 mg/kg. The drug dose-response curves for all post-treatment vascular DCE-MRI parameters showed a shape similar to that of the TCD{sub 50} curve. A similar dose dependency was seen with previously published clinical data. Conclusion: Our preclinical DCE-MRI data could predict the CA4DP enhancement of the tumor radiation response and suggest the clinical CA4DP doses necessary to improve the radiation response in patients.

Nielsen, Thomas [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark); Department of Neuroradiology, Aarhus University Hospital, Aarhus (Denmark)], E-mail: thomas@oncology.dk; Murata, Rumi [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark); Maxwell, Ross J. [University of Newcastle Upon Tyne, Northern Institute for Cancer Research, Newcastle Upon Tyne (United Kingdom); Stodkilde-Jorgensen, Hans [MR Research Centre, Aarhus University Hospital, Aarhus (Denmark); Ostergaard, Leif [Department of Neuroradiology, Aarhus University Hospital, Aarhus (Denmark); Horsman, Michael R. [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark)

2008-03-01

10

In-Vivo Efficacy of Compliant 3D Nano-Composite in Critical-Size Bone Defect Repair: a Six Month Preclinical Study in Rabbit  

PubMed Central

Bone defects above critical size do not heal completely by itself and thus represent major clinical challenge to reconstructive surgery. Numerous bone substitutes have already been used to promote bone regeneration, however their use, particularly for critical-sized bone defects along with their long term in vivo safety and efficacy remains a concern. The present study was designed to obtain a complete healing of critical-size defect made in the proximal tibia of New Zealand White rabbit, using nano-hydroxyapatite/gelatin and chemically carboxymethylated chitin (n-HA/gel/CMC) scaffold construct. The bone-implant interfaces and defect site healing was evaluated for a period up to 25 weeks using radiography, micro-computed tomography, fluorescence labeling, and histology and compared with respective SHAM (empty contra lateral control). The viscoelastic porous scaffold construct allows easy surgical insertion and post-operatively facilitate oxygenation and angiogenesis. Radiography of defect treated with scaffold construct suggested expedited healing at defect edges and within the defect site, unlike confined healing at edges of the SHAM sites. The architecture indices analyzed by micro-computed tomography showed a significant increase in percentage of bone volume fraction, resulted in reconciled cortico-trabecular bone formation at n-HA/gel/CMC constructs treated site (15.2% to 52.7%) when compared with respective SHAM (10.2% to 31.8%). Histological examination and fluorescence labeling revealed that the uniformly interconnected porous surface of scaffold construct enhanced osteoblasts’ activity and mineralization. These preclinical data suggest that, n-HA/gel/CMC construct exhibit stimulation of bone's innate regenerative capacity, thus underscoring their use in guided bone regeneration. PMID:24204879

Sagar, Nitin; Pandey, Alok K.; Gurbani, Deepak; Khan, Kainat; Singh, Dhirendra; Chaudhari, Bhushan P.; Soni, Vivek P.; Chattopadhyay, Naibedya; Dhawan, Alok; Bellare, Jayesh R.

2013-01-01

11

A Preclinical Study of the Safety and Efficacy of Occlusin Trade-Mark-Sign 500 Artificial Embolization Device in Sheep  

SciTech Connect

Introduction: This study evaluated the safety, effectiveness, and biodegradation of a new embolic agent, Occlusin Trade-Mark-Sign 503 Artificial Embolization Device (OCL 503). The agent consists of biodegradable poly-lactic-co-glycolic acid microspheres (150-212 {mu}m) coated with type I bovine collagen and was compared with Embosphere{sup Registered-Sign} Microspheres (300-500 {mu}m) in this controlled study of uterine artery embolization (UAE) in sheep. Methods: Unilateral UAE was performed in 32 adult ewes randomly assigned. Vessels were embolized to effective stasis. The cohort was divided into four groups, which were sacrificed at 1, 3, 6, and 12 months. Results: Both agents were 100% effective in achieving stasis. At 6 months, all OCL 503-treated arteries were occluded, the microspheres degraded with time, and at 12 months all four animals examined demonstrated recanalization. OCL 503 was found in the untreated uterine artery in one animal with no other evidence of non target embolization. In the Embosphere-treated group, all vessels remained occluded and microspheres were detected in the contralateral uterine artery in 6 of 15 examined vessels and in 10 vaginal, 2 ovarian, and 1 vesical artery. No procedural-related complications were seen in either group. Conclusions: OCL 503 is as effective an embolic agent as Embosphere{sup Registered-Sign} Microspheres when embolizing ovine uterine arteries and resorbs with time, allowing recanalization of the treated arteries. No device-related issues or adverse events were observed.

Owen, Richard J., E-mail: drrichardowen@tbwifi.ca [University of Alberta, Radiology and Diagnostic Imaging, Walter C. Mackenzie Health Sciences Centre (Canada); Nation, Patrick N. [University of Alberta, Laboratory Medicine and Pathology, Walter C. Mackenzie Health Sciences Centre (Canada); Polakowski, Robert [BioLipids Inc (Canada); Biliske, Jennifer A. [University of Alberta, Biological Sciences, CW405, Biological Sciences Building (Canada); Tiege, Paul B. [University of Alberta, Lipid Products Research Alberta (LiPRA), 410 Agriculture/Forestry Centre (Canada); Griffith, Irwin J. [IMBiotechnologies Ltd (Canada)

2012-06-15

12

Writing Successful Grant Applications for Preclinical Studies*  

E-print Network

Writing Successful Grant Applications for Preclinical Studies* David Kessel, PhD (CHEST 2006; 130:296­298) Key words: applications; grants; medical writing Abbreviations: ERA Electronic Research Administration

Berdichevsky, Victor

13

Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming  

SciTech Connect

Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab?{sub 2} based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of {sup 99m}Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab?{sub 2} product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab?{sub 2} based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10. -- Highlights: ? Nanobody therapy prevents the hemodynamic disturbances induced by a lethal dose. ? Late injection of Nanobody restores hemodynamic parameters to baseline values. ? Nanobody therapy prevents lung and heart lesions of treated mice after envenoming. ? Labeled Nanobody and Fab’2 pharmacokinetics curves reach plateau in favour of Nanobody.

Hmila, Issam [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Cosyns, Bernard [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Tounsi, Hayfa [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Roosens, Bram; Caveliers, Vicky [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Abderrazek, Rahma Ben [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Boubaker, Samir [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Muyldermans, Serge [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium) [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium); Department of Structural Biology, VIB, Brussels (Belgium); El Ayeb, Mohamed [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Bouhaouala-Zahar, Balkiss, E-mail: balkiss.bouhaouala@pasteur.rns.tn [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia) [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Faculté de Médecine de Tunis, Université de Tunis-El Manar (Tunisia); Lahoutte, Tony [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)

2012-10-15

14

Preclinical Studies of Amixicile, a Systemic Therapeutic Developed for Treatment of Clostridium difficile Infections That Also Shows Efficacy against Helicobacter pylori  

PubMed Central

Amixicile shows efficacy in the treatment of Clostridium difficile infections (CDI) in a mouse model, with no recurrence of CDI. Since amixicile selectively inhibits the action of a B vitamin (thiamine pyrophosphate) cofactor of pyruvate:ferredoxin oxidoreductase (PFOR), it may both escape mutation-based drug resistance and spare beneficial probiotic gut bacteria that do not express this enzyme. Amixicile is a water-soluble derivative of nitazoxanide (NTZ), an antiparasitic therapeutic that also shows efficacy against CDI in humans. In comparative studies, amixicile showed no toxicity to hepatocytes at 200 ?M (NTZ was toxic above 10 ?M); was not metabolized by human, dog, or rat liver microsomes; showed equivalence or superiority to NTZ in cytochrome P450 assays; and did not activate efflux pumps (breast cancer resistance protein, P glycoprotein). A maximum dose (300 mg/kg) of amixicile given by the oral or intraperitoneal route was well tolerated by mice and rats. Plasma exposure (rats) based on the area under the plasma concentration-time curve was 79.3 h · ?g/ml (30 mg/kg dose) to 328 h · ?g/ml (100 mg/kg dose), the maximum concentration of the drug in serum was 20 ?g/ml, the time to the maximum concentration of the drug in serum was 0.5 to 1 h, and the half-life was 5.6 h. Amixicile did not concentrate in mouse feces or adversely affect gut populations of Bacteroides species, Firmicutes, segmented filamentous bacteria, or Lactobacillus species. Systemic bioavailability was demonstrated through eradication of Helicobacter pylori in a mouse infection model. In summary, the efficacy of amixicile in treating CDI and other infections, together with low toxicity, an absence of mutation-based drug resistance, and excellent drug metabolism and pharmacokinetic metrics, suggests a potential for broad application in the treatment of infections caused by PFOR-expressing microbial pathogens in addition to CDI. PMID:24890599

Bruce, Alexandra M.; Olekhnovich, Igor; Warren, Cirle A.; Burgess, Stacey L.; Hontecillas, Raquel; Viladomiu, Monica; Bassaganya-Riera, Josep; Guerrant, Richard L.; Macdonald, Timothy L.

2014-01-01

15

Preclinical studies of amixicile, a systemic therapeutic developed for treatment of Clostridium difficile infections that also shows efficacy against Helicobacter pylori.  

PubMed

Amixicile shows efficacy in the treatment of Clostridium difficile infections (CDI) in a mouse model, with no recurrence of CDI. Since amixicile selectively inhibits the action of a B vitamin (thiamine pyrophosphate) cofactor of pyruvate:ferredoxin oxidoreductase (PFOR), it may both escape mutation-based drug resistance and spare beneficial probiotic gut bacteria that do not express this enzyme. Amixicile is a water-soluble derivative of nitazoxanide (NTZ), an antiparasitic therapeutic that also shows efficacy against CDI in humans. In comparative studies, amixicile showed no toxicity to hepatocytes at 200 ?M (NTZ was toxic above 10 ?M); was not metabolized by human, dog, or rat liver microsomes; showed equivalence or superiority to NTZ in cytochrome P450 assays; and did not activate efflux pumps (breast cancer resistance protein, P glycoprotein). A maximum dose (300 mg/kg) of amixicile given by the oral or intraperitoneal route was well tolerated by mice and rats. Plasma exposure (rats) based on the area under the plasma concentration-time curve was 79.3 h · ?g/ml (30 mg/kg dose) to 328 h · ?g/ml (100 mg/kg dose), the maximum concentration of the drug in serum was 20 ?g/ml, the time to the maximum concentration of the drug in serum was 0.5 to 1 h, and the half-life was 5.6 h. Amixicile did not concentrate in mouse feces or adversely affect gut populations of Bacteroides species, Firmicutes, segmented filamentous bacteria, or Lactobacillus species. Systemic bioavailability was demonstrated through eradication of Helicobacter pylori in a mouse infection model. In summary, the efficacy of amixicile in treating CDI and other infections, together with low toxicity, an absence of mutation-based drug resistance, and excellent drug metabolism and pharmacokinetic metrics, suggests a potential for broad application in the treatment of infections caused by PFOR-expressing microbial pathogens in addition to CDI. PMID:24890599

Hoffman, Paul S; Bruce, Alexandra M; Olekhnovich, Igor; Warren, Cirle A; Burgess, Stacey L; Hontecillas, Raquel; Viladomiu, Monica; Bassaganya-Riera, Josep; Guerrant, Richard L; Macdonald, Timothy L

2014-08-01

16

Preclinical Efficacy of the Camptothecin-Polymer Conjugate IT101 in Multiple Cancer Models  

Microsoft Academic Search

Preclinical efficacy of i.v. IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a cyclo- dextrin-based polymer, was investigated in several mouse xenografts.The effects of different mul- tiple dosing schedules on tumor growth of LS174Tcolon carcinoma xenografts are elucidated. All multiple dosing schedules administered over15 to19 days resulted in enhanced efficacy compared with untreated or single-dose groups. Further improvements in antitumor efficacy

Thomas Schluep; Jungyeong Hwang; Jianjun Cheng; Jeremy D. Heidel; Derek W. Bartlett; Beth Hollister; Mark E. Davis

17

Efficacy and safety of mesenchymal stromal cells in preclinical models of acute lung injury: a systematic review protocol  

PubMed Central

Background Acute respiratory distress syndrome (ARDS) in humans is caused by an unchecked proinflammatory response that results in diffuse and severe lung injury, and it is associated with a mortality rate of 35 to 45%. Mesenchymal stromal cells (MSCs; ‘adult stem cells’) could represent a promising new therapy for this syndrome, since preclinical evidence suggests that MSCs may ameliorate lung injury. Prior to a human clinical trial, our aim is to conduct a systematic review to compare the efficacy and safety of MSC therapy versus controls in preclinical models of acute lung injury that mimic some aspects of the human ARDS. Methods/Design We will include comparative preclinical studies (randomized and non-randomized) of acute lung injury in which MSCs were administered and outcomes compared to animals given a vehicle control. The primary outcome will be death. Secondary outcomes will include the four key features of preclinical acute lung injury as defined by the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar capillary barrier, lung inflammatory response, and physiological dysfunction) and pathogen clearance for acute lung injury models that are caused by infection. Electronic searches of MEDLINE, Embase, BIOSIS Previews, and Web of Science will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the Cochrane risk of bias tool, and individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Discussion The results of this systematic review will comprehensively summarize the safety and efficacy of MSC therapy in preclinical models of acute lung injury. Our results will help translational scientists and clinical trialists to determine whether sufficient evidence exists to perform a human clinical trial. These results may also guide future acute lung injury preclinical and clinical research. PMID:24887266

2014-01-01

18

Usefulness of Preclinical Models for Assessing the Efficacy of Late-Life Interventions for Sarcopenia  

PubMed Central

Caloric restriction and physical exercise have proven beneficial against age-associated changes in body composition and declining physical performance; however, little is known regarding what benefit these interventions might have when initiated late in life. The study of mimetics of diet and exercise and the combination thereof may provide additional treatments for a vulnerable elderly population; however, how and when to initiate such interventions requires consideration in developing the most safe and efficacious treatment strategies. In this review, we focus on preclinical late-life intervention studies, which assess the relationship between physical function, sarcopenia, and body composition. We provide a conceptual framework for the ever-changing definition of sarcopenia and a rationale for the use of an appropriate rodent model of this condition. We finish by providing our perspective regarding the implications of this body of work and future areas of research that may also contribute to the ultimate goal of extending healthspan. PMID:21636833

Marzetti, Emanuele; Leeuwenburgh, Christiaan; Manini, Todd; Foster, Thomas C.; Groban, Leanne; Scarpace, Philip J.; Morgan, Drake

2012-01-01

19

Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models  

Microsoft Academic Search

Objectives: As a result of the prolonged half-life and unique pharmacokinetic and pharmacodynamic (PK-PD) characteristics of azithromycin, shorter dosing regimens are being evaluated for the treatment of community-acquired infections. To provide further support for a shorter dosing regimen, the efficacy of azithromycin was determined in preclinical infection models comparing single- versus multi-dose regimens. Methods: The efficacy of single versus multi-dose

D. Girard; S. M. Finegan; M. W. Dunne; M. E. Lame

2005-01-01

20

Antagonistic analogs of growth hormone-releasing hormone increase the efficacy of treatment of triple negative breast cancer in nude mice with doxorubicin; A preclinical study  

PubMed Central

Introduction This study evaluated the effects of an antagonistic analog of growth hormone-releasing hormone, MIA-602, on tumor growth, response to doxorubicin, expression of drug resistance genes, and efflux pump function in human triple negative breast cancers. Methods HCC1806 (doxorubicin-sensitive) and MX-1 (doxorubicin-resistant), cell lines were xenografted into nude mice and treated with MIA-602, doxorubicin, or their combination. Tumors were evaluated for changes in volume and the expression of the drug resistance genes MDR1 and NANOG. In-vitro cell culture assays were used to analyze the effect of MIA-602 on efflux pump function. Results Therapy with MIA-602 significantly reduced tumor growth and enhanced the efficacy of doxorubicin in both cell lines. Control HCC1806 tumors grew by 435%, while the volume of tumors treated with MIA-602 enlarged by 172.2% and with doxorubicin by 201.6%. Treatment with the combination of MIA-602 and doxorubicin resulted in an increase in volume of only 76.2%. Control MX-1 tumors grew by 907%, while tumors treated with MIA-602 enlarged by 434.8% and with doxorubicin by 815%. The combination of MIA-602 and doxorubicin reduced the increase in tumor volume to 256%. Treatment with MIA-602 lowered the level of growth hormone-releasing hormone and growth hormone-releasing hormone receptors and significantly reduced the expression of multidrug resistance (MDR1) gene and the drug resistance regulator NANOG. MIA-602 also suppressed efflux pump function in both cell lines. Conclusions We conclude that treatment of triple negative breast cancers with growth hormone-releasing hormone antagonists reduces tumor growth and potentiates the effects of cytotoxic therapy by nullifying drug resistance. PMID:25593995

Perez, Roberto; Schally, Andrew V; Popovics, Petra; Cai, Renzhi; Sha, Wei; Rincon, Ricardo; Rick, Ferenc G.

2014-01-01

21

Isolation, physicochemical characterization and preclinical efficacy evaluation of soluble scleroglucan.  

PubMed

Herein we describe the isolation, physicochemical characterization and preclinical evaluation of a water-soluble biologic response modifier extracted from Sclerotium glucanicum. Alkaline extraction of insoluble S. glucanicum exopolymers produced a soluble scleroglucan composed of a triple-helical beta-1,3-linked glucopyranose backbone with single beta-1,6-linked glucopyranosyl branches every third subunit. Scleroglucan has a weight average molecular mass of 1.56 x 10(6) Da, a weight average root mean square distance from the center of gravity of the molecule to its farthest elements of 51.8 nm, a polydispersity (weight-average molecular mass/number average molecular mass) of 1.83 and intrinsic viscosity of 3.081 dl/g. Scleroglucan (250 mg/kg, intravenously) stimulated in vivo murine macrophage phagocytic activity (66%, P less than .001) and increased in vitro macrophage tumor cytotoxicity against syngeneic tumor targets by 124% (P less than .05). Scleroglucan enhanced (P less than .001) murine bone marrow proliferation in a biphasic manner by up to 328%. Scleroglucan therapy increased survival of mice challenged with syngeneic lymphoma, melanoma or adenocarcinoma. AKR/J mice bearing syngeneic lymphoma (1 x 10(3) cells, intraperitoneally) demonstrated increased (P less than .001) long-term survival (100% vs. 0%, greater than 64 days). C57Bl/6J mice bearing syngeneic melanoma B16 (5 x 10(5) cells, subcutaneously) demonstrated increased long-term survival (64% vs. 0%, P less than .05). C57Bl/6J mice bearing syngeneic adenocarcinoma BW10232 (1 x 10(5) cells, subcutaneously) demonstrated increased (P less than .05) median survival time. In addition, scleroglucan prophylaxis increased resistance of mice to challenge with Staphylococcus aureus, Candida albicans and mouse hepatitis virus A-59. Scleroglucan did not induce toxicity or hepatomegaly. We conclude that: 1) a branched, water-soluble beta-1,3-linked scleroglucan biologic response modifier can be extracted from S. glucanicum; 2) scleroglucan will stimulate immunity, modify experimental neoplastic disease and increase resistance to microbial challenge; and 3) scleroglucan shows promise as an immunopotentiating drug. PMID:1902259

Pretus, H A; Ensley, H E; McNamee, R B; Jones, E L; Browder, I W; Williams, D L

1991-04-01

22

Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data  

Microsoft Academic Search

Accurate predictions of human pharmacokinetic and pharmacodynamic (PK\\/PD) profiles are critical in early drug development,\\u000a as safe, efficacious, and “developable” dosing regimens of promising compounds have to be identified. While advantages of\\u000a successful integration of preclinical PK\\/PD data in the “anticipation” of human doses (AHD) have been recognized, pharmaceutical\\u000a scientists have faced difficulties with practical implementation, especially for PK\\/PD profile

Tycho Heimbach; Suresh B. Lakshminarayana; Wenyu Hu; Handan He

2009-01-01

23

Assessing the preclinical efficacy of antivenoms: from the lethality neutralization assay to antivenomics.  

PubMed

The assessment of the capacity of antivenoms to neutralize the lethal activity of snake venoms is the gold standard in the preclinical analysis of antivenom efficacy, and is routinely performed by manufacturers and quality control laboratories. However, the complexity of snake venom composition and toxicological profile demands that, for many venoms, such as those of viperid snakes and some elapids, the neutralization of lethality be complemented with the analysis of the neutralization of other relevant toxic activities, such as hemorrhagic, myotoxic, necrotizing, procoagulant and defibrinogenating effects. This expanded protocol for preclinical testing of antivenoms should be used when a new antivenom is developed or when an existing antivenom is introduced in a new geographical setting for the neutralization of either homologous or heterologous venoms. In recent years, the assessment of the immunological reactivity of antivenoms has been enriched by the use of proteomic tools, with a methodology named 'antivenomics'. This allows the identification of venom components to which antivenoms have, or lack, antibodies, and thus complements the data gathered in neutralization tests, paving the way for a knowledge-based improvement of antivenom design and efficacy. International projects involving participants of manufacturing, quality control and academic research groups should be promoted in order to gain a deeper understanding on the preclinical neutralizing spectrum of antivenoms. PMID:23201503

Gutiérrez, José María; Solano, Gabriela; Pla, Davinia; Herrera, María; Segura, Álvaro; Villalta, Mauren; Vargas, Mariángela; Sanz, Libia; Lomonte, Bruno; Calvete, Juan J; León, Guillermo

2013-07-01

24

Student perception about efficacy of preclinical fixed prosthodontic training to facilitate smooth transition to clinical context  

PubMed Central

Background: Studies indicate that the initial transition period between preclinical and clinical phases are the most stressful. The students have experienced the difficulty in performing clinical procedures due to the vast difference in the clinical and preclinical setup. It is better to identify the particular skill found poorly correlated, enabling educators to address the concerns. We sought the opinion and suggestion from the beneficiary student on fixed prosthodontics steps difficult to practice in clinical setup at the initial stage, their suggestion to overcome these shortcomings was also sought. Aims: To determine the fixed prosthodontics skills difficult to perform in a transition period due to poor correlation between preclinical and clinical training from our focus group study on the student's perception, and their suggestion regarding alternative methods to improve the preclinical training. Materials and Methods: Focus groups in the study were the students involved in clinical practice of fixed partial denture procedure. A well-constructed Questionnaire, designed to evaluate the difficult clinical steps in a transitional period and suggestion to improve the existing preclinical training was distributed to all focus group students. The response to the questionnaire was based on the five-point Likert scale. Statistical Analysis Used: Medians, frequencies were used to assess their perception on preclinical training and suggestion. Results: A total of 97 students participated in the study, 88% response received during the survey. The clinical steps student felt difficult during a transition period from preclinical to clinical phase were positional variations of teeth (52.6%-63.9%), fluid control (48.5-67.1%), shade selection procedure (29.9%-50.5%), subgingival cervical finish line preparation (38.1-51.5%), and gingival retraction procedure. The students felt that the inclusion of problem-based learning, preclinical patient exposure, and better simulation will alleviate the stress during the transition period. Conclusions: This study highlighted the tooth preparation steps found difficult to practice in a transition period between preclinical and clinical phases. This study also obtained suggestions from the students for innovative upgradation of the course curricula. PMID:25077166

Haralur, Satheesh B.; Al-Malki, Abdullah Edrees

2014-01-01

25

PRECLINICAL STUDIES Cluvenone induces apoptosis via a direct target  

E-print Network

PRECLINICAL STUDIES Cluvenone induces apoptosis via a direct target in mitochondria: a possible Drive, La Jolla, San Diego, CA 92093, USA e-mail: abatova@ucsd.edu A. L. Yu The Genomics Research Center

Theodorakis, Emmanuel

26

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials  

Microsoft Academic Search

The recent identification of somatic mutations such as JAK2V617F that deregulate Janus kinase (JAK)–signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy

A Pardanani

2008-01-01

27

Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma  

Microsoft Academic Search

Purpose: Sorafenib tosylate (sorafenib, BAY 43-9006, Nexavar®) is a multi-kinase inhibitor that targets tumor cell proliferation and angiogenesis. These studies evaluated the efficacy and tolerability of combinations of sorafenib plus agents used to treat non-small cell lung cancer (NSCLC) using preclinical models of that disease. Methods: Intravenous (iv) vinorelbine and interperitoneal (ip) cisplatin were administered intermittently (q4d × 3) in combination with

Christopher A. Carter; Charles Chen; Cheryl Brink; Patrick Vincent; Yulia Y. Maxuitenko; Karen S. Gilbert; William R. Waud; Xiaomei Zhang

2007-01-01

28

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations  

NASA Astrophysics Data System (ADS)

Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNF?) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03-0.1 mg ciclesonide, 0.01-0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT administration of nanosuspensions of ICS is a useful tool to demonstrate pulmonary-targeted efficacy and to differentiate the side effects. However, it is only suitable at sub-maximum efficacious levels.

Chiang, Po-Chang; Hu, Yiding; Blom, Jason D.; Thompson, David C.

2010-06-01

29

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations  

PubMed Central

Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNF?) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03–0.1 mg ciclesonide, 0.01–0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT administration of nanosuspensions of ICS is a useful tool to demonstrate pulmonary-targeted efficacy and to differentiate the side effects. However, it is only suitable at sub-maximum efficacious levels. PMID:20672144

2010-01-01

30

PRECLINICAL STUDY Prediction of lymph node involvement in breast cancer  

E-print Network

PRECLINICAL STUDY Prediction of lymph node involvement in breast cancer from primary tumor tissue- ther lymph node involvement in breast cancer is influenced by gene or miRNA expression of the primary tissue from a group of 96 breast cancer patients balanced for lymph node involvement using Affymetrix

31

Confidentiality in preclinical Alzheimer disease studies  

PubMed Central

Clinical trials to advance the diagnosis and treatment of Alzheimer disease (AD) may expose research subjects to discrimination risks. An individual enrolled in a research study that uses positive test results from amyloid PET imaging or CSF measures of ?-amyloid 42 as inclusion criteria has biomarkers indicative of AD pathology. If insurers and employers learn this information, it could expose subjects to discrimination. Unfortunately, current legal and regulatory mechanisms are not sufficient to protect against harms that have significant consequences for subjects. Existing law that prohibits employment and insurance discrimination based on genetic status does not apply to amyloid biomarkers or any other biomarkers for neurodegenerative diseases. Gaps in legal protections fail to protect research subjects from discrimination by long-term care and disability insurers. This risk is particularly concerning because individuals with AD dementia ultimately need long-term care services. To maximize subject protections and advance valuable research, policymakers, investigators, and research institutions must address shortcomings in the design of the electronic medical record, revise laws to limit discrimination, and develop practices that inform research participants of risks associated with loss of confidentiality. PMID:24477112

Arias, Jalayne J.

2014-01-01

32

Preclinical safety and efficacy models for pulmonary drug delivery of antimicrobials with focus on in vitro models.  

PubMed

New pharmaceutical formulations must be proven as safe and effective before entering clinical trials. Also in the context of pulmonary drug delivery, preclinical models allow testing of novel antimicrobials, reducing risks and costs during their development. Such models allow reducing the complexity of the human lung, but still need to reflect relevant (patho-) physiological features. This review focuses on preclinical pulmonary models, mainly in vitro models, to assess drug safety and efficacy of antimicrobials. Furthermore, approaches to investigate common infectious diseases of the respiratory tract, are emphasized. Pneumonia, tuberculosis and infections occurring due to cystic fibrosis are in focus of this review. We conclude that especially in vitro models offer the chance of an efficient and detailed analysis of new antimicrobials, but also draw attention to the advantages and limitations of such currently available models and critically discuss the necessary steps for their future development. PMID:25453270

Hittinger, Marius; Juntke, Jenny; Kletting, Stephanie; Schneider-Daum, Nicole; de Souza Carvalho, Cristiane; Lehr, Claus-Michael

2014-10-17

33

Exploring Polymeric Micelles for Improved Delivery of Anticancer Agents: Recent Developments in Preclinical Studies  

PubMed Central

As versatile drug delivery systems, polymeric micelles have demonstrated particular strength in solubilizing hydrophobic anticancer drugs while eliminating the use of toxic organic solvents and surfactants. However, the true promise of polymeric micelles as drug carriers for cancer therapy resides in their potential ability to preferentially elevate drug exposure in the tumor and achieve enhanced anticancer efficacy, which still remains to be fully exploited. Here, we review various micellar constructs that exhibit the enhanced permeation and retention effect in the tumor, the targeting ligands that potentiate the anticancer efficacy of micellar drugs, and the polyplex micelle systems suitable for the delivery of plasmid DNA and small interference RNA. Together, these preclinical studies in animal models help us further explore polymeric micelles as emerging drug carriers for targeted cancer therapy. PMID:24300405

Tan, Chalet; Wang, Yingzhe; Fan, Wei

2013-01-01

34

Pharmacological intervention studies using mouse models of the inflammatory bowel diseases: translating preclinical data into new drug therapies.  

PubMed

Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses, and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in clinical trials is to identify the most immunologically-relevant mouse models of IBD and pharmacologic strategies that most closely mimic the clinical situation. This review presents a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies. PMID:21312318

Koboziev, Iurii; Karlsson, Fridrik; Zhang, Songlin; Grisham, Matthew B

2011-05-01

35

Pharmacological Intervention Studies Using Mouse Models of the Inflammatory Bowel Diseases: Translating Preclinical Data into New Drug Therapies  

PubMed Central

Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in well-controlled clinical trials is to identify the most relevant mouse models IBD and pharmacologic strategies that most closely mimic the clinical situation. To begin this process, we present a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies. PMID:21312318

Koboziev, Iurii; Karlsson, Fridrik; Zhang, Songlin; Grisham, Matthew B.

2010-01-01

36

[Preclinical study of anxiolytic activity and safety of Racium phytomedicine].  

PubMed

Results of a preclinical study of the anxiolytic activity and safety of original Racium phytomedicine are presented. The preparation possessed high anxiolytic activity, exhibits a wide range of therapeutic effects, produces no lethality in male and female rats and mice upon single intragastric and intraperitoneal introduction in doses up to 5 g/kg (VI class of toxicity according to OECD), induces no pathologic effects upon prolonged (120 days) administration in these rodents, and has no local irritant and/or allergen action. PMID:23012991

Kravchenko, E V; Nasek, V M; Ponteleeva, I V; Mazhar, M V; Sholomitskaia, E Iu; Zhukova, I A; San'ko, E V; Veselukha, O V; Nekhai, A S; Shafranovskaia, E V; Zhebrakova, I V

2012-01-01

37

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer.  

PubMed

Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists--MIA-602, MIA-606, and MIA-690--on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC. PMID:24395797

Fahrenholtz, Cale D; Rick, Ferenc G; Garcia, Maria I; Zarandi, Marta; Cai, Ren-Zhi; Block, Norman L; Schally, Andrew V; Burnstein, Kerry L

2014-01-21

38

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer  

PubMed Central

Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists—MIA-602, MIA-606, and MIA-690—on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC. PMID:24395797

Fahrenholtz, Cale D.; Rick, Ferenc G.; Garcia, Maria I.; Zarandi, Marta; Cai, Ren-Zhi; Block, Norman L.; Schally, Andrew V.; Burnstein, Kerry L.

2014-01-01

39

Oral immunotherapy for food allergy: clinical and preclinical studies.  

PubMed

Food allergies affect approximately 5% of the U.S. population and have increased in the last decade. In recent years, oral immunotherapy (OIT) has been tested in clinical trials for peanut, milk, and egg allergies in young children. OIT appears to be fairly well tolerated by most subjects and leads to desensitization with a greatly increased threshold of allergen required to induce reactions. Further approaches being investigated in preclinical studies in mouse models indicate the potential for using adjuvants, such as TLR9 agonists in combination with OIT; peptide OIT; and non-allergen specific applications such as herbal formulations. Further questions about OIT remain, including the optimal dosing and length of treatment; whether tolerance can be developed; and the exact cellular mechanisms resulting in protection following OIT. With many clinical trials underway across the United States and other countries, and a growing pipeline of preclinical research with translational potential, there is great hope for a widely applicable food allergy treatment. PMID:23099276

Kulis, Mike; Wesley Burks, A

2013-06-15

40

Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies.  

PubMed

Breast cancer is the most common cancer among women worldwide, and many women with breast cancer live more than 5 years after their diagnosis. Breast cancer patients and survivors have a greater interest in taking soy foods and isoflavone supplements. However, the effect of isoflavones on breast cancer remains controversial. Thus, it is critical to determine if and when isoflavones are beneficial or detrimental to breast cancer patients. According to the available preclinical data, high concentrations of isoflavones inhibit the proliferation of breast cancer cells, regardless of their estrogen receptor (ER) status. In comparison, genistein, a major isoflavone, has stimulated tumor growth at low concentrations and mitigated tamoxifen efficacy in ER-positive breast cancer. Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth. However, studies using ovariectomized mice and subcutaneous xenograft models might not truly reflect estrogen concentrations in human breast tumors. Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen. Therefore, the concentrations of isoflavones and estrogen in human breast tumors should be considered better in future preclinical studies and the parameters that can estimate those levels in breast tumors are required in human clinical/epidemiological investigation. In addition, it will be important to identify the molecular mechanisms that either inhibit or promote the growth of breast cancer cells by soy isoflavones, and use those molecules to evaluate the relevance of the preclinical findings to the human disease and to predict the health effects of isoflavones in human breast tumors. PMID:25493176

Kwon, Youngjoo

2014-11-01

41

Resveratrol: A review of preclinical studies for human cancer prevention  

SciTech Connect

The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations.

Athar, Mohammad; Back, Jung Ho; Tang Xiuwei [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Kwang Ho [Department of Dermatology, Hallym University College of Medicine (Korea, Republic of); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892 (United States); Bickers, David R. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Arianna L. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States)], E-mail: ak309@columbia.edu

2007-11-01

42

Novel Epigenetic Target Therapy for Prostate Cancer: A Preclinical Study  

PubMed Central

Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2?-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours. PMID:24851905

Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

2014-01-01

43

The Efficacy of the Ribonucleotide Reductase Inhibitor Didox in Preclinical Models of AML  

PubMed Central

Acute Myeloid Leukemia (AML) is an aggressive malignancy which leads to marrow failure, and ultimately death. There is a desperate need for new therapeutics for these patients. Ribonucleotide reductase (RR) is the rate limiting enzyme in DNA synthesis. Didox (3,4-Dihydroxybenzohydroxamic acid) is a novel RR inhibitor noted to be more potent than hydroxyurea. In this report we detail the activity and toxicity of Didox in preclinical models of AML. RR was present in all AML cell lines and primary patient samples tested. Didox was active against all human and murine AML lines tested with IC50 values in the low micromolar range (mean IC50 37 µM [range 25.89–52.70 µM]). It was active against primary patient samples at concentrations that did not affect normal hematopoietic stem cells (HSCs). Didox exposure resulted in DNA damage and p53 induction culminating in apoptosis. In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit. Didox was well tolerated, as marrow from treated animals was morphologically indistinguishable from controls. Didox exposure at levels that impaired leukemia growth did not inhibit normal HSC engraftment. In summary, Didox was well tolerated and effective against preclinical models of AML. PMID:25402485

Cook, Guerry J.; Caudell, David L.; Elford, Howard L.; Pardee, Timothy S.

2014-01-01

44

Progressive Impairment on Neuropsychological Tasks in a Longitudinal Study of Preclinical Alzheimer's Disease  

E-print Network

lobes. Prior research on the progression of preclinical AD yields a mixed picture. In recent reviewsProgressive Impairment on Neuropsychological Tasks in a Longitudinal Study of Preclinical Alzheimer P. Salmon University of California, San Diego School of Medicine Previous research suggests

Wixted, John T.

45

Preclinical evaluation of efficacy and stability of docetaxel micelle-encapsulated by a tripodal cyclotriphosphazene amphiphile.  

PubMed

Docetaxel formulated by micelle-encapsulation using a tripodal cyclotriphosphazene amphiphile [NP(MPEG750)(GlyPheLeu)2Et]3 (CP750) was named "Phostaxel" and compared in efficacy and stability with Taxotere(®) formulated using the surfactant polysorbate 80, which is currently in clinical use. Phostaxel has always shown better efficacy than Taxotere(®) in various xenograft trials at the same dosage and administration schedule against the tumor cell lines tested. The better efficacy of Phostaxel could be explained based on the difference in pharmacokinetic and biodistribution profiles of Phostaxel and Taxotere(®). Phostaxel exhibited significantly slower clearance rate and larger AUClast value compared with Taxotere(®). Phostaxel has also shown higher DTX distribution in tumor than Taxotere(®). In addition, Phostaxel displayed better solution stability compared with Taxotere(®) both in distilled water and in saline solution at room and refrigerator temperatures. PMID:24930885

Chae, Song Wha; Jun, Yong Joo; Cui, Jin Xin; Park, Jung Hyun; Lee, Hwa Jeong; Sohn, Youn Soo

2014-06-01

46

Novel technology to prepare oral formulations for preclinical safety studies.  

PubMed

A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension. PMID:17942253

Niwa, Toshiyuki; Hashimoto, Naofumi

2008-02-28

47

Rodent Preclinical Models for Developing Novel Antiarthritic Molecules: Comparative Biology and Preferred Methods for Evaluating Efficacy  

PubMed Central

Rodent models of immune-mediated arthritis (RMIA) are the conventional approach to evaluating mechanisms of inflammatory joint disease and the comparative efficacy of antiarthritic agents. Rat adjuvant-induced (AIA), collagen-induced (CIA), and streptococcal cell wall-induced (SCW) arthritides are preferred models of the joint pathology that occurs in human rheumatoid arthritis (RA). Lesions of AIA are most severe and consistent; structural and immunological changes of CIA best resemble RA. Lesion extent and severity in RMIA depends on experimental methodology (inciting agent, adjuvant, etc.) and individual physiologic parameters (age, genetics, hormonal status, etc.). The effectiveness of antiarthritic molecules varies with the agent, therapeutic regimen, and choice of RMIA. All RMIA are driven by overactivity of proinflammatory pathways, but the dominant molecules differ among the models. Hence, as with the human clinical experience, the efficacy of various antiarthritic molecules differs among RMIA, especially when the agent is a specific cytokine inhibitor. PMID:21253435

Bolon, Brad; Stolina, Marina; King, Caroline; Middleton, Scot; Gasser, Jill; Zack, Debra; Feige, Ulrich

2011-01-01

48

Cannabinoids and prefrontal cortical function: Insights from preclinical studies  

Microsoft Academic Search

Marijuana use has been associated with disordered cognition across several domains influenced by the prefrontal cortex (PFC). Here, we review the contribution of preclinical research to understanding the effects of cannabinoids on cognitive ability, and the mechanisms by which cannabinoids may affect the neurochemical processes in the PFC that are associated with these impairments. In rodents, acute administration of cannabinoid

Alice Egerton; Claire Allison; Ros R. Brett; Judith A. Pratt

2006-01-01

49

Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma  

PubMed Central

The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

2012-01-01

50

Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma.  

PubMed

The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

2012-05-01

51

Dabrafenib; Preclinical Characterization, Increased Efficacy when Combined with Trametinib, while BRAF/MEK Tool Combination Reduced Skin Lesions  

PubMed Central

Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAFV600E kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAFV600E-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor. PMID:23844038

King, Alastair J.; Arnone, Marc R.; Bleam, Maureen R.; Moss, Katherine G.; Yang, Jingsong; Fedorowicz, Kelly E.; Smitheman, Kimberly N.; Erhardt, Joseph A.; Hughes-Earle, Angela; Kane-Carson, Laurie S.; Sinnamon, Robert H.; Qi, Hongwei; Rheault, Tara R.; Uehling, David E.; Laquerre, Sylvie G.

2013-01-01

52

Preclinical and clinical endpoint assays for cystic fibrosis gene therapy  

Microsoft Academic Search

The credibility and hence value of pre-clinical and clinical cystic fibrosis gene therapy studies depend on the assays used to evaluate gene transfer. Awareness of assay suitability, sensitivity and variability is therefore crucial to the design of experimental programmes. Here, we review the assays that are in use to assess the efficacy of gene transfer in pre-clinical and clinical CF

Uta Griesenbach; A. Christopher Boyd

2005-01-01

53

Mouse Model for the Preclinical Study of Metastatic Disease  

Cancer.gov

The successful development of new cancer therapeutics requires reliable preclinical data that are obtained from mouse models for cancer. Human tumor xenografts, which require transplantation of human tumor cells into an immune compromised mouse, represent the current standard mouse model for cancer. Since the immune system plays an important role in tumor growth, progression and metastasis, the current standard mouse model is not ideal for accurate prediction of therapeutic effectiveness in patients.

54

Natural substances and Alzheimer's disease: from preclinical studies to evidence based medicine.  

PubMed

Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID:21939756

Mancuso, Cesare; Siciliano, Raffaella; Barone, Eugenio; Preziosi, Paolo

2012-05-01

55

Preclinical Assessment of the Efficacy of Mycograb, a Human Recombinant Antibody against Fungal HSP90  

PubMed Central

Mycograb (NeuTec Pharma plc) is a human genetically recombinant antibody against fungal heat shock protein 90 (HSP90). Antibody to HSP90 is closely associated with recovery in patients with invasive candidiasis who are receiving amphotericin B (AMB). Using in vitro assays developed for efficacy assessment of chemotherapeutic antifungal drugs, Mycograb showed activity against a wide range of yeast species (MICs against Candida albicans [fluconazole {FLC}-sensitive and FLC-resistant strains], Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, 128 to 256 ?g/ml). Mycograb (4 or 8 ?g/ml) showed synergy with AMB, the fractional inhibitory index being 0.09 to 0.31. Synergy was not evident with FLC, except for FLC-sensitive C. albicans. Murine kinetics showed that Mycograb at 2 mg/kg produced a maximum concentration of drug in serum of 4.7 ?g/ml, a half-life at alpha phase of 3.75 min, a half-life at beta phase of 2.34 h, and an area under the concentration-time curve from 0 to t h of 155 ?g?·?min/ml. Mycograb (2 mg/kg) alone produced significant improvement in murine candidiasis caused by each species: (i) a reduction (Scheffe's test, P < 0.05) in the mean organ colony count for the FLC-resistant strain of C. albicans (kidney, liver, and spleen), C. krusei (liver and spleen), C. glabrata (liver and spleen), C. tropicalis (kidney), and C. parapsilosis (kidney, liver, and spleen) and (ii) a statistically significant increase in the number of negative biopsy specimens (Fisher's exact test, P < 0.05) for C. glabrata (kidney), C. tropicalis (liver and spleen), and C. parapsilosis (liver). AMB (0.6 mg/kg) alone cleared the C. tropicalis infection but failed to clear infections caused by C. albicans, C. krusei, C. glabrata, or C. parapsilosis. Synergy with AMB, defined as an increase (Fisher's exact test, P < 0.05) in the number of negative biopsy specimens compared with those obtained using AMB alone, occurred with the FLC-resistant strain of C. albicans (kidney), C. krusei (spleen), C. glabrata (spleen), and C. parapsilosis (liver and spleen). Only by combining Mycograb with AMB was complete resolution of infection achieved for C. albicans, C. krusei, and C. glabrata. PMID:12821470

Matthews, Ruth C.; Rigg, Gordon; Hodgetts, Samantha; Carter, Tracey; Chapman, Caroline; Gregory, Carl; Illidge, Chris; Burnie, James

2003-01-01

56

Development, physicochemical characterization and preclinical efficacy evaluation of a water soluble glucan sulfate derived from Saccharomyces cerevisiae.  

