tbuckley/cabot-search huggingface dataset:
CBIO-44RESTING MEMBRANE POTENTIAL CONTROLS STEM CELL STATE AND DIFFERENTIATION OF GLIOBLASTOMA CANCER STEM CELLS
Authors: Brian Williams, Jinkyu Jung, Deric Park
Journal: Neuro-Oncology (2015)

Glioblastoma (GBM) is the most common malignant brain tumor in adults with a poor prognosis despite aggressive treatment. Resting membrane potential (RMP) has been shown to be an important signaling mechanism in physiological stem cells. Further the importance of ion channels and RMP have been studied in glioma. We evaluated the relevance of RMP in GBM in the context of the cancer stem cell(CSC) hypothesis. Undifferentiated GBM CSCs were depolarized compared to differentiated counterparts [RMP of -5 +/- 4 (n = 33) -24 + /- 20 (n = 31, P < 0.001)]. Depolarization using exogenous potassium (KCl) of GBM CSCs grown under differentiating conditions was sufficient to prevent differentiation and enhance self renewal when compared to osmotic controls (NaCl). Hyperpolarization using genetic (mutant TREK transduction) and pharmacological (omeprazole and salinomycin) was sufficient to induce differentiation and limit self renewal in GBM CSCs grown under undifferentiated conditions. To evaluate for a mechanism mediating this phenomenon we performed a phospho-protein array comparing the undifferentiated GBM CSCs and those treated with omeprazole or salinomycin. We noted upregulation of phospho-proteins related to senescence pathways in treated cells but no specific key pathway. Finally, this evidence suggests that RMP may be an important regulator of stem cell state of GBM CSCs. Further it may be a target of novel treatment strategies.
C-11. An Update on Gene Therapy for the Treatment of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency
Authors: Wuh-Liang Hwu, Shin-Ichi Muramatsu, Ni-Chung Lee, Yin-Hsiu Chien, Sheng-Hong Tseng, Kai-Yuan Tzen, Richard O. Snyder, Barry J. Byrne, Chun-Hwei Tai, Ruey-Meei Wu
Journal: Molecular Therapy (2015)

Aromatic L-amino acid decarboxylase (AADC) is an enzyme responsible for the final step of the synthesis of neurotransmitters dopamine and serotonin. AADC deficiency is a rare genetic disorder causing motor and autonomic dysfunction and early death in children. Taiwanese carry a high prevalence of AADC deficiency due to a founder mutation (IVS6+4A>T) in the AADC gene. A gene therapy with recombinant adeno-associated virus (AAV) serotype 2 CMV promoter-driven human AADC (AAV2-hAADC) was conducted in children with AADC deficiency since 2010. Clinical grade vector was manufactured. Two target points were determined in each putamen and a total of 1.7×1011 vg vector was injected. Eight patients have been treated at a mean age of 4.9 years (2-8 years), and the mean follow up period was 3.8 years (3-4.5 years). All patients, except one, had homozygous IVS6+4A>T mutations. Before gene therapy, these patients didn't have head control, and could not sit or stand, and they all had regular and severe oculogyric crisis (OGC) attacks. The stereotaxic surgeries were performed smoothly and there was no intracerebral bleeding. At the most recently follow-up visits after gene therapy, one patient was learning walking, two stood with support, one sat without assist, and three had better head control. The severity of OGC decreased and emotion stabilized in all patients. [18F]fluoro-dopa positron emission tomography (PET) signal intensity over putamen increased and cerebrospinal fluid neurotransmitter levels rose in all treated patients. Post gene therapy transient (orofacial) dyskinesia was the main adverse event of the treatment, and one patient experienced a hypovolemic shock due to dyskinesia and he remained bed-ridden. There is no virus-associated side effect, and currently no patient reveals a loss of treatment effect.
Abstract SY04-03: Molecular networks defining cell identity
Authors: George Q. Daley
Journal: Cancer Research (2015)