PubMed

This report describes the development, characterization and preclinical efficacy evaluation of water soluble glucan sulfate. Glucan sulfate was derived from insoluble beta-1,3-D-glucan isolated from Saccharomyces cerevisiae. The proposed repeating unit empirical formula of glucan sulfate is [(C6H10O5)5.3H2SO4]n. Two polymer peaks were resolved by aqueous high-performance size exclusion chromatography (HPSEC) with on-line multi-angle laser light scattering (MALLS) photometry and differential viscometry. Peak 1 (MW = 1219697 Da) represents approximately 1% of the total polymers, while peak 2 (MW = 8884 Da) accounts for approximately 99% of polymers. 13C-NMR spectroscopy suggests that glucan sulfate polymer strands may be partially cross-linked. Glucan sulfate (250 mg/kg, i.v.) increased (P less than 0.01) macrophage vascular clearance of 131I-reticuloendothelial emulsion by 42% (P less than 0.01) and in vitro bone marrow proliferation by 46% (P less than 0.05). Glucan sulfate (250 mg/kg, i.v.) increased (P less than 0.05) median survival time of C57B1/6J mice with syngeneic melanoma B16 or sarcoma M5076. In addition, glucan sulfate immunoprophylaxis increased resistance of mice to challenge with Escherichia coli, Candida albicans or Mouse Hepatitis Virus strain A-59. We concluded that: (1) insoluble beta-1,3-D-glucan can be converted to a water soluble sulfated form; (2) glucan sulfate activates macrophages and stimulates bone marrow; (3) glucan sulfate exerts antitumor therapeutic activity, and (4) glucan sulfate immunoprophylaxis will modify the course of experimental infectious disease. PMID:1774155

Williams, D L; Pretus, H A; McNamee, R B; Jones, E L; Ensley, H E; Browder, I W; Di Luzio, N R

1991-01-01

57

Investigating the Efficacy of Practical Skill Teaching: A Pilot-Study Comparing Three Educational Methods  

ERIC Educational Resources Information Center

Effective education of practical skills can alter clinician behaviour, positively influence patient outcomes, and reduce the risk of patient harm. This study compares the efficacy of two innovative practical skill teaching methods, against a traditional teaching method. Year three pre-clinical physiotherapy students consented to participate in a…

Maloney, Stephen; Storr, Michael; Paynter, Sophie; Morgan, Prue; Ilic, Dragan

2013-01-01

58

Nanomedicine-nanoemulsion formulation improves safety and efficacy of the anti-cancer drug paclitaxel according to preclinical assessment.  

PubMed

Paclitaxel is an important anticancer drug and is currently used to treat a variety of cancers, including ovarian carcinomas, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi's sarcoma. The objectives of the studies were to assess and compare the safety and efficacy of EmPAC (a newly developed nanoemulsion formulation of paclitaxel) versus Taxol (the injectable formulation of paclitaxel involving the use of polyethylated or polyoxyl castor oil currently used in the clinic). The objectives were also to investigate the mechanism for the improved safety and efficacy of EmPAC over Taxol. These results showed that EmPAC had better anti-tumor efficacy than Taxol, according to in vitro cell culture studies and studies in animal tumor models. EmPAC had improved anti-tumor efficacy even in tumor cell lines that are known to be multi-drug resistant. Part of the mechanism of action for the improved efficacy may be related to EmPAC inducing greater cellular uptake of paclitaxel into tumor cells than Taxol did, according to the in vitro cell culture radioactive-labeled studies and in vitro cell culture antibody studies. It may also partly be because EmPAC delivered more paclitaxel to the tumor mass than Taxol, while the delivery of paclitaxel to other tissues (e.g., blood, muscle, liver, spleen, kidney and lung) were similar between the two formulations of paclitaxel, according to studies in animals with tumor xenograft. EmPAC also had better safety than Taxol according to toxicology studies in rabbits. This may be because EmPAC does not contain the toxic ingredients used in formulating Taxol (such as polyethylated or polyoxyl castor oil). These results support the clinical development of the nanoemulsion formulation of paclitaxel. PMID:22103064

Lee, King C; Maturo, Claudia; Rodriguez, Robert; Nguyen, Hoang-Lan; Shorr, Robert

2011-08-01

59

Efficacy and mechanism of action of volasertib, a potent and selective inhibitor of Polo-like kinases, in preclinical models of acute myeloid leukemia.  

PubMed

Polo-like kinase 1 (Plk1), a member of the Polo-like kinase family of serine/threonine kinases, is a key regulator of multiple steps in mitosis. Here we report on the pharmacological profile of volasertib, a potent and selective Plk inhibitor, in multiple preclinical models of acute myeloid leukemia (AML) including established cell lines, bone marrow samples from AML patients in short-term culture, and subcutaneous as well as disseminated in vivo models in immune-deficient mice. Our results indicate that volasertib is highly efficacious as a single agent and in combination with established and emerging AML drugs, including the antimetabolite cytarabine, hypomethylating agents (decitabine, azacitidine), and quizartinib, a signal transduction inhibitor targeting FLT3. Collectively, these preclinical data support the use of volasertib as a new therapeutic approach for the treatment of AML patients, and provide a foundation for combination approaches that may further improve and prolong clinical responses. PMID:25576074

Rudolph, Dorothea; Impagnatiello, Maria Antonietta; Blaukopf, Claudia; Sommer, Christoph; Gerlich, Daniel W; Roth, Mareike; Tontsch-Grunt, Ulrike; Wernitznig, Andreas; Savarese, Fabio; Hofmann, Marco H; Albrecht, Christoph; Geiselmann, Lena; Reschke, Markus; Garin-Chesa, Pilar; Zuber, Johannes; Moll, Jürgen; Adolf, Günther R; Kraut, Norbert

2015-03-01

60

Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia  

PubMed Central

Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients. PMID:25365263

Alachkar, Houda; Mutonga, Martin B.G.; Metzeler, Klaus H.; Fulton, Noreen; Malnassy, Gregory; Herold, Tobias; Spiekermann, Karsten; Bohlander, Stefan K.; Hiddemann, Wolfgang; Matsuo, Yo; Stock, Wendy; Nakamura, Yusuke

2014-01-01

61

Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of ?-thalassemia and sickle cell disease.  

PubMed

A previously published clinical trial demonstrated the benefit of autologous CD34(+) cells transduced with a selfinactivating lentiviral vector (HPV569) containing an engineered ?-globin gene (?(A-T87Q)-globin) in a subject with ? thalassemia major. This vector has been modified to increase transduction efficacy without compromising safety. In vitro analyses indicated that the changes resulted in both increased vector titers (3 to 4 fold) and increased transduction efficacy (2 to 3 fold). An in vivo study in which 58 ?-thalassemic mice were transplanted with vector- or mock-transduced syngenic bone marrow cells indicated sustained therapeutic efficacy. Secondary transplantations involving 108 recipients were performed to evaluate long-term safety. The six month study showed no hematological or biochemical toxicity. Integration site (IS) profile revealed an oligo/polyclonal hematopoietic reconstitution in the primary transplants and reduced clonality in secondary transplants. Tumor cells were detected in the secondary transplant mice in all treatment groups (including the control group), without statistical differences in the tumor incidence. Immunohistochemistry and quantitative PCR demonstrated that tumor cells were not derived from transduced donor cells. This comprehensive efficacy and safety data provided the basis for initiating two clinical trials with this second generation vector (BB305) in Europe and in the USA in patients with ?-thalassemia major and sickle cell disease. PMID:25429463

Negre, Olivier; Bartholomae, Cynthia; Beuzard, Yves; Cavazzana, Marina; Christiansen, Lauryn; Courne, Céline; Deichmann, Annette; Denaro, Maria; de Dreuzy, Edouard; Finer, Mitchell; Fronza, Raffaele; Gillet-Legrand, Béatrix; Joubert, Christophe; Kutner, Robert; Leboulch, Philippe; Maouche, Leïla; Paulard, Anaïs; Pierciey, Francis J; Rothe, Michael; Ryu, Byoung; Schmidt, Manfred; von Kalle, Christof; Payen, Emmanuel; Veres, Gabor

2015-01-01

62

A phase III, randomized, double-blind, matched-pairs, active-controlled clinical trial and preclinical animal study to compare the durability, efficacy and safety between polynucleotide filler and hyaluronic acid filler in the correction of crow's feet: a new concept of regenerative filler.  

PubMed

The Rejuran® is a new filler product made from purified polynucleotides. Here we present data from an animal study and a clinical trial to examine the durability, efficacy and safety of the Rejuran® on crow's feet. For the animal study, 25 mice were divided into three groups: Group 1 received phosphate buffered saline (PBS); Group 2 were treated with Yvoire®; and Group 3 were treated with Rejuran®. The durability and efficacy of each treatment were assessed by microscopy and staining. In the clinical trial, 72 patients were randomized to receive Rejuran® treatment for crow's feet on one side and Yvoire-Hydro® on the contralateral side, at a ratio of 1:1. Repeated treatments were performed every two weeks for a total of three times, over a total of 12 weeks' observation. All injections and observations of efficacy and safety were performed by the same two investigators. In the animal study, the Rejuran® group showed similar durability and inflammatory response to the Yvoire® group. Upon efficacy assessment, the Rejuran® group showed the greatest elasticity and collagen composition, and a significant difference in skin surface roughness and wrinkle depth. In the clinical trial, the primary and secondary objective efficacy outcome measure showed no statistical significance between the two groups, and in safety outcomes there were no unexpected adverse effects. Our data suggest that the Rejuran®, as a new regenerative filler, can be useful to reduce wrinkles, by showing evidence for its efficacy and safety. PMID:25473210

Pak, Chang Sik; Lee, Jongho; Lee, Hobin; Jeong, Jaehoon; Kim, Eun-Hee; Jeong, Jinwook; Choi, Hyeyeon; Kim, Byunghwi; Oh, Sujin; Kim, Iksoo; Heo, Chan Yeong

2014-11-01

63

Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury  

PubMed Central

CMX-2043 is an ?-lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia–reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre-clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX-2043 did not bind to a wide range of receptors and specific targets at approximately 4 ?g/mL (10 ?M). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14-day repeat intravenous doses and in dogs (single intravenous dose) with a 2-week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo-controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre-clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX-2043 in a human efficacy trial. PMID:24751172

Kates, Steven A; Lader, Alan S; Casale, Ralph; Beeuwkes, Reinier

2014-01-01

64

Novel therapies for FSGS: preclinical and clinical studies.  

PubMed

Focal segmental glomerulosclerosis (FSGS) is a rare but important cause of end-stage kidney disease in children and adults. Current therapy, consisting of corticosteroids and calcineurin inhibitors, fails to achieve a sustained remission in most patients. Therefore, there is a pressing need to develop new treatments for this glomerulopathy. Traditional approaches have focused on agents that modulate the immune system. In this review, we summarize preclinical and clinical data with newer agents that may ameliorate FSGS. We focus on drugs that inhibit immune injury or inflammation, such as abatacept, rituximab, adalimumab, and stem cells. The potential of agents that block the glomerular action of circulating permeability factors such as soluble urokinase receptor is reviewed. Finally, because fibrosis represents the final common pathway of glomerular damage in FSGS, the experience with a wide range of antifibrotic agents is presented. Despite extensive research on the podocyte dysfunction in the pathogenesis of FSGS, there are few agents that directly target podocyte structure or viability. We conclude that FSGS is a heterogeneous disorder and that intensified translational research is vital to improve our understanding of distinct subtypes that have a defined prognosis and predictable response to targeted therapeutic interventions. PMID:25704355

Malaga-Dieguez, Laura; Bouhassira, Diana; Gipson, Debbie; Trachtman, Howard

2015-03-01

65

Magnetic Fluid Hyperthermia for Bladder Cancer: A Preclinical Dosimetry Study  

PubMed Central

Purpose This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with Magnetic Fluid Hyperthermia (MFH), performed by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Materials and Methods The bladders of twenty-five female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42°C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fiberoptic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterization method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions. Results Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen ?1°C/min to a steady-state of 42°C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder. Conclusion These data demonstrate that our MFH system with magnetite-based nanoparticles provide well-localized heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues. PMID:24050253

Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea D.; Etienne, Wiguins; Ashcraft, Kathleen A.; McNerny, Katie L.; Mashal, Alireza; Nouls, John; Maccarini, Paolo F.; Beyer, Wayne F.; Inman, Brant; Dewhirst, Mark W.

2014-01-01

66

Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs  

PubMed Central

Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting. PMID:25183392

2014-01-01

67

Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats  

PubMed Central

Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund’s adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations. PMID:24797666

Pravetoni, Marco; Vervacke, Jeffrey S.; Distefano, Mark D.; Tucker, Ashli M.; Laudenbach, Megan; Pentel, Paul R.

2014-01-01

68

The Preclinical Research Process  

Microsoft Academic Search

\\u000a The preclinical research process extends from early assessments of feasibility of pharmaceutical development to providing\\u000a regulatory authorities and clinical trial units with information necessary for administering the product to human subjects.\\u000a Chief concerns include safety, which is evaluated in well-defined preclinical toxicology programs, and efficacy, which must\\u000a be defined in appropriate in vitro systems and animal models prior to entering

James S. Hutchison

69

The Relationship between Risk of Bias Criteria, Research Outcomes, and Study Sponsorship in a Cohort of Preclinical Thiazolidinedione Animal Studies: A Meta-Analysis  

PubMed Central

Introduction There is little evidence regarding the influence of conflicts of interest on preclinical research. This study examines whether industry sponsorship is associated with increased risks of bias and/or effect sizes of outcomes in published preclinical thiazolidinedione (TZD) studies. Methods We identified preclinical TZD studies published between January 1, 1965 and November 14, 2012. Coders independently extracted information on study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties from the 112 studies meeting the inclusion criteria. The average standardized mean difference (SMD) across studies was calculated for plasma glucose (efficacy outcome) and weight gain (harm outcome). In subgroup analyses, TZD outcomes were assessed by sponsorship source and risk of bias criteria. Results Seven studies were funded by industry alone, 17 studies funded by both industry and non-industry, 49 studies funded by non-industry alone, and 39 studies had no disclosures. None of the studies used sample size calculations, intention-to-treat analyses, blinding of investigators, or concealment of allocation. Most studies reported favorable results (88 of 112) and conclusions (95 of 112) supporting TZD use. Efficacy estimates were significantly larger in 6 studies sponsored by industry alone (?3.41; 95% CI ?5.21, ?1.53; I2 = 93%) versus 42 studies sponsored by non-industry sources (?0.97; 95% CI ?1.37, ?0.56; I2 = 81%) (p value = 0.01). Harms estimates were significantly larger in 4 studies sponsored by industry alone (5.00; 95% CI 1.22, 8.77; I2 = 93%) versus 38 studies sponsored by non-industry sources (0.30; 95% CI ?0.08, 0.68; I2 = 79%) (p value = 0.02). TZD efficacy and harms did not differ by disclosure of financial COIs or risks of bias. Conclusions Industry-sponsored TZD animal studies have exaggerated efficacy and harms outcomes compared to studies funded by non-industry sources. There was poor reporting of COIs. PMID:25642330

Abdel-Sattar, Maher; Krauth, David; Anglemyer, Andrew; Bero, Lisa

2015-01-01

70

PRECLINICAL STUDY Prolonged mammosphere culture of MCF-7 cells induces an EMT  

E-print Network

transcription factors, including members of the Snail, Twist, and Zeb families. EMT results in diminishedPRECLINICAL STUDY Prolonged mammosphere culture of MCF-7 cells induces an EMT and repression transition (EMT) also induces stem cell features in normal and transformed mammary cells. We examined whether

Terasaki, Mark

71

Ultra-high-resolution imaging of small animals: Implications for preclinical and research studies  

Microsoft Academic Search

Higher spatial resolution is continuously sought in nuclear medicine to improve the spatial detail and image quality that can be used for preclinical and cfinical imaging studies. The greater tissue specificity and highly selective uptake of many of the new labeled monoclonal antibodies, receptor-specific molecules, peptides, and other new radiopharmaceuticals investigated for use in imaging and therapy often require higher

David A. Weber; Marijana Ivanovic

1999-01-01

72

PRECLINICAL STUDY GRB7 is required for triple-negative breast cancer cell invasion  

E-print Network

prognosis, and frequently associated with the basal-like breast cancer gene expression profile) and members of the ERBB family [4]. Other prominent domains with clear relevance to cancer include the RasPRECLINICAL STUDY GRB7 is required for triple-negative breast cancer cell invasion and survival

Kenny, Paraic

73

PRECLINICAL STUDY GRB7 is required for triple-negative breast cancer cell invasion  

E-print Network

that is usually associated with poor prognosis, and frequently associated with the basal-like breast cancer genePRECLINICAL STUDY GRB7 is required for triple-negative breast cancer cell invasion and survival+Business Media, LLC. 2011 Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease

Kenny, Paraic

74

Preclinical studies of carbohydrate mimetic peptide vaccines for breast cancer and melanoma  

Microsoft Academic Search

Limited immune responses to tumor-associated carbohydrate antigens (TACA) are due in part to their being self-antigens. Immunization with xenoantigens of TACA provides an approach to break tolerance and augment responses to TACA. Carbohydrate mimetic peptides (CMPs) as xenoantigens can induce serum antibodies that target shared carbohydrate residues on differing carbohydrate structures. In preclinical studies, we observe that CMP immunization in

Behjatolah Monzavi-Karbassi; Leah J. Hennings; Cecile Artaud; Tianmin Liu; Fariba Jousheghany; Anastas Pashov; Ramachandran Murali; Laura F. Hutchins; Thomas Kieber-Emmons

2007-01-01

75

Exploratory Study of Factors Related to Educational Scores of First Preclinical Year Medical Students  

ERIC Educational Resources Information Center

The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students.…

Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarawut

2014-01-01

76

Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.  

PubMed

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (?(9)-THC)) Cannabis spp. PMID:23653088

Sarris, Jerome; McIntyre, Erica; Camfield, David A

2013-04-01

77

Novel medication targets for the treatment of alcoholism: preclinical studies.  

PubMed

Alcoholism is a complex heterogeneous disease and a number of neurotransmitter and neuromodulator systems have been implicated in its manifestation. Consequently, it is unlikely that existing medications such as disulfiram (Antabuse®), naltrexone (ReVia®), acamprosate (Campral®)) can be efficacious in every individual. Thus, the development of novel therapeutic agents with greater selectivity and less unwanted effects for the treatment of this disease is one of the major objectives of alcohol research. This review summarizes the findings of five novel compounds with different neuronal targets for treating alcoholism. These compounds include sazetidine-A, which selectively desensitizes ?4?2 nicotinic receptors; carisbamate, a novel anti-epileptic agent; JNJ5234801, a novel anxiolytic agent; GS-455534, a highly selective inhibitor of mitochondrial aldehyde dehydrogenase; and JNJ-39220675, a selective histamine H3 antagonist. Inbred alcohol-preferring rats (iP), Fawn-Hooded (FH) rats, and P rats were used to evaluate the compounds. Naltrexone was used as a positive control in some experiments. All five compounds reduced alcohol consumption and preference. The mechanisms thought to underlie these effects suggest that, in addition to dopaminergic and opioidergic systems, other neuronal systems such as sodium channels (carisbamate), mitochondrial aldehyde dehydrogenase (GS-455534), 5-HT2 receptors (JNJ-5234801), histamine H3 receptors (JNJ-39220675), and ?4?2 nicotinic receptors (sazetidine-A) can be involved in alcohol drinking. Further work is necessary to confirm the exact mechanisms of action of each drug and to determine any viable targets for putative treatment of alcohol-use disorders. The article presents some promising patents on novel medication targets for the treatment of alcoholism. PMID:22574676

Rezvani, Amir H; Lawrence, Andrew J; Arolfo, Maria P; Levin, Edward D; Overstreet, David H

2012-08-01

78

Preclinical studies of N3-O-toluyl-fluorouracil-loaded lipid-based nanosuspensions in H22-bearing mice  

PubMed Central

Purpose N3-O-toluyl-fluorouracil (TFU) is a potential antitumor prodrug of 5-fluorouracil (5-FU), but its poor solubility has limited its use in clinic. This study aimed to improve the bioavailability of TFU by preparing TFU-loaded lipid-based nanosuspensions (TFU-LNS) and perform a preclinical evaluation. Methods TFU-LNS were prepared through high-pressure homogenization and were lyophilized afterwards. For in vitro test, the physicochemical properties and cytotoxicity against HegG2 cells were conducted. For in vivo evaluation, the pharmacokinetics, tissue distribution, and antitumor efficacy were investigated in H22-bearing Kunming mice. Results TFU showed different degradability in four media; in particular, nearly all of it converted to an equimolar amount of 5-FU in blank plasma of Wistar rats. The lyophilized TFU-LNS had a mean particle size of 180.03±3.11 nm and zeta potential of ?8.02±1.43 mV and showed no discernible changes after storage at 4°C for 3 months. In the in vivo antitumor study, the antitumor efficacy of TFU-LNS was consistent with that of 5-FU injection. Furthermore, TFU-LNS released a lower concentration of 5-FU in heart and kidney throughout the tissue distribution studies. Conclusion TFU-LNS exhibited convincing antitumor activity and easy scale-up opportunity, which suggests that TFU-LNS might be a promising drug delivery system for cancer therapy. PMID:24920908

Zhang, Juan; Li, Min; Liu, Zhihong; Wang, Lili; Liu, Yongjun; Zhang, Na

2014-01-01

79

Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons From Preclinical Studies  

SciTech Connect

Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.ed [Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX (United States); Boike, Thomas P. [Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX (United States)

2011-04-01

80

From Bench to Bedside: Lessons Learned in Translating Preclinical Studies in Cancer Drug Development  

PubMed Central

The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited. PMID:24052618

2013-01-01

81

Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis.  

PubMed

Current therapies for the treatment of rheumatoid arthritis (RA) do not work for all patients, can lose efficacy over time, and can have significant side effects. The discovery of new, effective therapies for RA remains an unmet medical need. The Amaryllidaceae isocarbostyril narciclasine was previously shown to prophylactically reduce paw swelling in rats with adjuvant-induced arthritis (AA). In this study, the efficacy of sodium narcistatin (SNS), a water-soluble cyclic phosphate pro-drug of narciclasine, was assessed in AA rats for anti-inflammatory and bone-sparing properties after disease onset. AA rats were given daily intraperitoneal injections of SNS (1.75, 3.5, or 5 mg/kg/day, in 500 ?l sterile endotoxin-free saline) or saline from disease onset through severe disease stages. Footpad widths and radiographic scoring were used as indicators of inflammation and joint destruction, respectively. Ex vivo cytokine production by peripheral blood mononuclear cells (PMBC), splenocytes, and draining lymph node (DLN) cells were determined using ELISAs. SNS treatment dose-dependently reduced joint inflammation (~70%) and bone loss (~50%) compared with AA controls. SNS treatment also reduced spleen weight (without affecting body weight), pro-inflammatory cytokine production by PMBC, splenocytes, and DLN cells, and site-dependently altered T-helper (Th)1-/Th2-type and anti-inflammatory cytokine profiles. SNS dramatically reduces inflammation and has bone-sparing properties, possibly by reducing immune cell pro-inflammatory cytokine production. Our findings support the development of SNS as a therapeutic for RA. PMID:22159913

Lubahn, Cheri; Schaller, Jill A; Shewmacker, Eric; Wood, Carlo; Bellinger, Denise L; Byron, Donna; Melody, Noeleen; Pettit, George R; Lorton, Dianne

2012-12-01

82

Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer  

PubMed Central

Pancreatic ductal adenocarcinoma (PDA) continues to be one of the deadliest cancers due to the absence of effective treatment. Curaxins are a class of small molecules with anti-cancer activity demonstrated in different models of cancer in mice. The lead curaxin compound, CBL0137, recently entered Phase I clinical trials. Curaxins modulate several important signaling pathways involved in the pathogenesis of PDA through inhibition of chromatin remodeling complex FACT. FACT is overexpressed in multiple types of tumor, with one of the highest rate of overexpression in PDA (59%). In this study, the efficacy of CBL0137 alone or in combination with current standard of care, gemcitabine, was tested against different models of PDA in vitro and in mouse models. It was found that CBL0137 alone is a potent inducer of apoptosis in pancreatic cancer cell lines and is toxic not only for proliferating bulk tumor cells, but also for pancreatic cancer stem cells. In mice, CBL0137 was effective against several PDA models, including orthotopic gemcitabine resistant PANC-1 model and patient derived xenografts, in which CBL0137 anti-tumor effect correlated with overexpression of FACT. Moreover, we observed synergy of CBL0137 with gemcitabine which may be explained by the ability of CBL0137 to inhibit several transcriptional programs induced by gemcitabine, including NF-kappaB response and expression of ribonucleotide reductase, one of the targets of gemcitabine in cells. This data suggest testing of CBL0137 efficacy in Phase II trial in PDA patients alone and in combination with gemcitabine. PMID:25402820

Burkhart, Catherine; Fleyshman, Daria; Kohrn, Rachael; Commane, Mairead; Garrigan, Jennifer; Kurbatov, Vadim; Toshkov, Ilya; Ramachandran, Rajesh; Martello, Laura; Gurova, Katerina V.

2014-01-01

83

Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds.  

PubMed Central

We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4+ and CD8+ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo. PMID:8851606

Rabin, L; Hincenbergs, M; Moreno, M B; Warren, S; Linquist, V; Datema, R; Charpiot, B; Seifert, J; Kaneshima, H; McCune, J M

1996-01-01

84

Toxicity of Bothrops sp snake venoms from Ecuador and preclinical assessment of the neutralizing efficacy of a polyspecific antivenom from Costa Rica.  

PubMed

The toxicological profile of the venoms of the snakes Bothrops asper and Bothrops atrox from Ecuador was investigated, together with the venom of a population of B. asper formerly classified as 'Bothrops xanthogrammus'. The three venoms exerted lethal, hemorrhagic, myotoxic, coagulant and defibrinogenating effects, in agreement with the characteristic toxicological profile of Bothrops sp venoms. A polyspecific antivenom (bothropic-crotalic-lachesic) manufactured in Costa Rica was assessed for its preclinical efficacy against the toxic activities of these Ecuadorian venoms. Antivenom was effective in the neutralization of the five activities tested in the three venoms. These observations are in agreement with previous reports on the extensive cross-reactivity and paraspecific neutralization of antivenoms manufactured in Latin America against the venoms of Bothrops sp snakes. PMID:24950051

Laines, Johana; Segura, Álvaro; Villalta, Mauren; Herrera, María; Vargas, Mariángela; Alvarez, Gladys; Gutiérrez, José María; León, Guillermo

2014-09-01

85

Therapeutic Applications of Incretin Mimetics for Metabolic Diseases: Preclinical Studies  

Technology Transfer Automated Retrieval System (TEKTRAN)

Exenatide (exendin-4) is an incretin mimetic peptide that shares several glucoregulatory actions with the endogenous incretin GLP-1. In addition to its actions on glucose control, exenatide produces effects to reduce food intake and body weight in all species studied. GLP-1 and exenatide have also b...

86

Intradermal inactivated poliovirus vaccine: a preclinical dose-finding study.  

PubMed

Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. PMID:25391313

Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

2015-05-01

87

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations  

Microsoft Academic Search

Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and\\u000a improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern.\\u000a In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new\\u000a drugs with pulmonary-targeted topical efficacy. One of

Po-Chang Chiang; Yiding Hu; Jason D. Blom; David C. Thompson

2010-01-01

88

Technetium-99m galactosyl-neoglycoalbumin: preparation and preclinical studies  

SciTech Connect

Technetium-99m galactosyl-neoglycoalbumin ((Tc) NGA), a labeled analog ligand to the hepatocyte-specific receptor, hepatic binding protein (HBP), was prepared and tested for labeling yield, stability, biodistribution, toxicity, and dosimetry. The ligand was synthesized by the covalent coupling of a carbohydrate bifunctional reagent, 2-imino-2-ethyloxymethyl-1-thiogalactose, to human serum albumin. Testing in mice and rabbits revealed the product to be nontoxic and apyrogenic. Biodistribution studies in rabbits demonstrated the liver as the single focus of tracer uptake. Dosimetry was based on kinetic studies in three baboons. Absorbed doses to liver, small intestine, urinary bladder wall, and uterus were 0.089, 0.28, 0.56, and 0.88 rad/mCi, respectively. Total body, lens of the eye, red marrow, ovaries, and testes were less than 0.06 rad/mCi. High liver specificity imparted by receptor binding combined with high labeling yield, stability, acceptable dosimetry, and safety provide (Tc)NGA with the attributes required for routine clinical assessment of hepatocyte function.

Vera, D.R.; Stadalnik, R.C.; Krohn, K.A.

1985-10-01

89

Luciferase fragment complementation imaging in preclinical cancer studies  

PubMed Central

The luciferase fragment complementation assay (LFCA) enables molecular events to be non-invasively imaged in live cells in vitro and in vivo in a comparatively cheap and safe manner. It is a development of previous enzyme complementation assays in which reporter genes are split into two, individually enzymatically inactive, fragments that are able to complement one another upon interaction. This complementation can be used to externally visualize cellular activities. In recent years, the number of studies which have used LFCAs to probe questions relevant to cancer have increased, and this review summarizes the most significant and interesting of these. In particular, it focuses on work conducted on the epidermal growth factor, nuclear and chemokine receptor families, and intracellular signaling pathways, including IP3, cAMP, Akt, cMyc, NRF2 and Rho GTPases. LFCAs which have been developed to image DNA methylation and detect RNA transcripts are also discussed. PMID:25594026

Lake, Madryn C.; Aboagye, Eric O.

2014-01-01

90

Luciferase fragment complementation imaging in preclinical cancer studies.  

PubMed

The luciferase fragment complementation assay (LFCA) enables molecular events to be non-invasively imaged in live cells in vitro and in vivo in a comparatively cheap and safe manner. It is a development of previous enzyme complementation assays in which reporter genes are split into two, individually enzymatically inactive, fragments that are able to complement one another upon interaction. This complementation can be used to externally visualize cellular activities. In recent years, the number of studies which have used LFCAs to probe questions relevant to cancer have increased, and this review summarizes the most significant and interesting of these. In particular, it focuses on work conducted on the epidermal growth factor, nuclear and chemokine receptor families, and intracellular signaling pathways, including IP3, cAMP, Akt, cMyc, NRF2 and Rho GTPases. LFCAs which have been developed to image DNA methylation and detect RNA transcripts are also discussed. PMID:25594026

Lake, Madryn C; Aboagye, Eric O

2014-01-01

91

A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study  

E-print Network

A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study W. A of ablative technologies such as HIFU for the treatment of liver tumors in humans has been studied in animal models without tumors or in small animals like rats and rabbits with established tumors. Because

Paris-Sud XI, Université de

92

A Preclinical Study Combining the DNA Repair Inhibitor Dbait with Radiotherapy for the Treatment of Melanoma1  

PubMed Central

Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of “palliative” RT (10 × 3 Gy) or “radical” RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the “palliative” protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the “radical” protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial). PMID:25379020

Biau, Julian; Devun, Flavien; Jdey, Wael; Kotula, Ewa; Quanz, Maria; Chautard, Emmanuel; Sayarath, Mano; Sun, Jian-Sheng; Verrelle, Pierre; Dutreix, Marie

2014-01-01

93

Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies  

PubMed Central

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable. PMID:21943025

2011-01-01

94

Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS  

PubMed Central

Objective: The study was designed to test the efficacy of ATX-MS-1467 in a relevant preclinical model and to assess its safety for the treatment of patients with secondary progressive multiple sclerosis (SPMS). Methods: ATX-MS-1467 was tested for its ability to suppress experimental autoimmune encephalomyelitis (EAE) in the (Ob x DR2)F1 mouse both before and after disease onset. Safety was assessed by clinical assessment, MRI analysis, and the measurement of immune responses to self- and nonself-antigens in patients with SPMS. Results: ATX-MS-1467 displayed a dose-dependent inhibition of EAE and was more effective than glatiramer acetate in the treatment of ongoing disease in humanized mice. A phase 1 open-label dose-escalating study demonstrated that ATX-MS-1467 was safe and well-tolerated in a group of 6 patients with SPMS, up to a dose of 800 µg. Conclusions: The results of this study support further development of ATX-MS-1467 in a clinical trial powered to investigate the immunologic and clinical benefits of treatment in relapsing-remitting MS. Classification of evidence: This study provides Class IV evidence that ATX-MS-1467 is safe and tolerated in a group of 6 patients with SPMS. PMID:25798453

Streeter, Heather B.; Rigden, Rachel; Martin, Keith F.; Scolding, Neil J.

2015-01-01

95

Attempted and successful compensation in preclinical and early manifest neurodegeneration - a review of task FMRI studies.  

PubMed

Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of "attempted" and "successful" compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington's disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset. PMID:25324786

Scheller, Elisa; Minkova, Lora; Leitner, Mathias; Klöppel, Stefan

2014-01-01

96

Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat  

PubMed Central

Previous work has established the existence of dystrophin–nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice—the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients. PMID:23552722

Consalvi, Silvia; Mozzetta, Chiara; Bettica, Paolo; Germani, Massimiliano; Fiorentini, Francesco; Del Bene, Francesca; Rocchetti, Maurizio; Leoni, Flavio; Monzani, Valmen; Mascagni, Paolo; Puri, Pier Lorenzo; Saccone, Valentina

2013-01-01

97

Preclinical studies at UNC use specialized ultrasound to detect presence of cancer  

Cancer.gov

In the body, tracing the twists and turns of blood vessels is difficult, but important. Vessel “bendiness” can indicate the presence and progression of cancer. This principle led UNC Lineberger Comprehensive Cancer Center scientists to a new method of using a high-resolution ultrasound to identify early tumors in preclinical studies. The method, based on vessel bendiness or “tortuosity,” potentially offers an inexpensive, non-invasive and fast method to detect cancer that could someday help doctors identify cancers when tumors are less than a centimeter in size. Their findings were published in the July 6, 2012 online issue of the journal Radiology.

98

Exploratory study of factors related to educational scores of first preclinical year medical students.  

PubMed

The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P < 0.001 for all) by Pearson's method. Using multiple linear regression analysis, anatomy scores could be predicted by pre-MD GPA, student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R(2) = 0.598, P < 0.001). Physiology scores could be estimated by pre-MD GPA, the percentage of expected reading, monthly earnings, and percentage of those who fell asleep during class and near exam time (R = 0.722, R(2) = 0.521, P < 0.001). Biochemistry scores could be calculated by pre-MD GPA, the percentage of expected reading, motivation to study medicine, student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R(2) = 0.630, P < 0.001). In conclusion, pre-MD GPA and the percentage of expected reading are factors involved in producing good academic results in the first preclinical year. Anatomy and biochemistry, but not physiology, scores are influenced by satisfaction. PMID:24585466

Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarayut

2014-03-01

99

Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.  

PubMed

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase or glutamic acid decarboxylase inhibition; a range of monoaminergic effects; and potential cannabinoid receptor modulation. Future research should focus on conducting human clinical trials on the plants reviewed with promising anxiolytic activity. PMID:23436255

Sarris, Jerome; McIntyre, Erica; Camfield, David A

2013-03-01

100

Food for Thought Look Back in Anger – What Clinical Studies Tell Us About Preclinical Work  

PubMed Central

Summary Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies. PMID:23861075

Hartung, Thomas

2013-01-01

101

A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer.  

PubMed

Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto- and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR- or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules. PMID:24643470

Modjtahedi, Helmout; Cho, Byoung Chul; Michel, Martin C; Solca, Flavio

2014-06-01

102

Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by 18F-ICMT-11-Positron Emission Tomography  

PubMed Central

Tumour response to therapy is assessed primarily in the clinic by monitoring reductions in tumour size. However, this approach lacks sensitivity since in many cases several weeks may elapse before there is evidence of tumour shrinkage. There is therefore a need to develop non-invasive imaging techniques for monitoring tumour treatment response in the clinic. Here, we assessed the pre-clinical utility of 18F-ICMT-11 positron emission tomography - a method for detecting caspase 3/7 activation - in non-small cell lung cancer (NSCLC). 18F-ICMT-11 uptake was compared to molecular biochemical measures of cell death in PC9 and A549 NSCLC cells following treatment with carboplatin in vitro and in vivo. Carboplatin-induced apoptosis in the ERCC1 low/mutant EGFR PC9 cells was characterised by time and dose-related increased caspase-3/7 activation, poly-ADP-ribose polymerase cleavage and Annexin V staining. 18F-ICMT-11 uptake was consequently increased up to 14-fold at 200 µM carboplatin compared to vehicle treated cells (P<0.01). In contrast, necrosis was the predominant death mechanism in ERCC1 high/wt EGFR A549 cells and no change in 18F-ICMT-11 uptake was detected. In vivo, histological analysis of PC9 tumour xenografts indicated high pre-therapy necrosis. A 4.6-fold increase in cleaved caspase-3/7 was measured in non-necrotic regions of PC9 tumours at 48h post carboplatin therapy. Average PET-derived tumour 18F-ICMT-11 uptake was insensitive to changes in apoptosis in the presence of substantial pre-existing necrosis. PET-based voxel intensity sorting however, identified intra-tumoural regions of high 18F-ICMT-11 uptake, enabling accurate assessment of apoptosis and therefore therapy response. In A549 tumours that lacked high pre-therapy necrosis, carboplatin induced growth inhibition that was only minimally associated with apoptosis and thus not detectable by 18F-ICMT-11 PET. PMID:24618809

Witney, Timothy H.; Fortt, Robin R.; Aboagye, Eric O.

2014-01-01

103

Preclinical pharmacology, ocular tolerability and ocular hypotensive efficacy of a novel non-peptide bradykinin mimetic small molecule.  

PubMed

We sought to characterize the ocular pharmacology, tolerability and intraocular pressure (IOP)-lowering efficacy of FR-190997, a non-peptidic bradykinin (BK) B2-receptor agonist. FR-190997 possessed a relatively high receptor binding affinity (Ki = 27 nM) and a high in vitro potency (EC50 = 18.3 ± 4.4 nM) for inositol-1-phosphate generation via human cloned B2-receptors expressed in host cells with mimimal activity at B1-receptors. It also mobilized intracellular Ca2+ in isolated human trabecular meshwork (h-TM), ciliary muscle (h-CM), and in immortalized non-pigmented ciliary epithelial (h-iNPE) cells (EC50s = 167-384 nM; Emax = 32-86% of BK-induced response). HOE-140, a selective B2-receptor antagonist, potently blocked the latter effects of FR-190997 (e.g., IC50 = 7.3 ± 0.6 nM in h-CM cells). FR-190997 also stimulated the release of prostaglandins (PGs) from h-TM and h-CM cells (EC50s = 60-84 nM; Emax = 29-44% relative to max. BK-induced effects). FR-190997 (0.3-300 ?g t.o.) did not activate cat corneal polymodal nociceptors and did not cause ocular discomfort in Dutch-Belted rabbits, but it was not well tolerated in New Zealand albino rabbits and Hartley guinea pigs. A single topical ocular (t.o.) dose of 1% FR-190997 in Dutch-Belted rabbits and mixed breed cats did not lower IOP. However, FR-190997 efficaciously lowered IOP of conscious ocular hypertensive cynomolgus monkey eyes (e.g., 34.5 ± 7.5% decrease; 6 h post-dose of 30 ?g t.o.; n = 8). Thus, FR-190997 is an unexampled efficacious ocular hypotensive B2-receptor non-peptide BK agonist that activates multiple signaling pathways to cause IOP reduction. PMID:25307520

Sharif, Najam A; Li, Linya; Katoli, Parvaneh; Xu, Shouxi; Veltman, James; Li, Byron; Scott, Daniel; Wax, Martin; Gallar, Juana; Acosta, Carmen; Belmonte, Carlos

2014-11-01

104

The Metabotropic Glutamate Receptor 4-Positive Allosteric Modulator VU0364770 Produces Efficacy Alone and in Combination with l-DOPA or an Adenosine 2A Antagonist in Preclinical Rodent Models of Parkinson's Disease  

PubMed Central

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists. PMID:22088953

Jones, Carrie K.; Bubser, Michael; Thompson, Analisa D.; Dickerson, Jonathan W.; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L.; Bridges, Thomas M.; Morrison, Ryan D.; Jadhav, Satyawan; Engers, Darren W.; Italiano, Kimberly; Bode, Jacob; Daniels, J. Scott; Lindsley, Craig W.; Hopkins, Corey R.; Conn, P. Jeffrey

2012-01-01

105

The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease.  

PubMed

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu?), including N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu? PAMsexhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu? in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu? PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu? PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu? PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A2A antagonists. PMID:22088953

Jones, Carrie K; Bubser, Michael; Thompson, Analisa D; Dickerson, Jonathan W; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L; Bridges, Thomas M; Morrison, Ryan D; Jadhav, Satyawan; Engers, Darren W; Italiano, Kimberly; Bode, Jacob; Daniels, J Scott; Lindsley, Craig W; Hopkins, Corey R; Conn, P Jeffrey; Niswender, Colleen M

2012-02-01

106

Increased preclinical efficacy of irinotecan and floxuridine coencapsulated inside liposomes is associated with tumor delivery of synergistic drug ratios.  

PubMed

Whether anticancer drug combinations act synergistically or antagonistically often depends on the ratio of the agents being combined. We show here that combinations of irinotecan and floxuridine exhibit drug ratio-dependent cytotoxicity in a broad panel of tumor cell lines in vitro where a 1:1 molar ratio consistently provided synergy and avoided antagonism. In vivo delivery of irinotecan and floxuridine coencapsulated inside liposomes at the synergistic 1:1 molar ratio (referred to as CPX-1) lead to greatly enhanced efficacy compared to the two drugs administered as a saline-based cocktail in a number of human xenograft and murine tumor models. When compared to liposomal irinotecan or liposomal floxuridine, the therapeutic activity of CPX-1 in vivo was not only superior to the individual liposomal agents, but the extent of tumor growth inhibition was greater than that predicted for combining the activities of the individual agents. In contrast, liposome delivery of irinotecan:floxuridine ratios shown to be antagonistic in vitro provided antitumor activity that was actually less than that achieved with liposomal irinotecan alone, indicative of in vivo antagonism. Synergistic antitumor activity observed for CPX-1 was associated with maintenance of the 1:1 irinotecan:floxuridine molar ratio in plasma and tumor tissue over 16-24 h. In contrast, injection of the drugs combined in saline resulted in irinotecan:floxuridine ratios that changed 10-fold within 1 h in plasma and sevenfold within 4 h in tumor tissue. These results indicate that substantial improvements in the efficacy of drug combinations may be achieved by maintaining in vitro-identified synergistic drug ratios after systemic administration using drug delivery vehicles. PMID:17913044

Harasym, Troy O; Tardi, Paul G; Harasym, Natashia L; Harvie, Pierrot; Johnstone, Sharon A; Mayer, Lawrence D

2007-01-01

107

Electrical stimulation of the medial forebrain bundle in pre-clinical studies of psychiatric disorders.  

PubMed

Modulating neuronal activity by electrical stimulation has expanded from the realm of motor indications into the field of psychiatric disorders in the past 10 years. The medial forebrain bundle (MFB), with a seminal role in motor, reward orientated and affect regulation behaviors, and its afferent and efferent loci, have been targeted in several DBS trials in patients with psychiatric disorders. However, little is known about the consequences of modulating the MFB in affective disorders. The paper reviews the relevant pre-clinical literature investigating electrical stimulation of regions associated with the MFB in the context of several models of psychiatric disorders, in particular depression. The clinical data is promising but limited, and pre-clinical studies are essential for improved understanding of the anatomy, the connectivity, and the consequences of stimulation of the MFB and regions associated with the neurocircuitry of psychiatric disorders. Current data suggests that the MFB is at a "privileged" position on this circuitry and its stimulation can simultaneously modulate activity at other key sites, such as the nucleus accumbens, the ventromedial prefrontal cortex or the ventral tegmental area. Future experimental work will need to shed light on the anti-depressive mechanisms of MFB stimulation in order to optimize clinical interventions. PMID:25498857

Döbrössy, Máté D; Furlanetti, Luciano L; Coenen, Volker A

2015-02-01

108

Developing a Measurement Tool for Assessing Physiotherapy Students' Self-Efficacy: A Pilot Study  

ERIC Educational Resources Information Center

The aim of this research was to determine if self-efficacy can be correlated with prior academic achievement and whether self-efficacy can be an outcome measure of education. A self-efficacy instrument was developed and administered to physiotherapy students following completion of their pre-clinical theory experience. The questionnaire results…

Jones, Anne; Sheppard, Lorraine

2012-01-01

109

In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872).  