Abstract Somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions between differentiated cell lineages represent powerful approaches to engineering cell identity for applications in research and regenerative medicine. I will describe CellNet, a network biology platform developed to assess the fidelity of cellular engineering and to generate specific hypotheses for improving cell derivations. Analyzing published accounts, we have confirmed that reprogramming to pluripotency is remarkably robust, and found that cells derived via directed differentiation more closely resemble their in vivo counterparts than products of direct conversion, as reflected by the establishment of target cell type gene regulatory networks. We have applied CellNet to two cell fate conversion paradigms: conversion of B cells to macrophages and fibroblasts to hepatocyte-like cells, and learned provocative new lessons about the nature of these engineered cells. CellNet analysis, iteratively coupled to experimental validation, provides a rational strategy to enhance the derivation of target cells for research and therapy. Citation Format: George Q. Daley. Molecular networks defining cell identity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY04-03. doi:10.1158/1538-7445.AM2015-SY04-03
New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment
Authors: Yameng Sun, Jialing Zhou, Lin Wang, Xiaoning Wu, Yongpeng Chen, Hongxin Piao, Lungen Lu, Wei Jiang, Youqing Xu, Bo Feng, Yuemin Nan, Wen Xie, Guofeng Chen, Huanwei Zheng, Hai Li, Huiguo Ding, Hui Liu, Fudong Lv, Chen Shao, Tailing Wang, Xiaojuan Ou, Bingqiong Wang, Shuyan Chen, Aileen Wee, Neil D. Theise, Hong You, Jidong Jia
Journal: Hepatology (2016)

Liver fibrosis is the net result of dynamic changes between fibrogenesis and fibrolysis. Evidence has shown that antiviral therapy can reverse liver fibrosis or even early cirrhosis caused by hepatitis B virus. However, current evaluation systems mainly focus on the severity of, but not the dynamic changes in, fibrosis. Here, we propose a new classification to evaluate the dynamic changes in the quality of fibrosis, namely: predominantly progressive (thick/broad/loose/pale septa with inflammation); predominately regressive (delicate/thin/dense/splitting septa); and indeterminate , which displayed an overall balance between progressive and regressive scarring. Then, we used this classification to evaluate 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir‐based therapy for 78 weeks. Progressive, indeterminate , and regressive were observed in 58%, 29%, and 13% of patients before treatment versus in 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 29 cases (53%) had fibrosis improvement of at least one Ishak stage, and, more interestingly, 25 cases (45%) had significant improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. Conclusion : This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of antiviral therapy.(H epatology 2017;65:1438‐1450)
Treatment of Therapy-Related Myeloid Neoplasms with High-Dose Cytarabine/Mitoxantrone Followed by Hematopoietic Cell Transplantation (HCT).
Authors: Lucy A Godley, Uchenna O. Njiaju, Margaret Green, Howard Weiner, Shang Lin, Olatoyosi Odenike, Elizabeth Shima Rich, Andrew Artz, Koen van Besien, Christopher Daugherty, Yanming Zhang, Michelle M. Le Beau, Wendy Stock, Richard A. Larson
Journal: Blood (2009)
How Can the United States Spend Its Health Care Dollars Better?
Authors: Ezekiel J. Emanuel
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Reduced TET2 expression in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia.
Authors: Renata Scopim-Ribeiro, Joao Machado-Neto, Paula de Melo Campos, Patricia Favaro, Adriana S. S. Duarte, Valeria Visconte, Irene Lorand-Metze, Fernando Ferreira Costa, Jaroslaw P. Maciejewski, Ramon V. Tiu, Sara T. Olalla Saad, Fabiola Traina
Journal: Blood (2012)
102. Method Validation for Quantification of Recombinant Adeno-Associated Virus 5 in Mouse Genomic DNA Using Real-Time PCR
Authors: Hyun-Jung Kim, Sang-Jin Park, Sunyeong Lee, Ok-sun Kim, Su-Yeon Han, Kyoung-Sik Moon
Journal: Molecular Therapy (2016)