PubMed Central

The echinocandin MK-0991, formerly L-743,872, is a water-soluble lipopeptide that has been demonstrated in preclinical studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biological evaluation of MK-0991 was performed to better define the potential activities of this novel compound. Susceptibility testing with MK-0991 against approximately 200 clinical isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to determine MICs and minimum fungicidal concentrations MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clinical isolates was 0.5 microg/ml. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. neoformans isolates indicated that the MK-0991 MFCs for these isolates are comparable to those obtained for susceptible isolates. Growth kinetic studies of MK-0991 against Candida albicans and Candida tropicalis isolates showed that the compound exhibited fungicidal activity (i.e., a 99% reduction in viability) within 3 to 7 h at concentrations ranging from 0.06 to 1 microg/ml (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination was not antagonistic against C. albicans, C. neoformans, or A. fumigatus in vitro. Studies with 0 to 50% pooled human or mouse serum established that fungal susceptibility to MK-0991 was not significantly influenced by the presence of human or mouse serum. Results from resistance induction studies suggested that the susceptibility of C. albicans was not altered by repeated exposure (40 passages) to MK-0991. Erythrocyte hemolysis studies with MK-0991 with washed and unwashed human or mouse erythrocytes indicated minimal hemolytic potential with this compound. These favorable results of preclinical studies support further studies with MK-0991 with humans. PMID:9371328

Bartizal, K; Gill, C J; Abruzzo, G K; Flattery, A M; Kong, L; Scott, P M; Smith, J G; Leighton, C E; Bouffard, A; Dropinski, J F; Balkovec, J

1997-01-01

110

Systematic reviews and meta-analysis of preclinical studies: why perform them and how to appraise them critically  

PubMed Central

The use of systematic review and meta-analysis of preclinical studies has become more common, including those of studies describing the modeling of cerebrovascular diseases. Empirical evidence suggests that too many preclinical experiments lack methodological rigor, and this leads to inflated treatment effects. The aim of this review is to describe the concepts of systematic review and meta-analysis and consider how these tools may be used to provide empirical evidence to spur the field to improve the rigor of the conduct and reporting of preclinical research akin to their use in improving the conduct and reporting of randomized controlled trials in clinical research. As with other research domains, systematic reviews are subject to bias. Therefore, we have also suggested guidance for their conduct, reporting, and critical appraisal. PMID:24549183

Sena, Emily S; Currie, Gillian L; McCann, Sarah K; Macleod, Malcolm R; Howells, David W

2014-01-01

111

Efficacy Development in New Teacher Study Groups  

ERIC Educational Resources Information Center

This qualitative study explores the experiences and learning of five new teachers with less than three years in the classroom as they engaged in a study group. This research highlights the ways that participation in a study group enhanced teacher efficacy and supported their retention. The research reveals that power and authority over…

Simon, Flora Ann

2011-01-01

112

Resveratrol: A Review of Pre-clinical Studies for Human Cancer Prevention  

PubMed Central

The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3, 4?, 5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and anti-oxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol’s anti-cancer effects to support its potential as an anticancer agent in human populations. PMID:17306316

Athar, Mohammad; Back, Jung Ho; Tang, Xiuwei; Kim, Kwang Ho; Kopelovich, Levy; Bickers, David R.; Kim, Arianna L.

2007-01-01

113

Phase I\\/II Clinical Study of Pulsed Paclitaxel Radiosensitization for Thoracic Malignancy: A Therapeutic Approach on the Basis of Preclinical Research of Human Cancer Cell Lines1  

Microsoft Academic Search

Purpose: A Phase I\\/II clinical study using pulsed low- dose paclitaxel and radiation for thoracic malignancy was conducted. The study was based on preclinical research of the effects of paclitaxel on apoptosis and the cell cycle in human cancer cell lines. Experimental Design: Three human epithelial cancer cell lines were investigated for preclinical study. Cells were analyzed for apoptosis and

Yuhchyau Chen; Kishan Pandya; Peter C. Keng; David Johnstone; Jigang Li; Yi-Jang Lee; Therese Smudzin; Paul Okunieff

2003-01-01

114

Immune Competency of a Hairless Mouse Strain for Improved Preclinical Studies in Genetically-Engineered Mice  

PubMed Central

Genetically-engineered mouse models (GEMMs) of cancer are of increasing value to preclinical therapeutics. Optical imaging is a cost-effective method of assessing deep-seated tumor growth in GEMMs whose tumors can be encoded to express luminescent or fluorescent reporters, although reporter signal attenuation would be improved if animals were fur-free. In this study, we sought to determine whether hereditable furlessness resulting from a hypomorphic mutation in the Hairless gene would or would not also affect immune competence. By assessment of humoral and cellular immunity of the SKH1 mouse line bearing the hypomorphic Hairless mutation, we determined that blood counts, immunoglobulin levels, and CD4+ and CD8+ T cells were comparable between SKH1 and the C57Bl/6 strain. On examination of T cell subsets, statistically significant differences in naïve T cells (1.7 vs. 3.4 × 105 cells/spleen in SKH1 vs. C57Bl/6, p=0.008) and memory T cells (1.4 vs. 0.13 × 106 cells/spleen in SKH1 vs. C57Bl/6, p=0.008) were detected. However, the numerical differences did not result in altered T cell functional response to antigen re-challenge (keyhole limpet hemocyanin) in a lymph node cell in vitro proliferative assay. Furthermore, interbreeding the SKH1 mouse line to a rhabdomyosarcoma GEMM demonstrated preserved anti-tumor responses of CD56+ Natural Killer cells and CD163+ macrophages, without any differences in tumor pathology. The fur-free GEMM was also especially amenable to multiplex optical imaging. Thus, SKH1 represents an immune competent, fur-free mouse strain which may be of use for interbreeding to other genetically-engineered mouse models of cancer for improved preclinical studies. PMID:20663932

Schaffer, Beverly S.; Grayson, Marcia H.; Wortham, Joy M.; Kubicek, Courtney B.; McCleish, Amanda T.; Prajapati, Suresh I.; Nelon, Laura D.; Brady, Michelle M.; Jung, Inkyung; Hosoyama, Tohru; Sarro, Leslea M.; Hanes, Martha A.; Rubin, Brian P.; Michalek, Joel E.; Clifford, Charles B.; Infante, Anthony J.; Keller, Charles

2010-01-01

115

Executive Function Changes before Memory in Preclinical Alzheimer’s Pathology: A Prospective, Cross-Sectional, Case Control Study  

PubMed Central

Background Early treatment of Alzheimer’s disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer’s disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology. Methods and Findings We recruited adults with probable Alzheimer’s disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer’s disease. We separated the asymptomatic group into those with (n?=?34; preclinical Alzheimer’s disease) and without (n?=?36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-? genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR?=?0.13, 95% CI?=?0.04–0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study. Conclusions Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer’s disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach. PMID:24260210

Harrington, Michael G.; Chiang, Jiarong; Pogoda, Janice M.; Gomez, Megan; Thomas, Kris; Marion, Sarah DeBoard; Miller, Karen J.; Siddarth, Prabha; Yi, Xinyao; Zhou, Feimeng; Lee, Sherri; Arakaki, Xianghong; Cowan, Robert P.; Tran, Thao; Charleswell, Cherise; Ross, Brian D.; Fonteh, Alfred N.

2013-01-01

116

EFFECTS OF A BICARBONATE-ALKALINE MINERAL WATER ON GASTRIC FUNCTIONS AND FUNCTIONAL DYSPEPSIA: A PRECLINICAL AND CLINICAL STUDY  

Microsoft Academic Search

The present study was performed in order to evaluate: (1) the influence of a bicarbonate-alkaline mineral water (Uliveto®) on digestive symptoms in patients with functional dyspepsia; (2) the effects of Uliveto® on preclinical models of gastric functions. Selected patients complained of dyspeptic symptoms in the absence of digestive lesions or Helicobacter pylori infection within the previous 3 months. They were

MICHELE BERTONI; FILIPPO OLIVERI; MARTA MANGHETTI; ELENA BOCCOLINI; MARIA GRAZIA BELLOMINI; CORRADO BLANDIZZI; FERRUCCIO BONINO; MARIO DEL TACCA

2002-01-01

117

Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer’s disease  

PubMed Central

Recent clinical and pre-clinical studies suggest that both active and passive immunization strategies targeting A? amyloid may have clinical benefit in Alzheimer’s disease. Here, we demonstrate that vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native A? amyloid-specific binding peptide, lowers brain A? amyloid plaque burden and brain A?1-40 and A?1-42 peptide levels, improves cognitive learning and memory in Morris Water maze tests and increases the expression of synaptic brain proteins. This was the case in young mice immunized prior to development of significant brain amyloid burden, and in older mice, where brain amyloid was already present. Active immunization was optimized using ALUM as an adjuvant to stimulate production of anti-SDPM1 and anti-A? amyloid antibodies. Intracerebral injection of P4D6, an SDPM1 peptide-mimotope antibody, also lowered brain amyloid plaque burden in APPswePSEN1dE9 mice. Additionally, P4D6 inhibited A? amyloid-mediated toxicity in cultured neuronal cells. The protein sequence of the variable domain within the P4D6 heavy chain was found to mimic a multimer of the SDPM1 peptide motif. These data demonstrate the efficacy of active and passive vaccine strategies to target specific A? amyloid oligomers using an engineered peptide-mimotope strategy. PMID:24021662

Camboni, Marybeth; Wang, Chiou-Miin; Miranda, Carlos; Yoon, Jung Hae; Xu, Rui; Zygmunt, Deborah; Kaspar, Brian K.; Martin, Paul T.

2013-01-01

118

Creative Self-Efficacy: An Intervention Study  

ERIC Educational Resources Information Center

This study examined the effects of creativity training on creative self-efficacy. We developed a creativity course based on social cognitive theory. The course was conducted in two formats: a five-day course and a condensed one-day course. Samples consisted of students and municipality employees (five-day course), and special education teachers…

Mathisen, Gro Ellen; Bronnick, Kolbjorn S.

2009-01-01

119

Preclinical pharmacology, efficacy, and safety of varenicline in smoking cessation and clinical utility in high risk patients  

PubMed Central

Smoking is still the most prominent cause of preventable premature death in the United States and an increasing cause of morbidity and mortality throughout the world. Although the current treatments such as nicotine replacement therapy (NRT) and bupropion are effective, long-term abstinence rates are low. Mechanism studies suggest that the pleasurable effects of smoking are mediated predominantly by nicotine, which activates the brain reward system by activation of brain ?4?2 nicotinic acetylcholine receptors (nAChRs). Varenicline is a novel ?4?2 nAChR partial agonist and has been found to be even more effective than NRT or bupropion in attenuating smoking satisfaction and in relieving craving and withdrawal symptoms after abstinence. Thus, varenicline has been recently approved to be a first-line medication for smoking cessation in the United States and European countries. Varenicline is generally well tolerated in healthy adult smokers, with the most commonly reported adverse effects being nausea, insomnia, and headache. However, growing postmarketing data has linked varenicline to an increase in neuropsychiatric symptoms such as seizures, suicidal attempts, depression, and psychosis as well as serious injuries potentially relating to unconsciousness, dizziness, visual disturbances, or movement disorders. Therefore, new safety warnings are issued to certain high risk populations, such as patients with mental illness and operators of commercial vehicles and heavy machinery. In particular, pilots, air traffic controllers, truck and bus drivers have been banned from taking varenicline. PMID:21278851

Xi, Zheng-Xiong

2010-01-01

120

Preclinical Pharmacology, Efficacy and Safety of Varenicline in Smoking Cessation and Clinical Utility in High Risk Patients.  

PubMed

Smoking is still the most prominent cause of preventable premature death in the United States and an increasing cause of morbidity and mortality throughout the world. Although the current treatments such as nicotine replacement therapy (NRT) and bupropion are effective, long-term abstinence rates are low. Mechanism studies suggest that the pleasurable effects of smoking are mediated predominantly by nicotine, which activates the brain reward system by activation of brain ?(4)?(2) nicotinic acetylcholine receptors (nAChRs). Varenicline is a novel ?(4)?(2) nAChR partial agonist and has been found to be even more effective than NRT or bupropion in attenuating smoking satisfaction and in relieving craving and withdrawal symptoms after abstinence. Thus, varenicline has been recently approved to be a first-line medication for smoking cessation in the United States and European countries. Varenicline is generally well tolerated in healthy adult smokers, with the most commonly reported adverse effects being nausea, insomnia, and headache. However, growing post-marketing data has linked varenicline to an increase in neuropsychiatric symptoms such as seizures, suicidal attempts, and depression, psychosis, as well as serious injuries potentially relating to unconsciousness, dizziness, visual disturbances, or movement disorders. Therefore, new safety warnings are issued to certain high risk populations, such as patients with mental illness and operators of commercial vehicles or heavy machinery. In particular, pilots, air traffic controllers, truck and bus drivers have been banned from taking varenicline. PMID:21278851

Xi, Zheng-Xiong

2010-04-01

121

Handling of the cotton rat in studies for the pre-clinical evaluation of oncolytic viruses.  

PubMed

Oncolytic viruses are a novel anticancer therapy with the ability to target tumor cells, while leaving healthy cells intact. For this strategy to be successful, recent studies have shown that involvement of the host immune system is essential. Therefore, oncolytic virotherapy should be evaluated within the context of an immunocompetent model. Furthermore, the study of antitumor therapies in tolerized animal models may better recapitulate results seen in clinical trials. Cotton rats, commonly used to study respiratory viruses, are an attractive model to study oncolytic virotherapy as syngeneic models of mammary carcinoma and osteosarcoma are well established. However, there is a lack of published information on the proper handling procedure for these highly excitable rodents. The handling and capture approach outlined minimizes animal stress to facilitate experimentation. This technique hinges upon the ability of the researcher to keep calm during handling and perform procedures in a timely fashion. Finally, we describe how to prepare cotton rat mammary tumor cells for consistent subcutaneous tumor formation, and how to perform intratumoral and intraperitoneal injections. These methods can be applied to a wide range of studies furthering the development of the cotton rat as a relevant pre-clinical model to study antitumor therapy. PMID:25490047

Cuddington, Breanne; Verschoor, Meghan; Mossman, Karen

2014-01-01

122

Development of a specific tracer for metabolic imaging of alveolar echinococcosis: A preclinical study.  

PubMed

Positron emission tomography (PET)-computed tomography (CT) using [18F]-fluorodeoxyglucose (FDG) (FDG-PET/CT) is a valuable method for initial staging and follow up of patients with alveolar echinococcosis (AE). However, the cells responsible for FDG uptake have not been clearly identified. The main goal of our study was to evaluate the uptake of PET tracers by the cells involved in the host-parasite reaction around AE lesions as the first step to develop a specific PET tracer that would allow direct assessment of parasite viability in AE. Candidate molecules ([18F]-fluorotyrosine (FET), [18F]-fluorothymidine (FLT), and [18F]-fluorometylcholine (FMC), were compared to FDG by in vitro studies on human leukocytes and parasite vesicles. Our results confirmed that FDG was mainly consumed by immune cells and showed that FLT was the best candidate tracer for parasite metabolism. Indeed, parasite cells exhibited high uptake of FLT. We also performed PET/CT scans in mice infected intraperitoneally with E. multilocularis metacestodes. PET images showed no FDG or FLT uptake in parasitic lesions. This preliminary study assessed the metabolic activity of human leukocytes and AE cells using radiolabeling. Future studies could develop a specific PET tracer for AE lesions to improve lesion detection and echinococcosis treatment in patients. Our results demonstrated that a new animal model is needed for preclinical PET imaging to better mimic human hepatic and/or periparasitic metabolism. PMID:25571261

Porot, Clémence; Knapp, Jenny; Wang, Junhua; Germain, Stéphane; Camporese, Davide; Seimbille, Yann; Boulahdour, Hatem; Vuitton, Dominique A; Gottstein, Bruno; Blagosklonov, Oleg

2014-01-01

123

Preclinical endodontic teaching  

PubMed Central

Objectives: To provide an overview of the general curricula in preclinical endodontic training from 6 established dental schools in Saudi Arabia. Methods: This study was conducted in January 2014 including only schools that had more than 2 groups of student graduates prior to the study. We included 2 dental schools from the Central region, one from Qassim region, one from the Makkah region (west), one from Abha region (south west), and one from the eastern region. An internet-based questionnaire was sent to the course directors of preclinical endodontics department of the 6 schools. The survey comprised 20 questions that examined various aspects of preclinical endodontics. Results: It was demonstrated that a significant number of faculty members had Doctor of Philosophy (PhD) degrees (n=21), Master’s degrees (n=15), and Saudi board certifications (n=8). We determined that the faculty to student ratio varied from 2:1 to 8: 1 among the colleges. The participating dental schools were found to teach the Step Back, as well as the Step Down techniques for root canal preparation. Five of the 6 schools implemented the use of nickel titanium rotary instruments. All dental schools predominantly used radiographs as the means of the working length determination. Conclusion: The curriculum for preclinical endodontics in Saudi Arabia is comparable to that followed in most European countries. A more comprehensive survey is needed that would involve more schools to formulate generalized guidelines for preclinical endodontic training in Saudi Arabia. PMID:25630011

Narayanaraopeta, Udaya; AlShwaimi, Emad

2015-01-01

124

High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies.  

PubMed

High-density lipoprotein (HDL) particles transport (among other molecules) cholesterol (HDL-C). In epidemiological studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease. It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, several recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased cardiovascular disease risk, giving rise to a controversy regarding whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. The evidence from preclinical and (limited) clinical studies shows that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. Although more research will be needed regarding basic mechanisms and to establish that these changes translate clinically to reduced cardiovascular disease events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent but rather emphasizes the important distinction between HDL function and plasma levels of HDL-C. PMID:24385513

Feig, Jonathan E; Hewing, Bernd; Smith, Jonathan D; Hazen, Stanley L; Fisher, Edward A

2014-01-01

125

[Development and preclinical study of new generation virosomal split influenza vaccine "Grifor"].  

PubMed

New Russian virosomal split vaccine against influenza "Grifor" was developed. The vaccine is represented by mix of highly purified protective external and internal antigens of influenza A (H1N1 and H3N2) and B viruses. Developed technology of manufacture allowed to provide presentation of external antigens of influenza virus in the form of virosomes, and presentation of internal antigens in the form of micelles with maximal preservation of their antigenic activity. Using electron microscopy, electrophoresis in 10% polyacrilamide gel with sodium dodecyl sulfate, and polymerase chain reaction, morphologic and biochemical properties of the vaccine were studied. Preclinical study, including assessment of antigenic characteristics of "Grifor" vaccine compared to vaccine "Vaxigrip" (France), was performed. It was established that administration of the vaccine did not result in death of experimental animals, decrease of body mass, development of pathologic (including inflammatory, dystrophic and necrobiotic) changes in viscera or render adverse effects on blood hematologic and biochemical parameters and on the immune system. The vaccine was not pyrogenic and allergenic, did not have local irritating effects. Obtained results supported the appropriateness of conducting the clinical trials of "Grifor" vaccine on limited number of volunteers. PMID:19338232

Mel'nikov, S Ia; Zverev, V V; Korovkin, S A; Mironov, A N; Dyldina, N V; Mikha?lova, N A; Fa?zuloev, E B; Lotte, V D

2009-01-01

126

Coil optimization for low-field MRI: a dedicated process for small animal preclinical studies.  

PubMed

We demonstrate a method for the fast in vivo quantification of small volumes, down to 25?µL, using low-field magnetic resonance imaging (MRI) coils. The coils were designed so as to maximize the signal-to-noise ratio (SNR) in the images. For this we developed an analytical model for describing the variations of the SNR with coil design and with size/shape suited to the object under observation. Based on the conclusions drawn from the model, the coil parameters were chosen in order to reach an SNR close to the maximum. For the validation of the model, coils were finally characterized in terms of quality factor using saline phantoms. The coil design procedure is illustrated here with two examples: first, the quantification of about 200?µL of intradermal injected gel on rabbits with a single loop surface coil and second, the imaging of the intervertebral disks in rat tails using a small volume coil to detect possible lesions. Such studies would not have been feasible for the clinical low-field MRI system at our disposal using any of the commercially available medium-sized manufactured coils. As a result of this simple optimization procedure, a wide range of applications is accessible even at low magnetic fields, leading to new opportunities for low-cost, though efficient, preclinical studies. PMID:25359877

Feuillet, T; Seurin, M-J; Leveneur, O; Viguier, E; Beuf, O

2015-04-01

127

YLT192, a Novel, Orally Active Bioavailable Inhibitor of VEGFR2 Signaling with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models  

PubMed Central

Antagonizing vascular endothelial growth factor receptor 2 (VEGFR2) to block angiogenesis has been applied toward cancer therapy for its role in promoting cancer growth and metastasis. However, most these clinical anticancer drugs have unexpected side effects. Development of novel VEGFR2 inhibitors with less toxicity remains an urgent need. In this study, we describe a novel, well-tolerated, and orally active VEGFR2 inhibitor, YLT192, which inhibits tumor angiogenesis and growth. YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVEC. Zebrafish embryonic models and alginate-encapsulated tumor cell assays indicated YLT192 also inhibited angiogenesis in vivo. Moreover, YLT192 could directly inhibit proliferation and induce apoptosis of cancer cells in vitro and in vivo. Oral administration of YLT192 at a dose of 100?mg/kg/day could markedly inhibited human tumor xenograft growth without causing obvious toxicities. It decreased microvessel densities (MVD) in tumor sections. It also shows good safety profiles in the studies with mice and rats. Taken together, these preclinical evaluations suggest that YLT192 inhibits angiogenesis and may be a promising anticancer drug candidate. PMID:25112436

Xia, Yong; Song, Xuejiao; Li, Deliang; Ye, Tinghong; Xu, Youzhi; Lin, Hongjun; Meng, Nana; Li, Guobo; Deng, Senyi; Zhang, Shuang; Liu, Li; Zhu, Yongxia; Zeng, Jun; Lei, Qian; Pan, Youli; Wei, Yuquan; Zhao, Yinglan; Yu, Luoting

2014-01-01

128

HD047703, a New Promising Anti-Diabetic Drug Candidate: In Vivo Preclinical Studies  

PubMed Central

G-protein coupled receptor 119 (GPR119) has emerged as a novel target for the treatment of type 2 diabetes mellitus. GPR119 is involved in glucose-stimulated insulin secretion (GSIS) from the pancreatic ?-cells and intestinal cells. In this study, we identified a novel small-molecule GPR119 agonist, HD047703, which raises intracellular cAMP concentrations in pancreatic ?-cells and can be expected to potentiate glucose-stimulated insulin secretion from human GPR119 receptor stably expressing cells (CHO cells). We evaluated the acute efficacy of HD047703 by the oral glucose tolerance test (OGTT) in normal C57BL/6J mice. Then, chronic administrations of HD047703 were performed to determine its efficacy in various diabetic rodent models. Single administration of HD047703 caused improved glycemic control during OGTT in a dose-dependent manner in normal mice, and the plasma GLP-1 level was also increased. With respect to chronic efficacy, we observed a decline in blood glucose levels in db/db, ob/ob and DIO mice. These results suggest that HD047703 may be a potentially promising anti-diabetic agent. PMID:25414769

Kim, SoRa; Kim, Dae Hoon; Kim, Young-Seok; Ha, Tae-Young; Yang, Jin; Park, Soo Hyun; Jeong, Kwang Won; Rhee, Jae-Keol

2014-01-01

129

Nanomedicines for cancer therapy: state-of-the-art and limitations to pre-clinical studies that hinder future developments  

NASA Astrophysics Data System (ADS)

The ability to efficiently deliver a drug or gene to a tumor site is dependent on a wide range of factors including circulation time, interactions with the mononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics and tumor accumulation. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokinetics of FDA-approved nanomedicines. Next we review nanomedicines under development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics. We show how the lack of uniformity in preclinical trials prevents systematic comparison and hence limits advances in the field.

Dawidczyk, Charlene; Russell, Luisa; Searson, Peter

2014-08-01

130

Irinotecan delivery by microbubble-assisted ultrasound - A pilot preclinical study  

NASA Astrophysics Data System (ADS)

Irinotecan is conventionally used for the treatment of colorectal cancer. However, its administration is associated with severe side effects. Targeted drug delivery using ultrasound (US) combined with microbubbles offers new opportunities to increase the therapeutic effectiveness of antitumor treatment and to reduce toxic exposure to healthy tissues. The objective of this study is to investigate the safety and efficacy of in-vivo delivery of irinotecan by microbubble-assisted US in human glioblastoma model (U-87 MG). In order to validate the potential of this new method in-vivo, subcutaneous tumors were implanted in the flank of nude mouse and treated when they reached a volume of 100 mm3. In the first study, the measured volumes with caliper and anatomic ultrasound imaging were compared for the monitoring and the quantification of tumor growth during 27 days. Ultrasound imaging measurements were positively correlated to caliper measurements. The tumor treatment consisted of an i.v. injection of irinotecan (20 mg/kg) followed one hour later by i.v. administration of MM1 microbubble and an US insonation using a single-element transducer operating at 1MHz (400 kPa, 10 kHz PRF 40% DC, 3 min). The therapeutic efficacy was evaluated for 39 days by measuring the tumor volume before and after treatment using a caliper and based on ultrasound images using an 18 MHz probe (Vevo 2100). Our results showed that anatomical ultrasound imaging was as efficient as caliper for the monitoring and the quantification of tumor growth. Moreover, irinotecan delivery by sonoporation induced a significant decrease of glioblastoma tumor volume and an increase of tumor-doubling time compared to the tumor treated by irinotecan alone. In conclusion, this novel therapeutic approach has promising features since it can be used to reduce the injected drug dose and to achieve a better therapeutic efficacy.

Escoffre, Jean-Michel; Novell, Anthony; Serrière, Sophie; Bouakaz, Ayache

2012-11-01

131

Trajectories of memory decline in preclinical Alzheimer's disease: results from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing.  

PubMed

Memory changes in preclinical Alzheimer's disease (AD) are often characterized by heterogenous trajectories. However, data regarding the nature and determinants of predominant trajectories of memory changes in preclinical AD are lacking. We analyzed data from 333 cognitively healthy older adults who participated in a multicenter prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments. Latent growth mixture modeling revealed 3 predominant trajectories of memory change: a below average, subtly declining memory trajectory (30.9%); a below average, rapidly declining memory trajectory (3.6%); and an above average, stable memory trajectory (65.5%). Compared with the stable memory trajectory, high ?? (relative risk ratio [RRR] = 2.1), and lower Mini-Mental State Examination (RRR = 0.6) and full-scale IQ (RRR = 0.9) scores were independently associated with the subtly declining memory trajectory; and high ?? (RRR = 8.3), APOE ?4 carriage (RRR = 6.1), and greater subjective memory impairment (RRR = 1.2) were independently associated with the rapidly declining memory trajectory. Compared with the subtly declining memory trajectory group, APOE ?4 carriage (RRR = 8.4), and subjective memory complaints (RRR = 1.2) were associated with a rapidly declining memory trajectory. These results suggest that the preclinical phase of AD may be characterized by 2 predominant trajectories of memory decline that have common (e.g., high ??) and unique (e.g., APOE ?4 genotype) determinants. PMID:25585532

Pietrzak, Robert H; Lim, Yen Ying; Ames, David; Harrington, Karra; Restrepo, Carolina; Martins, Ralph N; Rembach, Alan; Laws, Simon M; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C; Maruff, Paul

2015-03-01

132

Preclinical Toxicology and Biodistribution Studies of Recombinant Adeno-Associated Virus 1 Human Acid ?-Glucosidase  

PubMed Central

Abstract A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid ?-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×1012 vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×105 vg/?g genomic DNA (gDNA), while uninjected sites had up to 1.0×104 vg/?g gDNA. Vector DNA was present in blood at 24?hr postinjection at up to 1.0×106 vg/?g gDNA, followed by a decrease to 1.0×103 vg/?g gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections. PMID:24021025

Erger, Kirsten; Porvasnik, Stacy; Cossette, Travis; Roberts, Cheryl; Combee, Lynn; Islam, Saleem; Kelley, Jeffry; Cloutier, Denise; Clément, Nathalie; Abernathy, Corinne R.; Byrne, Barry J.

2013-01-01

133

Efficacy of enzyme replacement therapy in  -mannosidosis mice: a preclinical animal study  

Microsoft Academic Search

a-Mannosidosis is a lysosomal storage disorder which manifests itself in the excessive storage of mannose- containing oligosaccharides in the lysosomes of multiple peripheral tissues and in the brain. Here we report on the correction of storage in a mouse model of a-mannosidosis after intravenous administration of lyso- somal acid a-mannosidase (LAMAN) from bovine kidney, and human and mouse recombinant LAMAN.

Diego Prieto Roces; Renate Lullmann-Rauch; Jianhe Peng; Chiara Balducci; Claes Andersson; Ole Tollersrud; Jens Fogh; Aldo Orlacchio; Tommaso Beccari; Paul Saftig; Kurt von Figura

2004-01-01

134

Synthesis, characterization and preclinical studies of two-photon-activated targeted PDT therapeutic triads  

NASA Astrophysics Data System (ADS)

Photodynamic therapy (PDT) continues to evolve into a mature clinical treatment of a variety of cancer types as well as age-related macular degeneration of the eye. However, there are still aspects of PDT that need to be improved in order for greater clinical acceptance. While a number of new PDT photo-sensitizers, sometimes referred to as second- or third- generation therapeutic agents, are currently under clinical investigation, the direct treatment through the skin of subcutaneous tumors deeper than 5 mm remains problematic. Currently approved PDT porphyrin photo-sensitizers, as well as several modified porphyrins (e.g. chlorins, bacteriochlorins, etc.) that are under clinical investigation can be activated at 630-730 nm, but none above 800 nm. It would be highly desirable if new PDT paradigms could be developed that would allow photo-activation deep in the tissue transparency window in the Near-infrared (NIR) above 800 nm to reduce scattering and absorption phenomena that reduce deep tissue PDT efficacy. Rasiris and MPA Technologies have developed new porphyrins that have greatly enhanced two-photon absorption ( P A ) cross-sections and can be activated deep in the NIR (ca. 780-850 nm). These porphyrins can be incorporated into a therapeutic triad that also employs an small molecule targeting agent that directs the triad to over-expressed tumor receptor sites, and a NIR onephoton imaging agent that allows tracking the delivery of the triad to the tumor site, as well as clearance of excess triad from healthy tissue prior to the start of PDT treatment. We are currently using these new triads in efficacy studies with a breast cancer cell line that has been transfected with luciferase genes that allow implanted tumor growth and post- PDT treatment efficacy studies in SCID mouse models by following the rise and decay of the bioluminescence signal. We have also designed highly absorbing and scattering collagen breast cancer phantoms in which we have demonstrated dramatic cell kill to a depth of at least 4 cm. We have also demonstrated that at the wavelength and laser fluences used in the treatment of implanted tumors in the mouse mammary fat pads, there is little, if any, damage to the skin or internal mouse organs. In addition, we have also demonstrated that the implanted tumors can be treated to a depth of more than 1 cm by direct radiation through the dorsal side of the mouse.

Spangler, C. W.; Starkey, J. R.; Rebane, A.; Meng, F.; Gong, A.; Drobizhev, M.

2006-02-01

135

Cell-Seeded Tubularized Scaffolds for Reconstruction of Long Urethral Defects: A Preclinical Study  

PubMed Central

Background The treatment options for patients requiring repair of a long segment of the urethra are limited by the availability of autologous tissues. We previously reported that acellular collagen-based tubularized constructs seeded with cells are able to repair small urethral defects in a rabbit model. Objective We explored the feasibility of engineering clinically relevant long urethras for surgical reconstruction in a canine preclinical model. Design, setting, and participants Autologous bladder epithelial and smooth muscle cells from 15 male dogs were grown and seeded onto preconfigured collagen-based tubular matrices (6 cm in length). The perineal urethral segment was removed in 21 male dogs. Urethroplasties were performed with tubularized collagen scaffolds seeded with cells in 15 animals. Tubularized constructs without cells were implanted in six animals. Serial urethrography and three-dimensional computed tomography (CT) scans were performed pre- and postoperatively at 1, 3, 6, and 12 mo. The animals were euthanized at their predetermined time points (three animals at 1 mo, and four at 3, 6, and 12 mo) for analyses. Outcome measurements and statistical analysis Statistical analysis of CT imaging and histology was not needed. Results and limitations CT urethrograms showed wide-caliber urethras without strictures in animals implanted with cell-seeded matrices. The urethral segments replaced with acellular scaffolds collapsed. Gross examination of the urethral implants seeded with cells showed normal-appearing tissue without evidence of fibrosis. Histologically, an epithelial cell layer surrounded by muscle fiber bundles was observed on the cell-seeded constructs, and cellular organization increased over time. The epithelial and smooth muscle phenotypes were confirmed using antibodies to pancytokeratins AE1/AE3 and smooth muscle–specific desmin. Formation of an epithelial cell layer occurred in the unseeded constructs, but few muscle fibers formed. Conclusions Cell-seeded tubularized collagen scaffolds can be used to repair long urethral defects, whereas scaffolds without cells lead to poor tissue development and strictures. This study demonstrates that long tissue-engineered tubularized urethral segments may be used for urethroplasty in patients. PMID:22877501

Orabi, Hazem; AbouShwareb, Tamer; Zhang, Yuanyuan; Yoo, James J.; Atala, Anthony

2012-01-01

136

Systematic Approach to Remediation in Basic Science Knowledge for Preclinical Students: A case study  

NASA Astrophysics Data System (ADS)

Remediation of pre-clerkship students for deficits in basic science knowledge should help them overcome their learning deficiencies prior to clerkship. However, very little is known about remediation in basic science knowledge during pre-clerkship. This study utilized the program theory framework to collect and organize mixed methods data of the remediation plan for pre-clerkship students who failed their basic science cognitive examinations in a Canadian medical school. This plan was analyzed using a logic model narrative approach and compared to literature on the learning theories. The analysis showed a remediation plan that was strong on governance and verification of scores, but lacked: clarity and transparency of communication, qualified remedial tutors, individualized diagnosis of learner's deficits, and student centered learning. Participants admitted uncertainty about the efficacy of the remediation process. A remediation framework is proposed that includes student-centered participation, individualized learning plan and activities, deliberate practice, feedback, reflection, and rigorous reassessment.

Amara, Francis

137

Validation of immunoassay for protein biomarkers: bioanalytical study plan implementation to support pre-clinical and clinical studies.  

PubMed

Biomarkers have emerged as an important tool to optimize the benefit/risk ratio of therapeutics. The scientific impact of biomarker studies is directly related to the quality of the underlying data. It is therefore important that guidance be established for validation of assays used to support drug development. This paper specifically focuses on validation of immunoassay for protein biomarker to support pre-clinical and clinical studies. Therapeutics (small- and macro-molecules) and their respective target/ligand are out of scope. This paper describes the implementation of a bioanalytical study plan for the validation of immunoassays to support decision-making biomarkers and biomarker selection during preclinical and clinical studies. It establishes the complete operating procedure as well as the parameters and their respective acceptance criteria and defines milestones and decision points to be followed during the assay validation that should result in high quality bioanalytical data in a limited timeframe and with reduced costs. The bioanalytical study plan can be applied to the validation of a wild range of immunoassay technology such as monoplex ELISA, automated analyzer, multiplex assays or cutting edge technology. Before any validation, a feasibility study is performed to assess the performance of the immunoassay using biological samples which should mimic the clinical population. The feasibility study addresses the likelihood that an assay will be able to achieve its intended purpose with parallelism being the most critical element (milestone 1). At the end of the feasibility study, a decision is taken to either continue with the validation or change the assay (milestone 2). The milestone 3 consists of the establishment of the nominal value of quality control to be used during the validation. The quality controls used to validate an assay should preferentially be prepared using neat (non-spiked) biological matrix (ideally derived from the specific trial population). The last milestone (milestone 4), the formal validation, includes demonstration of the assay performance meeting accuracy and precision acceptance criteria within (intra-run) and between (inter-run) validation runs for each QC sample. Validation also includes the assessment of stability of the protein biomarker in the biological matrix. It is recognized that the extent of the validation should be correlated to the intended use of the data and the assay acceptance criteria should take into consideration the study objective(s), nature of the methodology and the biological variability of the biomarker. PMID:21530130

Valentin, Marie-Anne; Ma, Shenglin; Zhao, An; Legay, François; Avrameas, Alexandre

2011-07-15

138

Attempted and Successful Compensation in Preclinical and Early Manifest Neurodegeneration – A Review of Task fMRI Studies  

PubMed Central

Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of “attempted” and “successful” compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington’s disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset. PMID:25324786

Scheller, Elisa; Minkova, Lora; Leitner, Mathias; Klöppel, Stefan

2014-01-01

139

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules  

PubMed Central

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302. PMID:22382881

Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F.; Cranmer, Lee D.; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.

2014-01-01

140

Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson’s disease  

Microsoft Academic Search

Four decades after L-dopa introduction to PD therapy, the cause of Parkinson’s disease (PD) remains unknown despite the intensive\\u000a research and the discovery of a number of gene mutations and delections in the pathogenesis of familial PD. Different model\\u000a neurotoxins have been used as preclinical experimental models to study the neurodegenerative process in PD, such as 6-hydroxydopamine\\u000a (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),

Irmgard Paris; Sergio Cardenas; Jorge Lozano; Carolina Perez-Pastene; Rebecca Graumann; Alejandra Riveros; Pablo Caviedes; Juan Segura-Aguilar

2007-01-01

141

Pre-Clinical Studies of Epigenetic Therapies Targeting Histone Modifiers in Lung Cancer  

PubMed Central

Treatment options for lung cancer patients have been generally limited to standard therapies or targeted interventions which involve a small number of known mutations. Although the targeted therapies are initially successful, they most often result in drug resistance, relapse, and mortality. We now know that the complexity of lung cancer comes not only from genomic changes, but also from aberrant epigenetic regulatory events. Epigenetic therapies have shown promise as single agents in the treatment of hematological malignancies but have yet to meet this expectation in solid tumors thus fostering researchers to pursue new approaches in the development and use of epigenetic interventions. Here, we review some recent pre-clinical findings involving the use of drugs targeting histone modifying enzymes both as single agents and as co-therapies against lung cancer. A greater understanding of the impact of these epigenetic compounds in lung cancer signaling is needed and further evaluation in vivo is warranted in several cases based on the pre-clinical activity of a subset of compounds discussed in this review, including drugs co-targeting HDACs and EGF receptor, targeting Brd4 and targeting Jumonji histone demethylases. PMID:24058902

Huffman, Kenneth; Martinez, Elisabeth D.

2013-01-01

142

Evaluation of wound healing activity of Lantana camara L. - a preclinical study.  

PubMed

Lantana camara is used in herbal medicine for the treatment of skin itches, as an antiseptic for wounds, and externally for leprosy and scabies. The objective of our study was to investigate excision wound healing activity of the leaf extract of L. camara in rats. The animals were divided into two groups of 12 each in both the models. The test group animals were treated with the aqueous extract of L. camara (100 mg/kg/day) topically and the control group animals were left untreated. Wound healing efficacy was measured by determining the morphological and biochemical parameters. Wound healing time, wound contraction and synthesis of collagen were monitored periodically. Antimicrobial activities of the extract against the microorganisms were also assessed. Treatment of the wounds with extract enhanced significantly the rate of wound contraction (98%), synthesis of collagen and decreased mean wound healing time. These studies demonstrate that L. camara is effective in healing excision wounds in the experimental animal and could be evaluated as a therapeutic agent in tissue repair processes associated with skin injuries. PMID:18844241

Nayak, B Shivananda; Raju, S Sivachandra; Eversley, Mathew; Ramsubhag, Adash

2009-02-01

143

Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a ?-secretase inhibitor, in a preclinical colorectal explant model  

PubMed Central

Background: Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical ?-secretase inhibitor (GSI) PF-03084014. Methods: A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPj? gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting. Results: We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active ?-catenin. In addition, knockdown of the RBPj? gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours. Conclusion: This study provides evidence that inhibition of ?-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways. PMID:23868008

Arcaroli, J J; Quackenbush, K S; Purkey, A; Powell, R W; Pitts, T M; Bagby, S; Tan, A C; Cross, B; McPhillips, K; Song, E-K; Tai, W M; Winn, R A; Bikkavilli, K; VanScoyk, M; Eckhardt, S G; Messersmith, W A

2013-01-01

144

Preclinical and phase I studies of monoclonal antibodies in melanoma: Application to boron neutron capture therapy of melanoma  

SciTech Connect

Monoclonal antibodies (MAbs) provide an attractive method of selectively localizing sufficient boron atoms around tumour cells to capture neutrons. Assuming that 10(8)-10(10) 10B atoms are needed for one capture event and that 10(3)-10(4) atoms can be coupled to each antibody molecule, then 10(5)-10(6) antibody molecules gathered on an individual cell will destroy that cell. Binding to normal tissues, on the other hand, would need to be at least 20-fold less than that to tumour tissues to avoid toxic effects of neutrons on surrounding tissues. Preclinical studies in animals show that several MAbs may bind to melanoma cells in sufficient quantities in vitro to localize the required amount of boron per cell. Whether this will occur in vivo, however, may depend not only on antigen density but a variety of other properties of the tumour cells and MAbs. These include the Ig class and affinity of the antibody and whether the antibody is internalized into the tumour cell. The ratio of uptake between tumour and normal tissue is governed by such factors as the percentage of tumour cells within a tumour expressing the antigen and whether the MAb react with normal tissues. Use of Fab or F(ab)2 preparations of the MAb may increase the uptake ratio by preventing uptake of MAb by cells with Fc receptors. In contrast to preclinical animal studies, tumour/normal tissue uptake ratios in phase I studies in humans have been disappointingly low.80 references.

Hersey, P. (Mater Misericordiae Hospital, Royal Newcastle Hospital (Australia))

1989-07-01

145

Nanomedicines for cancer therapy: state-of-the-art and limitations to pre-clinical studies that hinder future developments  

PubMed Central

The ability to efficiently deliver a drug or gene to a tumor site is dependent on a wide range of factors including circulation time, interactions with the mononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics, tumor accumulation, and biodistribution. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokinetics of FDA-approved nanomedicines. Next we review nanomedicines under development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics. We show how the lack of uniformity in preclinical trials prevents systematic comparison and hence limits advances in the field. PMID:25202689

Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

2014-01-01

146

The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting ?2-adrenoceptor agonist in preclinical animal species  

PubMed Central

Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled ?2-adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)-6-[[3-[[4-[5-[[2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long-acting ?2-adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS-5759 dose-dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ? 10 ?g/kg. GS-5759 was also a potent bronchodilator with an ED50 of 0.09 ?g/kg in guinea pigs and 3.4 ?g/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS-5759 was dosed as a fine-particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 ?g/kg for bronchodilation and ED50 = 4.9 ?g/kg for inhibition of LPS-induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS-5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS-5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti-inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device. PMID:25505595

Salmon, Michael; Tannheimer, Stacey L; Gentzler, Terry T; Cui, Zhi-Hua; Sorensen, Eric A; Hartsough, Kimberly C; Kim, Musong; Purvis, Lafe J; Barrett, Edward G; McDonald, Jacob D; Rudolph, Karin; Doyle-Eisele, Melanie; Kuehl, Philip J; Royer, Christopher M; Baker, William R; Phillips, Gary B; Wright, Clifford D

2014-01-01

147

The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting ? 2-adrenoceptor agonist in preclinical animal species.  

PubMed

Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled ? 2-adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)-6-[[3-[[4-[5-[[2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long-acting ? 2-adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS-5759 dose-dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ? 10 ?g/kg. GS-5759 was also a potent bronchodilator with an ED50 of 0.09 ?g/kg in guinea pigs and 3.4 ?g/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS-5759 was dosed as a fine-particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 ?g/kg for bronchodilation and ED50 = 4.9 ?g/kg for inhibition of LPS-induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS-5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS-5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti-inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device. PMID:25505595

Salmon, Michael; Tannheimer, Stacey L; Gentzler, Terry T; Cui, Zhi-Hua; Sorensen, Eric A; Hartsough, Kimberly C; Kim, Musong; Purvis, Lafe J; Barrett, Edward G; McDonald, Jacob D; Rudolph, Karin; Doyle-Eisele, Melanie; Kuehl, Philip J; Royer, Christopher M; Baker, William R; Phillips, Gary B; Wright, Clifford D

2014-08-01

148

A novel ibuprofen derivative with anti-lung cancer properties: synthesis, formulation, pharmacokinetic and efficacy studies.  

PubMed

Phospho-non-steroidal anti-inflammatory drugs (phospho-NSAIDs) are a novel class of NSAID derivatives with potent antitumor activity. However, phospho-NSAIDs have limited stability in vivo due to their rapid hydrolysis by carboxylesterases at their carboxylic ester link. Here, we synthesized phospho-ibuprofen amide (PIA), a metabolically stable analog of phospho-ibuprofen, formulated it in nanocarriers, and evaluated its pharmacokinetics and anticancer efficacy in pre-clinical models of human lung cancer. PIA was 10-fold more potent than ibuprofen in suppressing the growth of human non-small-cell lung cancer (NSCLC) cell lines, an effect mediated by favorably altering cytokinetics and inducing oxidative stress. Pharmacokinetic studies in rats revealed that liposome-encapsulated PIA exhibited remarkable resistance to hydrolysis by carboxylesterases, remaining largely intact in the systemic circulation, and demonstrated selective distribution to the lungs. The antitumor activity of liposomal PIA was evaluated in a metastatic model of human NSCLC in mice. Liposomal PIA strongly inhibited lung tumorigenesis (>95%) and was significantly (p<0.05) more efficacious than ibuprofen. We observed a significant induction of urinary 8-iso-prostaglandin F2?in vivo, which indicates that ROS stress probably plays an important role in mediating the antitumor efficacy of PIA. Our findings suggest that liposomal PIA is a potent agent in the treatment of lung cancer and merits further evaluation. PMID:25311177

Cheng, Ka-Wing; Nie, Ting; Ouyang, Nengtai; Alston, Ninche; Wong, Chi C; Mattheolabakis, George; Papayannis, Ioannis; Huang, Liqun; Rigas, Basil

2014-12-30

149

Employing a Gain-of-Function Factor IX Variant R338L to Advance the Efficacy and Safety of Hemophilia B Human Gene Therapy: Preclinical Evaluation Supporting an Ongoing Adeno-Associated Virus Clinical Trial  

PubMed Central

Abstract Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (<10%) empty capsid and have performed comprehensive dose–response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2–500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (n=20) and hemophilic mice (n=88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8+ T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (n=60 animals). With respect to the role of empty capsids, we demonstrated that in vivo FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX–/– mice 8–10 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma FIX activity, 100–500%). These preclinical studies demonstrate a safety:efficacy profile supporting an ongoing phase 1/2 human clinical trial of the scAAV8.FIXR338L vector (designated BAX335). PMID:25419787

Sun, Junjiang; Gui, Tong; Hu, Genlin; Hannah, William B.; Wichlan, David G.; Wu, Zhijian; Grieger, Joshua C.; Li, Chengwen; Suwanmanee, Thipparat; Stafford, Darrel W.; Booth, Carmen J.; Samulski, Jade J.; Kafri, Tal; McPhee, Scott W.J.

2015-01-01

150

Therapeutic Vaccination in Chronic Hepatitis B: Preclinical Studies in the Woodchuck  

PubMed Central

Recommended treatment of chronic hepatitis B with interferon-? and/or nucleos(t)ide analogues does not lead to a satisfactory result. Induction of HBV-specific T cells by therapeutic vaccination or immunotherapies may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients did not result in effective control of HBV infection, suggesting that new formulations of therapeutic vaccines are needed. The woodchuck (Marmota monax) is a useful preclinical model for developing the new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments with nucleos(t)ide analogues, DNA vaccines, and protein vaccines were tested in the woodchuck model. In this paper we summarize the available data concerning therapeutic immunization and gene therapy using recombinant viral vectors approaches in woodchucks, which show encouraging results. In addition, we present potential innovations in immunomodulatory strategies to be evaluated in this animal model. PMID:21188201

Kosinska, Anna D.; Zhang, Ejuan; Lu, Mengji; Roggendorf, Michael

2010-01-01

151

Retrospect and Prospect of Studies of Teacher Efficacy in China  

ERIC Educational Resources Information Center

Teacher efficacy is a powerful variable in educational and psychological studies. And it aroused much attention and interest from Chinese scholars in the past decade, which led to an accumulation of documents in this field. Following an introduction of efficacy studies in the west, the article reviews the brief history of those in China,…

He, Ning; Miao, Danmin

2006-01-01

152

Exact power and sample size for vaccine efficacy studies  

Microsoft Academic Search

In vaccine efficacy studies the goal is to show that the vaccine reduces the incidence of the disease compared to placebo. In this report we describe two procedures for calculating sample size and powei based on exact distributions In small studies where the disease incidence and the anticipated vaccine efficacy are both high, an unconditional exact procedure is desirable because

Ivan S. F. Chan; Norman R. Bohidar

1998-01-01

153

The Relationship between Lesson Study and Self-Efficacy  

ERIC Educational Resources Information Center

This article addresses a gap in the literature by developing a theory that bridges lesson study and self-efficacy. Since self-efficacy has been linked to student achievement, the theory is important as an explanatory mechanism linking lesson study to student achievement. The theory was developed using grounded theory based on primary source data…

Sibbald, Tim

2009-01-01

154

Quantitative determination of zolmitriptan in rat blood and cerebrospinal fluid by reversed phase HPLC-ESI-MS/MS analysis: application to in vivo preclinical pharmacokinetic study.  

PubMed

A fast HPLC-ESI-MS/MS method has been developed and validated for the quantification of the potent and selective antimigraine zolmitriptan in rat blood and cerebrospinal fluid (CSF). The assay has been then applied for in vivo preclinical studies. The analytical determination has been used to obtain pharmacokinetics of zolmitriptan in the two biological matrices after its intravenous or nasal administration. Liquid-liquid extraction of zolmitriptan was performed from 100 ?L rat blood samples in the presence of N(6)-cyclopentyladenosine (internal standard) with the employment of ethyl acetate. Calibration standards were prepared by using blood matrix and following the same liquid-liquid extraction procedure. CSF samples were analyzed without any pre-treatment steps and by using an external calibration method in pure water matrix. Chromatographic separation was performed under reversed phase and a gradient elution condition on a C18 packed column (100 × 2.0 mm, 2.5 ?m particles diameter). The mobile phase was a mixture between acetonitrile, water and formic acid (0.1% v/v). The applied HPLC-MS/MS method allowed low limits of detection, as calculated from calibration curves, of 6.6 and 24.4 ng/mL for water matrix and rat blood extracts, respectively. Linearity of the calibration curves was established up to 5 ?M (1.44 ?g/mL), as well as good assay accuracy. The intravenous infusion of 20 ?g zolmitriptan to male Sprague-Dawley rats produced blood concentrations ranging from 9.4±0.7 to 1.24±0.07 ?g/mL within 10 h, with a terminal half-life of 3.4±0.2h. The nasal administration of a water suspension of 20 ?g zolmitriptan produced blood concentrations ranging from 2.92±0.21 to 0.85±0.07 ?g/mL within 6h. One hour after zolmitriptan intravenous infusion or nasal administration, its CSF concentrations were 0.0539±0.0016 and 0.0453±0.0012 ?g/mL, respectively. This study determined the suitability of the herein proposed method to investigate the pharmacokinetics of zolmitriptan after its administration by means of novel formulations and, hence, to evaluate the efficacy of innovative nose-to-brain drug delivery in preclinical studies. PMID:22743338

Dalpiaz, Alessandro; Marchetti, Nicola; Cavazzini, Alberto; Pasti, Luisa; Velaga, Sitaram; Gavini, Elisabetta; Beggiato, Sarah; Ferraro, Luca

2012-07-15

155

A gender study investigating physics self-efficacy  

NASA Astrophysics Data System (ADS)

The underrepresentation of women in physics has been well documented and a source of concern for both policy makers and educators. My dissertation focuses on understanding the role self-efficacy plays in retaining students, particularly women, in introductory physics. I use an explanatory mixed methods approach to first investigate quantitatively the influence of self-efficacy in predicting success and then to qualitatively explore the development of self-efficacy. In the initial quantitative studies, I explore the utility of self-efficacy in predicting the success of introductory physics students, both women and men. Results indicate that self-efficacy is a significant predictor of success for all students. I then disaggregate the data to examine how self-efficacy develops differently for women and men in the introductory physics course. Results show women rely on different sources of self-efficacy than do men, and that a particular instructional environment, Modeling Instruction, has a positive impact on these sources of self-efficacy. In the qualitative phase of the project, this dissertation focuses on the development of self-efficacy. Using the qualitative tool of microanalysis, I introduce a methodology for understanding how self-efficacy develops moment-by-moment using the lens of self-efficacy opportunities. I then use the characterizations of self-efficacy opportunities to focus on a particular course environment and to identify and describe a mechanism by which Modeling Instruction impacts student self-efficacy. Results indicate that the emphasizing the development and deployment of models affords opportunities to impact self-efficacy. The findings of this dissertation indicate that introducing key elements into the classroom, such as cooperative group work, model development and deployment, and interaction with the instructor, create a mechanism by which instructors can impact the self-efficacy of their students. Results from this study indicate that creating a model to impact the retention rates of women in physics should include attending to self-efficacy and designing activities in the classroom that create self-efficacy opportunities.

Sawtelle, Vashti

156

Preclinical overview of brinzolamide.  

PubMed

The development of topically active carbonic anhydrase inhibitors (CAIs) is a significant recent achievement in glaucoma medical treatment. Brinzolamide, the newest topical CAI, exhibits selectivity, high affinity, and potent inhibitory activity for the carbonic anhydrase type II isozyme (CA-II), which is involved in aqueous humor secretion. These characteristics, along with good ocular bioavailability, make brinzolamide maximally effective in lowering intraocular pressure (IOP) by locally inhibiting CA-II in the ciliary processes and suppressing aqueous humor secretion. Notable among its attributes as a safe and efficacious glaucoma drug is brinzolamide's superior ocular comfort profile because of its optimized suspension formulation at physiologic pH. The degree of tolerability in the eye is considered an important determinant of a patient's willingness to comply with the dosing regimen for a long-term glaucoma medication. Results from the preclinical pharmacologic evaluation of brinzolamide indicated that it acts specifically to inhibit CA without significant other pharmacologic actions that could introduce undesired side effects. Moreover, the typical side effects associated with systemically administered CAIs are expected to occur at a lower incidence or not occur at all with brinzolamide, as its therapeutic dose and low systemic absorption do not produce a problematic level of systemic CA inhibition. Brinzolamide's long tissue half-life in the eye, particularly in the iris-ciliary body, favors a prolonged duration of IOP lowering. This was substantiated in clinical trials, which showed that twice-daily brinzolamide provides as significant an IOP reduction as three-times-daily brinzolamide or dorzolamide in a relatively high percentage of patients. Brinzolamide has been shown by the laser Doppler flowmetry technique to improve blood flow to the optic nerve head in pigmented rabbits after topical administration, without producing an increase of blood pCO2, indicating a potential for a local vasodilatory effect involving the optic nerve head circulation. The mean concentration of brinzolamide found in the retina of pigmented rabbits (0.338 microg equivalents/g) after a single dose of 14C-brinzolamide is sufficient to inhibit CA-II. These data suggest that topical brinzolamide could improve the blood flow in the optic nerve head in humans should it inhibit carbonic anhydrase in that vascular bed. Brinzolamide is a new topically active CAI that is safe and efficacious for reducing intraocular pressure. It offers the convenience of topical dose administration and greater freedom from side effects related to the inhibition of CA seen with the systemic administration of CAIs. Its formulation has been optimized to provide greater comfort upon instillation, and this can result in a higher compliance rate by the patient. Results of studies in animals show that brinzolamide has promise for increasing blood flow to the optic nerve head; however, this requires further assessment in the clinic. Brinzolamide represents a significant technical achievement and an important addition to the medical treatment of glaucoma as both a primary and an adjunctive drug. PMID:10665514

DeSantis, L

2000-01-01

157

High Efficacy and the Preservice Reading Teacher: A Comparative Study  

ERIC Educational Resources Information Center

The purpose of this study was to investigate the differential impact of two field experiences, tutoring and observing, on preservice teachers' reading self-efficacy and content knowledge. Participants completed an adapted, reading version of The Teacher Sense of Efficacy Scale (TSES). Results showed that both groups reported growth in reading…

Haverback, Heather Rogers; Parault, Susan J.

2011-01-01

158

A 2?×?2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning: efficacy in a preclinical trial in murine thromboembolic stroke model  

PubMed Central

Background After the failure of so many drugs and therapies for acute ischemic stroke, innovative approaches are needed to develop new treatments. One promising strategy is to test combinations of agents in the pre-hospital setting prior to the administration of intravenous tissue plasminogen activator (IV-tPA) and/ or the use of mechanical reperfusion devices in the hospital. Methods We performed a 2?×?2 factorial design preclinical trial where we tested minocycline (MINO), remote ischemic perconditioning (RIPerC) and their combination treatment in a thromboembolic clot model of stroke in mice, without IV-tPA or later treated with IV-tPA at 4 hours post-stroke. Cerebral blood flow (CBF) was measured by laser speckle contrast imaging (LSCI), behavioral outcomes as neurological deficit score (NDS) and adhesive tape removal test, and infarct size measurement were performed at 48 hours post-stroke. Mice within the experimental sets were randomized for the different treatments, and all outcome measures were blinded. Results RIPerC significantly improved CBF as measured by LSCI in both with and without tPA treated mice (P?pre-clinical 2 × 2 design can be easily translated into a pre-hospital clinical trial. PMID:25337387

2014-01-01

159

Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy of the prostate: a preclinical study with radiological and pathological correlation using customised MRI-based moulds  

PubMed Central

Objective To characterise the feasibility and safety of a novel transurethral ultrasound (US)-therapy device combined with real-time multi-plane magnetic resonance imaging (MRI)-based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model. To correlate ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. Materials and methods Three dogs were treated with three targeted ablations each, using a prototype MRI-guided transurethral US-therapy system (Philips Healthcare, Vantaa, Finland). MRI provided images for treatment planning, guidance, real-time multi-planar thermometry, as well as post-treatment evaluation of efficacy. After treatment, specimens underwent histopathological analysis to determine the extent of necrosis and cell viability. Statistical analyses (Pearson’s correlation, Student’s t-test) were used to evaluate the correlation between ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. Results MRI combined with a transurethral US-therapy device enabled multi-planar temperature monitoring at the target as well as in surrounding tissues, allowing for safe, targeted, and controlled ablations of prescribed lesions. Ablated volumes measured by cumulative thermal dose positively correlated with volumes determined by histopathological analysis (r2 0.83, P < 0.001). Post-procedural contrast-enhanced and diffusion-weighted MRI showed a positive correlation with non-viable areas on histopathological analysis (r2 0.89, P < 0.001, and r20.91, P = 0.003, respectively). Additionally, there was a positive correlation between ablated volumes according to cumulative thermal dose and volumes identified on post-procedural contrast-enhanced MRI (r2 0.77, P < 0.01). There was no difference in mean ablation volumes assessed with the various analysis methods (P > 0.05, Student’s t-test). Conclusions MRI-guided transurethral US therapy enabled safe and targeted ablations of prescribed lesions in a preclinical canine prostate model. Ablation volumes were reliably predicted by intra- and post-procedural imaging. Clinical studies are needed to confirm the feasibility, safety, oncological control, and functional outcomes of this therapy in patients in whom focal therapy is indicated. PMID:23746198

Partanen, Ari; Yerram, Nitin K.; Trivedi, Hari; Dreher, Matthew R.; Oila, Juha; Hoang, Anthony N.; Volkin, Dmitry; Nix, Jeffrey; Turkbey, Baris; Bernardo, Marcelino; Haines, Diana C.; Benjamin, Compton J.; Linehan, W. Marston; Choyke, Peter; Wood, Bradford J.; Ehnholm, Gösta J.; Venkatesan, Aradhana M.; Pinto, Peter A.

2013-01-01

160

MANGA STUDY COMPARATIVE EFFICACY AND ACCEPTABILITY  

E-print Network

Evidence-based Practice Centre and the Agency for Healthcare Research and Quality (AHRQ) summarized Health, 2004).. Current clinical practice guidelines on the treatment of depressive disorder recommend the available evidence on the comparative efficacy, effectiveness, and harms of 12 second

Romeo, Alessandro

161

Taking Journal Clubs off Autopilot: A Case Study of Teaching Literature Evaluation Skills to Preclinical MD/PhD Students  

PubMed Central

Researchers designed learner-directed journal clubs to develop literature evaluation skills in preclinical students. Sessions balanced student-led discussion with structured objectives and faculty support. During the pilot with preclinical MD/PhD students, self-rated mastery improved over all 17 measured objectives. Six exercises have since been incorporated into the full medical school curriculum. PMID:24634798

Currier, Rebecca L.; Schneider, Marguerite Reid; Heubi, James E.

2014-01-01

162

The Optimal Partnership of Radiation and Immunotherapy: from Preclinical Studies to Clinical Translation  

PubMed Central

The main role of the immune system is to restore tissue homeostasis when altered by pathogenic processes, including neoplastic transformation. Immune-mediated tumor rejection has been recognized as an extrinsic tumor suppressor mechanism that tumors need to overcome to progress. By the time a tumor becomes clinically apparent it has successfully escaped immune control by establishing an immunosuppressive microenvironment. Ionizing radiation applied locally to a tumor alters these tumor-host interactions. Accumulating evidence indicates that standard therapeutic doses of radiation have the potential to recover tumor immunogenicity and convert the tumor into an in situ personalized vaccine. Radiotherapy induces an immunogenic tumor cell death promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. In addition, radiotherapy stimulates chemokine-mediated recruitment of effector T cells to the tumor, and cellular recognition and killing by T cells that is facilitated by upregulation of major histocompatibility antigens, NKG2D ligands, adhesion molecules and death receptors. Despite these effects, radiotherapy alone is only rarely capable of generating enough proinflammatory signals to sufficiently overcome suppression, as it can also activate immunosuppressive factors. However, our group and others have shown that when combined with targeted immunotherapy agents radiotherapy significantly contributes to a therapeutically effective anti-tumor immune response. To illustrate this partnership between radiation and immunotherapy we will discuss as an example our experience in preclinical models and the molecular mechanisms identified. Additionally, the clinical translation of these combinations will be discussed. PMID:24937779

Demaria, Sandra; Pilones, Karsten A.; Vanpouille-Box, Claire; Golden, Encouse B.; Formenti, Silvia C.

2014-01-01

163

Efficient vitreolysis by combining plasmin and sulfur hexafluoride injection in a preclinical study in rabbit eyes  

PubMed Central

Purpose To investigate the efficacy of plasmin and sulfur hexafluoride (SF6) on the vitreoretinal junction, as well as the long-term safety in the eye and effect on the recipient’s general health after application in the eye. Methods The study design included four groups of rabbits with three animals in each group. Group 1 received an intravitreal injection (IVI) of plasmin and SF6 in the right eye; group 2 received an IVI of plasmin in the right eye; group 3 received an IVI of SF6 in the right eye; and group 4 received an IVI of balanced salt solution in the right eye, which served as a normal control. Long-term safety (up to approximately three months) after plasmin and/or SF6 injection was evaluated morphologically by clinical examination, histology, and immunohistochemistry, and functionally by electroretinograms (ERGs). General health evaluations after intravitreal injection included the assessment of weight gain, food intake, body temperature, and complete blood count analysis. Results Plasmin plus SF6 injection resulted in complete posterior vitreous detachment (PVD), whereas plasmin or SF6 injection alone resulted in only partial PVD. Balanced salt solution did not induce PVD. Eighty days after intravitreal injection, there were no major differences among the eyes of the three groups of animals compared with the normal control animals upon clinical evaluation, or regarding retinal morphology and ERGs. The lenses examined remained clear for up to 80 days following the intravitreal injection of plasmin plus SF6, except one eye in the plasmin-treated group. ERGs decreased transiently one week after intravitreal injection in groups 1 through 3, but animals recovered fully to normal status afterward. General health was not affected after the injection of plasmin plus SF6. Conclusions Efficient vitreoretinal separation could be achieved, and an acceptable long-term safety profile was noted after plasmin plus SF6 injection in the eye. No major ocular toxicity or systemic toxicity was found after the injection of plasmin plus SF6. These results provide good support for the future clinical use of plasmin plus SF6 for treatment of a variety of vitreoretinopathies. PMID:23049236

Wu, Wei-Chi; Liu, Chi-Hsien; Chen, Chih-Chun; Wang, Nan-Kai; Chen, Kwan-Jen; Chen, Tun-Lu; Hwang, Yih-Shiou; Li, Lien-Min

2012-01-01

164

Preclinical studies of a new quinolone (UB-8902) against Acinetobacter baumannii resistant to ciprofloxacin  

Microsoft Academic Search

The in vitro activity and in vivo efficacy of a new ciprofloxacin derivative (UB-8902) were evaluated. In vitro time–kill curves were performed for ciprofloxacin (CIP), moxifloxacin (MXF) and UB-8902 against CIP-susceptible (Ab58) and CIP-resistant (Ab661 and Ab33) Acinetobacter baumannii strains. UB-8902 showed similar bactericidal activity to CIP and MXF against these strains. In the in vivo experiments in mice, the

R. López-Rojas; J. Sánchez-Céspedes; F. Docobo-Pérez; J. Domínguez-Herrera; J. Vila; J. Pachón

2011-01-01

165

NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics  

PubMed Central

In May of 2014, the NIH Director together with the Director of the Office of Research on Women’s Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner.

2014-01-01

166

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement  

PubMed Central

Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca2+ mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu5 allosteric binding site and high selectivity for mGlu5. VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel mGlu5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia. PMID:23965381

Gregory, K.J.; Herman, E.J.; Ramsey, A.J.; Hammond, A.S.; Byun, N.E.; Stauffer, S.R.; Manka, J.T.; Jadhav, S.; Bridges, T.M.; Weaver, C.D.; Niswender, C.M.; Steckler, T.; Drinkenburg, W.H.; Ahnaou, A.; Lavreysen, H.; Macdonald, G.J.; Bartolomé, J.M.; Mackie, C.; Hrupka, B.J.; Caron, M.G.; Daigle, T.L.; Lindsley, C.W.; Conn, P.J.

2013-01-01

167

Assessment of blood substitutes: II. In-vitro complement activation of human plasma and blood for safety studies in research, development, industrial production and preclinical analysis.  

PubMed

Animal safety study cannot predict the effects of blood substitutes in human response. Response of human, especially in immunology and complement activation, need not be the same as those in animals. We have earlier reported an in-vitro preclinical screening test based on testing the effects of modified hemoglobin on complement activation of human plasma or blood in vitro. In this test, modified hemoglobin is added to human plasma in a test tube. Complement activation is followed by the C3a levels. Since this directly measures the effect of modified hemoglobin on human plasma, it would be the closest response in human next to injecting this into human. Thus, this could be an important bridge before clinical use in patients. However, why wait for the completion of research, industrial production and preclinical animal studies? Why don't we do this test right at the beginning during the research stage? If a new system is found to cause complement activation at this stage, one can avoid tremendous waste of time and money in further development, industrial production and preclinical animal study. This paper analyzes this approach in research, development, industrial production and preclinical analysis. PMID:8087240

Chang, T M; Lister, C W

1994-01-01

168

Allopregnanolone Promotes Regeneration and Reduces b-Amyloid Burden in a Preclinical Model of Alzheimer's  

E-print Network

Allopregnanolone Promotes Regeneration and Reduces b-Amyloid Burden in a Preclinical Model provide preclinical evidence for the optimal treatment regimen of APa to achieve efficacy as a disease Promotes Regeneration and Reduces b-Amyloid Burden in a Preclinical Model of Alzheimer's Disease. PLoS ONE

Brinton, Roberta Diaz

169

Preclinical study of using multiphoton microscopy to diagnose liver cancer and differentiate benign and malignant liver lesions  

NASA Astrophysics Data System (ADS)

Recently, the miniaturized multiphoton microscopy (MPM) and multiphoton probe allow the clinical use of multiphoton endoscopy for diagnosing cancer via ``optical biopsy''. The purpose of this study was to establish MPM optical diagnostic features for liver cancer and evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis. Firstly, we performed a pilot study to establish the MPM diagnostic features by investigating 60 surgical specimens, and found that high-resolution MPM images clearly demonstrated apparent differences between benign and malignant liver lesions in terms of their tissue architecture and cell morphology. Cancer cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, were identified by MPM images, which were comparable to hematoxylin-eosin staining images. Secondly, we performed a blinded study to evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis by investigating another 164 specimens, and found that the sensitivity, specificity, and accuracy of MPM diagnosis was 96.32%, 96.43%, and 96.34%, respectively. In conclusion, it is feasible to use MPM to diagnose liver cancer and differentiate benign and malignant liver lesions. This preclinical study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive ``optical biopsy'' for liver lesions in the near future.

Yan, Jun; Zhuo, Shuangmu; Chen, Gang; Wu, Xiufeng; Zhou, Dong; Xie, Shusen; Jiang, Jiahao; Ying, Mingang; Jia, Fan; Chen, Jianxin; Zhou, Jian

2012-02-01

170

The contribution of regional gray/white matter volume in preclinical depression assessed by the Automatic Thoughts Questionnaire: a voxel-based morphometry study.  

PubMed

Negative automatic thought is a characteristic of depression that contributes toward the risk for episodes of depression. Evidence suggests that gray and white matter abnormalities are linked with depression, but little is known about the association between the negative cognitive experience and brain structure in preclinical depression. We examined the correlation between negative thought and gray (GMV)/white matter volume (WMV) in healthy individuals with preclinical depression. The participants were 309 university students with preclinical depression, as measured by their Automatic Thoughts Questionnaire (ATQ) scores. We collected brain MRIs and used voxel-based morphometry to analyze the correlation of regional GMV/WMV with the ATQ scores. The voxel-based morphometry results showed that the GMV of the right parahippocampal gyrus and fusiform gyrus and the WMV of the right superior temporal pole increased with the severity of depression. Furthermore, the corpus callosum volume decreased with the ATQ scores. This study implied that GMV increase and corpus callosum volume reduction may be associated with negative thought in nonclinical individuals, even at a preclinical depressed level. PMID:24999908

Cun, Lingli; Wang, Yanqiu; Zhang, Songyan; Wei, Dongtao; Qiu, Jiang

2014-09-10

171

Hyaluronic-acid butyric esters as promising antineoplastic agents in human lung carcinoma: a preclinical study.  

PubMed

New promising compounds, derived from the esterification of hyaluronic acid with butyric acid, were investigated in vitro on a non-small cell lung carcinoma cell line (NCI-H460) and an its metastatic subclone (NCI-H460M). All new compounds exerted a dose-dependent inhibitory effect on both cell lines, which expressed CD44, the specific surface receptor for hyaluronic acid, in a very high percentage of cells (90%). HE1, the most effective of these compounds, was 10-fold more effective than sodium butyrate (NaB) in inhibiting cell proliferation. Similarly to NaB, after 24 hours of treatment, HE1 affected the expression of three cell cycle-related proteins (p27(kip1), p53 and p21(waf1)) responsible for growth arrest, indicating that the presence of the hyaluronic acid backbone does not interfere with the biologic activity. Intratumoral treatment with HE1 demonstrated a marked efficacy on primary tumor growth and on lung metastases formation of the murine Lewis Lung Carcinoma model. Altogether, present findings suggest a possible clinical application of these novel butyric pro-drugs in primary and metastatic lung cancer. PMID:15122068

Coradini, Danila; Pellizzaro, Cinzia; Abolafio, Gabriella; Bosco, Marco; Scarlata, Ignazio; Cantoni, Silvia; Stucchi, Luca; Zorzet, Sonia; Turrin, Claudia; Sava, Gianni; Perbellini, Alberto; Daidone, Maria Grazia

2004-08-01

172

Photodynamic therapy with the phthalocyanine photosensitizer Pc 4: The case experience with preclinical mechanistic and early clinical-translational studies  

SciTech Connect

Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.

Miller, Janine D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Baron, Elma D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Louis-Stokes VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106 (United States); Scull, Heather [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Hsia, Andrew [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Berlin, Jeffrey C. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Department of Chemistry, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States)] (and others)

2007-11-01

173

Minnelide reduces tumor burden in preclinical models of osteosarcoma  

PubMed Central

Osteosarcoma is the most common bone cancer in children and adolescents with a five-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets NF-?B pathway. PMID:23499892

Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N.; Saluja, Ashok K.; Subramanian, Subbaya

2015-01-01

174

[Preclinical study of AV0012 early stage inhibitor of hepatitis C virus infection: I. In vitro ADME and pharmacokinetics].  

PubMed

In vitro immunohistochemical investigations on the human hepatoma cell line (Huh7) infected with hepatitis C virus (HCV) strain JFH-1 showed that AV0012 compound blocks the early stages of viral infection. AV0012 also blocked viral infection spread in tissue culture through the secreted virus and through tight cell-to-cell contact. AV0012 is a specific inhibitor of HCV but not of related pestivirus, flaviviruses and other RNA-containing viruses such as bovine diarrhea (BVDV), Venezuelan equine encephalitis (strain TC-83), dengue type 2 (New Guinea), yellow fever (strain 17D), west Nile fever, parainfluenza (type 3) virus, RSV (strain A2), and Rhinovirus (type 2 strain HGP). It is established that human serum does not significantly affect the antiviral activity of AV0012 in vitro. The drug combination studies with AV0012 and interferon alpha 2a in vitro showed that the two inhibitors act additively, which makes possible the use of this combination in clinical tests. AV0012 is highly soluble and stable in aqueous solutions and murine blood plasma, has limited metabolic stability, low binding to human plasma proteins, high permeability through biological membranes, and only interacts with isoenzymes 2D6 and 3A4 of human cytochrome P450. In animal pharmacokinetic studies, AV0012 was rapidly absorbed into the blood stream upon oral administration, showed sufficiently long half-elimination times, and had high oral bioavailability that reached 92% in monkeys. Further preclinical development of AV0012 is in progress. PMID:25076758

Ivashchenko, A V; Iamanushkin, P M; Mit'kin, O D; Ezhova, E V; Korzinov, O M; Shevkun, N A; Koriakova, A G; Karapetian, R N; Bychko, V V; Ivashchenko, A A; Agrba, V Z; Lapin, B A; Orlov, S V

2014-01-01

175

Common Handling Procedures Conducted in Preclinical Safety Studies Result in Minimal Hepatic Gene Expression Changes in Sprague-Dawley Rats  

PubMed Central

Gene expression profiling is a tool to gain mechanistic understanding of adverse effects in response to compound exposure. However, little is known about how the common handling procedures of experimental animals during a preclinical study alter baseline gene expression. We report gene expression changes in the livers of female Sprague-Dawley rats following common handling procedures. Baseline gene expression changes identified in this study provide insight on how these changes may affect interpretation of gene expression profiles following compound exposure. Rats were divided into three groups. One group was not subjected to handling procedures and served as controls for both handled groups. Animals in the other two groups were weighed, subjected to restraint in Broome restrainers, and administered water via oral gavage daily for 1 or 4 days with tail vein blood collections at 1, 2, 4, and 8 hours postdose on days 1 and 4. Significantly altered genes were identified in livers of animals following 1 or 4 days of handling when compared to the unhandled animals. Gene changes in animals handled for 4 days were similar to those handled for 1 day, suggesting a lack of habituation. The altered genes were primarily immune function related genes. These findings, along with a correlating increase in corticosterone levels suggest that common handling procedures may cause a minor immune system perturbance. PMID:24551150

Werner, Jon; Everds, Nancy; Di Palma, Chris; Chen, Yuan; Higgins-Garn, Marnie; Tran, Sandra; Afshari, Cynthia A.; Hamadeh, Hisham K.

2014-01-01

176

Pre-clinical toxicokinetics and safety study of M2ES, a PEGylated recombinant human endostatin, in rhesus monkeys.  

PubMed

PEGylated recombinant human endostatin (M2ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A non-clinical study was performed to evaluate the toxicokinetics and safety of M2ES in rhesus monkeys. After intravenous (IV) infusions of M2ES at a dose level of 3, 10, and 30mg/kg in rhesus monkeys, the concentration-time curves of M2ES were best fitted to a non-compartment model, and area under the curve (AUC) was positively correlated with the dosage. M2ES had a tendency to accumulate in vivo following successive IV infusions. Serum anti-M2ES IgG antibodies were generated quickly during IV administration, and the antibody level in serum did not significantly decrease after four-week recovery period. Animals administered IV infusions twice weekly (M2ES at 10 or 30mg/kg body weight per day) for 3months developed mild or moderate vacuolation of proximal tubule epithelial cell in proximal convoluted tubule of kidney, but this adverse-effect was reversible. In summary, M2ES was well tolerated and did not cause any serious toxicity. These pre-clinical safety data contribute to the initiation of the ongoing clinical study. PMID:24878240

Guo, Lifang; Geng, Xingchao; Chen, Yang; Qi, Feifei; Liu, Li; Miao, Yufa; Lin, Zhi; Yu, Min; Li, Zuogang; Fu, Yan; Li, Bo; Luo, Yongzhang

2014-08-01

177

Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma  

PubMed Central

Ewing sarcoma is characterized by multiple deregulated pathways that mediate cell survival and proliferation. Heat shock protein 90 (HSP90) is a critical component of the multi-chaperone complexes that regulate the disposition and activity of a large number of proteins involved in cell-signaling systems. We tested the efficacy of PU-H71, a novel HSP90 inhibitor in Ewing sarcoma cell lines, primary samples, benign mesenchymal stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis and reverse phase protein array in Ewing cell lines and in vivo experiments in NSG and nude mice using the A673 cell line. We noted a significant therapeutic window in the activity of PU-H71 against Ewing cell lines and benign cells. PU-H71 treatment resulted in G2/M phase arrest. Exposure to PU-H71 resulted in depletion of critical proteins including AKT, pERK, RAF-1, c-MYC, c-KIT, IGF1R, hTERT and EWS-FLI1 in Ewing cell lines. Our results indicated that Ewing sarcoma tumor growth and the metastatic burden were significantly reduced in the mice injected with PU-H71 compared to the control mice. We also investigated the effects of bortezomib, a proteasome inhibitor, alone and in combination with PU-H71 in Ewing sarcoma. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. Ewing sarcoma xenografts were significantly inhibited when mice were treated with the combination compared to vehicle or either drug alone. This provides a strong rationale for clinical evaluation of PU-H71 alone and in combination with bortezomib in Ewing sarcoma. PMID:24388362

Ambati, Srikanth R.; Lopes, Eloisi Caldas; Kosugi, Kohji; Mony, Ullas; Zehir, Ahmet; Shah, Smit K.; Taldone, Tony; Moreira, Andre L.; Meyers, Paul A.; Chiosis, Gabriela; Moore, Malcolm A.S.

2014-01-01

178

Biomarkers in preclinical cancer imaging.  

PubMed

In view of the trend towards personalized treatment strategies for (cancer) patients, there is an increasing need to noninvasively determine individual patient characteristics. Such information enables physicians to administer to patients accurate therapy with appropriate timing. For the noninvasive visualization of disease-related features, imaging biomarkers are expected to play a crucial role. Next to the chemical development of imaging probes, this requires preclinical studies in animal tumour models. These studies provide proof-of-concept of imaging biomarkers and help determine the pharmacokinetics and target specificity of relevant imaging probes, features that provide the fundamentals for translation to the clinic. In this review we describe biological processes derived from the "hallmarks of cancer" that may serve as imaging biomarkers for diagnostic, prognostic and treatment response monitoring that are currently being studied in the preclinical setting. A number of these biomarkers are also being used for the initial preclinical assessment of new intervention strategies. Uniquely, noninvasive imaging approaches allow longitudinal assessment of changes in biological processes, providing information on the safety, pharmacokinetic profiles and target specificity of new drugs, and on the antitumour effectiveness of therapeutic interventions. Preclinical biomarker imaging can help guide translation to optimize clinical biomarker imaging and personalize (combination) therapies. PMID:25673052

Bernsen, Monique R; Kooiman, Klazina; Segbers, Marcel; van Leeuwen, Fijs W B; de Jong, Marion

2015-04-01

179

Self-Efficacy Perceptions of Social Studies Candidate Teachers  

ERIC Educational Resources Information Center

The aim of this study was to determine the self efficacy beliefs of pre-service social studies teachers. For this purpose, the scales developed in various areas were examined, the opinions of experts were taken and a final scale was created to be used for this study. The validity and reliability of the scale were checked. The validity coefficient…

Simsek, Nihat

2011-01-01

180

Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies  

PubMed Central

Kidney toxicity accounts for a significant percentage of morbidity and drug candidate failure. Serum creatinine (SCr) and blood urea nitrogen (BUN) have been used to monitor kidney dysfunction for over a century but these markers are insensitive and non-specific. In multi-site preclinical rat toxicology studies the diagnostic performance of urinary kidney injury molecule-1 (Kim-1) was compared to traditional biomarkers as predictors of kidney tubular histopathologic changes, currently considered the “gold standard” of nephrotoxicity. In multiple models of kidney injury, urinary Kim-1 significantly outperformed SCr and BUN. The area under the receiver operating characteristic curve for Kim-1 was between 0.91 and 0.99 as compared to 0.79 to 0.9 for BUN and 0.73 to 0.85 for SCr. Thus urinary Kim-1 is the first injury biomarker of kidney toxicity qualified by the FDA and EMEA and is expected to significantly improve kidney safety monitoring. PMID:20458318

Vaidya, Vishal S.; Ozer, Josef S.; Frank, Dieterle; Collings, Fitz B.; Ramirez, Victoria; Troth, Sean; Muniappa, Nagaraja; Thudium, Douglas; Gerhold, David; Holder, Daniel J.; Bobadilla, Norma A.; Marrer, Estelle; Perentes, Elias; Cordier, André; Vonderscher, Jacky; Maurer, Gérard; Goering, Peter L.; Sistare, Frank D.; Bonventre, Joseph V.

2010-01-01

181

Re-Evaluate the Effect of Hyperbaric Oxygen Therapy in Cancer - A Preclinical Therapeutic Small Animal Model Study  

PubMed Central

Tumor hypoxia is a known driver of angiogenesis that also facilitates tumor growth. Moreover, poorly oxygenated central tumor area remains relatively radio or chemo resistant. HBO therapy is known to elevate the levels of dissolved oxygen and eliminates tumor hypoxia. It has been one of the modalities in cancer treatment; therefore its optimization is important. In this experimental study, no cancer enhancing effect was seen during the course of HBO therapy; however, post therapy there was an accelerated growth and progression of tumor. HBO treated mice lived shorter and the response to therapy was dose & tumor volume dependent. HBO therapy probably exert its effect on the cancer proliferating cells through multiple pathways such as increased DNA damage, apoptosis & geno-toxicity leading to slow cancer progression while post therapy tumorigenic effect could be due to impaired DNA repair mechanism, mutagenic effect & aneuploidy as well as altered blood supply & nutrients. Tumor growth reached plateau with time and this finding validated theoretical model predicting tumor reaching an asymptotic limit. While, marked asymmetry observed in tumor volume progression or cancer cell proliferation rate in each of the experimental C3H mouse suggested a need for an alternate small animal pre-clinical cancer therapeutic model. PMID:23144880

Pande, Sneha; Sengupta, Amit; Srivastava, Anurag; Gude, Rajiv P.; Ingle, Arvind

2012-01-01

182

A review of treatment planning for precision image-guided photon beam pre-clinical animal radiation studies.  

PubMed

Recently, precision irradiators integrated with a high-resolution CT imaging device became available for pre-clinical studies. These research platforms offer significant advantages over older generations of animal irradiators in terms of precision and accuracy of image-guided radiation targeting. These platforms are expected to play a significant role in defining experiments that will allow translation of research findings to the human clinical setting. In the field of radiotherapy, but also others such as neurology, the platforms create unique opportunities to explore e.g. the synergy between radiation and drugs or other agents. To fully exploit the advantages of this new technology, accurate methods are needed to plan the irradiation and to calculate the three-dimensional radiation dose distribution in the specimen. To this end, dedicated treatment planning systems are needed. In this review we will discuss specific issues for precision irradiation of small animals, we will describe the workflow of animal treatment planning, and we will examine several dose calculation algorithms (factorization, superposition-convolution, Monte Carlo simulation) used for animal irradiation with kilovolt photon beams. Issues such as dose reporting methods, photon scatter, tissue segmentation and motion will also be discussed briefly. PMID:24629309

Verhaegen, Frank; van Hoof, Stefan; Granton, Patrick V; Trani, Daniela

2014-12-01

183

Safety and efficacy field study of artesunate for dogs with non-resectable tumours.  

PubMed

The anti-malarial drug artesunate has shown anticancer activity in vitro and in preliminary animal experiments, but experience in patients with cancer is very limited. Pre-clinical studies in dogs indicated morbidity at high dosage levels. This study evaluated the effects of artesunate in canine cancer cell lines and in canine cancer patients. Four canine cell lines were tested in vitro for sensitivity towards artesunate and dihydroartemisinin (DHA; active metabolite of artesunate). The half-maximal inhibitory concentration (IC50) values for artesunate or DHA were 2-60 ?M in three cell lines, while one cell line was much less sensitive to artesunate (IC50 337 ?M) than to DHA (IC50 50 ?M). A safety/efficacy field study with artesunate was conducted in 23 dogs with non-resectable tumours. Artesunate was administered for 7-385 days at a dosage of 651-1178 (median 922) mg/m(2). No neurological or cardiac toxicity was observed and seven dogs exhibited no adverse effects at all. Fever and haematological/gastrointestinal toxicity, mostly transient, occurred in 16 dogs. One dog died from pneumonia. Plasma artesunate and DHA levels fell below the limit of detection within 8-12 h after artesunate administration, while levels after two hours were close to 1 ?M. Artesunate produced a long-lasting complete remission in one case of cancer and short-term stabilization of another seven cases. PMID:23645726

Rutteman, Gerard R; Erich, Suzanne A; Mol, Jan A; Spee, Bart; Grinwis, Guy C M; Fleckenstein, Lawrence; London, Cheryl A; Efferth, Thomas

2013-05-01

184

Safety and efficacy studies of liposomes in specific immunotherapy  

Microsoft Academic Search

Liposomes are lipid vesicles that have been extensively investigated because of their immunoadjuvant properties and their capacity to transport a variety of therapeutic agents. This article reports the results of 4 safety and efficacy studies of multilamellar liposomes used to incorporate an allergen extract in specific immunotherapy. The first study showed that cutaneous tolerance of encapsulated allergen extracts (5 grass

Sylvie Galvain; Claude André; Christine Vatrinet; Bertrand Villet

1999-01-01

185

Sources of Self-Efficacy in Mathematics: A Validation Study  

ERIC Educational Resources Information Center

The purpose of this study was to develop and validate items with which to assess A. Bandura's (1997) theorized sources of self-efficacy among middle school mathematics students. Results from Phase 1 (N=1111) were used to develop and refine items for subsequent use. In Phase 2 of the study (N=824), a 39-item, four-factor exploratory model fit best.…

Usher, Ellen L.; Pajares, Frank

2009-01-01

186

Advancing Novel Molecular Imaging Agents from Preclinical Studies to First-in-Humans Phase I Clinical Trials in Academia-A Roadmap for Overcoming Perceived Barriers.  

PubMed

There is a critical need to advance promising novel molecular imaging (MI) agents for cancer from preclinical studies to first-in-humans Phase I clinical trials in order to realize their full potential for cancer detection and for predicting or monitoring response to targeted ("personalized") cancer therapies. Steps to clinical translation include radiopharmaceutical formulation, preclinical pharmacology and toxicology studies, clinical trial design and human ethics approval, and regulatory agency submission. In this Topical Review, we provide a "roadmap" to advancing one class of novel MI agents to Phase I trials in academia and illustrate the processes that we have successfully applied for (111)In-labeled pertuzumab, a MI probe for monitoring response of HER2-positive breast cancer to treatment with trastuzumab (Herceptin). We hope that our experience will encourage other academic radiopharmaceutical scientists to embrace this challenge. PMID:25781873

Reilly, Raymond M; Lam, Karen; Chan, Conrad; Levine, Mark

2015-04-15

187

A preclinical assay for chemosensitivity in multiple myeloma.  