The recombinant adeno-associated viral (rAAV) vectors are one of the most promising tools in human gene therapy because of their excellent safety profiles. Recently, one of these, rAAV serotype 5 (rAAV5) has attracted attention as a therapeutic vector by many researchers. To develop rAAV5 vector for treatment in clinical trials, it is necessary to perform GLP compliant preclinical toxicity and biodistribution studies in animals. Quantitative real-time PCR (qPCR) technique is gold standard for quantification of gene therapy products and also has been used as the most sensitive method for bioanalysis of other rAAV vectors. In present study, an analytical method by qPCR was validated for determination of rAAV5 encoding human transgene in mouse genomic DNA. The validation was conducted to evaluate specificity, linearity, accuracy, and precision. There were no interfering reacts with the targeted sequence between true positive and negative control (no template control) samples. The correlation coefficient of rAAV5 in mouse genomic DNA was 0.9995 (1/x2 weighted) over a concentration range of 100 to 10,000,000 copies/ug. This method was accurate and precise verified by intra- and inter-batch analysis. The LLOQ for rAAV5 in mouse genomic DNA was 100 copies/ug, measured with acceptable accuracy and precision. Thus, the analytical method was quantifiable, linear, accurate, and precise. In conclusion, the validation method for rAAV5 in mouse genomic DNA has been successfully performed and will be also useful for further preclinical toxicity and biodistribution studies.
Abstract 4854: A computational framework for prioritizing noncoding regulatory variants in cancer
Authors: Yao Fu, Zhu Liu, Shaoke Lou, Vincenza Colonna, Jason Bedford, Xinmeng Mu, Kevin Y. Yip, Hyun Min Kang, Tuuli Lappalainen, Andrea Sboner, Haiyuan Yu, Mark Rubin, Chris Tyler-Smith, Ekta Khurana, Mark Gerstein
Journal: Cancer Research (2015)

Abstract Mutations in key regulatory sequences have been suggested to cause oncogenesis. However, identification of noncoding cancer “drivers” from thousands of somatic alterations is a difficult and unsolved problem. We report a computational framework, FunSeq, to annotate and prioritize these mutations. The framework combines an adjustable data context integrating large-scale genomics (e.g. ENCODE) and cancer resources with a streamlined variant-prioritization pipeline. The pipeline has a weighted scoring system combining: inter- and intra-species (we used patterns of natural polymorphisms to identify human-specific conserved elements) conservation; loss- and gain-of function events for transcription-factor binding; enhancer-gene linkages and network centrality; and per-element recurrence across samples. We further highlight putative drivers with information specific to a particular sample, such as differential gene expression. When applied to an individual tumor genome, our method is able to prioritize the TERT promoter mutation. We then evaluated our framework on a larger-scale first by doing various comparisons with other existing noncoding variant-prioritization tools. Next, we used the recurrence of somatic mutations to validate some of our prioritized mutations. Finally, we developed the recurrence analysis into a database combining all whole-genome sequenced cancer samples and used this to provide higher confidence in mutation prioritization. FunSeq is available from funseq.gersteinlab.org. Note: This abstract was not presented at the meeting. Citation Format: Yao Fu, Zhu Liu, Shaoke Lou, Vincenza Colonna, Jason Bedford, Xinmeng Mu, Kevin Y. Yip, Hyun Min Kang, Tuuli Lappalainen, Andrea Sboner, Haiyuan Yu, 1000 Genomes Project Consortium, Mark Rubin, Chris Tyler-Smith, Ekta Khurana, Mark Gerstein. A computational framework for prioritizing noncoding regulatory variants in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4854. doi:10.1158/1538-7445.AM2015-4854
DNA Vaccination and All-Trans Retinoic Acid Treatment-Induced Long Term Survival Requires CD4+ and CD8+ T-Cell Activation in An APL Mouse Model.
Authors: Rose Ann Padua, Kouichi Furugaki, Helene Moins-Teisserenc, Katerina Pokorna, Carole Le Pogam, Murielle Reboul, Masayuki Aoki, Veronique Bajzik, Patricia Krief, Anne Janin, Maria-Elena Noguera, Robert West, Marie-Helene Schlageter, Dominique Charron, Marika Pla, Christine Chomienne
Journal: Blood (2008)
185. Targeted Correction and Restored Function of CFTR Gene in Cystic Fibrosis Induced Pluripotent Stem Cells
Authors: Brian R. Davis, Ana M. Crane, Philipp Kramer, Jacquelin H. Bui, Wook Joon Chung, Xuan Shirley Li, Manuel L. Gonzalez-Garay, Finn Hawkins, Wei Liao, Daniela Mora, Jianbin Wang, Helena C. Sun, David E. Paschon, Dmitry Y. Guschin, Philip D. Gregory, Darrell N. Kotton, Michael C. Holmes, Eric J. Sorscher
Journal: Molecular Therapy (2015)