PubMed

Accurate preclinical predictions of the clinical efficacy of experimental cancer drugs are highly desired but often haphazard. Such predictions might be improved by incorporating elements of the tumor microenvironment in preclinical models by providing a more physiological setting. In generating improved xenograft models, it is generally accepted that the use of primary tumors from patients are preferable to clonal tumor cell lines. Here we describe an interdisciplinary platform to study drug response in multiple myeloma, an incurable cancer of the bone marrow. This platform uses microfluidic technology to minimize the number of cells per experiment, while incorporating three-dimensional extracellular matrix and mesenchymal cells derived from the tumor microenvironment. We used sequential imaging and a novel digital imaging analysis algorithm to quantify changes in cell viability. Computational models were used to convert experimental data into dose-exposure-response "surfaces," which offered predictive utility. Using this platform, we predicted chemosensitivity to bortezomib and melphalan, two clinical multiple myeloma treatments, in three multiple myeloma cell lines and seven patient-derived primary multiple myeloma cell populations. We also demonstrated how this system could be used to investigate environment-mediated drug resistance and drug combinations that target it. This interdisciplinary preclinical assay is capable of generating quantitative data that can be used in computational models of clinical response, demonstrating its utility as a tool to contribute to personalized oncology. PMID:24310398

Khin, Zayar P; Ribeiro, Maria L C; Jacobson, Timothy; Hazlehurst, Lori; Perez, Lia; Baz, Rachid; Shain, Kenneth; Silva, Ariosto S

2014-01-01

188

Intraoperative fluorescence imaging of peritoneal dissemination of ovarian carcinomas. A preclinical study  

Microsoft Academic Search

ObjectiveImprovement of the management and outcome of ovarian cancers may require intraoperative detection and therapeutic intervention to treat minimal residual disease after complete surgery. The aim of this study was to validate the importance of fluorescence in the peroperative detection of human ovarian adenocarcinoma cells and to determine its efficiency in detecting infra millimetric tumor metastases.

Eliane Mery; Eva Jouve; Stephanie Guillermet; Maxime Bourgognon; Magali Castells; Muriel Golzio; Philippe Rizo; Jean Pierre Delord; Denis Querleu; Bettina Couderc

2011-01-01

189

Choosing preclinical study models of diabetic retinopathy: key problems for consideration  

PubMed Central

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. PMID:25429204

Mi, Xue-Song; Yuan, Ti-Fei; Ding, Yong; Zhong, Jing-Xiang; So, Kwok-Fai

2014-01-01

190

Virtual reality, augmented reality, and robotics applied to digestive operative procedures: from in vivo animal preclinical studies to clinical use  

NASA Astrophysics Data System (ADS)

Technological innovations of the 20 th century provided medicine and surgery with new tools, among which virtual reality and robotics belong to the most revolutionary ones. Our work aims at setting up new techniques for detection, 3D delineation and 4D time follow-up of small abdominal lesions from standard mecial images (CT scsan, MRI). It also aims at developing innovative systems making tumor resection or treatment easier with the use of augmented reality and robotized systems, increasing gesture precision. It also permits a realtime great distance connection between practitioners so they can share a same 3D reconstructed patient and interact on a same patient, virtually before the intervention and for real during the surgical procedure thanks to a telesurgical robot. In preclinical studies, our first results obtained from a micro-CT scanner show that these technologies provide an efficient and precise 3D modeling of anatomical and pathological structures of rats and mice. In clinical studies, our first results show the possibility to improve the therapeutic choice thanks to a better detection and and representation of the patient before performing the surgical gesture. They also show the efficiency of augmented reality that provides virtual transparency of the patient in real time during the operative procedure. In the near future, through the exploitation of these systems, surgeons will program and check on the virtual patient clone an optimal procedure without errors, which will be replayed on the real patient by the robot under surgeon control. This medical dream is today about to become reality.

Soler, Luc; Marescaux, Jacques

2006-04-01

191

Preclinical Studies of YK-4-272, an Inhibitor of Class II Histone Deacetylases by Disruption of Nucleocytoplasmic Shuttling  

PubMed Central

Purpose The HDAC shuttling inhibitor, YK-4-272 functions by restricting nuclear shuttling of Class II HDACs. Pre-clinical investigations of YK-4-272 bioavailability, pharmacokinetics, in vivo toxicity and tumor growth inhibition were performed to determine its potential as an HDAC shuttling disruptor for use in clinical applications. Methods The solubility, lipophilicity, in vitro metabolic stability, in vitro intestinal permeability, and in vivo pharmacokinetics of YK-4-272 were determined by HPLC methods. The anti-tumor activity of YK-4-272 was determined by monitoring athymic Balb/c nude mice bearing PC-3 xenografts. Results Oral bioavailability of YK-4-272 is supported by its solubility (0.537 mg/mL) and apparent partition coefficient of 2.0. The compound was chemically and metabolically stable and not a substrate for CYP450. In Caco-2 cell transport studies, YK-4-272 was highly permeable. The time-concentration profile of YK- 4-272 in plasma resulted in a Cmax of 2.47 µg/mL at 0.25 h with a AUC of 3.304 µg×h/mL. Treatment of PC-3 tumor xenografts with YK-4-272 showed significant growth delay. Conclusions YK-4-272 is stable and bio-available following oral administration. Growth inhibition of cancer cells and tumors was observed. These studies support advancing YK-4-272 for further evaluation as a novel HDAC shuttling inhibitor for use in cancer treatment. PMID:22836184

Kong, Hye-Sik; Tian, Shuo; Kong, Yali; Du, Guanhua; Zhang, Li; Jung, Mira; Dritschilo, Anatoly

2013-01-01

192

Preclinical Studies Identify Non-Apoptotic Low-Level Caspase-3 as Therapeutic Target in Pemphigus Vulgaris  

PubMed Central

The majority of pemphigus vulgaris (PV) patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis). The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg) 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG), PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice) as well as PV patients’ biopsies (n=6). A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP) and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation including c-Myc induction, p38MAPK activation and acantholysis. Together, these data identify low-level caspase-3 activation downstream of disrupted Dsg3 trans- or cis-adhesion as a major event in PV pathogenesis that is non-synonymous with apoptosis and represents, unlike apoptotic components, a promising target for clinical therapy. At a broader level, these results posit that an impairment of adhesive functions in concert with low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other diseases including cancer. PMID:25748204

Luyet, Camille; Schulze, Katja; Sayar, Beyza S.; Howald, Denise; Müller, Eliane J.; Galichet, Arnaud

2015-01-01

193

AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models  

PubMed Central

Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM. PMID:23667438

Vasireddy, Vidyullatha; Kohnke, Monika; Black, Aaron D.; Alexandrov, Krill; Zhou, Shangzhen; Maguire, Albert M.; Chung, Daniel C.; Mac, Helen; Sullivan, Lisa; Gadue, Paul; Bennicelli, Jeannette L.; French, Deborah L.; Bennett, Jean

2013-01-01

194

Mentalizing in preclinical Huntington's disease: an fMRI study using cartoon picture stories.  

PubMed

Huntington's disease (HD) is an autosomal dominant degenerative brain disorder that is characterized by motor, cognitive and affective symptoms. Previous research has shown that patients with HD, similar to patients with schizophrenia, are impaired in their ability to appreciate the mental states of others. Functional brain imaging studies have shown that patients with schizophrenia underactivate the neural network involved in mentalizing, and that deviant patterns of brain activation are also present in individuals at high risk of developing a psychotic disorder. Accordingly, the present study sought to examine the brain activation in premanifest mutation carriers for HD. Thirty premanifest mutation carriers (13 males) defined by a positive gene test and absence of unequivocal HD symptoms ("pre-HD") performed a cartoon mentalizing task during functional brain imaging. For comparison, a group of 26 healthy controls took part in the study. BOLD responses revealed that pre-HD subjects activated the mentalizing network comprising prefrontal, temporoparietal and parietal brain regions during task performance. A comparison between pre-HD patients and healthy controls revealed no significant activation differences. Premanifest mutation carriers of HD activated the neural network involved in mentalizing similar to healthy control subjects. This suggests that impaired mentalizing emerges with the clinical manifestation of the disease, but is not necessarily part of the pre-manifest stage. PMID:23179063

Saft, Carsten; Lissek, Silke; Hoffmann, Rainer; Nicolas, Volkmar; Tegenthoff, Martin; Juckel, Georg; Brüne, Martin

2013-06-01

195

Issues in pharmaceutical development of thymosin alpha1 from preclinical studies through marketing.  

PubMed

SciClone Pharmaceuticals licensed the commercial and patent rights to thymosin alpha1, for geographical regions of the world excluding the United States and Europe, in the early 1990s. With this license, SciClone embarked on global drug development, and the issues encountered for thymosin alpha1 are reflective of the roller coaster of modern approval of pharmaceuticals. Most of the required toxicology studies had been completed prior to licensure, but some newer studies had to be conducted to obtain approvals in certain countries. The recent development of the "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use" (ICH) guidelines allows for a clearer definition of the required battery of toxicology studies, although some countries still have not adopted these guidelines, and the local regulations have had to be understood and followed. Other hurdles include the complications that manufacturing requirements can differ between countries, and certain countries require local clinical experience trials in addition to SciClone's cumulative clinical data. A further obstacle was the pleiotropic nature of the mechanism of action of thymosin alpha1, with the resulting difficulty in the unraveling of its pharmacologic effects. With close attention to these regulatory details, SciClone has obtained approvals in more than 30 countries and has successfully begun commercial sales. PMID:17947591

Tuthill, Cynthia

2007-09-01

196

Neural Stem Cell-Mediated Enzyme-Prodrug Therapy for Glioma: Preclinical Studies  

PubMed Central

High-grade gliomas are extremely difficult to treat because they are invasive and therefore are not curable by surgical resection; the toxicity of currently chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles that can target enzyme/prodrug therapy selectively to tumors. We have used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the tumor-localized prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, indicating that these cells are genetically and functionally stable. In vivo biodistribution studies demonstrated that these NSCs retained tumor tropism, even in mice pre-treated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor bearing, and in orthotopic glioma-bearing, immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was approximately one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, non-toxic and effective in mice. These data have led to approval of a first-inhuman study of an allogeneic NSC-mediated enzyme/prodrug targeted cancer therapy in patients with recurrent high-grade glioma. PMID:23658244

Aboody, Karen S.; Najbauer, Joseph; Metz, Marianne Z.; D’Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J.; Synold, Timothy W.; Couture, Larry A.; Blanchard, Suzette; Moats, Rex A.; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V.; Frank, Richard T.; Barish, Michael E.; Brown, Christine E.; Kim, Seung U.; Badie, Behnam; Portnow, Jana

2013-01-01

197

Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies.  

PubMed

High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, and are genetically and functionally stable. In vivo biodistribution studies demonstrated NSC retention of tumor tropism, even in mice pretreated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor-bearing and orthotopic glioma-bearing immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was about one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, nontoxic, and effective in mice. These data have led to approval of a first-in-human study of an allogeneic NSC-mediated enzyme/prodrug-targeted cancer therapy in patients with recurrent high-grade glioma. PMID:23658244

Aboody, Karen S; Najbauer, Joseph; Metz, Marianne Z; D'Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J; Synold, Timothy W; Couture, Larry A; Blanchard, Suzette; Moats, Rex A; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V; Frank, Richard T; Barish, Michael E; Brown, Christine E; Kim, Seung U; Badie, Behnam; Portnow, Jana

2013-05-01

198

Hydration with Saline Decreases Toxicity of Mice Injected With Calcitriol in Preclinical Studies  

PubMed Central

The effectiveness of saline injection in reducing the toxicity profile of calcitriol when coadministered in mice was evaluated. Mortality was used as an end point to study the toxic effects of calcitriol; the relative risk of mortality in mice injected with saline was evaluated from our previously published animal experiments. We discovered that coadministration with 0.25 mL normal saline solution injected intraperitoneally is associated with a lower mortality rate than calcitriol given alone. The estimated relative risk of mortality was 0.0789 (95% confidence interval, 0.0051–1.22; z = 1.82; P = 0.070) when saline is administered with calcitriol compared to calcitriol alone. There was a reduction in serum calcium levels in mice that received saline (11.4 ± 0.15 mg/dL) compared to mice that did not receive saline (12.42 ± 1.61 mg/dL). Hydration with saline seems to reduce mortality and toxicity in mice receiving calcitriol. Given the decrease in mortality rates, intraperitoneal injections of saline should be considered in studies involving mice receiving injections of calcitriol. PMID:24266410

Azari, Amir A; Kanavi, Mozhgan R.; Darjatmoko, Soesiawati R.; Lee, Vivian; Kim, KyungMann; Potter, Heather D.; Albert, Daniel M.

2014-01-01

199

Hydration with saline decreases toxicity of mice injected with calcitriol in preclinical studies.  

PubMed

The effectiveness of saline injection in reducing the toxicity profile of calcitriol when coadministered in mice was evaluated. Mortality was used as an end point to study the toxic effects of calcitriol; the relative risk of mortality in mice injected with saline was evaluated from our previously published animal experiments. We discovered that coadministration with 0.25 mL normal saline solution injected intraperitoneally is associated with a lower mortality rate than calcitriol given alone. The estimated relative risk of mortality was 0.0789 (95% confidence interval, 0.0051-1.22; z = 1.82; P = 0.070) when saline is administered with calcitriol compared to calcitriol alone. There was a reduction in serum calcium levels in mice that received saline (11.4 ± 0.15 mg/dL) compared to mice that did not receive saline (12.42 ± 1.61 mg/dL). Hydration with saline seems to reduce mortality and toxicity in mice receiving calcitriol. Given the decrease in mortality rates, intraperitoneal injections of saline should be considered in studies involving mice receiving injections of calcitriol. PMID:24266410

Azari, Amir A; Kanavi, Mozhgan R; Darjatmoko, Soesiawati R; Lee, Vivian; Kim, Kyungmann; Potter, Heather D; Albert, Daniel M

2013-01-01

200

Preclinical evaluation of alpha-1-proteinase inhibitor. Pharmacokinetics and safety studies.  

PubMed

To assess the pharmacodynamics and safety of alpha-1-proteinase inhibitor (human) (A1PI) isolated from pooled human plasma, a series of animal studies was conducted. Using both unlabeled and 125I-labeled A1PI (highly purified), plasma residence time and tissue distribution were determined in rabbits. A catabolic half-life of 48.5 hours was obtained for the labeled material, which agreed well with the antigenic decay (35.5 hours), measured with a specific enzyme-linked immunosorbent assay, and the functional activity decay (38.1 hours), measured antigenically by the ability of resident human A1PI to complex with human neutrophil elastase. No unusual tissue distribution was observed at the first, 24th, or 168th hour of sacrifice. Cynomolgous monkeys received infusions of labeled A1PI and a catabolic half-life of 55.45 hours was obtained; infusion of unlabeled material yielded anticipated plasma recovery and a significant increment in A1PI in bronchial-alveolar lavage fluid, both antigenically and functionally determined. Safety studies assessing acute physiologic response and both acute and subacute toxicity presented no significant adverse effects. We conclude that A1PI (human) presents normal pharmacodynamics and safety and is therefore associated with a wide margin of safety for the intended clinical applications. PMID:3260072

Fournel, M A; Newgren, J O; Betancourt, C M; Irwin, R G

1988-06-24

201

Masitinib antagonizes ATP-binding cassette subfamily C member 10-mediated paclitaxel resistance: a preclinical study.  

PubMed

Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 ?mol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. PMID:24431074

Kathawala, Rishil J; Sodani, Kamlesh; Chen, Kang; Patel, Atish; Abuznait, Alaa H; Anreddy, Nagaraju; Sun, Yue-Li; Kaddoumi, Amal; Ashby, Charles R; Chen, Zhe-Sheng

2014-03-01

202

Research Article Efficacy of Audiovisual and Radar Surveys for Studying  

E-print Network

), a threatened seabird that nests in old-growth forests in the Pacific Northwest, USA. Theoretically, counts fromResearch Article Efficacy of Audiovisual and Radar Surveys for Studying Marbled Murrelets in Inland, Scotia Pacific Company LLC, Scotia, CA 95565, USA STEVEN P. COURTNEY, Sustainable Ecosystems Institute

Mladenoff, David

203

Year 3 ASK/FOSS Efficacy Study. CRESST Report 782  

ERIC Educational Resources Information Center

This efficacy study was designed to examine the traditional FOSS curriculum (Delta Publishing, Full Option Science System/FOSS, magnetism and electricity, structures of life, and water modules, 2005), and the new ASK/FOSS curriculum (magnetism and electricity, structures of life, and water modules, 2005), a revised version of the original FOSS…

Osmundson, Ellen; Dai, Yunyun; Herman, Joan

2011-01-01

204

Studies on the Efficacy of Child Psychoanalysis.  

ERIC Educational Resources Information Center

Summarizes three studies on psychoanalytic psychotherapeutic treatment of diabetic children and adolescents with grossly abnormal blood glucose profiles necessitating repeated admissions to hospital. Used time series analysis, comparative analysis, and single-case experimental design to illustrate effectiveness of psychotherapeutic intervention…

Fonagy, Peter; Moran, George S.

1990-01-01

205

Racer efficacy study - Bixby, Fall 2007  

Technology Transfer Automated Retrieval System (TEKTRAN)

Weed competition is a primary concern for conventional and organic vegetable producers. Racer (ammonium nonanoate) is labeled for non-food use and efforts are currently underway to label it as a bio-herbicide for organically grown food crops. The objective of this study was to investigate differen...

206

Silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) nanofibers as wound dressings: a preclinical study  

PubMed Central

In this study, a mixture of poly(vinyl alcohol) (PVA) and chitosan oligosaccharides (COS) was electrospun with silver nanoparticles (AgNPs) to produce fibrous mats for use in wound healing. The AgNPs were reduced by COS prior to electrospinning or Ag+ was reduced via ultraviolet irradiation in nanofibers. The morphologies of the PVA/COS/AgNO3 and PVA/COS-AgNP nanofibers were analyzed by scanning electron microscopy. Formation of the AgNPs was investigated by field emission transmission electron microscopy, ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. We also evaluated the biocompatibility of the nanofibers, particularly their cytotoxicity to human skin fibroblasts and potential to cause primary skin irritation. The in vitro antibacterial activity and in vivo wound healing capacity of the nanofibers were also investigated. The nanofibers had a smooth surface with an average diameter of 130–192 nm. The diameters of the AgNPs were in the range of 15–22 nm. The nanofibers significantly inhibited growth of Escherichia coli and Staphylococcus aureus bacteria. PVA/COS-AgNP nanofibers accelerated the rate of wound healing over that of the control (gauze). The results of our in vitro and in vivo animal experiments suggest that PVA/COS-AgNP nanofibers should be of greater interest than PVA/COS/AgNO3 nanofibers for clinical use as a bioactive wound dressing. PMID:24204142

Li, Chenwen; Fu, Ruoqiu; Yu, Caiping; Li, Zhuoheng; Guan, Haiyan; Hu, Daqiang; Zhao, Dehua; Lu, Laichun

2013-01-01

207

A 3-week pre-clinical study of 2?-fucosyllactose in farm piglets.  

PubMed

One of the most abundant oligosaccharides found in human milk is 2?-fucosyllactose, a trisaccharide composed of fucose and lactose, and multiple studies have demonstrated a health benefit to this compound. Recent advances have allowed for the large-scale production of oligosaccharides via fermentation, including 2?-fucosyllactose. A neonatal piglet model was used to evaluate the tolerability of 2?-fucosyllactose, produced through this process, in order to demonstrate the suitability of this compound for human infants under 12 weeks of age. Crossbred farm piglets, at lactation day 2, were assigned to one of four treatment groups receiving a liquid diet containing 0, 200, 500 or 2000?mg/L of 2?-fucosyllactose. The calculated consumption of 2?-fucosyllactose corresponded to dose levels of 29.37, 72.22 and 291.74?mg/kg/day, respectively, in males and 29.30, 74.31, and 298.99?mg/kg/day, respectively in females. Piglets were administered diet for 3 weeks; and there were no test article-related effects on growth and development (clinical observations, body weight and food consumption), clinical pathology parameters (hematology, clinical chemistry, coagulation and urinalysis), or any histopathologic changes. Therefore, dietary exposure to 2?-fucosyllactose at concentrations up to 2000?mg/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth. PMID:25445760

Hanlon, Paul R; Thorsrud, Bjorn A

2014-12-01

208

Photoacoustic spectroscopy in the monitoring of breast tumor development: a pre-clinical study  

NASA Astrophysics Data System (ADS)

Breast cancer is the most frequently diagnosed cancer type and its detection at an early stage can reduce the mortality rate substantially. With the aim to detect breast cancer early, by studying tumor progression in nude mice, a pulsed laser induced photoacoustic spectroscopy set up has been designed and developed. MCF-7 cells xenografts were developed using six to eight weeks old female nude mice and tumor tissues were extracted on different days (10th, 15th and 20th Day) post injection and the corresponding photoacoustic spectra were recorded at 281nm excitation. A total of 144 time domain spectra were recorded from 36 animals belonging to the three time points (10th, 15th and 20th day post injection) and converted into frequency domains by Fast Fourier Transform (FFT) tools of the MATLAB algorithms and analyzed. The frequency patterns of the tumor masses on 10th, 15th and 20th day of tumor development showed a gradual increase in intensity at certain frequencies, 5.93 x103 Hz, 15.9 x103 Hz, 29.69 x103 Hz and 32.5 x103 Hz in the FFT patterns indicating that these frequencies were more sensitive towards tumor development. Further analysis of the data yielded a clear variation in the spectral parameters with progression of the disease suggesting that the technique may be suitable for early detection of the disease. Thus, we expect that the developed setup may be useful in assessing the different phases of tumor development which may have clinical implications.

Priya, Mallika; Rao, Bola Sadashiva Satish; Ray, Satadru; Mahato, Krishna Kishore

2014-03-01

209

Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders  

PubMed Central

Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium’s therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium’s main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington’s, Alzheimer’s, and Parkinson’s diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium’s neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases. PMID:20705090

Chiu, Chi-Tso; Chuang, De-Maw

2011-01-01

210

Bone metastasis imaging with SPECT/CT/MRI: A preclinical toolbox for therapy studies.  

PubMed

Bone is one of the most common metastatic target sites in breast cancer, with more than 200 thousand new cases of invasive cancer diagnosed in the US alone in 2011. We set out to establish a multimodality imaging platform for bone metastases in small animals as a tool to non-invasively quantify metastasis growth, imaging the ensuing bone lesions and possibly the response to treatment. To this end, a mouse model of osteolytic metastatic bone tumors was characterized with SPECT/CT and MRI over time. A cell line capable of forming bone metastases, MDA-MB-231, was genetically modified to stably express the reporter gene herpes simplex virus-1 thymidine kinase (hsv-1 tk). The intracellular accumulation of the radiolabeled tracer [(123)I]FIAU promoted by HSV-1 TK specifically pinpoints the location of tumor cells which can be imaged in vivo by SPECT. First, a study using tumors implanted subcutaneously was performed. The SPECT/MRI overlays and the ex vivo ?-counting showed a linear correlation in terms of %ID/cm(3) (R(2)=0.93) and %ID/g (R(2)=0.77), respectively. Then, bone metastasis growth was imaged weekly by SPECT/CT and T2-weighted MRI over a maximum of 40days post-intracardiac injection of tumor cells. The first activity spots detectable with SPECT, around day 20 post-cell injection, were smaller than 2mm(3) and not yet visible by MRI and increased in volume and in %ID over the weeks. Osteolytic bone lesions were visible by CT (in vivo) and ?CT (ex vivo). The SPECT/MRI overlays also showed a linear correlation in terms of %ID/cm(3) (R(2)=0.86). In conclusion, a new multimodality imaging platform has been established that non-invasively combines images of active tumor areas (SPECT), tumor volume (MRI) and the corresponding bone lesions (CT and ?CT). To our knowledge this is the first report where the combination of soft tissue information from MRI, bone lesions by CT, and reporter gene imaging by SPECT is used to non-invasively follow metastatic bone lesions. PMID:25680341

Sanches, Pedro Gomes; Peters, Steffie; Rossin, Raffaella; Kaijzel, Eric L; Que, Ivo; Löwik, Clemens W G M; Grüll, Holger

2015-06-01

211

Fiber optic fluorescence detection of low-level porphyrin concentrations in preclinical and clinical studies  

NASA Astrophysics Data System (ADS)

A significant clinical problem in the local treatment of cutaneous metastases of breast cancer (by any modality--surgery, radiation therapy or photodynainic therapy) is the fact that the disease almost always extends beyond the boundary of visible lesions in the form of microscopic deposits. These deposits may be distant from the site of visible disease but are often in close proximity to it and are manifested sooner or later by the development of recurrent lesions at the border of the treated area, thus the "marginal miss" in radiation therapy, the "rim recurrence" in photodynamic therapy, and the "incisional recurrence" following surgical excision. More intelligent use of these treatment modalities demands the ability to detect microscopic deposits of tumor cells using non-invasive methodology. In vivo fluorescence measurements have been made possible by the development of an extremely sensitive fiber optic in vivo fluorescence photometer. The instrument has been used to verify that fluorescence correlated with injected porphyrin levels in various tissues. The delivery of light to excite and detect background fluorescence as well as photosensitizer fluorescence in tissues has been accomplished using two HeNe lasers emitting at 632.8 nm and 612 nm delivered through a single quartz fiber optic. Chopping at different frequencies, contributions of fluorescence may be separated. Fluorescence is picked up via a 400 micron quartz fiber optic positioned appropriately near the target tissue. Validation of these levels was made by extraction of the drug from the tissues with resultant quantitation. Recently, an extensive study was undertaken to determine if fluorescence could be used for the detection of occult, clinically non-palpable metastases in the lymph node of rats. This unique model allowed for the detection of micrometastases in lymph nodes using very low injected doses of the photosensitizer Photofrin II. Data obtained revealed the ability to detect on the order of 50-100 cells using 0.25 mg/kg of sensitizer, a level 20 times lower than normally used for treatment of animal tumors. These results indicate that Photofrin II could be used for fluorescence detection of small metastatic tumors, while substantially reducing the major side effect of PDT; namely, prolonged photosensitivity. Results to be presented demonstrate the ability of this technique to detect microscopic deposits of malignant tumor cells in patients with metastatic breast cancer. These deposits were found in clinically negative areas of the chest wall.

Mang, Thomas S.; McGinnis, Carolyn; Khan, S.

1990-07-01

212

Prior exposure to an attenuated Listeria vaccine does not reduce immunogenicity: pre-clinical assessment of the efficacy of a Listeria vaccine in the induction of immune responses against HIV  

E-print Network

of the efficacy of a Listeria vaccine in the induction ofof the efficacy of a Listeria vaccine in the induction ofvaccine vector: virulence attenuation or existing antivector immunity does not diminish therapeutic efficacy.

2011-01-01

213

Designing dementia treatment studies: Diagnosis, efficacy criteria, and duration.  

PubMed

Development of treatments for dementia is beset by special problems in defining the diagnosis, establishing efficacy criteria, and specifying the necessary duration of study. There is need for agreement among clinicians and scientists on diagnostic subgroups of dementia. Similarly, there is a need for harmonization of the regulatory guidelines in Europe, Japan, and the United States regarding the decision set of variables on which to base efficacy claims. The duration of trials must be based upon the intended claim: transient symptomatic benefit, maintained symptomatic benefit, or a therapeutic effect on disease progression. Claims other than transient benefit require long-term trials, suggested to be of at least six months in duration. Problems with long-term studies include slow patient accrual, high dropout rates, changing milieu, low return on investment, and lack of unanimity regarding regulatory requirements. Regulatory authorities must come to some accord, consonant with current clinical/scientific wisdom and consensus, regarding diagnosis, efficacy criteria, and feasible study duration, in order to attract continued sponsor investment in the development of antidementia treatments. PMID:19698442

Spiegel, R; Irwin, P

1996-01-01

214

Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy  

PubMed Central

This review discusses various issues to consider when developing standard operating procedures for pre-clinical studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathology in mdx mice and identifies some basic techniques that might comprise standardised approaches for evaluation. While the central aim is to provide a basis for the development of standardised procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiological mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clinical data from different laboratories around the world, in order to accelerate identification of the best pre-clinical therapies in the mdx mouse that will fast-track translation into effective clinical treatments for DMD. PMID:18499465

Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria

2008-01-01

215

21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.  

Code of Federal Regulations, 2014 CFR

...efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 ...efficacy study evaluations in labeling and advertising. (a)(1) The National Academy...information required in prescription drug advertising by paragraph (c) of this...

2014-04-01

216

21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.  

Code of Federal Regulations, 2013 CFR

...efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 ...efficacy study evaluations in labeling and advertising. (a)(1) The National Academy...information required in prescription drug advertising by paragraph (c) of this...

2013-04-01

217

21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.  

Code of Federal Regulations, 2011 CFR

...efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 ...efficacy study evaluations in labeling and advertising. (a)(1) The National Academy...information required in prescription drug advertising by paragraph (c) of this...

2011-04-01

218

21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.  

Code of Federal Regulations, 2012 CFR

...efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 ...efficacy study evaluations in labeling and advertising. (a)(1) The National Academy...information required in prescription drug advertising by paragraph (c) of this...

2012-04-01

219

Preclinical stem cell therapy in Chagas Disease: Perspectives for future research.  

PubMed

Chagas cardiomyopathy still remains a challenging problem that is responsible for high morbidity and mortality in Central and Latin America. Chagas disease disrupts blood microcirculation via various autoimmune mechanisms, causing loss of cardiomyocytes and severe impairment of heart function. Different cell types and delivery approaches in Chagas Disease have been studied in both preclinical models and clinical trials. The main objective of this article is to clarify the reasons why the benefits that have been seen with cell therapy in preclinical models fail to translate to the clinical setting. This can be explained by crucial differences between the cellular types and pathophysiological mechanisms of the disease, as well as the differences between human patients and animal models. We discuss examples that demonstrate how the results from preclinical trials might have overestimated the efficacy of myocardial regeneration therapies. Future research should focus, not only on studying the best cell type to use but, very importantly, understanding the levels of safety and cellular interaction that can elicit efficient therapeutic effects in human tissue. Addressing the challenges associated with future research may ensure the success of stem cell therapy in improving preclinical models and the treatment of Chagas disease. PMID:24392316

de Carvalho, Katherine Athayde Teixeira; Abdelwahid, Eltyeb; Ferreira, Reginaldo Justino; Irioda, Ana Carolina; Guarita-Souza, Luiz Cesar

2013-12-24

220

Does interprofessional simulation increase self-efficacy: a comparative study  

PubMed Central

Objectives In this work, we have compared uniprofessional and interprofessional versions of a simulation education intervention, in an attempt to understand more about whether it improves trainees’ self-efficacy. Background Interprofessionalism has been climbing the healthcare agenda for over 50?years. Simulation education attempts to create an environment for healthcare professionals to learn, without potential safety risks for patients. Integrating simulation and interprofessional education can provide benefits to individual learners. Setting The intervention took place in a high-fidelity simulation facility located on the campus of a large urban hospital. The centre provides educational activities for an Academic Health Sciences Centre. Approximately 2500 staff are trained at the centre each year. Participants One hundred and fifteen nurses and midwives along with 156 doctors, all within the early years of their postgraduate experience participated. All were included on the basis of their ongoing postgraduate education. Methods Each course was a one-day simulation course incorporating five clinical and one communication scenarios. After each a facilitated debriefing took place. A mixed methods approach utilised precourse and postcourse questionnaires measuring self-efficacy in managing emergency situations, communication, teamwork and leadership. Results Thematic analysis of qualitative data showed improvements in communication/teamwork and leadership, for doctors and nurses undergoing simulation training. These findings were confirmed by statistical analysis showing that confidence ratings improved in nurses and doctors overall (p<0.001). Improved outcomes from baseline were observed for interprofessional versus uniprofessional trained nurses (n=115; p<0.001). Postcourse ratings for doctors showed that interprofessional training was significantly associated with better final outcomes for a communication/teamwork dimension (n=156; p<0.05). Conclusions This study provides evidence that simulation training enhances participants’ self-efficacy in clinical situations. It also leads to increases in their perceived abilities relating to communication/teamwork and leadership/management of clinical scenarios. Interprofessional training showed increased positive effects on self-efficacy for nurses and doctors. PMID:25586366

Watters, Colm; Reedy, Gabriel; Ross, Alastair; Morgan, Nicola J; Handslip, Rhodri; Jaye, Peter

2015-01-01

221

Premarket Safety and Efficacy Studies for ADHD Medications in Children  

PubMed Central

Background Attention-deficit hyperactivity disorder (ADHD) is a chronic condition and pharmacotherapy is the mainstay of treatment, with a variety of ADHD medications available to patients. However, it is unclear to what extent the long-term safety and efficacy of ADHD drugs have been evaluated prior to their market authorization. We aimed to quantify the number of participants studied and their length of exposure in ADHD drug trials prior to marketing. Methods We identified all ADHD medications approved by the Food and Drug Administration (FDA) and extracted data on clinical trials performed by the sponsor and used by the FDA to evaluate the drug’s clinical efficacy and safety. For each ADHD medication, we measured the total number of participants studied and the length of participant exposure and identified any FDA requests for post-marketing trials. Results A total of 32 clinical trials were conducted for the approval of 20 ADHD drugs. The median number of participants studied per drug was 75 (IQR 0, 419). Eleven drugs (55%) were approved after <100 participants were studied and 14 (70%) after <300 participants. The median trial length prior to approval was 4 weeks (IQR 2, 9), with 5 (38%) drugs approved after participants were studied <4 weeks and 10 (77%) after <6 months. Six drugs were approved with requests for specific additional post-marketing trials, of which 2 were performed. Conclusions Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy. While post-marketing studies can fill in some of the gaps, better assurance is needed that the proper trials are conducted either before or after a new medication is approved. PMID:25007171

Bourgeois, Florence T.; Kim, Jeong Min; Mandl, Kenneth D.

2014-01-01

222

Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: A preclinical study in a novel rat model  

SciTech Connect

Purpose: Intestinal radiation injury (radiation enteropathy) is relevant to cancer treatment, as well as to radiation accidents and radiation terrorism scenarios. This study assessed the protective efficacy of orazipone, a locally-acting small molecule immunomodulator. Methods and Materials: Male rats were orchiectomized, a 4-cm segment of small bowel was sutured to the inside of the scrotum, a proximal anteperistaltic ileostomy was created for intraluminal drug administration, and intestinal continuity was re-established by end-to-side anastomosis. After three weeks postoperative recovery, the intestine in the 'scrotal hernia' was exposed locally to single-dose or fractionated X-radiation. Orazipone (30 mg/kg/day) or vehicle was administered daily through the ileostomy, either during and after irradiation, or only after irradiation. Structural, cellular, and molecular aspects of intestinal radiation toxicity were assessed two weeks after irradiation. Results: Orazipone significantly ameliorated histologic injury and transforming growth factor-{beta} immunoreactivity levels, both after single-dose and fractionated irradiation. Intestinal wall thickness was significantly reduced after single-dose and nonsignificantly after fractionated irradiation. Mucosal surface area and numbers of mast cells were partially restored by orazipone after single-dose irradiation. Conclusions: This work (1) demonstrates the utility of the ileostomy rat model for intraluminal administration of response modifiers in single-dose and fractionated radiation studies; (2) shows that mucosal immunomodulation during and/or after irradiation ameliorates intestinal toxicity; and (3) highlights important differences between single-dose and fractionated radiation regimens.

Boerma, Marjan [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Wang, Junru [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Richter, Konrad K. [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Hauer-Jensen, Martin [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States) and Department of Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States)]. E-mail: mhjensen@life.uams.edu

2006-10-01

223

Optimization of Preclinical Animal Models  

E-print Network

Optimization of Preclinical Animal Models Steven Perrin, PhD CEO, CSO ALS Therapy Development Institute #12;Historical Issue with Pre-clinical Animal Model Development and Validation Optimized Experimental Design for Preclinical Drug Screening in the ALS Mouse Model, 2007 10 Years To Validate the Model

224

Treatment of cognitive dysfunction in major depressive disorder-a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetine.  

PubMed

Although major depressive disorder is primarily considered a mood disorder, depressed patients commonly present with clinically significant cognitive dysfunction that may add to their functional disability. This review paper summarizes the available preclinical data on the effects of antidepressants, including monoamine reuptake inhibitors and the multimodal antidepressant vortioxetine, in behavioral tests of cognition such as cognitive flexibility, attention, and memory, or in potentially cognition-relevant mechanistic assays such as electroencephalography, in vivo microdialysis, in vivo or in vitro electrophysiology, and molecular assays related to neurogenesis or synaptic sprouting. The available data are discussed in context with clinically relevant doses and their relationship to target occupancy levels, in order to evaluate the translational relevance of preclinical doses used during testing. We conclude that there is preclinical evidence suggesting that traditional treatment with monoamine reuptake inhibitors can induce improved cognitive function, for example in cognitive flexibility and memory, and that the multimodal-acting antidepressant vortioxetine may have some advantages by comparison to these treatments. However, the translational value of the reviewed preclinical data can be questioned at times, due to the use of doses outside the therapeutically-relevant range, the lack of data on target engagement or exposure, the tendency to investigate acute rather than long term antidepressant administration, and the trend towards using normal rodents rather than models with translational relevance for depression. Finally, several suggestions are made for advancing this field, including expanded use of target occupancy assessments in preclinical and clinical experiments, and the use of translationally valuable techniques such as electroencephalography. PMID:25107284

Pehrson, Alan L; Leiser, Steven C; Gulinello, Maria; Dale, Elena; Li, Yan; Waller, Jessica A; Sanchez, Connie

2015-04-15

225

An Exploratory Study of Teacher Self-Efficacy Beliefs and Professional Learning Community  

ERIC Educational Resources Information Center

The exploratory study sought to examine the relationships between teachers' self-efficacy beliefs and professional learning community. Specifically, this study presents a quantitative analysis of the relationship between teachers' perceptions of self-efficacy and PLC implementation. The Teachers' Sense of Efficacy Scale (TSES) (long form)…

Romeo, Susan M.

2010-01-01

226

Safety and Efficacy of Bevacizumab With Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas  

Microsoft Academic Search

Purpose: Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination

Philip H. Gutin; Fabio M. Iwamoto; Kathryn Beal; Nimish A. Mohile; Sasan Karimi; Bob L. Hou; Stella Lymberis; Yoshiya Yamada; Jenghwa Chang; Lauren E. Abrey

2009-01-01

227

In vitro immunogenicity risk assessment of therapeutic proteins in preclinical setting.  

PubMed

Immunogenicity against therapeutic proteins is a clinical problem in the successful treatment of many diseases and, as such, immunogenicity risk assessment in preclinical setting would be useful to improve safety and efficacy of protein-based therapeutics in the product development stages. Here, we attempted a mechanism-based in vitro study as screening tool to capture clinically observed antibody-based immune response against two representative therapeutic proteins: recombinant human Erythropoietin-alpha (rHuEPO)and recombinant Factor VIII (rFVIII). Flow-cytometry was used to determine the maturation level of dendritic cells (DCs), a primary initiator of T-cell responses. Studies to capture T-lymphocyte proliferation upon challenge with free rFVIII were performed and secretion of immunomodulatory cytokines was analyzed by ELISA assay. These in vitro techniques could be used as risk assessment tool to determine the immunogenic potential of formulations of recombinant proteins in preclinical setting. PMID:21318912

Gaitonde, Puneet; Balu-Iyer, Sathy V

2011-01-01

228

In vitro Immunogenicity Risk-assessment of Therapeutic Proteins in Preclinical Setting  

PubMed Central

Immunogenicity against therapeutic proteins is a clinical problem in the successful treatment of many diseases and as such, immunogenicity risk assessment in preclinical setting would be useful to improve safety and efficacy of protein based therapeutics in the product development stages. Here, we attempted a mechanism based in vitro studies as screening tool to capture clinically observed antibody based immune response against two representative therapeutic proteins; recombinant human Erythropoietin-alpha (rHuEPO) and recombinant Factor VIII (rFVIII). Flow cytometry was used to determine the maturation level of dendritic cells (DCs), a primary initiator of T-cell responses. Studies to capture T-lymphocyte proliferation upon challenge with free rFVIII were performed and secretion of immunomodulatory cytokines was analyzed by ELISA assay. These in vitro techniques could be used as risk assessment tool to determine the immunogenic potential of formulations of recombinant proteins in preclinical setting. PMID:21318912

Gaitonde, Puneet; Balu-Iyer, Sathy V

2010-01-01

229

Targeting therapy of hepatocellular carcinoma with doxorubicin prodrug PDOX increases anti-metastatic effect and reduces toxicity: a preclinical study  

PubMed Central

Background This study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug. Methods The orthotopic nude mice model of highly metastatic HCC was established and the animals were randomized and treated with PDOX, DOX and saline, respectively. Hematology, biochemistry and tumor markers were studied. At autopsy, liver tumor weight and size, ascites, abdominal lymph nodes metastases, experimental peritoneal carcinomatosis index (ePCI), and tumor-host body weight ratio were investigated. Immunohistochemical studies and western blotting were done to investigate key molecules involved in the mechanism of action. Results Compared with Control, both PDOX and DOX could similarly and significantly reduce liver tumor weight and tumor volume by over 40%, ePCI values, retroperitoneal lymph node metastases and lung metastases and serum AFP levels (P?efficacy and reduced side effects especially cardio-toxicities in this HCC model. PMID:23961994

2013-01-01

230

Classical Mathematical Models for Description and Forecast of Preclinical Tumor Growth  

E-print Network

! 1! Classical Mathematical Models for Description and Forecast of Preclinical Tumor Growth. hal-00922553,version2-30Dec2013 #12;! 3! These results could be of value for preclinical cancer research by suggesting what model is best adapted when assessing anti-cancer drugs efficacies. They also

Boyer, Edmond

231

Exploring the tumors of multiple endocrine neoplasia type 1 in mouse models for basic and preclinical studies  

PubMed Central

Most patients (70–90%) with the multiple endocrine neoplasia type 1 (MEN1) syndrome possess germline heterozygous mutations in MEN1 that predisposes to tumors of multiple endocrine and nonendocrine tissues. Some endocrine tumors of the kinds seen in MEN1 that occur sporadically in the general population also possess somatic mutations in MEN1. Interestingly, the endocrine tumors of MEN1 are recapitulated in mouse models of Men1 loss that serve as a valuable resource to understand the pathophysiology and molecular basis of tumorigenesis. Exploring these endocrine tumors in mouse models using in vivo, ex vivo and in vitro methods can help to follow the process of tumorigenesis, and can be useful for preclinical testing of therapeutics and understanding their mechanisms of action. PMID:25685317

Agarwal, Sunita K

2015-01-01

232

White matter changes in preclinical Alzheimer's disease: a magnetic resonance imaging-diffusion tensor imaging study on cognitively normal older people with positive amyloid ? protein 42 levels.  

PubMed

The aim of this study was to use diffusion tensor imaging measures to determine the existence of white matter microstructural differences in the preclinical phases of Alzheimer's disease, assessing cognitively normal older individuals with positive amyloid ? protein (A?42) levels (CN_A?42+) on the basis of normal cognition and cerebrospinal fluid A?42 levels below 500 pg/mL. Nineteen CN_A?42+ and 19 subjects with A?42 levels above 500 pg/mL (CN_A?42-) were included. We encountered increases in axial diffusivity (AxD) in CN_A?42+ relative to CN_A?42- in the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus bilaterally, and also in the left fornix, left uncinate fasciculus, and left inferior fronto-occipital fasciculus. However, no differences were found in other diffusion tensor imaging indexes. Cognitive reserve scores were positively associated with AxD exclusively in the CN_A?42+ group. The finding of AxD alteration together with preserved fractional anisotropy, mean diffusivity, and radial diffusivity indexes in the CN_A?42+ group may indicate that, subtle axonal changes may be happening in the preclinical phases of Alzheimer's disease, whereas white matter integrity is still widely preserved. PMID:25002037

Molinuevo, José Luis; Ripolles, Pablo; Simó, Marta; Lladó, Albert; Olives, Jaume; Balasa, Mircea; Antonell, Anna; Rodriguez-Fornells, Antoni; Rami, Lorena

2014-12-01

233

Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma.  

PubMed

Drug resistance in cancer refers to recurrent or primary refractory disease following drug therapy. At the cellular level, it is a consequence of molecular functions that ultimately enable the cell to resist cell death-one of the classical hallmarks of cancer. Thus, drug resistance is a fundamental aspect of the cancer cell phenotype, in parallel with sustained proliferation, immortality, angiogenesis, invasion, and metastasis. Here we present a preclinical model of human B-cell cancer cell lines used to identify genes involved in specific drug resistance. This process includes a standardized technical setup for specific drug screening, analysis of global gene expression, and the statistical considerations required to develop resistance gene signatures. The state of the art is illustrated by the first-step classical drug screen (including the CD20 antibody rituximab, the DNA intercalating topoisomerase II inhibitor doxorubicin, the mitotic inhibitor vincristine, and the alkylating agents cyclophosphamide and melphalan) along with the generation of gene lists predicting the chemotherapeutic outcome as validated retrospectively in clinical trial datasets. This B-cell lineage-specific preclinical model will allow us to initiate a range of laboratory studies, with focus on specific gene functions involved in molecular resistance mechanisms. PMID:25072621

Laursen, Maria Bach; Falgreen, Steffen; Bødker, Julie Støve; Schmitz, Alexander; Kjeldsen, Malene Krag; Sørensen, Suzette; Madsen, Jakob; El-Galaly, Tarec Christoffer; Bøgsted, Martin; Dybkær, Karen; Johnsen, Hans Erik

2014-11-01

234

STUDY OF THE EFFICACY OF AN INACTIVATED VIRUS VACCINE AGAINST PORCINE PARVOVIRUS  

E-print Network

STUDY OF THE EFFICACY OF AN INACTIVATED VIRUS VACCINE AGAINST PORCINE PARVOVIRUS P. VANNIER A. BRUN, an inactivated virus vaccine (Parvo- vax ND) has been developed and its efficacy tested on pregnant sows obtained by other searchers. After measuring the efficacy of the vaccine in experimental conditions, we

Paris-Sud XI, Université de

235

Teacher Self-Efficacy and Teacher Burnout: A Study of Relations  

ERIC Educational Resources Information Center

The purpose of this study was partly to test the factor structure of a recently developed Norwegian scale for measuring teacher self-efficacy and partly to explore relations between teachers' perception of the school context, teacher self-efficacy, collective teacher efficacy, teacher burnout, teacher job satisfaction, and teachers' beliefs that…

Skaalvik, Einar M.; Skaalvik, Sidsel

2010-01-01

236

Reduced neuronal efficacy in progressive mild cognitive impairment: a prospective fMRI study on visuospatial processing.  

PubMed

Mild cognitive impairment (MCI) often refers to the preclinical stage of dementia, where the majority develop Alzheimer's disease (AD). Given that neurodegenerative burden and compensatory mechanisms might exist before accepted clinical symptoms of AD are noticeable, the current prospective study aimed to investigate the functioning of brain regions in the visuospatial networks responsible for preclinical symptoms in AD using event-related functional magnetic resonance imaging (fMRI). Eighteen MCI patients were evaluated and clinically followed for approximately 3 years. Five progressed to AD (PMCI) and eight remained stable (SMCI). Thirteen age-, gender- and education-matched controls also participated. An angle discrimination task with varying task demands was used. Brain activation patterns as well as task demand-dependent and -independent signal changes between the groups were investigated by using an extended general linear model including individual performance (reaction time [RT]) of each single trial. Similar behavioral (RT and accuracy) responses were observed between MCI patients and controls. A network of bilateral activations, e.g. dorsal pathway, which increased linearly with increasing task demand, was engaged in all subjects. Compared with SMCI patients and controls, PMCI patients showed a stronger relation between task demand and brain activity in left superior parietal lobules (SPL) as well as a general task demand-independent increased activation in left precuneus. Altered brain function can be detected at a group level in individuals that progress to AD before changes occur at the behavioral level. Increased parietal activation in PMCI could reflect a reduced neuronal efficacy due to accumulating AD pathology and might predict future clinical decline in patients with MCI. PMID:17719211

Vannini, Patrizia; Almkvist, Ove; Dierks, Thomas; Lehmann, Christoph; Wahlund, Lars-Olof

2007-10-15

237

An exploratory study of nursing and medical students health promotion counselling self-efficacy  

Microsoft Academic Search

Self-efficacy of nursing and medical students for client health promotion counselling was examined in an exploratory study using Bandura’s (1977) self-efficacy theoretical perspective. Third-year nursing students (n =41) and fourth-year medical students (n =60) were compared on their self-efficacy for engaging in clients health promotion activities within 5 areas: smoking, exercise, nutrition, sexually-transmitted diseases and injuries. Their self-efficacy about their

Heather K. Spence Laschinger; Carol P. Tresolini

1999-01-01

238

A preclinical assay for chemosensitivity in multiple myeloma  

PubMed Central

Accurate preclinical predictions of the clinical efficacy of experimental cancer drugs are highly desired but often haphazard. Such predictions might be improved by incorporating elements of the tumor microenvironment in preclinical models by providing a more physiological setting. In generating improved xenograft models, it is generally accepted that the use of primary tumors from patients are preferable to clonal tumor cell lines. Here we describe an interdisciplinary platform to study drug response in multiple myeloma (MM), an incurable cancer of the bone marrow. This platform uses microfluidic technology to minimize the number of cells per experiment, while incorporating 3D extracellular matrix and mesenchymal cells derived from the tumor microenvironment. We used sequential imaging and a novel digital imaging analysis algorithm to quantify changes in cell viability. Computational models were used convert experimental data into dose-exposure-response "surfaces" which offered predictive utility. Using this platform, we predicted chemosensitivity to bortezomib and melphalan, two clinical MM treatments, in 3 MM cell lines and 7 patient-derived primary MM cell populations. We also demonstrated how this system could be used to investigate environment-mediated drug resistance and drug combinations that target it. This interdisciplinary preclinical assay is capable of generating quantitative data that can be used in computational models of clinical response, demonstrating its utility as a tool to contribute to personalized oncology. Major Findings By designing an experimental platform with the specific intent of generating experimental parameters for a computational clinical model of personalized therapy in multiple myeloma, while taking in consideration the limitations of working with patient primary cells, and the need to incorporate elements of the tumor microenvironment, we have generated patient-individualized estimations of initial response and time to relapse to chemotherapeutic agents. PMID:24310398

Khin, Zayar P.; Ribeiro, Maria L. C.; Jacobson, Timothy; Hazlehurst, Lori; Perez, Lia; Baz, Rachid; Shain, Kenneth; Silva, Ariosto S.

2013-01-01

239

[Studies of biologic activation associated with molecular receptor increase and tumor response in ChL6/L6 protocol patients; Studies in phantoms; Quantitative SPECT; Preclinical studies; and Clinical studies]. DOE annual report, 1994--95  

SciTech Connect

The authors describe results which have not yet been published from their associated studies listed in the title. For the first, they discuss Lym-1 single chain genetically engineered molecules, analysis of molecular genetic coded messages to enhance tumor response, and human dosimetry and therapeutic human use radiopharmaceuticals. Studies in phantoms includes a discussion of planar image quantitation, counts coincidence correction, organ studies, tumor studies, and {sup 90}Y quantitation with Bremsstrahlung imaging. The study on SPECT discusses attenuation correction and scatter correction. Preclinical studies investigated uptake of {sup 90}Y-BrE-3 in mice using autoradiography. Clinical studies discuss image quantitation verses counts from biopsy samples, S factors for radiation dose calculation, {sup 67}Cu imaging studies for lymphoma cancer, and {sup 111}In MoAb imaging studies for breast cancer to predict {sup 90}Y MoAb therapy.

DeNardo, S.J.

1995-12-31

240

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development  

Microsoft Academic Search

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a

Alena V Savonenko; Tatiana Melnikova; Andrew Hiatt; Tong Li; Paul F Worley; Juan C Troncoso; Phil C Wong; Don L Price

2012-01-01

241

The value of the UK Clinical Aptitude Test in predicting pre-clinical performance: a prospective cohort study at Nottingham Medical School  

PubMed Central

Background The UK Clinical Aptitude Test (UKCAT) was introduced in 2006 as an additional tool for the selection of medical students. It tests mental ability in four distinct domains (Quantitative Reasoning, Verbal Reasoning, Abstract Reasoning, and Decision Analysis), and the results are available to students and admissions panels in advance of the selection process. As yet the predictive validity of the test against course performance is largely unknown. The study objective was to determine whether UKCAT scores predict performance during the first two years of the 5-year undergraduate medical course at Nottingham. Methods We studied a single cohort of students, who entered Nottingham Medical School in October 2007 and had taken the UKCAT. We used linear regression analysis to identify independent predictors of marks for different parts of the 2-year preclinical course. Results Data were available for 204/260 (78%) of the entry cohort. The UKCAT total score had little predictive value. Quantitative Reasoning was a significant independent predictor of course marks in Theme A ('The Cell'), (p = 0.005), and Verbal Reasoning predicted Theme C ('The Community') (p < 0.001), but otherwise the effects were slight or non-existent. Conclusion This limited study from a single entry cohort at one medical school suggests that the predictive value of the UKCAT, particularly the total score, is low. Section scores may predict success in specific types of course assessment. The ultimate test of validity will not be available for some years, when current cohorts of students graduate. However, if this test of mental ability does not predict preclinical performance, it is arguably less likely to predict the outcome in the clinical years. Further research from medical schools with different types of curriculum and assessment is needed, with longitudinal studies throughout the course. PMID:20667093

2010-01-01

242

Pre-clinical diastolic dysfunction.  

PubMed

Pre-clinical diastolic dysfunction (PDD) has been broadly defined as left ventricular diastolic dysfunction without the diagnosis of congestive heart failure (HF) and with normal systolic function. PDD is an entity that remains poorly understood, yet has definite clinical significance. Although few original studies have focused on PDD, it has been shown that PDD is prevalent, and that there is a clear progression from PDD to symptomatic HF including dyspnea, edema, and fatigue. In diabetic patients and in patients with coronary artery disease or hypertension, it has been shown that patients with PDD have a significantly higher risk of progression to heart failure and death compared with patients without PDD. Because of these findings and the increasing prevalence of the heart failure epidemic, it is clear that an understanding of PDD is essential to decreasing patients' morbidity and mortality. This review will focus on what is known concerning pre-clinical diastolic dysfunction, including definitions, staging, epidemiology, pathophysiology, and the natural history of the disease. In addition, given the paucity of trials focused on PDD treatment, studies targeting risk factors associated with the development of PDD and therapeutic trials for heart failure with preserved ejection fraction will be reviewed. PMID:24291270

Wan, Siu-Hin; Vogel, Mark W; Chen, Horng H

2014-02-11

243

The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies  

PubMed Central

In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches—from basic neurobiological approaches to human studies—might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5's important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC's arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems.

Terbeck, Sylvia; Akkus, Funda; Chesterman, Laurence P.; Hasler, Gregor

2015-01-01

244

Disulfiram, and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies.  

PubMed

Disulfiram is a FDA approved drug for the treatment of alcoholism and available for clinical use since over 5 decades. Despite data from the 1970s and 80s that showed that disulfiram and analogs are able to enhance the activity of anticancer cytotoxic drugs and might be useful chemopreventative agents, the underlying molecular mechanisms remained unknown until recently. Large scale screening efforts for agents that can inhibit the proteasome and be used as novel anticancer drugs, revealed that disulfiram has proteasome inhibitory activity. Moreover, disulfiram was also found to have specific activity against zinc fingers and RING-finger ubiquitin E3 ligases that play an important role in cancer development. Here, we review the preclinical and clinical studies exploring disulfiram as an anticancer agent as well as research programs that focus on the development of disulfiram derivatives as inhibitors of the ubiquitin-proteasome system. PMID:21247383

Kona, F R; Buac, D; M Burger, A

2011-03-01

245

Optimizing the Predictive Value of Preclinical Research Lessons Learned  

E-print Network

Optimizing the Predictive Value of Preclinical Research Lessons Learned Sharon Hesterlee Ph.D. Research Director for Parent Project Muscular Dystrophy and the Association for Frontotemporal Degeneration of these estimates What We Need (Stanley Lazic, F. Hoffman-LaRoche): #12;Consistent Theme: Treat preclinical study

246

Preclinical and clinical research on inflammation after intracerebral hemorrhage  

Microsoft Academic Search

Intracerebral hemorrhage (ICH) is one of the most lethal stroke subtypes. Despite the high morbidity and mortality associated with ICH, its pathophysiology has not been investigated as well as that of ischemic stroke. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. For example, in preclinical ICH models,

Jian Wang

2010-01-01

247

Contrasting gray and white matter changes in preclinical Huntington disease  

E-print Network

Contrasting gray and white matter changes in preclinical Huntington disease An MRI study DD ABSTRACT Background: In Huntington disease (HD), substantial striatal atrophy precedes clinical motor of view; GM gray matter; HD Huntington disease; MRI magnetic resonance imaging; pre-HD preclinical HD

Aron, Adam

248

Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAF(V600E) or wild-type BRAF.  

PubMed

Molecular signature of advanced and metastatic thyroid carcinoma involves deregulation of multiple fundamental pathways activated in the tumor microenvironment. They include BRAF(V600E) and AKT that affect tumor initiation, progression and metastasis. Human thyroid cancer orthotopic mouse models are based on human cell lines that generally harbor genetic alterations found in human thyroid cancers. They can reproduce in vivo and in situ (into the thyroid) many features of aggressive and refractory human advanced thyroid carcinomas, including local invasion and metastasis. Humanized orthotopic mouse models seem to be ideal and commonly used for preclinical and translational studies of compounds and therapies not only because they may mimic key aspects of human diseases (e.g. metastasis), but also for their reproducibility. In addition, they might provide the possibility to evaluate systemic effects of treatments. So far, human thyroid cancer in vivo models were mainly used to test single compounds, non selective and selective. Despite the greater antitumor activity and lower toxicity obtained with different selective drugs in respect to non-selective ones, most of them are only able to delay disease progression, which ultimately could restart with similar aggressive behavior. Aggressive thyroid tumors (for example, anaplastic or poorly differentiated thyroid carcinoma) carry several complex genetic alterations that are likely cooperating to promote disease progression and might confer resistance to single-compound approaches. Orthotopic models of human thyroid cancer also hold the potential to be good models for testing novel combinatorial therapies. In this article, we will summarize results on preclinical testing of selective and nonselective single compounds in orthotopic mouse models based on validated human thyroid cancer cell lines harboring the BRAF(V600E) mutation or with wild-type BRAF. Furthermore, we will discuss the potential use of this model also for combinatorial approaches, which are expected to take place in the upcoming human thyroid cancer basic and clinical research. PMID:24362526

Antonello, Z A; Nucera, C

2014-11-20

249

Comparative Effectiveness of 3-Dimensional vs 2-Dimensional and High-Definition vs Standard-Definition Neuroendoscopy: A Preclinical Randomized Crossover Study  

PubMed Central

BACKGROUND: Although the potential benefits of 3-dimensional (3-D) vs 2-dimensional (2-D) and high-definition (HD) vs standard-definition (SD) endoscopic visualization have long been recognized in other surgical fields, such endoscopes are generally considered too large and bulky for use within the brain. The recent development of 3-D and HD neuroendoscopes may therefore herald improved depth perception, better appreciation of anatomic details, and improved overall surgical performance. OBJECTIVE: To compare simultaneously the effectiveness of 3-D vs 2-D and HD vs SD neuroendoscopy. METHODS: Ten novice neuroendoscopic surgeons were recruited from a university hospital. A preclinical randomized crossover study design was adopted to compare 3-D vs 2-D and HD vs SD neuroendoscopy. The primary outcomes were time to task completion and accuracy. The secondary outcomes were perceived task workload using the NASA (National Aeronautics and Space Administration) Task Load Index and subjective impressions of the endoscopes using a 5-point Likert scale. RESULTS: Time to task completion was significantly shorter when using the 3-D vs the 2-D neuroendoscopy (P = .001), and accuracy of probe placement was significantly greater when using the HD vs the SD neuroendoscopy (P = .009). We found that 3-D endoscopy significantly improved perceived depth perception (P < .001), HD endoscopy significantly improved perceived image quality (P < .001), and both improved participants’ overall impression (P < .001). CONCLUSION: Three-dimensional neuroendoscopy and HD neuroendoscopy have differing but complementary effects on surgical performance, suggesting that neither alone can completely compensate for the lack of the other. There is therefore strong preclinical evidence to justify 3-D HD neuroendoscopy. ABBREVIATIONS: HD, high definition SD, standard definition PMID:24220007

Hughes-Hallett, Archie; Cundy, Thomas P.; Di Marco, Aimee; Pratt, Philip; Nandi, Dipankar; Darzi, Ara; Yang, Guang-Zhong

2013-01-01

250

Lesson Study, Collaboration and Teacher Efficacy: Stories from Two School-Based Math Lesson Study Groups  

ERIC Educational Resources Information Center

This article describes the experiences of two US teacher groups and their lesson study work. Their stories illustrate some of the dynamics and promise of teacher change spurred by lesson study. The first case is primarily about teacher efficacy, as a group of teachers discover through lesson study that their planning and work can have an impact on…

Puchner, Laurel D.; Taylor, Ann R.

2006-01-01

251

Lesson study, collaboration and teacher efficacy: Stories from two school-based math lesson study groups  

Microsoft Academic Search

This article describes the experiences of two US teacher groups and their lesson study work. Their stories illustrate some of the dynamics and promise of teacher change spurred by lesson study. The first case is primarily about teacher efficacy, as a group of teachers discover through lesson study that their planning and work can have an impact on student engagement

Laurel D. Puchner; Ann R. Taylor

2006-01-01

252

Novel HDAC inhibitors exhibit pre-clinical efficacy in lymphoma models and point to the importance of CDKN1A expression levels in mediating their anti-tumor response.  

PubMed

We investigated the pre-clinical activities of two novel histone deacetylase inhibitors (HDACi), ITF-A and ITF-B, in a large panel of pre-clinical lymphoma models. The two compounds showed a dose-dependent anti-proliferative activity in the majority of cell lines. Gene expression profiling (GEP) of diffuse large B-cell lymphoma (DLBCL) cells treated with the compounds showed a modulation of genes involved in chromatin structure, cell cycle progression, apoptosis, B-cell signaling, and genes encoding metallothioneins. Cell lines showed differences between the concentrations of ITF-A and ITF-B needed to cause anti-proliferative or cytotoxic activity, and cell cycle and apoptosis genes appeared implicated in determining the type of response. In particular, CDKN1A expression was higher in DLBCL cells that, to undergo apoptosis, required a much higher amount of drug than that necessary to induce only an anti-proliferative effect.In conclusion, the two novel HDACi ITF-A and ITF-B demonstrated anti-proliferative activity across different mature B-cell lymphoma cell lines. Basal CDKN1A levels appeared to be important in determining the gap between HDACi concentrations causing cell cycle arrest and those that lead to cell death. PMID:25671298

Mensah, Afua Adjeiwaa; Kwee, Ivo; Gaudio, Eugenio; Rinaldi, Andrea; Ponzoni, Maurilio; Cascione, Luciano; Fossati, Gianluca; Stathis, Anastasios; Zucca, Emanuele; Caprini, Gianluca; Bertoni, Francesco

2015-03-10

253

Characterization of Novel PI3K? Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies  

PubMed Central

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T–B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase ? (PI3K?) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3K? inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP®) without detecting signs of undesired toxicity. In an IFN?-accelerated mouse SLE model, our PI3K? inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3K? inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3K? inhibitors in SLE and lupus nephritis. PMID:24904582

Haselmayer, Philipp; Camps, Montserrat; Muzerelle, Mathilde; El Bawab, Samer; Waltzinger, Caroline; Bruns, Lisa; Abla, Nada; Polokoff, Mark A.; Jond-Necand, Carole; Gaudet, Marilène; Benoit, Audrey; Bertschy Meier, Dominique; Martin, Catherine; Gretener, Denise; Lombardi, Maria Stella; Grenningloh, Roland; Ladel, Christoph; Petersen, Jørgen Søberg; Gaillard, Pascale; Ji, Hong

2014-01-01

254

Typhoid fever vaccines: a meta›analysis of studies on efficacy and toxicity  

Microsoft Academic Search

Objective: To estimate the efficacy and toxicity of typhoid fever vaccines. Design: Meta›analysis of randomised efficacy trials and both randomised and non›randomised toxicity studies of the parenteral whole cell, oral Ty21a, and parenteral Vi vaccines. Subjects: 1 866 951 subjects in 17 efficacy trials; 11 204 subjects in 20 toxicity studies. Main outcome measures: Pooled estimates of three year cumulative

Eric A Engels; Matthew E Falagas; Joseph Lau; Michael L Bennish

1998-01-01

255

linical study on intrathecal baclofen for the treatment of severe spasticity: Developed protocol and obtained grant funding for the initial research project; confirmed efficacy and  

E-print Network

protocol and obtained grant funding for the initial research project; confirmed efficacy and showed cost effectiveness (with P. Nance). ew research technology: the first implementation in Canada of the isolated rat spinal cord preparation, allowing preclinical trials for the development of new drug treatments for use

Manitoba, University of

256

The relationship between efficacy and methodology in studies investigating EMDR treatment of PTSD  

Microsoft Academic Search

The controlled treatment outcome studies that examined the efficacy of EMDR in the treatment of posttraumatic stress disorder have yielded a range of results, with the efficacy of EMDR varying across studies. The current study sought to determine if differences in outcome were related to methodological differences. The research was reviewed to identify meth- odological strengths, weaknesses, and empirical findings.

Louise Maxfield; Lee Hyer

2002-01-01

257

Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.  

PubMed

Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (?5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G2-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer. PMID:24002934

Mittapalli, Rajendar K; Liu, Xinli; Adkins, Chris E; Nounou, Mohamed I; Bohn, Kaci A; Terrell, Tori B; Qhattal, Hussaini S; Geldenhuys, Werner J; Palmieri, Diane; Steeg, Patricia S; Smith, Quentin R; Lockman, Paul R

2013-11-01

258

Studies on antimicrobial efficacy of medicinal tuberous shrub Talinum cuneifolium.  

PubMed

Talinum cuneifolium (Vahl.) Willd. an erect shrub with subterranian tuber (Portulacaceae) is endowed with wide range of pharmacological activities. The antimicrobial efficacy of the plant is evaluated against three bacteria and two fungal species by disc diffusion method. Preliminary phytochemical screening was carried out among hexane, ethylacetate, methanolic extracts of leaf and roottuber for different potent chemicals. The leaf methanolic extract of T cuneifolium showed maximum effect on the growth of Proteus (25.8 mm) followed by Bacillus (24.62 mm) and E. coli (19.42 mm). The tuberous methanolic extract of T cuneifolium showed maximum effect on growth of Proteus (28.15 mm) followed by Bacillus (26.88 mm) and E. coli (24.51 mm). The Gram-positive bacterial strains (Bacillus) were more susceptible to the extractions of T cuneifolium as compared to Gram-negative bacteria (E. coli, Pseudomonas aeruginosa, Proteus vulgaris and Klebsiella pneumoneia). The antifungal activity of selected plant leaf and root tubers exhibit pronounced activity against Candida albicans rather than Aspergillus niger. These studies showed that the methanolic extracts of T cuneifolium plant parts were certainly much better and powerful. This may be due to the better solubility of the action components in organic solvent. PMID:23360007

Savithramma, N; Ankanna, S; Rao, M Linga; Saradvathi, J

2012-07-01

259

A Study of Efficacy and Professional Development among Alternatively-Certified Teachers in Arizona  

ERIC Educational Resources Information Center

The purpose of this descriptive and comparative study was to investigate the self-assessed efficacy levels of alternatively-certified teachers in Arizona. More specifically, this study examined the teachers' perceived ability to influence student learning and the extent to which, if at all, their self-reported efficacy levels differed based on the…

Ludlow, Carlyn

2010-01-01

260

A Study Investigating Relationships between Elementary Principals' and Teachers' Self-Efficacy and Student Achievement  

ERIC Educational Resources Information Center

In order to examine effective behaviors and efficacy, this study examined the relationships between the self-reflection of effective practices by principals and teachers, as assessed by self-efficacy scales, and student achievement, as evaluated by the state assessment program. Other studies determined that effective behaviors preceded and…

Domsch, Gayle D.

2009-01-01

261

Preclinical Molecular Imaging of Tumor Angiogenesis  

PubMed Central

Angiogenesis, a course that new blood vessels grow from the existing vasculature, plays important roles both physiologically and pathologically. Angiogenesis can be switched on by growth factors secreted by tumor cells, and in turn supplies more oxygen and nutrition to the tumor. More and more preclinical studies and clinical trials have shown that inhibition of angiogenesis is an effective way to inhibit tumor growth, substantiating the development of anti-angiogenesis therapeutics. Imaging technologies accelerate the translation of preclinical research to the clinic. In oncology, various imaging modalities are widely applied to drug development, tumor early detection and therapy response monitoring. So far, several angiogenesis related imaging agents are promising in cancer diagnosis. However, more effective imaging agents with less side-effect still need to be pursued to visualize angiogenesis process non-invasively. The main purpose of this review is to summarize the recent progresses in preclinical molecular imaging of angiogenesis and to discuss the potential of the current preclinical probes specific to various angiogenesis targets including vascular endothelial growth factor and its receptors (VEGF/VEGFRs), integrin ?v?3 and matrix metalloproteinases (MMPs). It is predicable that related investigations in the field will benefit cancer research and quicken the anti-angiogenic drug development. PMID:20639815

Zhu, Lei; Niu, Gang; Fang, Xuexun; Chen, Xiaoyuan

2010-01-01

262

System Vaccinology for the Evaluation of Influenza Vaccine Safety by Multiplex Gene Detection of Novel Biomarkers in a Preclinical Study and Batch Release Test  

PubMed Central

Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, ?2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and vaccine safety as an alternative to animal testing. PMID:25010690

Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J.; Hamaguchi, Isao; Yamaguchi, Kazunari

2014-01-01

263

Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013  

PubMed Central

Biosimilar development involves a target-directed iterative process to ensure a similar product to the originator. Here we report the preclinical development of the proposed biosimilar rituximab (GP2013). Post-translational modifications and bioactivities of GP2013 versus originator rituximab were engineered and monitored to ensure similar pharmacological profiles. Antibody-dependent cellular cytotoxicity (ADCC) was used to illustrate how different glycosylation patterns and structure–function relationships were controlled during process development. Pharmacological comparability between GP2013 and originator rituximab were confirmed in preclinical studies using clinical scale drug product. Similar in vitro ADCC potency was demonstrated when compared in a dose–response manner against two lymphoma cell lines using freshly purified human natural killer (NK) cells. In vivo efficacy was demonstrated in two well characterized mouse xenograft models, testing at sensitive sub-therapeutic dose levels. Pharmacokinetics and pharmacodynamics (CD20 cell depletion) were likewise comparable in cynomolgus monkeys. This preclinical comparability exercise confirms that GP2013 and originator rituximab are pharmacologically similar. PMID:24024472

Kronthaler, Ulrich; Koppenburg, Vera; Fink, Martin; Meyer, Ines; Papandrikopoulou, Anastassia; Hofmann, Matthias; Stangler, Thomas; Visser, Jan

2014-01-01

264

Preclinical study of SZ2080 material 3D microstructured scaffolds for cartilage tissue engineering made by femtosecond direct laser writing lithography.  

PubMed

Over the last decade DLW employing ultrafast pulsed lasers has become a well-established technique for the creation of custom-made free-form three-dimensional (3D) microscaffolds out of a variety of materials ranging from proteins to biocompatible glasses. Its potential applications for manufacturing a patient's specific scaffold seem unlimited in terms of spatial resolution and geometry complexity. However, despite few exceptions in which live cells or primitive organisms were encapsulated into a polymer matrix, no demonstration of an in vivo study case of scaffolds generated with the use of such a method was performed. Here, we report a preclinical study of 3D artificial microstructured scaffolds out of hybrid organic-inorganic (HOI) material SZ2080 fabricated using the DLW technique. The created 2.1 × 2.1 × 0.21 mm(3) membrane constructs are tested both in vitro by growing isolated allogeneic rabbit chondrocytes (Cho) and in vivo by implanting them into rabbit organisms for one, three and six months. An ex vivo histological examination shows that certain pore geometry and the pre-growing of Cho prior to implantation significantly improves the performance of the created 3D scaffolds. The achieved biocompatibility is comparable to the commercially available collagen membranes. The successful outcome of this study supports the idea that hexagonal-pore-shaped HOI microstructured scaffolds in combination with Cho seeding may be successfully implemented for cartilage tissue engineering. PMID:25797444

Ma?iulaitis, Justinas; Deveikyt?, Milda; Rekštyt?, Sima; Bratchikov, Maksim; Darinskas, Adas; Šimbelyt?, Agn?; Daunoras, Gintaras; Laurinavi?ien?, Aida; Laurinavi?ius, Arvydas; Gudas, Rimtautas; Malinauskas, Mangirdas; Ma?iulaitis, Romaldas

2015-01-01

265

Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer  

NASA Astrophysics Data System (ADS)

Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets.

Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric

2014-05-01

266

Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated Born-normalization and in vivo preclinical study of cancer.  

PubMed

Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets. PMID:24880378

Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric

2014-05-01

267

Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer  

SciTech Connect

Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets.

Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric, E-mail: frederic.lesage@polymtl.ca [Institute of Biomedical Engineering, École Polytechnique de Montréal, Montreal, Quebec H3C 3A7 (Canada) [Institute of Biomedical Engineering, École Polytechnique de Montréal, Montreal, Quebec H3C 3A7 (Canada); Montreal Heart Institute, Montreal, Quebec H1T 1C8 (Canada)

2014-05-15

268

Diffusion imaging for evaluation of tumor therapies in preclinical animal models  

Microsoft Academic Search

The increasing development of novel targeted therapies for treating solid tumors has necessitated the development of technology to determine their efficacy in preclinical animal models. One such technology that can non-invasively quantify early changes in tumor cellularity as a result of an efficacious therapy is diffusion MRI. In this overview we present some theories as to the origin of diffusion

B. A. Moffat; D. E. Hall; J. Stojanovska; P. J. McConville; J. B. Moody; T. L. Chenevert; A. Rehemtulla; B. D. Ross

2004-01-01

269

Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss  

PubMed Central

Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1?/?NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1?/?NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers. PMID:25436981

Andrade-Vieira, Rafaela; Goguen, Donna; Bentley, Heidi A.; Bowen, Chris V.; Marignani, Paola A.

2014-01-01

270

Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss.  

PubMed

Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1-/-NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1-/-NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers. PMID:25436981

Andrade-Vieira, Rafaela; Goguen, Donna; Bentley, Heidi A; Bowen, Chris V; Marignani, Paola A

2014-12-30

271

Studies examining the efficacy of Ankle Foot Orthoses should report activity level and mechanical evidence  

Microsoft Academic Search

Ankle Foot Orthoses (AFOs) to promote walking ability are a common treatment in patients with neurological or muscular diseases. However, guidelines on the prescription of AFOs are currently based on a low level of evidence regarding their efficacy. Recent studies aiming to demonstrate the efficacy of wearing an AFO in respect to walking ability are not always conclusive. In this

Jaap Harlaar; Merel Brehm; Jules G. Becher; Daan J. J. Bregman; Jaap Buurke; Fred Holtkamp; Groot de V; Frans Nollet

2010-01-01

272

Estimating Influenza Vaccine Efficacy From Challenge and Community-based Study Data  

Microsoft Academic Search

In this paper, the authors provide estimates of 4 measures of vaccine efficacy for live, attenuated and inactivated influenza vaccine based on secondary analysis of 5 experimental influenza challenge studies in seronegative adults and community-based vaccine trials. The 4 vaccine efficacy measures are for susceptibility (VES), symp- tomatic illness given infection (VEP), infection and illness (VESP), and infectiousness (VEI). The

Nicole E. Basta; M. Elizabeth Halloran; Laura Matrajt; Ira M. Longini

2008-01-01

273

A Survey Study of Chinese In-Service Teachers' Self-Efficacy about Inclusive Education  

ERIC Educational Resources Information Center

A survey study was conducted to a total of 323 in-service teachers (110 special education teachers and 213 general education teachers) in Shanghai regarding their self-efficacy and concerns about inclusive education. Multivariate analysis results reveal that special teachers have significantly higher self-efficacy about inclusive education than…

Wang, Mian; Zan, Fei; Liu, Jiaqiu; Liu, Chunling; Sharma, Umesh

2012-01-01

274

Emotional Intelligence and Teacher Efficacy: A Study of Turkish EFL Pre-Service Teachers  

ERIC Educational Resources Information Center

This study investigated the relationship between emotional intelligence and teacher efficacy among 90 English language pre-service teachers from a university in Turkey. Data sources included Tschannen-Moran and Woolfolk-Hoy's Teachers' Sense of Efficacy Scale and Reuven Bar-On's Emotional Quotient Inventory. The findings indicated that Turkish EFL…

Kocoglu, Zeynep

2011-01-01

275

Agricultural Education Perceived Teacher Self-Efficacy: A Descriptive Study of Beginning Agricultural Education Teachers  

ERIC Educational Resources Information Center

The purpose of this study was to describe beginning agriculture teachers' perceived agricultural education teacher self-efficacy. Additionally, the researcher sought to describe the relationship among teachers' demographic characteristics and their agricultural education teacher self-efficacy. An instrument specific to agricultural education was…

Wolf, Kattlyn J.

2011-01-01

276

Education for Sustainability: A Case Study of Preservice Primary Teachers' Knowledge and Efficacy  

ERIC Educational Resources Information Center

This study investigated the relationships between knowledge and efficacy for teaching sustainability in a sample of 266 pre-service primary teachers at a large, metropolitan university in Australia. A survey gathered information about the participant's attitudes and self-efficacy for education for sustainability, along with their perceived…

Effeney, Gerard; Davis, Julie

2013-01-01

277

A Confirmatory Study of Rating Scale Category Effectiveness for the Coaching Efficacy Scale  

ERIC Educational Resources Information Center

This study extended validity evidence for measures of coaching efficacy derived from the Coaching Efficacy Scale (CES) by testing the rating scale categorizations suggested in previous research. Previous research provided evidence for the effectiveness of a four-category (4-CAT) structure for high school and collegiate sports coaches; it also…

Myers, Nicholas D.; Feltz, Deborah L.; Wolfe, Edward W.

2008-01-01

278

Using Mathematics in Teaching Science Self-Efficacy Scale--UMSSS: A Validity and Reliability Study  

ERIC Educational Resources Information Center

In this study, an instrument, Using Mathematics in Science Self-efficacy Scale (UMSSS), was developed in order to determine preservice science teachers' self-efficacy toward the use of mathematics in their lessons. Data gathered from 250 preservice science teachers were used for Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis…

Can, Bilge Taskin; Gunhan, Berna Canturk; Erdal, Sevinc Ongel

2012-01-01

279

Collective Efficacy: A Neglected Construct in the Study of Schools and Student Achievement  

Microsoft Academic Search

A theoretical analysis is advanced that discusses social cognitive theory at the group level to explain the formation and impact of collective efficacy. The study used student- and school-level data from a sample of urban elementary schools. Consistent with social cognitive theory, mastery experience was found to be a significant predictor of differences between schools in teachers’ collective efficacy perceptions.

Roger D. Goddard

2001-01-01

280

An Exploratory Study into the Efficacy of Learning Objects  

ERIC Educational Resources Information Center

Learning objects have quickly become a widely accepted approach to instructional technology, particularly in on-line and computer-based learning environments. While there is a substantial body of literature concerning learning objects, very little of it verifies their efficacy. This research investigated the effectiveness of learning objects by…

Farha, Nicholas W.

2009-01-01

281

Human insulin: study of safety and efficacy in man  

Microsoft Academic Search

The safety and efficacy of a new highly purified neutral soluble human insulin produced by conversion of porcine insulin was compared with a highly purified neutral soluble porcine insulin in six normal men. The insulins were administered by subcutaneous injection at a dose of 0.075 U\\/kg body weight. Somatostatin was infused during the experiment to suppress endogenous insulin secretin. No

D R Owens; M K Jones; T M Hayes; L G Heding; K G Alberti; P D Home; J M Burrin; R G Newcombe

1981-01-01

282

Viewpoint: leaving the "empty glass" of problem-based learning behind: new assumptions and a revised model for case study in preclinical medical education.  

PubMed

The popularity of problem-based learning (PBL) reflects medical educators' recognition that case study can enhance the preclinical medical school curriculum. However, the PBL method itself has features, particularly its reliance on small-group work with tutor-facilitators, that are expensive to implement and that limit the potential educational value of case study. The author systematically analyzes specific aspects of the PBL methodology and concludes that the PBL approach misuses the faculty, tends to compromise the authenticity of cases, and results in an unnecessarily varied and impoverished educational experience for students. Approaches to case study with different assumptions need to be devised. A model is proposed that shifts the goal of case study from development of problem-solving skills to development of ideas that allow meaningful engagement in sophisticated discussions of medicine. In this model, the method shifts from self-directed learning to independent study guided by the expertise of the faculty. One possible approach to case study based on this model is briefly described. It consists of reading published cases from the medical literature, with analysis and discussion of the cases led by faculty experts in large-group format. The approach immerses students in an authentic, state-of-the-art discussion of medicine and is easily incorporated into any curriculum structure at limited cost. The author argues that, contrary to the claims of proponents, the glass is "mostly empty" for PBL and that we can generate the higher-level discussion that case study merits only by moving away from PBL's extraneous assumptions. PMID:17457072

Shanley, Paul F

2007-05-01

283

Preclinical Evaluation of the Immunomodulatory Properties of Cardiac Adipose Tissue Progenitor Cells Using Umbilical Cord Blood Mesenchymal Stem Cells: A Direct Comparative Study  

PubMed Central

Cell-based strategies to regenerate injured myocardial tissue have emerged over the past decade, but the optimum cell type is still under scrutiny. In this context, human adult epicardial fat surrounding the heart has been characterized as a reservoir of mesenchymal-like progenitor cells (cardiac ATDPCs) with potential clinical benefits. However, additional data on the possibility that these cells could trigger a deleterious immune response following implantation are needed. Thus, in the presented study, we took advantage of the well-established low immunogenicity of umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to comparatively assess the immunomodulatory properties of cardiac ATDPCs in an in vitro allostimulatory assay using allogeneic mature monocyte-derived dendritic cells (MDDCs). Similar to UCBMSCs, increasing amounts of seeded cardiac ATDPCs suppressed the alloproliferation of T cells in a dose-dependent manner. Secretion of proinflammatory cytokines (IL6, TNF?, and IFN?) was also specifically modulated by the different numbers of cardiac ATDPCs cocultured. In summary, we show that cardiac ATDPCs abrogate T cell alloproliferation upon stimulation with allogeneic mature MDDCs, suggesting that they could further regulate a possible harmful immune response in vivo. Additionally, UCBMSCs can be considered as valuable tools to preclinically predict the immunogenicity of prospective regenerative cells. PMID:25861626

Perea-Gil, Isaac; Monguió-Tortajada, Marta; Gálvez-Montón, Carolina; Bayes-Genis, Antoni; Borràs, Francesc E.; Roura, Santiago

2015-01-01

284

Transplantation of umbilical cord-derived mesenchymal stem cells as a novel strategy to protect the central nervous system: technical aspects, preclinical studies, and clinical perspectives.  

PubMed

The prevention of perinatal neurological disabilities remains a major challenge for public health, and no neuroprotective treatment to date has proven clinically useful in reducing the lesions leading to these disabilities. Efforts are, therefore, urgently needed to test other neuroprotective strategies including cell therapies. Although stem cells have raised great hopes as an inexhaustible source of therapeutic products that could be used for neuroprotection and neuroregeneration in disorders affecting the brain and spinal cord, certain sources of stem cells are associated with potential ethical issues. The human umbilical cord (hUC) is a rich source of stem and progenitor cells including mesenchymal stem cells (MSCs) derived either from the cord or from cord blood. hUC MSCs (hUC-MSCs) have several advantages as compared to other types and sources of stem cells. In this review, we will summarize the most recent findings regarding the technical aspects and the preclinical investigation of these promising cells in neuroprotection and neuroregeneration, and their potential use in the developing human brain. However, extensive studies are needed to optimize the administration protocol, safety parameters, and potential preinjection cell manipulations before designing a controlled trial in human neonates. PMID:22430384

Dalous, Jérémie; Larghero, Jérome; Baud, Olivier

2012-04-01

285

Autofluorescence imaging device for real-time detection and tracking of pathogenic bacteria in a mouse skin wound model: preclinical feasibility studies.  

PubMed

Bacterial infection significantly impedes wound healing. Clinical diagnosis of wound infections is subjective and suboptimal, in part because bacteria are invisible to the naked eye during clinical examination. Moreover, bacterial infection can be present in asymptomatic patients, leading to missed opportunities for diagnosis and treatment. We developed a prototype handheld autofluorescence (AF) imaging device (Portable Real-time Optical Detection, Identification and Guidance for Intervention - PRODIGI) to noninvasively visualize and measure bacterial load in wounds in real time. We conducted preclinical pilot studies in an established nude mouse skin wound model inoculated with bioluminescent Staphylococcus aureus bacteria. We tested the feasibility of longitudinal AF imaging for in vivo visualization of bacterial load in skin wounds, validated by bioluminescence imaging. We showed that bacteria (S. aureus), occult to standard examination, can be visualized in wounds using PRODIGI. We also detected quantitative changes in wound bacterial load over time based on the antibiotic treatment and the correlation of bacterial AF intensity with bacterial load. AF imaging of wounds offers a safe, noninvasive method for visualizing the presence, location, and extent of bacteria as well as measuring relative changes in bacterial load in wounds in real time. PMID:25089944

Wu, Yichao Charlie; Kulbatski, Iris; Medeiros, Philip J; Maeda, Azusa; Bu, Jiachuan; Xu, Lizhen; Chen, Yonghong; DaCosta, Ralph S

2014-08-01

286

The ?2?1 binding domain of chondroadherin inhibits breast cancer-induced bone metastases and impairs primary tumour growth: a preclinical study.  

PubMed

cyclicCHAD is a peptide representing the ?2?1 integrin binding sequence of the matrix protein chondroadherin (CHAD), which in our hands proved effective at counteracting bone loss in ovariectomised mice by inhibiting osteoclastogenesis. Given that bone metastases are characterised by exacerbated osteoclast activity as well, we tested this therapy in mice intracardiacally injected with the osteotropic human breast cancer cell line MDA-MB-231. Treatment with cyclicCHAD significantly decreased cachexia and incidence of bone metastases, and induced a trend of reduction of visceral metastasis volume, while in orthotopically injected mice cyclicCHAD reduced tumour volume. In vitro studies showed its ability to impair tumour cell motility and invasion, suggesting a direct effect not only on osteoclasts but also on the tumour cell phenotype. Interestingly, when administered together with a suboptimal, poorly effective, dose of doxorubicin (DXR), cyclicCHAD improved survival and reduced visceral metastases volume to a level similar to that of the optimal dose of DXR alone. Taken together, these preclinical data suggest that cyclicCHAD is a new inhibitor of bone metastases, with an appreciable direct effect also on tumour growth and a synergistic activity in combination with low dose chemotherapy, underscoring an important translational impact. PMID:25529009

Rucci, Nadia; Capulli, Mattia; Olstad, Ole K; Önnerfjord, Patrik; Tillgren, Viveka; Gautvik, Kaare M; Heinegård, Dick; Teti, Anna

2015-03-01

287

Universal hand-held three-dimensional optoacoustic imaging probe for deep tissue human angiography and functional preclinical studies in real time.  