Recently developed reprogramming and genome editing technologies make possible the derivation of corrected patient-specific pluripotent stem cell sources – potentially useful for the development of new therapeutic approaches. The primary defect in Cystic Fibrosis (CF), an autosomal recessive disorder, is the regulation of epithelial chloride transport by a chloride channel protein encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recurrent pulmonary infections are responsible for 80 to 90% of the deaths in CF patients. Starting with skin fibroblasts from patients diagnosed with CF, we have derived and characterized induced pluripotent stem cell (iPSC) lines. We then utilized zinc finger nucleases (ZFNs), designed to target the endogenous CFTR gene, to mediate correction of the inherited genetic mutation in these patient-derived lines via homology directed repair (HDR). We observed an exquisitely sensitive, homology-dependent preference for targeting one CFTR allele vs. the other. Differentiation for a total of 19 days in a protocol designed to derive anterior foregut endoderm, subsequently up-regulated expression of NKX2-1, SOX9, TP63, FOXP2, FOXA2, and CFTR, suggesting commitment of at least a sub-population of cells within the endodermal culture to a lung epithelial cell fate. Once differentiated, mutant CF iPSCs yielded neither mature CFTR protein nor CFTR-specific chloride channel activity (as assayed in Ussing chamber experiments) – whereas corrected CF iPSCs and the normal control WA09 hESCs yielded mature CFTR protein and CFTR-specific chloride channel activity. In vitro differentiation of the mutant CF iPSCs into lung epithelial cells and tissue, controlled for by the parallel differentiation of the otherwise isogenic corrected CF iPSCs, may provide a valuable tool for drug screening and examining the functional consequence of mutant CFTR expression. Furthermore, corrected CF iPSCs present a potential source of patient-specific cells capable, in vitro, of differentiation into various lung stem/progenitor cells – either for transplantation of autologous lung cells or for seeding de-vitalized lung scaffolds ex vivo to generate autologous lungs.
The impact of a novel vicenin-2 and oral docetaxel combinatorial regimen in androgen-independent prostate cancer.
Authors: L. P. G. Dalasanur Nagaprashantha, J. Singhal, R. Vatsyayan, S. Awasthi, S. S. Singhal
Journal: Journal of Clinical Oncology (2011)