PubMed

The exclusive combination of high optical contrast and excellent spatial resolution makes optoacoustics (photoacoustics) ideal for simultaneously attaining anatomical, functional and molecular contrast in deep optically opaque tissues. While enormous potential has been recently demonstrated in the application of optoacoustics for small animal research, vast efforts have also been undertaken in translating this imaging technology into clinical practice. We present here a newly developed optoacoustic tomography approach capable of delivering high resolution and spectrally enriched volumetric images of tissue morphology and function in real time. A detailed description of the experimental protocol for operating with the imaging system in both hand-held and stationary modes is provided and showcased for different potential scenarios involving functional and molecular studies in murine models and humans. The possibility for real time visualization in three dimensions along with the versatile handheld design of the imaging probe make the newly developed approach unique among the pantheon of imaging modalities used in today's preclinical research and clinical practice. PMID:25408083

Deán-Ben, Xosé; Fehm, Thomas Felix; Razansky, Daniel

2014-01-01

288

Autofluorescence imaging device for real-time detection and tracking of pathogenic bacteria in a mouse skin wound model: preclinical feasibility studies  

NASA Astrophysics Data System (ADS)

Bacterial infection significantly impedes wound healing. Clinical diagnosis of wound infections is subjective and suboptimal, in part because bacteria are invisible to the naked eye during clinical examination. Moreover, bacterial infection can be present in asymptomatic patients, leading to missed opportunities for diagnosis and treatment. We developed a prototype handheld autofluorescence (AF) imaging device (Portable Real-time Optical Detection, Identification and Guidance for Intervention-PRODIGI) to noninvasively visualize and measure bacterial load in wounds in real time. We conducted preclinical pilot studies in an established nude mouse skin wound model inoculated with bioluminescent Staphylococcus aureus bacteria. We tested the feasibility of longitudinal AF imaging for in vivo visualization of bacterial load in skin wounds, validated by bioluminescence imaging. We showed that bacteria (S. aureus), occult to standard examination, can be visualized in wounds using PRODIGI. We also detected quantitative changes in wound bacterial load over time based on the antibiotic treatment and the correlation of bacterial AF intensity with bacterial load. AF imaging of wounds offers a safe, noninvasive method for visualizing the presence, location, and extent of bacteria as well as measuring relative changes in bacterial load in wounds in real time.

Wu, Yichao Charlie; Kulbatski, Iris; Medeiros, Philip J.; Maeda, Azusa; Bu, Jiachuan; Xu, Lizhen; Chen, Yonghong; DaCosta, Ralph S.

2014-08-01

289

Female Mecp2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies.  

PubMed

Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Typical RTT primarily affects girls and is characterized by a brief period of apparently normal development followed by the loss of purposeful hand skills and language, the onset of anxiety, hand stereotypies, autistic features, seizures and autonomic dysfunction. Mecp2 mouse models have extensively been studied to demonstrate the functional link between MeCP2 dysfunction and RTT pathogenesis. However, the majority of studies have focused primarily on the molecular and behavioral consequences of the complete absence of MeCP2 in male mice. Studies of female Mecp2(+/-) mice have been limited because of potential phenotypic variability due to X chromosome inactivation effects. To determine whether reproducible and reliable phenotypes can be detected Mecp2(+/-) mice, we analyzed Mecp2(+/-) mice of two different F1 hybrid isogenic backgrounds and at young and old ages using several neurobehavioral and physiological assays. Here, we report a multitude of phenotypes in female Mecp2(+/-) mice, some presenting as early as 5 weeks of life. We demonstrate that Mecp2(+/-) mice recapitulate several aspects of typical RTT and show that mosaic expression of MeCP2 does not preclude the use of female mice in behavioral and molecular studies. Importantly, we uncover several behavioral abnormalities that are present in two genetic backgrounds and report on phenotypes that are unique to one background. These findings provide a framework for pre-clinical studies aimed at improving the constellation of phenotypes in a mouse model of RTT. PMID:23026749

Samaco, Rodney C; McGraw, Christopher M; Ward, Christopher S; Sun, Yaling; Neul, Jeffrey L; Zoghbi, Huda Y

2013-01-01

290

Rigor or mortis: best practices for preclinical research in neuroscience.  

PubMed

Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. PMID:25442936

Steward, Oswald; Balice-Gordon, Rita

2014-11-01

291

Evaluation of diethylnitrosamine- or hepatitis B virus X gene-induced hepatocellular carcinoma with 18F-FDG PET/CT: a preclinical study.  

PubMed

The aim of this study was to evaluate whether the development of hepatocellular carcinoma (HCC) in murine models resembles tumor progression in humans, using non?invasive molecular imaging methods. Murine HCC models were generated by treating mice with diethylnitrosamine (DEN) or by the transgenic expression of hepatitis B virus X (HBx) protein (HBx-Tg model). Tumor development was detected using 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The histopathological changes and expression of glucose transporter 1 (Glut1) and hexokinase 2 (HK2) were evaluated using hematoxylin and eosin and immunohistochemical staining, respectively. Tumor lesions as small as 1 mm in diameter were detected by MRI. Tumor development was monitored using 18F-FDG PET/CT at 6.5?10 months after DEN treatment or 11?20 months after birth of the HBx-Tg model mice. A correlation study between the 18F-FDG uptake levels and expression levels of HK2 and Glut1 in developed HCC showed a high 18F-FDG uptake in poorly differentiated HCCs that expressed high levels of HK2, in contrast to that in well-differentiated tumors. The progression of primary HCCs resembling human HCC in murine models was detected and monitored by 18F-FDG PET/CT. The correlation between tumor size and SUVmax was verified in the two HCC models. To the best of our knowledge, this is the first study to demonstrate that in vivo 18F-FDG uptake varies in HCCs according to differentiation grade in a preclinical study. PMID:25371060

Park, Ju Hui; Kang, Joo Hyun; Lee, Yong Jin; Kim, Kwang Il; Lee, Tae Sup; Kim, Kyeong Min; Park, Ji Ae; Ko, Yin Ohk; Yu, Dae-Yeul; Nahm, Sang-Soep; Jeon, Tae Joo; Park, Young-Seo; Lim, Sang Moo

2015-01-01

292

A cross cultural study of gender-role orientation and entrepreneurial self-efficacy  

Microsoft Academic Search

The study of gender differences in entrepreneurial self-efficacy to date has produced inconclusive results. Cross-cultural\\u000a studies are virtually non-existent. The present study seeks to understand the complex interplay of biological sex, socialized\\u000a gender-roles, and culture on entrepreneurial self-efficacy and motivation to become an entrepreneur. Findings indicate that\\u000a among American business students the traditional view of “entrepreneur as male” is fading.

Stephen L. Mueller; Mary Conway Dato-on

293

PreClinical Study: Antioxidant Levels and Immunomodulatory Effects of Wolfberry Juice and Other Juice Mixtures in Mice  

Microsoft Academic Search

Although wolfberry juice, derived from the fruit of Lycium barbarum, has been purported by Chinese researchers to augment immune response, there is a paucity of information in scientific literature about its effects. This study was designed to evaluate the immunomodulatory effects of wolfberry juice, individually and in mixtures with other juices, using a mouse model. The antioxidant activity of wolfberry

Sue Chao; Marc Schreuder; Gary Young; Karen Nakaoka; Lynn Moyes; Craig Oberg

294

21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.  

Code of Federal Regulations, 2010 CFR

21 Food and Drugs 4 2010-04-01 2010-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...

2010-04-01

295

77 FR 12310 - Drugs for Human Use; Drug Efficacy Study Implementation; Prescription Drugs That Contained...  

Federal Register 2010, 2011, 2012, 2013, 2014

...DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-1978-N-0441] (formerly 78N-0324); DESI 10392] Drugs for Human Use; Drug Efficacy Study Implementation; Prescription...

2012-02-29

296

Preclinical Potency and Safety Studies of an AAV2-Mediated Gene Therapy Vector for the Treatment of MERTK Associated Retinitis Pigmentosa  

PubMed Central

Abstract Proof of concept for MERTK gene replacement therapy has been demonstrated using different viral vectors in the Royal College of Surgeon (RCS) rat, a well characterized model of recessive retinitis pigmentosa that contains a mutation in the Mertk gene. MERTK plays a key role in renewal of photoreceptor outer segments (OS) by phagocytosis of shed OS tips. Mutations in MERTK cause impaired phagocytic activity and accumulation of OS debris in the interphotoreceptor space that ultimately leads to photoreceptor cell death. In the present study, we conducted a series of preclinical potency and GLP-compliant safety evaluations of an adeno-associated virus type 2 (AAV2) vector expressing human MERTK cDNA driven by the retinal pigment epithelium–specific, VMD2 promoter. We demonstrate the potency of the vector in RCS rats by improved electroretinogram (ERG) responses in treated eyes compared with contralateral untreated controls. Toxicology and biodistribution studies were performed in Sprague–Dawley (SD) rats injected with two different doses of AAV vectors and buffer control. Delivery of vector in SD rats did not result in a change in ERG amplitudes of rod and cone responses relative to balanced salt solution control–injected eyes, indicating that administration of AAV vector did not adversely affect normal retinal function. In vivo fundoscopic analysis and postmortem retinal morphology of the vector-injected eyes were normal compared with controls. Evaluation of blood smears showed the lack of transformed cells in the treated eyes. All injected eyes and day 1 blood samples were positive for vector genomes, and all peripheral tissues were negative. Our results demonstrate the potency and safety of the AAV2-VMD2-hMERTK vector in animal models tested. A GMP vector has been manufactured and is presently in clinical trial. PMID:23692380

Deng, Wen-Tao; Erger, Kirsten; Cossette, Travis; Pang, Ji-jing; Ryals, Renee; Clément, Nathalie; Cleaver, Brian; McDoom, Issam; Boye, Shannon E.; Peden, Marc C.; Sherwood, Mark B.; Abernathy, Corinne R.; Alkuraya, Fowzan S.; Boye, Sanford L.; Hauswirth, William W.

2013-01-01

297

Discovery and preliminary confirmation of novel early detection biomarkers for triple-negative breast cancer using preclinical plasma samples from the Women’s Health Initiative observational study  

PubMed Central

Triple-negative breast cancer is a particularly aggressive and lethal breast cancer subtype that is more likely to be interval-detected rather than screen-detected. The purpose of this study is to discover and initially validate novel early detection biomarkers for triple-negative breast cancer using preclinical samples. Plasma samples collected up to 17 months prior to diagnosis from 28 triple-negative cases and 28 matched controls from the Women’s Health Initiative Observational Study were equally divided into a training set and a test set and interrogated using a customized antibody array. Data were available on 889 antibodies, and in the training set statistically significant differences in case vs. control signals were observed for 93 (10.5%) antibodies at p<0.05. Of these 93 candidates, 29 were confirmed in the test set at p<0.05. Areas under the curve for these candidates ranged from 0.58 to 0.79. With specificity set at 98%, sensitivity ranged from 4% to 68% with ?20 candidates having a sensitivity 20% and 6 having a sensitivity ?40%. In an analysis of KEGG gene sets, the pyrimidine metabolism gene set was upregulated in cases compared to controls (p=0.004 in the testing set) and the JAK/Stat signaling pathway gene set was downregulated (p=0.003 in the testing set). Numerous potential early detection biomarkers specific to triple-negative breast cancer in multiple pathways were identified. Further research is required to follow-up on promising candidates in larger sample sizes and to better understand their potential biological importance as our understanding of the etiology of triple-negative breast cancer continues to grow. PMID:22903690

Li, Christopher I.; Mirus, Justin E.; Zhang, Yuzheng; Ramirez, Arturo B.; Ladd, Jon J.; Prentice, Ross L.; McIntosh, Martin; Hanash, Samir M.; Lampe, Paul D.

2012-01-01

298

In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies.  

PubMed

Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development. PMID:23110069

Nilsson, Anna; Forngren, Benita; Bjurström, Sivert; Goodwin, Richard J A; Basmaci, Elisa; Gustafsson, Ingela; Annas, Anita; Hellgren, Dennis; Svanhagen, Alexander; Andrén, Per E; Lindberg, Johan

2012-01-01

299

Double-blind, placebo-controlled study of immunotherapy with Parietaria judaica: Clinical efficacy and tolerance  

Microsoft Academic Search

Summary. Allergy to Parietaria causes significant morbidity in most Mediterranean areas. The aim of this study is to investigate the efficacy and tolerance of Parietaria depot extract at 25 BU\\/mL (1.5 µg\\/ mL Par j 1). We performed a multicenter double-blind, placebo-controlled study in rhinitic patients with\\/without asthma, sensitized to Parietaria. 42 patients followed 20-month immunotherapy. Clinical efficacy was based

M. Ferrer; E. Burches; A. Peláez; A. Muñoz; D. Hernández; A. Basomba; E. Enrique; R. Alonso; A. Cisteró-Bahima; S. Martín; P. Rico; B. Gandarias

300

Preclinical study of treatment response in HCT-116 cells and xenografts with (1) H-decoupled (31) P MRS.  

PubMed

The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G(2) /M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G(2) /M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton ((1) H)-decoupled phosphorus ((31) P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p?=?0.0004) and inorganic phosphate (p?=?0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83?±?5% G(2) /M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5?±?1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39?±?10% apoptosis. In vivo (1) H-decoupled (31) P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies. PMID:21994185

Darpolor, Moses M; Kennealey, Peter T; Le, H Carl; Zakian, Kristen L; Ackerstaff, Ellen; Rizwan, Asif; Chen, Jin-Hong; Sambol, Elliot B; Schwartz, Gary K; Singer, Samuel; Koutcher, Jason A

2011-11-01

301

Preclinical Study of Treatment Response in HCT-116 Cells and Xenografts with 1H-decoupled 31P MRS  

PubMed Central

The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G2/M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G2/M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton (1H)-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p = 0.0004) and inorganic phosphate (p = 0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83±5% G2/M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5±1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39±10% apoptosis. In vivo 1H-decoupled 31P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies. PMID:21994185

Darpolor, Moses M.; Kennealey, Peter T.; Carl Le, H; Zakian, Kristen L.; Ackerstaff, Ellen; Rizwan, Asif; Chen, Jin-Hong; Sambol, Elliot B.; Schwartz, Gary K.; Singer, Samuel; Koutcher, Jason A.

2011-01-01

302

A Novel Pre-Clinical Murine Model to Study the Life Cycle and Progression of Cervical and Anal Papillomavirus Infections  

PubMed Central

Background Papillomavirus disease and associated cancers remain a significant health burden in much of the world. The current protective vaccines, Gardasil and Cervarix, are expensive and not readily available to the underprivileged. In addition, the vaccines have not gained wide acceptance in the United States nor do they provide therapeutic value. Papillomaviruses are strictly species specific and thus human viruses cannot be studied in an animal host. An appropriate model for mucosal disease has long been sought. We chose to investigate whether the newly discovered mouse papillomavirus, MmuPV1, could infect mucosal tissues in Foxn1nu/Foxn1nu mice. Methods The vaginal and anal canals of Foxn1nu/Foxn1nu mice were gently abraded using Nonoxynol-9 and “Doctor’s BrushPicks” and MmuPV1 was delivered into the vaginal tract or the anal canal. Results Productive vaginal, cervical and anal infections developed in all mice. Vaginal/cervical infections could be monitored by vaginal lavage. Dysplasias were evident in all animals. Conclusions Anogenital tissues of a common laboratory mouse can be infected with a papillomavirus unique to that animal. This observation will pave the way for fundamental virological and immunological studies that have been challenging to carry out heretofore due to lack of a suitable model system. PMID:25803616

Cladel, Nancy M.; Budgeon, Lynn R.; Balogh, Karla K.; Cooper, Timothy K.; Hu, Jiafen; Christensen, Neil D.

2015-01-01

303

Chimeric rodents with humanized liver: bridging the preclinical/clinical trial gap in ADME/toxicity studies.  

PubMed

1. Immunocompromised mice with humanized livers were developed in the mid-1990s to allow the study of human hepatotropic viruses, which normally replicate only in higher primates. The production of the uPA/SCID mouse was the vanguard of these models and remains the most widely worked upon model for an ever increasing range of applications. 2. Since toxicology is conducted in laboratory animal species with the implicit intent of predicting the outcome of accidental, or intentional, human exposure, the potential for using an in vivo model with a humanised metabolism opens up the possibility of better predicting the human response following exposure to drugs and industrial chemicals. Chimeric humanised mice provide the tool for bridging between the non-clinical laboratory safety and metabolism studies, carried out in rodent and non-rodent species, and the first in man clinical trials. 3. Chimeric mice carrying a human liver have now been validated against a wide range of different drugs and chemical classes, and have been shown to clearly differentiate metabolically from the recipient mouse, and to show metabolic pathways more similar to those expected from human liver. 4. This review critically appraises the available animal models carrying human livers and where future developments would improve the existing systems. PMID:24320885

Foster, John R; Lund, Garry; Sapelnikova, Svetlana; Tyrrell, D Lorne; Kneteman, Norman M

2014-01-01

304

Preclinical pharmacodynamic and pharmacokinetic studies of investigational new drugs. Annual report, 1 November 1993-31 October 1994  

SciTech Connect

During the past year of this contract pharmacokinetic, pharmacodynamic, bioavailability and metabolism studies have been conducted on two anti-cyanotic agents (WR242511 and p-aminohetanophenone (PAHP)) and one nerve agent antidote (HI-6) which are under consideration for clinical development by the U.S. Army. Radiolabeled formulations of WR242511, PAHP and HI-6 were used in these investigations. Information has been obtained on the half-lives of absorption and elimination of both radioactivity and the parent compound following oral and i.v. administration of these three compounds to dogs and, for PAHP, also to rats. In addition, the rates and extent of urinary and fecal elimination of the agents has been characterized; the pharmacodynamics, as assessed by the production of methemoglobin, of two compounds (WR242511 and PAHP) has been studied; and the metabolism of each compound has been investigated. Data obtained to date indicate that: WR242511 does not directly produce methemoglobinemia but a metabolite sequestered in red cells is the responsible agent; dogs appear to metabolize PAHP differently than do rats; the major urinary metabolite of HI-6 is 2-pyridine aldoxime. Further efforts to isolate and identify the metabolites of all three compounds are in progress.

Noker, P.E.

1994-11-11

305

Teaching Induction: A Study on the Effectiveness of Induction Programs among Urban High School Teacher Self-Efficacy  

ERIC Educational Resources Information Center

The purpose of this study is to examine the impact that induction programs have on self-efficacy of new teachers in urban, Midwestern high schools. Because induction programs have been used to measure elements of new teacher self-efficacy, it remains important to study this topic, and explore the information in an urban setting where self-efficacy

Lowrey, Jason H.

2012-01-01

306

CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B-cell malignancies  

PubMed Central

Established cell lines are utilized extensively to study tumor biology and preclinical therapeutic development; however, they may not accurately recapitulate the heterogeneity of their corresponding primary disease. B-cell tumor cells are especially difficult to maintain under conventional culture conditions, limiting access to samples that faithfully represent this disease for preclinical studies. Here, we used primary canine diffuse large B-cell lymphoma to establish a culture system that reliably supports the growth of these cells. CD40 ligand, either expressed by feeder cells or provided as a soluble two-trimeric form, was sufficient to support primary lymphoma cells in vitro. The tumor cells retained their original phenotype, clonality and known karyotypic abnormalities after extended expansion in culture. Finally, we illustrate the utility of the feeder cell-free culture system for comparable assessment of cytotoxicity using dog and human B-cell malignancies. We conclude this system has broad applications for in vitro preclinical development for B-cell malignancies. PMID:22229753

Ito, Daisuke; Frantz, Aric M.; Williams, Christina; Thomas, Rachael; Burnett, Robert C.; Avery, Anne C.; Breen, Matthew; Mason, Nicola J.; O’Brien, Timothy D.; Modiano, Jaime F.

2013-01-01

307

Safety, Pharmacokinetic, and Efficacy Studies of Oral DB868 in a First Stage Vervet Monkey Model of Human African Trypanosomiasis  

PubMed Central

There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median Cmax (dosing regimen) that was 12-fold (3 mg/kg/day for 7 days), 15-fold (10 mg/kg/day for 7 days), and 31-fold (20 mg/kg/day for 5 days) greater than the IC50 (14 nmol/L) against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5–7 days), oral regimen for first stage HAT. PMID:23755309

Thuita, John K.; Wolf, Kristina K.; Murilla, Grace A.; Liu, Qiang; Mutuku, James N.; Chen, Yao; Bridges, Arlene S.; Mdachi, Raymond E.; Ismail, Mohamed A.; Ching, Shelley; Boykin, David W.; Hall, James Edwin; Tidwell, Richard R.; Paine, Mary F.; Brun, Reto; Wang, Michael Zhuo

2013-01-01

308

Silencing efficacy prediction: a retrospective study on target mRNA features  

PubMed Central

Post-transcriptional gene silencing is a widely used method to suppress gene expression. Unfortunately only a portion of siRNAs do successfully reduce gene expression. Target mRNA secondary structures and siRNA-mRNA thermodynamic features are believed to contribute to the silencing activity. However, there is still an open discussion as to what determines siRNA efficacy. In this retrospective study, we analysed the target accessibility comparing very high (VH) compared with low (L) efficacy siRNA sequences obtained from the siRecords Database. We determined the contribution of mRNA target local secondary structures on silencing efficacy. Both the univariable and the multivariable logistic regression evidenced no relationship between siRNA efficacy and mRNA target secondary structures. Moreover, none of the thermodynamic and sequence-base parameters taken into consideration (H-b index, ?G°overall, ?G°duplex, ?G°break-target and GC%) was associated with siRNA efficacy. We found that features believed to be predictive of silencing efficacy are not confirmed to be so when externally evaluated in a large heterogeneous sample. Although it was proposed that silencing efficacy could be influenced by local target accessibility we show that this could be not generalizable because of the diversity of experimental setting that may not be representative of biological systems especially in view of the many local protein factors, usually not taken into consideration, which could hamper the silencing process. PMID:25702798

Pascut, Devis; Bedogni, Giorgio; Tiribelli, Claudio

2015-01-01

309

Antecedents of computer self-efficacy: A study of the role of personality traits and gender  

Microsoft Academic Search

Empirical evidence suggests that computer self-efficacy plays an important role in one’s acceptance and use of new information technology. Little is however known about the antecedents of computer self-efficacy. This paper reports on a study of 143 non-users of a self-checkout library system available at a large Canadian university which was conducted to investigate the relationships between stable personality traits

Huma Saleem; Anne Beaudry; Anne-Marie Croteau

2011-01-01

310

Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus.  

PubMed

Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0×10(8), 2.5×10(9), and 1.25×10(10) viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0×10(8), 2.5×10(9), and 1.25×10(10) VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose>5×10(10) VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25×10(10) VP/kg) and beagles (2.5×10(9) VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35×10(10) VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67×10(8) VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. PMID:25151223

Qi, Yanxin; Guo, Huanhuan; Hu, Ningning; He, Dongyun; Zhang, Shi; Chu, Yunjie; Huang, Yubin; Li, Xiao; Sun, LiLi; Jin, Ningyi

2014-10-15

311

Designing for Self-Efficacy in a Game Based Simulator: An Experimental Study and Its Implications for Serious Games Design  

Microsoft Academic Search

This paper presents the results of an experimental study on designing for self-efficacy in a game based driving simulator. Self-efficacy refers to how peoplepsilas beliefs in their capabilities affect their actions. The results show that the design of the feedback system can be used to increase self-efficacy measures thus affecting performance in a driving simulator environment. Self-efficacy has consequences not

Per Backlund; Henrik Engström; Mikael Johannesson; Mikael Lebram; Björn Sjödén

2008-01-01

312

Advances in Preclinical SPECT Instrumentation  

PubMed Central

Preclinical SPECT imaging of rodents is both in demand and very demanding. The need for high spatial resolution in combination with good sensitivity has given rise to considerable innovation in the areas of detectors, collimation, acquisition geometry, and image reconstruction. Some of the developments described herein are beginning to carry over into clinical imaging as well. PMID:22586145

Peterson, Todd E.; Shokouhi, Sepideh

2012-01-01

313

Lost in translation: preclinical studies on 3,4-methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans  

PubMed Central

3,4-Methylenedioxymethamphetamine (MDMA) induces both acute adverse effects and long-term neurotoxic loss of brain 5-HT neurones in laboratory animals. However, when choosing doses, most preclinical studies have paid little attention to the pharmacokinetics of the drug in humans or animals. The recreational use of MDMA and current clinical investigations of the drug for therapeutic purposes demand better translational pharmacology to allow accurate risk assessment of its ability to induce adverse events. Recent pharmacokinetic studies on MDMA in animals and humans are reviewed and indicate that the risks following MDMA ingestion should be re-evaluated. Acute behavioural and body temperature changes result from rapid MDMA-induced monoamine release, whereas long-term neurotoxicity is primarily caused by metabolites of the drug. Therefore acute physiological changes in humans are fairly accurately mimicked in animals by appropriate dosing, although allometric dosing calculations have little value. Long-term changes require MDMA to be metabolized in a similar manner in experimental animals and humans. However, the rate of metabolism of MDMA and its major metabolites is slower in humans than rats or monkeys, potentially allowing endogenous neuroprotective mechanisms to function in a species specific manner. Furthermore acute hyperthermia in humans probably limits the chance of recreational users ingesting sufficient MDMA to produce neurotoxicity, unlike in the rat. MDMA also inhibits the major enzyme responsible for its metabolism in humans thereby also assisting in preventing neurotoxicity. These observations question whether MDMA alone produces long-term 5-HT neurotoxicity in human brain, although when taken in combination with other recreational drugs it may induce neurotoxicity. LINKED ARTICLES This article is commented on by Parrott, pp. 1518–1520 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01941.x and to view the the rebuttal by the authors (Green et al., pp. 1521–1522 of this issue) visit http://dx.doi.org/10.1111/j.1476-5381.2012.01940.x PMID:22188379

Green, AR; King, MV; Shortall, SE; Fone, KCF

2012-01-01

314

Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson’s disease  

PubMed Central

Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson’s disease (PD) by testing an expanded dose range of VEGF-B (1 ?g and 10 ?g) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 ?g), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 ?g VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p = 1.9 e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p = 0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and Parkinson’s disease patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated. PMID:24291725

Yue, Xu; Hariri, Dana J.; Caballero, Beatrice; Zhang, Shiling; Bartlett, Mitchell J.; Kaut, Oliver; Mount, David W.; Wüllner, Ullrich; Sherman, Scott J.; Falk, Torsten

2014-01-01

315

Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.  

PubMed

Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 ?g) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 ?g), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 ?g VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated. PMID:24291725

Yue, X; Hariri, D J; Caballero, B; Zhang, S; Bartlett, M J; Kaut, O; Mount, D W; Wüllner, U; Sherman, S J; Falk, T

2014-01-31

316

Lesson Study: Professional Development and Its Impact on Science Teacher Self-Efficacy  

ERIC Educational Resources Information Center

This study focuses on an analysis of a professional development program known as lesson study via data obtained during an in-service professional development program for secondary school science teachers. The purpose of this study was to examine the self-efficacy beliefs of one group of science teachers related to their experiences in a lesson…

Roberts, Megan Rae

2010-01-01

317

Lesson study: Professional development and its impact on science teacher self-efficacy  

NASA Astrophysics Data System (ADS)

This study focuses on an analysis of a professional development program known as lesson study via data obtained during an in-service professional development program for secondary school science teachers. The purpose of this study was to examine the self-efficacy beliefs of one group of science teachers related to their experiences in a lesson study. Another purpose for this research, aligned with the first, included a theoretical analysis of the lesson study construct to see if its design promoted positive self-efficacy beliefs of its participants. The research is framed within the context of social constructivism and self-efficacy and is qualitative in nature and utilized descriptive analysis as a means of research. Case studies were conducted detailing two of the six participants. Data sources included researcher field notes and transcriptions of all planning and debriefing sessions; individual interviews with each participant and the schools' principal; a participant questionnaire, and the Science Teaching Efficacy Belief Instrument. Themes that emerged included the positive perceptions of lesson study as a collaborative and teacher-centered experience; the understanding that lesson study can instill a sense of professionalism to those who participate in the process; the sense that discussing student learning using objective observations from classroom is a powerful way to assess learning and uncover personal teacher beliefs; and the insight that the time commitment that lesson study requires can inhibit teachers and schools from sustaining it as a form of on-going professional development. Although these themes are consistent with the research on lesson study in Japan and elsewhere in the United States, they also extend the research on self-efficacy and science teacher professional development. In the end, this study supported some of the conclusions of the self-efficacy research as it relates to professional development while also adding that interpersonal relationships is a relevant consideration in the development of science teacher's self-efficacy. From this study, it is apparent that teachers who are collaboratively involved in a supportive setting such as lesson study can increase their level of self-efficacy and thus improve their teaching practice.

Roberts, Megan Rae

318

Evaluation Of Microdosing Strategies For Studies In Preclinical Drug Development: Demonstration Of Linear Pharmacokinetics In Dogs Of A Nucleoside Analogue Over A 50-Fold Dose Range  

SciTech Connect

The technique of accelerator mass spectrometry (AMS) was validated successfully and utilized to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as LC-MS/MS and liquid scintillation counting analyses. Thus, Compound A displayed multiphasic kinetics and possessed low plasma clearance (4.4 mL/min/kg), a long terminal elimination half-life (19.4 hr) and high oral bioavailability (82%). Currently there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus sub-pharmacological doses employing microdosing strategies. The present study thus provides the first description of the pharmacokinetics of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that in the case of Compound A, the kinetics of absorption, distribution and elimination in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even following a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques. The applications of accelerator mass spectrometry (AMS) are broad ranging and vary from studying environmental and ecological issues such as the isotopic composition of the atmosphere, soil and water (Hughen et al., 2000; Beck et al., 2001; Keith-Roach et al., 2001; Mironov et al., 2002), to archaeology and volcanology (Stafford et al., 1984; Vogel et al., 1990; Smith et al., 1999) to its use as a bioanalytical tool for nutritional research (Buchholz et al., 1999; Deuker et al., 2000; Weaver and Liebman, 2002). Biomedical applications of AMS and its use in the arena of pharmaceutical research also have been detailed in review articles (Barker and Garner, 1999; Garner, 2000; Turteltaub and Vogel, 2000). To date, most studies on the metabolism and disposition of xenobiotics by AMS have focused on how carcinogens bind to DNA and proteins to form adducts (Turteltaub et al., 1990, 1997; Frantz et al., 1995; Dingley et al., 1999; Li et al., 2003). Its application to the field of pharmaceutical sciences has been limited to a few studies (Kaye et al., 1997; Young et al., 2001; Garner et al., 2002). However, the pharmaceutical industry is becoming increasingly aware of the potential benefits that may accrue from the ultra high sensitivity afforded by AMS in terms of evaluating the pharmacokinetics of lead drug candidates in early development. Specifically, AMS allows administration of sub-pharmacological doses (microdoses) of carbon-14 or tritium-labeled investigational drugs to animals or humans at radiologically insignificant levels with the goal of obtaining preliminary information regarding the absorption, distribution, metabolism, and excretion of test compounds (Turteltaub and Vogel, 2000). An unresolved issue, however, is whether the pharmacokinetics determined following a microdose are representative of those following a conventional (pharmacological) dose (Lappin and Garner, 2003). This paper examines the linearity of kinetics of an antiviral nucleoside analogue, Compound A, across sub-pharmacological and pharmacological dose ranges in the dog prior to initiation of a human microdose study. The specific objectives of this study, therefore, were (1) to assess the pharmacokinetics of Compound A in dogs by a conventional dosing approach utilizing LC-MS/MS for sample analysis, (2) to assess the pharmacokinetics of Compound A in dogs by the microdose approach utilizing AMS for sample ana

Sandhu, P; Vogel, J S; Rose, M J; Ubick, E A; Brunner, J E; Wallace, M A; Adelsberger, J K; Baker, M P; Henderson, P T; Pearson, P G; Baillie, T A

2004-04-22

319

Development of a preclinical therapeutic model of human brain metastasis with chemoradiotherapy.  

PubMed

Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents. PMID:23591844

Martínez-Aranda, Antonio; Hernández, Vanessa; Picón, Cristina; Modolell, Ignasi; Sierra, Angels

2013-01-01

320

Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy  

PubMed Central

Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents. PMID:23591844

Martínez-Aranda, Antonio; Hernández, Vanessa; Picón, Cristina; Modolell, Ignasi; Sierra, Angels

2013-01-01

321

Diagnostic accuracy of the Preclinical AD Scale (PAS) in cognitively mildly impaired subjects  

Microsoft Academic Search

The Preclinical AD Scale (PAS) is a newly developed scale for the diagnosis of preclinical Alzheimer's disease (AD). The\\u000a PAS combines six markers of preclinical AD, namely age, MMSE score, functional impairment, cognitive test performance, medial\\u000a temporal lobe atrophy, and the apolipoprotein E (APOE) genotype. The aim of the study was to investigate whether the PAS can\\u000a accurately identify subjects

Pieter Jelle Visser; Frans R. J. Verhey; Philip Scheltens; Marc Cruts; Rudolf W. H. M. Ponds; Christine L. Van Broeckhoven; Jellemer Jolles

2002-01-01

322

Laboratory and human studies to estimate anticaries efficacy of fluoride toothpastes.  

PubMed

Much more than mechanical biofilm removal, toothbrushing with fluoride toothpastes is an effective way of increasing the availability of fluoride in the oral cavity to reduce demineralization and enhance remineralization of enamel and dentine. These effects of fluoride toothpastes have been estimated by a wide range of laboratory and human studies, which have helped to develop anticaries effective formulations and understand their mechanism of action. These studies have focused on the availability of fluoride in the toothpaste formulations, its bioavailability in saliva and remnants of disturbed biofilm, its reaction with the dental substrate to form loosely bound reservoirs as well as the ultimate reduction of mineral loss and increase in mineral and fluoride content of caries lesions. The specifics of these modes of action and their application in in vitro, in situ and in vivo preclinical tests is presented and discussed. PMID:23817064

Tenuta, Livia M A; Cury, Jaime A

2013-01-01

323

Two preclinical tests to evaluate anticancer activity and to help validate drug candidates for clinical trials  

PubMed Central

Current approaches to assessing preclinical anticancer activity do not reliably predict drug efficacy in cancer patients. Most of the compounds that show remarkable anticancer effects in preclinical models actually fail when tested in clinical trials. We blame these failures on the complexity of the disease and on the limitations of the preclinical tools we require for our research. This manuscript argues that this lack of clinical response may also be caused by poor in vitro and in vivo preclinical designs, in which cancer patients' needs are not fully considered. Then, it proposes two patient-oriented tests to assess in vitro and in vivo anticancer activity and to help validate drug candidates for clinical evaluation.

López-Lázaro, Miguel

2015-01-01

324

The Interplay between Motivation, Self-Efficacy, and Approaches to Studying  

ERIC Educational Resources Information Center

Background: The strategies students adopt in their study are influenced by a number of social-cognitive factors and impact upon their academic performance. Aims: The present study examined the interrelationships between motivation orientation (intrinsic and extrinsic), self-efficacy (in reading academic texts and essay writing), and approaches to…

Prat-Sala, Merce; Redford, Paul

2010-01-01

325

The Study of Foreign Language Teachers-- Teacher Efficacy and Native Speakership  

ERIC Educational Resources Information Center

This study aims at examining the differences between native and nonnative foreign language teachers at a major northeast university. The primary areas of investigation are "teacher efficacy" and "teacher perceptions of language teaching." The results of this study suggested that both nativeness and wide repertoire of teaching experience and…

Liaw, En-Chong

2009-01-01

326

Preclinical and clinical evaluation of intraductally administered agents in early breast cancer.  

PubMed

Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N'-nitrosourea-treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for "breast-sparing mastectomy" in select women. PMID:22030751

Stearns, Vered; Mori, Tsuyoshi; Jacobs, Lisa K; Khouri, Nagi F; Gabrielson, Edward; Yoshida, Takahiro; Kominsky, Scott L; Huso, David L; Jeter, Stacie; Powers, Penny; Tarpinian, Karineh; Brown, Regina J; Lange, Julie R; Rudek, Michelle A; Zhang, Zhe; Tsangaris, Theodore N; Sukumar, Saraswati

2011-10-26

327

Preclinical and Clinical Evaluation of Intraductally Administered Agents in Early Breast Cancer  

PubMed Central

Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N’-nitrosourea–treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for “breast-sparing mastectomy” in select women. PMID:22030751

Stearns, Vered; Mori, Tsuyoshi; Jacobs, Lisa K.; Khouri, Nagi F.; Gabrielson, Edward; Yoshida, Takahiro; Kominsky, Scott L.; Huso, David L.; Jeter, Stacie; Powers, Penny; Tarpinian, Karineh; Brown, Regina J.; Lange, Julie R.; Rudek, Michelle A.; Zhang, Zhe; Tsangaris, Theodore N.; Sukumar, Saraswati

2013-01-01

328

Efficacy of Eight Months of Nightly Zolpidem: A Prospective Placebo-Controlled Study  

PubMed Central

Study Objectives: To evaluate the long-term (8 months) efficacy of zolpidem in adults with chronic primary insomnia using polysomnography. Design: Randomized, double-blind, placebo-controlled clinical trial. Setting: Sleep disorders and research center. Participants: Healthy participants (n = 91), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia. Interventions: Nightly zolpidem, 10 mg (5 mg for patients > 60 yrs) or placebo 30 minutes before bedtime for 8 months. Measurements and Results: Polysomnographic sleep parameters and morning subject assessments of sleep on 2 nights in months 1 and 8. Relative to placebo, zolpidem significantly increased overall total sleep time and sleep efficiency, reduced sleep latency and wake after sleep onset when assessed at months 1 and 8. Overall, subjective evaluations of efficacy were not shown among treatment groups. Conclusions: In adults with primary insomnia, nightly zolpidem administration remained efficacious across 8 months of nightly use. Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. Citation: Randall S; Roehrs TA; Roth T. Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study. SLEEP 2012;35(11):1551-1557. PMID:23115404

Randall, Surilla; Roehrs, Timothy A.; Roth, Thomas

2012-01-01

329

Radio-decontamination efficacy and safety studies on optimized decontamination lotion formulation.  

PubMed

Objective of the present study was to optimize decontamination lotion and to evaluate its relative decontamination efficacy using three radio-isotopes (Technetium-99m, Iodine-131 and Thallium-201) as contaminants with varying length of contaminant exposure (0-1h). Experiments were performed on Sprague Dawley rat's intact skin and human tissue equivalent models. Rat's hair was removed by using depilator after trimming with scissors. Relative decontamination efficacy of the optimized lotion was investigated and compared with water as control. Static counts were recorded before and after decontamination using single photon emission computed tomography (SPECT). Measured decontamination efficacy (DE) values were analyzed using one way ANOVA and Student's t-test (p value<0.05) and were found statistically significant. Decontamination efficacy of the lotion was observed to be 90 ± 5%, 80 ± 2% and 85 ± 2%, for the (131)I, (201)Tl and (99m)Tc radio-contaminants respectively on skin. Reduced contaminant removal was recorded for the skin which was cleaned by depilator (50-60%). Skin decontamination was found more efficacious for rat skin decontamination than the human tissue equivalent model. Decontamination efficacy of the lotion against (99m)Tc was recorded 70 ± 15% at 0-1h on the tissue equivalent model. In vitro chelation efficacy of the lotion was also established by using the instant thin layer chromatography-slica gel (ITLC-SG) and >95% of (99m)Tc was recorded. Neither erythema nor edema was scored in the primary skin irritancy test visually observed for two weeks. PMID:22609966

Rana, S; Bhatt, S; Dutta, M; Khan, A W; Ali, J; Sultana, S; Kotta, S; Ansari, S H; Sharma, R K

2012-09-15

330

Preclinical biomarkers of Parkinson disease.  

PubMed

The search for markers of preclinical Parkinson disease (PD) is becoming increasingly important because pathogenesis-targeted neuroprotective strategies are being developed for future use in at-risk populations, even before clinical onset of disease. Advances in clinical recognition of early symptoms and signs, development of new neuroimaging probes and technologies, identification of new neuropathological markers of PD, and breakthroughs in genetics and basic neuroscience are gradually translating into better understanding of predisposing and preclinical factors that lead to progressive neurodegeneration. Coupled with system biology tools, progress is being made in the identification of new genomic, transcriptomic, proteomic, lipidomic, and metabolomic molecules and new signaling pathways that are relevant to the pathogenesis of neurodegeneration in PD. These new tools will be critical not only in the discovery of sensitive, specific, and reliable biomarkers of preclinical PD but also in the development of tests that will aid in the early detection and differential diagnosis of parkinsonian disorders and in monitoring disease progression. PMID:21220674

Wu, Yuncheng; Le, Weidong; Jankovic, Joseph

2011-01-01

331

Study of the efficacy of antimalarial drugs delivered inside targeted immunoliposomal nanovectors  

NASA Astrophysics Data System (ADS)

Paul Ehrlich's dream of a 'magic bullet' that would specifically destroy invading microbes is now a major aspect of clinical medicine. However, a century later, the implementation of this medical holy grail continues being a challenge in three main fronts: identifying the right molecular or cellular targets for a particular disease, having a drug that is effective against it, and finding a strategy for the efficient delivery of sufficient amounts of the drug in an active state exclusively to the selected targets. In a previous work, we engineered an immunoliposomal nanovector for the targeted delivery of its contents exclusively to Plasmodium falciparum-infected red blood cells [pRBCs]. In preliminary assays, the antimalarial drug chloroquine showed improved efficacy when delivered inside immunoliposomes targeted with the pRBC-specific monoclonal antibody BM1234. Because difficulties in determining the exact concentration of the drug due to its low amounts prevented an accurate estimation of the nanovector performance, here, we have developed an HPLC-based method for the precise determination of the concentrations in the liposomal preparations of chloroquine and of a second antimalarial drug, fosmidomycin. The results obtained indicate that immunoliposome encapsulation of chloroquine and fosmidomycin improves by tenfold the efficacy of antimalarial drugs. The targeting antibody used binds preferentially to pRBCs containing late maturation stages of the parasite. In accordance with this observation, the best performing immunoliposomes are those added to Plasmodium cultures having a larger number of late form-containing pRBCs. An average of five antibody molecules per liposome significantly improves in cell cultures the performance of immunoliposomes over non-functionalized liposomes as drug delivery vessels. Increasing the number of antibodies on the liposome surface correspondingly increases performance, with a reduction of 50% parasitemia achieved with immunoliposomes encapsulating 4 nM chloroquine and bearing an estimated 250 BM1234 units. The nanovector prototype described here can be a valuable platform amenable to modification and improvement with the objective of designing a nanostructure adequate to enter the preclinical pipeline as a new antimalarial therapy.

Urbán, Patricia; Estelrich, Joan; Adeva, Alberto; Cortés, Alfred; Fernàndez-Busquets, Xavier

2011-12-01

332

Behavioural and pharmacological mechanisms of bupropion's anti-smoking effects: Recent preclinical and clinical insights  

Microsoft Academic Search

Ongoing studies continue to explore the behavioural and pharmacological effects of bupropion in smoking cessation studies and animal models of nicotine dependence. In the present review, the components of nicotine dependence that form the most likely targets of bupropion are identified within the context of an expanding preclinical and clinical literature regarding the anti-addictive properties of bupropion. Second, preclinical and

Neil E. Paterson

2009-01-01

333

Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation  

PubMed Central

Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers. PMID:21750699

McMillin, Douglas W.; Delmore, Jake; Negri, Joseph; Ooi, Melissa; Klippel, Steffen; Miduturu, Chandrasekhar V.; Gray, Nathanael S.; Richardson, Paul G.; Anderson, Kenneth C.; Kung, Andrew L.; Mitsiades, Constantine S.

2011-01-01

334

MEMS-enabled implantable drug infusion pumps for laboratory animal research, preclinical, and clinical applications  

PubMed Central

Innovation in implantable drug delivery devices is needed for novel pharmaceutical compounds such as certain biologics, gene therapy, and other small molecules that are not suitable for administration by oral, topical, or intravenous routes. This invasive dosing scheme seeks to directly bypass physiological barriers presented by the human body, release the appropriate drug amount at the site of treatment, and maintain the drug bioavailability for the required duration of administration to achieve drug efficacy. Advances in microtechnologies have led to novel MEMS-enabled implantable drug infusion pumps with unique performance and feature sets. In vivo demonstration of micropumps for laboratory animal research and preclinical studies include acute rapid radiolabeling, short-term delivery of nanomedicine for cancer treatment, and chronic ocular drug dosing. Investigation of MEMS actuators, valves, and other microstructures for on-demand dosing control may enable next generation implantable pumps with high performance within a miniaturized form factor for clinical applications. PMID:22926321

Meng, Ellis; Hoang, Tuan

2012-01-01

335

Malaria Vaccine Adjuvants: Latest Update and Challenges in Preclinical and Clinical Research  

PubMed Central

There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants) as well as the immunostimulatory effect of the formulation components (immunostimulants) modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI) and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages. PMID:23710439

Mata, Elena; Salvador, Aiala; Igartua, Manoli; Hernández, Rosa María; Pedraz, José Luis

2013-01-01

336

[An experimental study of the efficacy of enterosorbents in salmonellosis].  

PubMed

The effectiveness of enterosorbents (polymethylsiloxane used as enterosgel and activated charcoal) has been studied in experiments on white rats infected with low virulent Salmonella typhimurium strain N 79. As shown in this study, the use of sorbents normalizes the morphofunctional characteristics of the epithelium of the small intestine and decreases the degree of Salmonella colonization of the parietal layer in the lumen of the small intestine, causing the destruction of some adsorbed bacteria. PMID:8017132

Nikolaeva, L G; Grigor'ev, A V; Znamenski?, V A; Koval'chuk, V K; Alekseenko, E P

1994-01-01

337

Study of the Validity and Reliability of a Self-Efficacy Scale of Teaching Material Utilization  

ERIC Educational Resources Information Center

The main purpose of this study is to develop a scale in order to detect the level of pre-service teachers' utilization from teaching materials based on their perception of self-efficacy. The sample group is composed of 439 students for the first application and 215 students for the second. In order to detect the validity of the scale, exploratory…

Korkmaz, Ozgen

2011-01-01

338

Math and Science Pursuits: A Self-Efficacy Intervention Comparison Study  

ERIC Educational Resources Information Center

This study compared two interventions to increase math self-efficacy among undergraduate students. Ninety-nine first-year undergraduate students participated in an intervention involving performance accomplishment or an intervention combining performance accomplishment and belief-perseverance techniques in which participants constructed a…

Cordero, Elizabeth D.; Porter, Sarah H.; Israel, Tania; Brown, Michael T.

2010-01-01

339

Safety and antiulcer efficacy studies of Achillea millefolium L. after chronic treatment in Wistar rats  

Microsoft Academic Search

Achillea millefolium L. (Asteraceae), popularly known as yarrow, has been used in folk medicine to treat complaints such as inflammation, pain, wounds, hemorrhages and gastrointestinal disturbances. The aim of the present study was to assess the safety and efficacy of the aqueous extract (AE) of the plant after chronic exposure. Indeed, the AE was effective in protecting the gastric mucosa

Ana Maria Cavalcanti; Cristiane Hatsuko Baggio; Cristina Setim Freitas; Lia Rieck; Renato Silva de Sousa; José Eduardo Da Silva-Santos; Sonia Mesia-Vela; Maria Consuelo Andrade Marques

2006-01-01

340

Efficacy of an implanted neuroprosthesis for restoring hand grasp in tetraplegia: A multicenter study  

Microsoft Academic Search

Peckham PH, Keith MW, Kilgore KL, Grill JH, Wuolle KS, Thrope GB, Gorman P, Hobby J, Mulcahey MJ, Carroll S, Hentz VR, Wiegner A, for the Implantable Neuroprosthesis Research Group. Efficacy of an implanted neuroprosthesis for restoring hand grasp in tetraplegia: a multicenter study. Arch Phys Med Rehabil 2001;82:1380-8. Objective: To evaluate an implanted neuroprosthesis that allows tetraplegic users to

P. Hunter Peckham; Michael W. Keith; Kevin L. Kilgore; Julie H. Grill; Kathy S. Wuolle; Geoffrey B. Thrope; Peter Gorman; John Hobby; M. J. Mulcahey; Sara Carroll; Vincent R. Hentz; Allen Wiegner

2001-01-01

341

A Quantitative Study Examining Teacher Stress, Burnout, and Self-Efficacy  

ERIC Educational Resources Information Center

The purpose of this quantitative, correlational study was to examine the relationships between stress, burnout, and self-efficacy in public school teachers in the Turks and Caicos Islands. The Teacher Stress Inventory was used to collect data on teacher stress, the Maslach Burnout Inventory Educators Survey was used to obtain data on teacher…

Stephenson, Timar D.

2012-01-01

342

Prospective study of efficacy and safety of lansoprazole in Zollinger-Ellison syndrome  

Microsoft Academic Search

Lansoprazole, a new substituted benzimidazole H+, K+-ATPase inhibitor, profoundly inhibits gastric acid secretion and has potential use in the management of diseases such as Zollinger-Ellison syndrome (ZES). In the present study we evaluated the efficacy and safety of lansoprazole in controlling acid hypersecretion in 20 patients with ZES. The starting dose was 60 mg once daily. Control of acid hypersecretion

David C. Metz; Joseph R. Pisegna; Gary L. Ringham; Kathryn Feigenbaum; Pamela D. Koviack; Paul N. Maton; Jerry D. Gardner; Robert T. Jensen

1993-01-01

343

Developing Self-Efficacy within Role Players in Collegiate Athletics: A Mixed Methods Study  

ERIC Educational Resources Information Center

The purpose of this study was to examine the differences in the level of self-efficacy between starting players and role players in a college Midwest Division III men's football team. The research questions were: 1) What differences in satisfaction levels, if any, can be found among starting players and role players with coach leadership,…

Perchinsky, David A.

2012-01-01

344

Exercise Self-Efficacy and Perceived Wellness among College Students in a Basic Studies Course  

ERIC Educational Resources Information Center

University basic studies courses provide a valuable opportunity for facilitating the knowledge, skills, and beliefs that develop healthy behaviors to last a lifetime. Belief in one's ability to participate in physical activity, exercise self-efficacy, is a psychological construct that has had a documented impact on physical activity. Although…

Sidman, Cara L.; D'Abundo, Michelle Lee; Hritz, Nancy

2009-01-01

345

A Mixed-Method Study: Assessing the BAR Model's Impact on Preservice Teachers' Efficacy Beliefs  

ERIC Educational Resources Information Center

This study took place at a mid-sized, Midwestern university located in a mid-sized town. The researchers developed the BAR model to teach mathematics methods both in the classroom and in the field. The preservice teachers took Enochs, Smith, and Huinker's Mathematics Teaching Efficacy Beliefs Instrument (MTEBI) on the first and last day of class.…

Rethlefsen, Ann Lyle; Park, Hyesung

2011-01-01

346

Assessing Treatment Efficacy in Outcome Studies of Sex Offenders  

Microsoft Academic Search

Because of the enormous human and financial costs society incurs as a result of sexual crimes, any reduction in the recidivism of sex offenders caused by treatment is very worthwhile. Although treatment can be valuable if this reduction is small, the reduction must nevertheless be real. Real effects are statistically significant differences between treated and untreated subjects in controlled studies.

VERNON L. QUINSEY; GRANT T. HARRIS; MARNIE E. RICE; MARTIN L. LALUMIÈRE

1993-01-01

347

Allopregnanolone Promotes Regeneration and Reduces ?-Amyloid Burden in a Preclinical Model of Alzheimer's Disease  

PubMed Central

Previously, we demonstrated that allopregnanolone (AP?) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that AP? promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of AP? to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different AP? treatment regimens indicated that AP? administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of AP? to impact A? burden. Treatment was initiated either prior to or post intraneuronal A? accumulation. Results indicated that AP? administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced A? pathology with greatest efficacy in the pre-pathology treatment group. AP? significantly reduced A? generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of A?-binding-alcohol-dehydrogenase. In addition, AP? significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with AP? increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of AP? to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease. PMID:21918687

Chen, Shuhua; Wang, Jun Ming; Irwin, Ronald W.; Yao, Jia; Liu, Lifei; Brinton, Roberta Diaz

2011-01-01

348

Preclinical pharmacology of midazolam  

PubMed Central

1 Midazolam, a new imidazobenzodiazepine, forms salts that are stable in water solution, and has an overall pharmacological potency similar to that of diazepam but a much shorter duration of action. It produces all the characteristic effects of the benzodiazepine class. 2 Its metabolites account for only a negligible part, if any, of its pharmacological effects observed in the mouse. 3 The time course of its anticonvulsant activity, studied with different experimental protocols and by different routes of administration, revealed an almost immediate onset of action. 4 Midazolam was lightly more potent, and its duration of action was shorter than diazepam, in enhancing presynaptic inhibition in the spinal cord of cats and in depressing spontaneous activity of cerebellar Purkinje cells in the rat. 5 Midazolam decreased spontaneous multiunit activity (MUA) in different nuclei of the brain in `encéphale isolé' rats. This depression was reversed by Ro 15-1788, a recently discovered selective benzodiazepine antagonist. 6 Midazolam and diazepam decreased the cyclic GMP level in the cerebellum of rats with about the same potency; the effect of midazolam was of much shorter duration than that of diazepam. 7 Midazolam had one-third the potency of diazepam in displacing 3H-flunitrazepam in mouse brain in vivo, and also in this case the effect of midazolam was of brief duration, as compared with diazepam. 8 Midazolam in therapeutic doses was virtually ineffective in the cardiovascular system of conscious dogs after p.o. or i.v. administration. No direct effects of the drug on autonomic functions were found. 9 The animal data suggest the usefulness of midazolam as an oral sleep-inducer, as an agent for i.v. induction of anaesthesia and as an i.v. or i.m. anticonvulsant in status epilepticus or tetanus, because of its rapid onset of action and its excellent local tolerance as water-soluble injection form. PMID:6138073

Pieri, L.

1983-01-01

349

[Prospective study to assess the clinical efficacy of bone scintigraphy--comparative study of the efficacy in breast carcinoma and prostate carcinoma].  

PubMed

Prospective study of bone scintigraphy was performed on 414 patients with breast carcinoma and 88 patients with prostate carcinoma. In 468 of them, confirmative diagnoses of bone, whether metastasis was existent or not, were made after the observations over a year. Finally, the incidences of bone metastasis were 11 percent for breast carcinoma and 54 percent for prostate carcinoma respectively. The efficacy of preoperative bone scintigraphy in breast carcinoma was comparable to that in prostate carcinoma with regard to improvement of predictive probability of bone metastasis: raising up the probability in the positive cases and bringing down in the negative cases. PMID:3065834

Yui, N; Akiyama, Y; Matsumoto, T; Iinuma, T; Ishikawa, T; Nakajima, T; Machida, K; Nishikawa, J; Iio, M; Uno, K

1988-11-01

350

[Immunological and clinical study on therapeutic efficacy of inosine pranobex].  

PubMed

Many studies in vitro and in vivo have shown immunomodulating and antiviral activities of inosine pranobex. The object of this research was to examine the potential beneficial effects of inosine pranobex (Groprinosin) on immune system in children with cellular immunodeficiency as a prophylaxis of recurrent infections, mainly of viral origin. 50 mg/kg b.w/day of inosine pranobex in divided doses was given to the group of 30 children aged 3-15 years for 10 days in 3 following months. Clinical and immunological investigations were done before and after the treatment. Statistically significant rise of CD3T lymphocytes number (p = 0.02) and in this CD4T lymphocytes number (p = 0.02) as well as statistically significant improvement of their function (p = 0.005) evaluated with blastic transformation method were found. These laboratory findings were parallel to clinical benefits. Control study was performed in the group of children completed by randomization and treated in the same way with garlic (Alliofil). PMID:16358878

Go?ebiowska-Wawrzyniak, Maria; Markiewicz, Katarzyna; Kozar, Agata; Derentowicz, Piotr; Czerwi?ska-Kartowicz, Iwona; Jastrzebska-Janas, Krystyna; Wac?awek, Jolanta; Wawrzyniak, Zbigniew M; Siwi?ska-Go?ebiowska, Henryka

2005-09-01

351

Differential efficacy of endodontic obturation procedures: an ex vivo study.  

PubMed

By means of a double-chamber model, different root canal filling materials and procedures were compared. Briefly, the root canals of single-rooted human teeth, extracted for periodontal reasons, were instrumented and obturated by gutta-percha/Pulp Canal Sealer EWT (PCS) or by Resilon, in association with different sealers (Real Seal, RelyX Unicem or Meta). Obturation was achieved by traditional continuous wave of condensation technique (TCWCT), a modified version of it (MCWCT), or single cone technique (SCT). The obturated roots, inserted in a double-chamber model, were sterilized by gamma irradiation. Next, Enterococcus faecalis was added to the upper chamber and the specimens were incubated at 37 °C for up to 120 days; the development of turbidity in the lower chambers' broths indicated bacterial leakage through the obturated root canals. The kinetics of leakage were analyzed in different groups by means of Kaplan-Meier statistics and compared by log-rank test. The results showed that root canals obturated with either gutta-percha/PCS using the MCWCT, Resilon/Real Seal SCT or Resilon/RelyX Unicem using the TCWCT displayed significantly better performance than the remaining groups (p < 0.01). Histological evaluation, performed to investigate microbial localization inside specimens, confirmed that this parameter varied according to the obturation procedures and materials employed. This ex vivo study indicates that gutta-percha/PCS, if used with the MCWCT, is as effective as Resilon when coupled to Real Seal with the SCT or, interestingly, to RelyX Unicem with the TCWCT. These data suggest that further improvement of the currently employed root canal filling procedures is achievable, depending on both the filling materials and the technique employed, thus encouraging clinical studies in this direction. PMID:23836051

Ardizzoni, Andrea; Generali, Luigi; Righi, Elena; Baschieri, Maria C; Cavani, Francesco; Manca, Lidia; Lugli, Eleonora; Migliarese, Luigi; Blasi, Elisabetta; Neglia, Rachele G

2014-07-01

352

Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research.  

PubMed

Electroencephalography (EEG) and related methodologies offer the promise of predicting the likelihood that novel therapies and compounds will exhibit clinical efficacy early in preclinical development. These analyses, including quantitative EEG (e.g. brain mapping) and evoked/event-related potentials (EP/ERP), can provide a physiological endpoint that may be used to facilitate drug discovery, optimize lead or candidate compound selection, as well as afford patient stratification and Go/No-Go decisions in clinical trials. Currently, the degree to which these different methodologies hold promise for translatability between preclinical models and the clinic have not been well summarized. To address this need, we review well-established and emerging EEG analytic approaches that are currently being integrated into drug discovery programs throughout preclinical development and clinical research. Furthermore, we present the use of EEG in the drug development process in the context of a number of major central nervous system disorders including Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder, and pain. Lastly, we discuss the requirements necessary to consider EEG technologies as a biomarker. Many of these analyses show considerable translatability between species and are used to predict clinical efficacy from preclinical data. Nonetheless, the next challenge faced is the selection and validation of EEG endpoints that provide a set of robust and translatable biomarkers bridging preclinical and clinical programs. PMID:20937262

Leiser, Steven C; Dunlop, John; Bowlby, Mark R; Devilbiss, David M

2011-06-15

353

Micro-ultrasound for preclinical imaging  

PubMed Central

Over the past decade, non-invasive preclinical imaging has emerged as an important tool to facilitate biomedical discovery. Not only have the markets for these tools accelerated, but the numbers of peer-reviewed papers in which imaging end points and biomarkers have been used have grown dramatically. High frequency ‘micro-ultrasound’ has steadily evolved in the post-genomic era as a rapid, comparatively inexpensive imaging tool for studying normal development and models of human disease in small animals. One of the fundamental barriers to this development was the technological hurdle associated with high-frequency array transducers. Recently, new approaches have enabled the upper limits of linear and phased arrays to be pushed from about 20 to over 50 MHz enabling a broad range of new applications. The innovations leading to the new transducer technology and scanner architecture are reviewed. Applications of preclinical micro-ultrasound are explored for developmental biology, cancer, and cardiovascular disease. With respect to the future, the latest developments in high-frequency ultrasound imaging are described. PMID:22866232

Foster, F. Stuart; Hossack, John; Adamson, S. Lee

2011-01-01

354

[Effectiveness of preclinical emergency management. Fiction or fact?].  

PubMed

The current increase in the cost of health care must be considered as a severe threat to the prehospital emergency services system. Two examples have been selected--the patient with polytrauma and the patient in cardiac arrest--to demonstrate the dilemma between a need for objective data and the requirements of emergency patients. Study results obtained in trauma patients indicating that total prehospital time, including scene time, is correlated to patient outcome have led to the conclusion that at the scene treatment by emergency physicians may be dispensable. It has, however also been demonstrated that the time required for medical treatment at the scene is equivalent to 20% of the total scene time, thus representing only a fraction of the total prehospital time. Correlating the total prehospital time or scene time to outcome therefore appears absurd. The treatment principle of aggressive shock treatment in polytrauma needs critical reevaluation on the basis of results obtained by recent preclinical studies in patients with penetrating torso injuries. Small volume resuscitation could not be demonstrated to improve outcome in polytrauma patients, although a slight improvement in patients with brain injury may be assumed. Endotracheal intubation and early artificial ventilation are proven therapeutic principles in polytraumatized patients. Unfortunately, for ethical reasons randomised carefully controlled comparative studies can not be performed in polytrauma patients unless the patient is fully conscious. The importance of endotracheal intubation and artificial ventilation in unconscious trauma patients becomes apparent under conditions of anaesthesia where the application of the endotracheal tube averts regurgitation, aspiration and concomitant morbidity and mortality. The common causes of cardiovascular collapse and their pathomechanisms, as well as the mechanisms of cardiopulmonary resuscitation, have been widely investigated. Nevertheless, various aspects of their application are still controversial. The most recent study results have recommended initial ventilation prior to thoracic compression. New methods of assisting mechanical cardiopulmonary resuscitation, such as ACD CPR or vest CPR, have shown promising results in animal experiments. However, the importance of results obtained by preclinical randomised controlled investigations in humans need to be confirmed by further studies as to outcome. The efficacy of defibrillation in cases of ventricular fibrillation has been clearly demonstrated, particularly with a view to the interval between ventricular fibrillation and defibrillation. It has further been demonstrated that basic cardiopulmonary resuscitation preserves ventricular fibrillation and thus improves the chance of survival. The present generation of defibrillators has been further improved, particularly by the introduction of biphasic defibrillator wave forms, which may reduce the required energy, as well as possible complications, while offering an increase in the efficacy of defibrillation and a reduction in defibrillator size. Scientific emergency medicine is responsible not only for the development and validation of new methods and concepts, but in particular for their application under quality control conditions. Politicians require an improvement in the quality of the validation of emergency measures, although the instruments available for the investigation of these measures are known to be obsolete (experimental models, experimental design). Additionally, the financial support of research in emergency medicine suffers from being accourded low priority by public research funds such as the German Research Fund. However, in view of the rapid application of experimental results to daily practice it should be emphasized that patients also support research in emergency medicine via their direct financial contributions to the health insurance companies. PMID:8678283

Dick, W F

1996-01-01

355

PREVENT Cancer Preclinical Drug Development Program  

Cancer.gov

The PREVENT Cancer Drug Development Program is a National Cancer Institute-supported pipeline to bring new cancer preventing interventions and biomarkers through preclinical development towards clinical trials.

356

Mitigating risk in academic preclinical drug discovery.  

PubMed

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID:25829283

Dahlin, Jayme L; Inglese, James; Walters, Michael A

2015-04-01

357

Preclinical Pharmacokinetic/Pharmacodynamic Modeling and Simulation in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape.  

PubMed

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner. PMID:25630504

Schuck, Edgar; Bohnert, Tonika; Chakravarty, Arijit; Damian-Iordache, Valeriu; Gibson, Christopher; Hsu, Cheng-Pang; Heimbach, Tycho; Krishnatry, Anu Shilpa; Liederer, Bianca M; Lin, Jing; Maurer, Tristan; Mettetal, Jerome T; Mudra, Daniel R; Nijsen, Marjoleen Jma; Raybon, Joseph; Schroeder, Patricia; Schuck, Virna; Suryawanshi, Satyendra; Su, Yaming; Trapa, Patrick; Tsai, Alice; Vakilynejad, Majid; Wang, Shining; Wong, Harvey

2015-03-01

358

Preclinical MR fingerprinting (MRF) at 7 T: effective quantitative imaging for rodent disease models.  

PubMed

High-field preclinical MRI scanners are now commonly used to quantitatively assess disease status and the efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical 7.0-T MRI implementation of the highly novel MR fingerprinting (MRF) methodology which has been described previously for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a fast imaging with steady-state free precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 min. This initial high-field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for the quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25639694

Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A; Vincent, Jason A; Dell, Katherine M; Drumm, Mitchell L; Brady-Kalnay, Susann M; Griswold, Mark A; Flask, Chris A; Lu, Lan

2015-03-01

359

Preclinical efficacy of MEK inhibition in Nras-mutant AML  

PubMed Central

Oncogenic NRAS mutations are highly prevalent in acute myeloid leukemia (AML). Genetic analysis supports the hypothesis that NRAS mutations cooperate with antecedent molecular lesions in leukemogenesis, but have limited independent prognostic significance. Using short hairpin RNA–mediated knockdown in human cell lines and primary mouse leukemias, we show that AML cells with NRAS/Nras mutations are dependent on continued oncogene expression in vitro and in vivo. Using the Mx1-Cre transgene to inactivate a conditional mutant Nras allele, we analyzed hematopoiesis and hematopoietic stem and progenitor cells (HSPCs) under normal and stressed conditions and found that HSPCs lacking Nras expression are functionally equivalent to normal HSPCs in the adult mouse. Treating recipient mice transplanted with primary NrasG12D AMLs with 2 potent allosteric mitogen-activated protein kinase kinase (MEK) inhibitors (PD0325901 or trametinib/GlaxoSmithKline 1120212) significantly prolonged survival and reduced proliferation but did not induce apoptosis, promote differentiation, or drive clonal evolution. The phosphatidylinositol 3-kinase inhibitor GDC-0941 was ineffective as a single agent and did not augment the activity of PD0325901. All mice ultimately succumbed to progressive leukemia. Together, these data validate oncogenic N-Ras signaling as a therapeutic target in AML and support testing combination regimens that include MEK inhibitors. PMID:25361812

Burgess, Michael R.; Hwang, Eugene; Firestone, Ari J.; Huang, Tannie; Xu, Jin; Zuber, Johannes; Bohin, Natacha; Wen, Tiffany; Kogan, Scott C.; Haigis, Kevin M.; Sampath, Deepak; Lowe, Scott; Shannon, Kevin

2014-01-01

360

Self-Efficacy and Equine Assisted Therapy: A Single Subject Study  

Microsoft Academic Search

Equine Assisted Therapy (EAT) is growing in popularity as an alternative to traditional talk therapy in treating a range of presenting concerns; however, there is little empirical research to support its use. In this study, the author added to the body of empirical literature on EAT’s impact on self-efficacy. This study was a single subject A-B-A-B design wherein the subject

Jessica H. Geddes

2010-01-01

361

Self-efficacy, Training Effectiveness, and Deception Detection: A Longitudinal Study of Lie Detection Training  

Microsoft Academic Search

\\u000a Studies examining the ability to detection deception have consistently found that humans tend to be poor detectors. In this\\u000a study, we examine the roles of self-efficacy and training over time. We conducted a field experiment at a military training\\u000a center involving 119 service members. The subjects were given two sessions of deception detection training. Their performance\\u000a history, perceived effectiveness of

Kent Marett; David P. Biros; Monti L. Knode

2004-01-01

362

Confidence in the face of risk: the Risk Assessment and Management Self-Efficacy Study (RAMSES)  

PubMed Central

Aims and method To evaluate a comprehensive risk management programme. A Risk Assessment and Management Self-Efficacy Scale (RAMSES) was used to evaluate the impact of a clinical guideline and training course. Fifty-three psychological therapists were randomly allocated to training v. waiting list in a controlled, delayed-intervention design. Differences in mean self-efficacy scores between groups were examined using analysis of covariance (ANCOVA). Results The RAMSES measure had adequate factor structure, internal consistency and construct validity. When adjusting for baseline scores and cluster design, the group exposed to training had a higher mean self-efficacy score than controls. Mean differences between groups were not significant after the control group received training, nor at 6 months’ follow-up. Clinical implications Exposure to training and clinical guidelines can improve self-efficacy in risk assessment and management. An important advance put forward by this study is the specification of areas of competence in risk assessment and management, which can be measured using a psychometrically sound tool. PMID:25237500

Delgadillo, Jaime; Moreea, Omar; Outhwaite-Luke, Hannah; Dace, Toby; Nicholls, Brenda; Ramseyer, Georgina; Dale, Veronica

2014-01-01

363

Preclinical Dosimetry of Magnetic Fluid Hyperthermia for Bladder Cancer  

PubMed Central

Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target. Results The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder ?1°C/min to a steady-state of 42°C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues. PMID:23837123

Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea; Etienne, Wiguins; Maccarini, Paolo F.; Inman, Brant; Dewhirst, Mark W.

2013-01-01

364

Preclinical dosimetry of magnetic fluid hyperthermia for bladder cancer  

NASA Astrophysics Data System (ADS)

Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target. Results The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder >1°C/min to a steady-state of 42°C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.

Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea; Etienne, Wiguins; Maccarini, Paolo F.; Inman, Brant; Dewhirst, Mark W.

2013-02-01

365

Efficacy of immunotherapy with mesenchymal stem cells in man: a systematic review.  

PubMed

Mesenchymal stem cells (MSC) are widely studied for their immunomodulatory properties. Data from in vitro and pre-clinical models demonstrate that MSC suppress activated immune cells and ameliorate the severity of experimental immune disease. In complex human studies, the immunomodulatory efficacy of MSC therapy is not well established. We conducted a systematic review of clinical studies which used MSC with the purpose of immunomodulation and included at least 10 patients to investigate the efficacy of MSC therapy. Sixty-two studies comprising 10 different immune disorders were included in the analysis, of which 18 studies represented controlled trials. Although several of the studies reported an amelioration of disease severity, other studies failed to observe a beneficial effect of MSC. The low number of randomized controlled trials, small number of studies per disease category and limited immunological readout parameters made it difficult to draw a definitive conclusion on the efficacy of MSC immune therapy. PMID:25817052

Luk, Franka; de Witte, Samantha Fh; Bramer, Wichor M; Baan, Carla C; Hoogduijn, Martin J

2015-05-01

366

Recent Clinical Studies of New Pharmacologic Agents and Their Efficacy in the Treatment of Incontinence  

PubMed Central

Two agents for the control of overactive bladder—tolterodine (TOL) and extended-release oxybutynin (Oxy-XL)—have been evaluated in a number of studies for their efficacy in urge incontinence. Studies have demonstrated that TOL achieved a 20% reduction in the frequency of voiding and a 45% reduction in urge incontinent episodes. Efficacy was comparable between TOL and immediate-release oxybutinin (Oxy-IR), the standard anticholinergic comparator. There is a delay of some weeks in achieving relief with TOL, but thereafter there is a continued decrease in the total number of both micturitions and incontinent episodes in 24 hours. Trials demonstrated that there were no safety concerns at all with TOL. In particular, there was a lower incidence of dry mouth with TOL than with Oxy-IR. Dose-ranging studies established that TOL produced the lowest incidence of side effects while maintaining efficacy. In a long-term, community-use study of Oxy-XL, there was a very low incidence of central nervous system side effects, including mental acuity and memory. Among elderly nursing home patients, Oxy-XL achieved a 90% reduction in weekly urge incontinence episodes and an 86% decrease in pad use. Oxy-XL was shown to cause a significantly lower reduction in salivary output than Oxy-IR and TOL. In a recent head-to-head comparison study, there were significant differences found between Oxy-XL and TOL. Other studies have shown that the administration of Oxy-XL results in a significantly lower production of the metabolites responsible for anticholinergic side effect, particularly dry mouth, than with the standard release form, owing largely to the elimination of a first-pass effect. A long-acting form of TOL resulted in a 53% reduction in incontinent episodes. Both these anticholinergic agents have been shown to have excellent efficacy and tolerability. But the future of OAB therapy lies in targeting other mechanisms responsible for incontinence. PMID:16985990

Appell, Rodney A

2001-01-01

367

Progression of preclinical diastolic dysfunction to the development of symptoms  

Microsoft Academic Search

BackgroundPreclinical diastolic dysfunction (PDD) has been defined as subjects with normal systolic function, diastolic dysfunction but no symptoms of heart failure (HF). The clinical phenotype and natural history of the syndrome remains poorly defined. This study's objective was to determine the clinical phenotype and progression to HF in a group of patients with normal systolic function and moderate or severe

Daniel D Correa de Sa; David O Hodge; Joshua P Slusser; Magaret M Redfield; Robert D Simari; John C Burnett; Horng H Chen

2010-01-01

368

Efficacy of Atomoxetine in Children with Severe Autistic Disorders and Symptoms of ADHD: An Open-Label Study  

ERIC Educational Resources Information Center

Objective: This study aims to examine the efficacy of atomoxetine in treating symptoms of attention deficit hyperactivity disorder (ADHD) in children with severe autistic disorder. Method: Children with severe autistic disorder who had symptoms of ADHD were given atomoxetine for 10 weeks. The efficacy of atomoxetine was evaluated by using the…

Charnsil, Chawanun

2011-01-01

369

Exploring Inclusion Preservice Training Needs: A Study of Variables Associated with Attitudes and Self-Efficacy Beliefs  

ERIC Educational Resources Information Center

The study examined attitudes towards inclusion and sense of efficacy of 1155 Israeli preservice teachers and variables related to these beliefs. Participants responded to an "Options related to inclusion scale", and a "Teacher efficacy scale". Findings revealed strong support for the principle of inclusion, yet also support for segregated special…

Romi, Shlomo; Leyser, Yona

2006-01-01

370

The Design of Pre-Service Inclusive Education Courses and Their Effects on Self-Efficacy: A Comparative Study  

ERIC Educational Resources Information Center

This study compared two versions of a 13-week mandatory undergraduate inclusive education course to determine their effects on the self-efficacy of pre-service elementary education teachers. For the purposes of the research, the self-efficacy construct was applied specifically to working with students who have inclusive educational needs. The…

Lancaster, Julie; Bain, Alan

2010-01-01

371

Electrosurgical Facial Resurfacing A Prospective Multicenter Study of Efficacy and Safety  

Microsoft Academic Search

Background: A novel electrosurgical technology that uses a bipolar electrode-tipped stylet to deliver rela- tively low-radiofrequency energy through an electri- cally conductive medium has been developed. Objective: To evaluate the efficacy and safety of the radiofrequency resurfacing system for the treatment of facial wrinkles. Design: Multicenter, prospective, noncomparative study with longitudinal follow-up. Setting: Four US academic dermatologic surgery clinics. Patients:

Roy C. Grekin; Whitney D. Tope; John M. Yarborough; Ingrid H. Olhoffer; Peter K. Lee; David J. Leffell; Christopher B. Zachary

2000-01-01

372

Antihypertensive Efficacy of Candesartan in Comparison to Losartan: The CLAIM Study  

Microsoft Academic Search

and Introduction Abstract An 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study was conducted to evaluate the antihypertensive efficacy of candesartan vs. losartan in 654 hypertensive patients with a diastolic blood pressure between 95 and 114 mm Hg from 72 sites throughout the U.S. Eligible patients were randomized to candesartan cilexetil 16 mg once daily, or losartan 50 mg once daily.

George Bakris; Alan Gradman; Max Reif; Marian Wofford; Mark Munger; Susan Harris; Jennifer Vendetti; Eric L. Michelson; Rebecca Wang

2001-01-01

373

A Study of the Mathematics Teaching Efficacy Beliefs of Primary Teachers  

Microsoft Academic Search

The affective domain has in recent years attracted much attention from the mathematics research community; empirical data\\u000a seem to increasingly support expert opinion that affect plays a decisive role in the process of cognitive development. One\\u000a of the less researched dimensions of the affective domain is teachers’ beliefs about the efficacy of their mathematics teaching.\\u000a Though there are studies examining

George Philippou; Constantinos Christou

374

Long-term safety and efficacy study of adapalene 0.3% gel.  

PubMed

The efficacy and safety of adapalene 0.1% gel in the treatment of acne vulgaris has been demonstrated in multiple controlled clinical trials. A higher concentration formulation, adapalene 0.3% gel, has been developed to provide a broader range of treatment options for acne management. Phase 3 clinical studies have demonstrated the superior efficacy of adapalene 0.3% gel compared to adapalene 0.1% gel and its vehicle at the end of a 12-week treatment period. The goal of this study was to evaluate the long-term safety of adapalene 0.3% gel in subjects treated once daily for 52 weeks, with a secondary objective to evaluate long-term efficacy. Subjects 12 years of age or older (N=551) with acne vulgaris participated in a multicenter, open-label study of the long-term (up to 52 weeks) efficacy and safety of once-daily applications of adapalene 0.3% gel. Of those enrolled, 167 subjects completed 12 months of treatment. Expected signs and symptoms of local cutaneous irritation (erythema, dryness, scaling, and stinging/burning) were mostly mild or moderate, with mean tolerability scores below 1 (mild) at all time points for the parameters assessed. Treatment-related, dermatologic adverse events were experienced by 21% of subjects and dry skin, skin discomfort, and scaling were reported by 10.5%, 8.3% and 3.3% of subjects, respectively. Most of the adverse events reported occurred in the first quarter of treatment. Adverse events were mostly mild to moderate in severity. Subjects treated with adapalene 0.3% gel for 52 weeks achieved a >75% median reduction in total, inflammatory, and noninflammatory lesions in this open-label study by the end of the treatment period. Adapalene 0.3% gel was safe and effective in the long-term (up to 1 year) treatment of subjects with acne vulgaris. PMID:18575223

Weiss, Jonathan S; Thiboutot, Diane M; Hwa, Joyce; Liu, Yin; Graeber, Michael

2008-06-01

375

A preliminary study into stress in palliative care: Optimism, self-efficacy and social support  

Microsoft Academic Search

Caring for the terminally ill is a demanding, but rewarding area of health care. Stressors unique to this working environment—dealing with patient death rather than cure, and supporting entire family units, for example—put caregivers at risk from stress related illness. This study investigated the buffering effects of optimism, self-efficacy and social support against two measures of stress within the palliative

N. J. Hulbert; V. L. Morrison

2006-01-01

376

A forced titration study of antihypertensive efficacy of candesartan cilexetil in comparison to losartan: CLAIM Study II  

Microsoft Academic Search

An 8-week, multicentre (72 sites in the US), double-blind, randomised, parallel group, forced titration study compared the antihypertensive efficacy of candesartan cilexetil and losartan. A total of 611 patients with essential hypertension (diastolic blood pressure 95 to 114 mm Hg) were randomised initially to candesartan cilexetil 16 mg once daily or losartan 50 mg once daily. After 2 weeks of

DG Vidt; WB White; E Ridley; M Rahman; S Harris; J Vendetti; EL Michelson; R Wang

2001-01-01

377

Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial.  

PubMed

Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein found that low nanomolar plitidepsin concentrations potently inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony formation by CD34+ cells of individuals with MF, at least in part through modulation of p27 levels. Cells of MF patients had significantly reduced p27 content, that were modestly increased upon plitidepsin exposure. On these premise, an exploratory phase II trial evaluated plitidepsin 5?mg/m(2) 3-h intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response rate (RR) according to the International Working Group for Myelofibrosis Research and Treatment consensus criteria was 9.1% (95% CI, 0.2-41.3%) in 11 evaluable patients during the first trial stage. The single responder achieved a red cell transfusion independence and stable disease was reported in nine additional patients (81.8%). Eight patients underwent a short-lasting improvement of splenomegaly. In conclusion, plitidepsin 5?mg/m(2) 3-h infusion q4wk was well tolerated but had a modest activity in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely terminated and we concluded that further clinical trials with plitidepsin as single agent in MF are not warranted. PMID:25768401

Pardanani, A; Tefferi, A; Guglielmelli, P; Bogani, C; Bartalucci, N; Rodríguez, J; Extremera, S; Pérez, I; Alfaro, V; Vannucchi, A M

2015-01-01

378

Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial  

PubMed Central

Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein found that low nanomolar plitidepsin concentrations potently inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony formation by CD34+ cells of individuals with MF, at least in part through modulation of p27 levels. Cells of MF patients had significantly reduced p27 content, that were modestly increased upon plitidepsin exposure. On these premise, an exploratory phase II trial evaluated plitidepsin 5?mg/m2 3-h intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response rate (RR) according to the International Working Group for Myelofibrosis Research and Treatment consensus criteria was 9.1% (95% CI, 0.2–41.3%) in 11 evaluable patients during the first trial stage. The single responder achieved a red cell transfusion independence and stable disease was reported in nine additional patients (81.8%). Eight patients underwent a short-lasting improvement of splenomegaly. In conclusion, plitidepsin 5?mg/m2 3-h infusion q4wk was well tolerated but had a modest activity in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely terminated and we concluded that further clinical trials with plitidepsin as single agent in MF are not warranted. PMID:25768401

Pardanani, A; Tefferi, A; Guglielmelli, P; Bogani, C; Bartalucci, N; Rodríguez, J; Extremera, S; Pérez, I; Alfaro, V; Vannucchi, A M

2015-01-01

379

Overall efficacy and safety results of sofosbuvir-based therapies in phase II and III studies.  

PubMed

The uridine nucleotide analogue sofosbuvir is a selective hepatitis C virus NS5B polymerase inhibitor, active regardless of genotype. We analyzed data on efficacy and safety of sofosbuvir, either in combination with pegylated interferon alfa-2a and ribavirin, or in combination with ribavirin alone as part of an interferon free regimen in more than 1300 patients. Treatment with sofosbuvir for 12 weeks in combination with P/R, in naïve genotype 1 patients was mainly studied in Neutrino. The efficacy of sofosbuvir as part of an all-oral combination including ribavirin alone, was explored in 555 naïve, ineligible and previous treatment failure genotype 2/3 patients. Rates of Sustained Viral Response in genotype 1 and 2 were higher than 85%. For genotype 3 and 4, a European study, Valence, and a US study on patients of Egyptian origin showed that naïve patients are cured at high rates by the all-oral combination given for 24 weeks. The efficacy of sofosbuvir plus P/R for 12 weeks in previous treatment failure genotype 3 has also been demonstrated. Sofosbuvir-based combinations are safe and well tolerated without side effects directly related to the drug. A large body of evidence suggests that sofosbuvir marks a revolution in HCV treatment. PMID:25458780

Mangia, Alessandra; Piazzolla, Valeria

2014-12-15

380

Pre-clinical safety assessment of Ad[I/PPT-E1A], a novel oncolytic adenovirus for prostate cancer.  

PubMed

Prostate cancer is the most common malignancy in the Western world. Patients can only be cured when the tumour has not metastasised outside the prostate. However, treatment with curative intent fails in a significant number of men, often resulting in untreatable progressive disease with a fatal outcome. Oncolytic adenovirus therapy may be a promising adjuvant treatment to reduce local failure or the outgrowth of micrometastatic disease. Within the European gene therapy consortium GIANT, we have developed a novel prostate-specific oncolytic adenovirus: Ad[I/PPT-E1A] that specifically kills prostate cells via prostate-specific replication. This paper describes the clinical development of Ad[I/PPT-E1A] with particular reference to the pre-clinical safety assessment of this novel virus. The pre-clinical safety assessment involved an efficacy study in a human orthotopic xenograft mouse model, a specificity study in human primary cells and a toxicity study in normal mice. These studies confirmed that Ad[I/PPT-E1A] efficiently kills prostate tumour cells in vivo, is not harmful to other organs and is well-tolerated in mice after systemic delivery. The safety, as well as the immunological effects of Ad[I/PPT-E1A] as a local adjuvant therapy will now be studied in a phase I dose-escalating trial in patients with localised prostate cancer who are scheduled for curative radical prostatectomy and can be used as an updated paradigm for similar therapeutic viruses. PMID:24548052

Schenk, Ellen; Essand, Magnus; Kraaij, Robert; Adamson, Rachel; Maitland, Norman; Bangma, Chris H

2014-02-18

381

Preclinical safety assessment of Ad[I/PPT-E1A], a novel oncolytic adenovirus for prostate cancer.  

PubMed

Prostate cancer is the most common malignancy in the Western world. Patients can be cured only when the tumor has not metastasized outside the prostate. However, treatment with curative intent fails in a significant number of men, often resulting in untreatable progressive disease with a fatal outcome. Oncolytic adenovirus therapy may be a promising adjuvant treatment to reduce local failure or the outgrowth of micrometastatic disease. Within the European gene therapy consortium GIANT, we have developed a novel prostate-specific oncolytic adenovirus: Ad[I/PPT-E1A]. This adenovirus specifically kills prostate cells via prostate-specific replication. This article describes the clinical development of Ad[I/PPT-E1A] with particular reference to the preclinical safety assessment of this novel virus. The preclinical safety assessment involved an efficacy study in a human orthotopic xenograft mouse model, a specificity study in human primary cells, and a toxicity study in normal mice. These studies confirmed that Ad[I/PPT-E1A] efficiently kills prostate tumor cells in vivo, is not harmful to other organs, and is well tolerated in mice after systemic delivery. The safety, as well as the immunological effects of Ad[I/PPT-E1A] as a local adjuvant therapy, will now be studied in a phase I dose-escalating trial in patients with localized prostate cancer who are scheduled for curative radical prostatectomy and can be used as an updated paradigm for similar therapeutic viruses. PMID:24649837

Schenk, Ellen; Essand, Magnus; Kraaij, Robert; Adamson, Rachel; Maitland, Norman J; Bangma, Chris H

2014-03-01

382

Application of peripheral-blood-derived endothelial progenitor cell for treating ischemia-reperfusion injury and infarction: a preclinical study in rat models  

PubMed Central

Background Our aim was to explore the therapeutic effects of peripheral blood-derived endothelial progenitor cells (PB-EPC) in cardiac ischemia-reperfusion infarction models in rats and in in vitro culture systems. Methods Rat models of ischemia reperfusion and myocardial infarction were developed using male, Sprague–Dawley rats. Cardiomyocyte and endothelial cell cultures were also established. Therapeutic effects of PB-EPCs were examined in vivo and in vitro in both models. Rats underwent either cardiac ischemia-reperfusion (n?=?40) or infarction (n?=?56) surgeries and were transplanted with genetically modified EPCs. Treatment efficacy in the ischemia-reperfusion group was measured by infarct size, myocardial contraction velocity, and myeloperoxidase activity after transplantation. Cardiomyocyte survival and endothelial cell apoptosis were investigated in vitro. Vascular growth-associated protein expression and cardiac function were evaluated in the myocardial infarction group by western blot and echocardiography, respectively. Results Infarct size and myeloperoxidase activity were significantly decreased in the ischemia-reperfusion group, whereas myocardial contractility was significantly increased in the EPC and T?4 groups compared with that in the control group. In contrast, no differences were found between EPC?+?shRNA T?4 and control groups. Rates of cardiomyocyte survival and endothelial cell apoptosis were significantly higher and lower, respectively, in the EPC and T?4 groups than in the control group, whereas no differences were found between the EPC?+?shRNA T?4 and control group. Four weeks after myocardial infarction, cardiac function was significantly better in the EPC group than in the control group. Expressions of PDGF, VEGF, and Flk-1 were significantly higher in EPC group than in control group. Conclusions Study findings suggest that PB-EPCs are able to protect cardiomyocytes from ischemia-reperfusion or infarction-induced damage via a T?4-mediated mechanism. EPCs may also provide protection through increased expression of proteins involved in mediating vascular growth. Autologous peripheral-blood-derived EPCs are readily available for efficient therapeutic use without the concerns of graft rejection. PMID:23452866

2013-01-01

383

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models.  

PubMed

Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. PMID:24151975

Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

2013-09-01

384

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models  

PubMed Central

Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. PMID:24151975

Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

2013-01-01

385

EFFICACY OF AYURVEDIC HEALTH CARE SYSTEM: A STUDY IN A COMMUNITY  

PubMed Central

This study is aimed at evaluating the efficacy of the Ayurvedic system, especially for chronic diseases. Assessment of the subjective relief feed back was done on the lines as suggested in Caraka Samhita, one of the oldest classical Ayurvedic texts. An inter-disciplinary research work involving ancient medical learning and hi-tech modern electronic data processing unit evaluate the efficacy of the Ayurvedic treatment in a closed community. 80 percent of the respondents were in the relief range of 75% to 100%, while overall relief in terms of regaining positive health in addition to attending complaint relief is over 70% in all diseases groups, as reported by the respondents in this Programme. PMID:22556503

Nagaraju, V.; Sriram, P.

1990-01-01