e13534 Background: A major challenge in the management of androgen-independent prostate cancer (AIPC) is the emergence of dose-limiting toxicities like febrile neutropenia while on i.v. docetaxel (DTL) treatment which has lead to investigation of alternate routes of DTL administration and drug combinations. Hence, we tested the potency of a novel flavonoid vicenin-2 (VCN-2) alone and in combination with oral DTL in AIPC. Methods: Cell survival was tested at various drug concentrations to determine in vivo doses by MTT and colony forming assays in PC-3 cells which have been established from the bone metastases of a 62 yr old male Caucasian with grade IV metastatic AIPC. Protein levels were analyzed by Western blot. For in vivo model studies, nu/nu nude mice (n=20) were implanted with 2 x 106 PC-3 cells subcutaneously into one flank and divided in to 4 groups. From tenth day after implantation, each group (n=5) were treated with corn oil (control), VCN-2 (3 mg/m2), DTL (0.03 mg/m2) and VCN-2 plus DTL in corn oil orally on alternate day. Tumor growth and body weight were monitored everyday. On day 60, tumors were excised for histopathological examination. Results: VCN-2 alone inhibited the survival of AIPC (p<0.01). The combination of VCN-2 and DTL induced synergistic effect in AIPC both in vitro and in vivo (~90% inhibition, CI <1 [Chou-Talalay test], p<0.0001). Tumor lysate analysis revealed that VCN-2 and DTL inhibited critical signaling proteins like pIGF1R, pRb, pAkt, PCNA and cyclin D1 to a greater extent in combination than either drugs alone. Histology of tumor sections revealed decreased levels of PSMA, ki67, CD31 and increase in the pro-differentiation marker E-cadherin. No overt toxicity was observed due to co-administration of VCN-2 and DTL. Conclusions: Oral administration of VCN-2 and DTL is effective and tolerable in vivo model of advanced AIPC. The salient feature of this study was the potent synergistic effect of VCN-2 and a low dose of DTL (0.03 mg/m2 of DTL and 3 mg/m2 of VCN-2 orally on alternate days compared to clinical dose in AIPC: 75 mg/m2 of DTL i.v. once in 3 wks. plus 5 mg prednisone twice daily) which strongly supports further development of VCN-2 and DTL combinatorial regimens for clinical use in AIPC.
Abstract LB-046: Evaluation of known low-penetrance thyroid cancer risk alleles in a Hispanic population from South America
Authors: Ana Estrada-Flórez, Mabel E. Bohórquez-Lozano, Rodrigo Prieto-Sánchez, Gilbert F. Mateus, Alejandro Rios, Alejandro Vélez Hoyos, Carlos S. Duque, Mirko A. Ledda, Maria J. Erazo, Fernando Bolaños, Cesar Panqueba, María Magdalena Echeverry de Polanco, Luis G. Carvajal-Carmona
Journal: Cancer Research (2015)

Abstract TC is one of the most common malignancy that shows familial inheritance with ∼8 fold increase in the risk of developing TC in first-degree relatives affected by this disease. Recent genome-wide association studies (GWAS) aimed at characterizing the risk loci for TC have identified five single nucleotide polymorphisms (rs966423, rs2439302, rs965513, rs116909374 and rs944289) associated with increased risk for TC. However, effect of these polymorphisms have bot been studied in any Hispanic population. Therefore, the aim of this study was to analyze the above-mentioned SNPs in 235 TC patients and 588 healthy controls from Central Colombia using KASP genotyping system. Genotype frequencies, Hardy Weinberg equilibrium (HWE) and association testing was carried out using Plink. The cumulative genetic risk was assessed using unweighted and weighted approaches. Significant associations between thyroid cancer risk and rs965513A (OR = 1.503, 95% CI: 1.203-1.886, P = 0.00038) and rs944289T (OR = 1.372, 95% CI: 1.095-1.699, P = 0.00488) was observed in our study. Consistent, yet not -significant associations were observed between disease risk and rs2439302T (OR = 1.177, 95% CI: 0.931-1.477, P = 0.1666) and rs116909374A (OR = 1.626, 95% CI: 0.799-3.766, P = 0.2443). For rs966423G, significant departure from HWE was observed therefore this SNP was excluded from further analysis. The combined analyses of rs2439302, rs965513, rs116909374 and rs944289 showed consistent associations between the number of disease alleles and cancer risk. Having three risk alleles increased disease risk by two-fold (OR = 2.09, 95% CI:1.46 - 3.02),while carrying five risk alleles was associated with nearly 4-fold increase in the disease risk (OR = 3.84, 95% CI:1.47 - 10.06). To our knowledge, this was the first study that assessed TC risk associated with known polymorphisms in the Hispanic population and suggest that these variants could be used in future risk prediction profiling studies in these populations. Citation Format: Ana Estrada-Flórez, Mabel E. Bohórquez-Lozano, Rodrigo Prieto-Sánchez, Gilbert F. Mateus, Alejandro Rios, Alejandro Vélez Hoyos, Carlos S. Duque, Mirko A. Ledda, Maria J. Erazo, Fernando Bolaños, Cesar Panqueba, María Magdalena Echeverry de Polanco, Luis G. Carvajal-Carmona. Evaluation of known low-penetrance thyroid cancer risk alleles in a Hispanic population from South America. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-046. doi:10.1158/1538-7445.AM2015-LB-046