tbuckley/cabot-search huggingface dataset:
Abstract 4096: Identification of EMT inhibitors using novel zebrafish reporter lines
Authors: Laura Jimenez, Jindong Wang, Cicely Jette, Steven L. Warner, David Bearss, Rodney Stewart
Journal: Cancer Research (2015)

Abstract The Epithelial to Mesenchymal Transition (EMT) plays a crucial role during development and aberrant reactivation of EMT in tumor cells promotes metastasis and drug resistance. Mechanisms that control EMT remain incompletely understood, hampering efforts to target EMT in cancer patients. To identify upstream inducers and downstream effectors of EMT we have developed a novel zebrafish neural crest (NC) EMT reporter line, Tg(snail1b:GFP), for in vivo screening of EMT and cell migration inhibitors. After screening a number of candidate kinase inhibitors for their ability to block NC migration in live Tg(snail1b:GFP) embryos, we found that the AXL receptor tyrosine kinase inhibitor, TP-0903 (HCI-2084), potently blocks hindbrain morphogenesis and cranial NC cell migration. Treatment of embryos at the 3-somite stage with TP-0903 significantly decreases twist1a expression, a key regulator of EMT, blocks differentiation of dlx2a-expressing chondrogenic precursors, and instead promotes the differentiation of mitfa-expressing melanophore precursors that form adjacent to the neural tube. RNA-Seq analysis revealed that TP-0903 treated embryos have a significant upregulation of retinoic acid (RA) signaling. Co-treatment of TP-0903 with DEAB, an RA inhibitor, rescues the hindbrain and NC migration and differentiation defects caused by TP-0903 treatment. We are currently investigating the potential role of AXL in NC cell migration and differentiation, and evaluating TP-0903 as a possible therapy for neuroblastoma, by using the zebrafish neuroblastoma pre-clinical model and human neuroblastoma cells in vitro. Citation Format: Laura Jimenez, Jindong Wang, Cicely Jette, Steven L. Warner, David Bearss, Rodney Stewart. Identification of EMT inhibitors using novel zebrafish reporter lines. [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 4096. doi:10.1158/1538-7445.AM2015-4096
Kinetics of Regulatory T-Cells Are Highly Influenced by Treatment In Patients with Gastric MALT Lymphoma
Authors: Mar Garcia, Beatriz Bellosillo, Blanca Sanchez-González, Agustin Seoane, Luz Martínez-Avilés, Ana Ferrer, Eva Gimeno, Francesc Sole, Carlos Besses, Sergi Serrano, Antonio Salar
Journal: Blood (2010)
Abstract 2149: N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 4, a novel tumor suppressor, suppresses tumorigenesis and liver metastasis of colorectal cancer cells in mice
Authors: Tzu-Ming Jao, Ming-Hong Tsai, Sheng-Tai Tzeng, Ya-Chien Yang
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) is one of the most common causes of cancer deaths in the world, and most of CRC arise sporadically by the emergence of multiple chromosomal aberrations. Allelic losses in the long arm of chromosome 4 are commonly encountered in many human malignancies, but few tumor suppressor genes (TSGs) are identified. By loss of heterozygosity study at chromosome 4 in 114 colorectal carcinomas, we identified N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 4 (NDST4) as a novel TSG that had been published recently. We demonstrated for the first time that the genetic loss of NDST4 was significantly associated with advanced pathological stage and poorer overall survival of patients. Meanwhile, gene expression of NDST4 was obviously decreased in 30 (57.7%) of 52 CRC tumors when compared with their matched normal mucosae. In the present study, tumor suppressor activity of NDST4 was identified by in vitro cell models and mouse xenograft tumor models. Ectopic expression of NDST4 in the human CRC cells induced a significant suppression in cell proliferation, anchorage-independent growth and invasion in vitro. Subcutaneous injection of NDST4-inducible CRC cells in nude mice showed alleviated tumor growth in doxycycline treated mice when compared with doxycycline untreated mice. More importantly, via intrasplenic implantation, re-expression of NDST4 in silenced cells restrained liver metastasis, and also improved survival in nude mice. Taken together, these results indicate that NDST4 is a tumor suppressor gene associated with CRC, and its downregulation might promote tumor progression and distant metastasis. In addition, allelic loss of NDST4 gene could serve as a molecular predictor of metastasis and poor prognosis in patients with CRC. Citation Format: Tzu-Ming Jao, Ming-Hong Tsai, Sheng-Tai Tzeng, Ya-Chien Yang. N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 4, a novel tumor suppressor, suppresses tumorigenesis and liver metastasis of colorectal cancer cells in mice. [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 2149. doi:10.1158/1538-7445.AM2015-2149
179. Correcting the Bleeding Phenotype in Hemophilia Ausing Lentivirally FVIII-Corrected Endothelial Cells Differentiated from Hemophilic Induced Pluripotent Stem Cell (iPSC)
Authors: Maria Talmon, Cristina Olgasi, Simone Merlin, Angelo Lombardo, Federica Valeri, Angel Raya, Maria Messina, Donato Colangelo, Piercarla Schinco, Antonia Follenzi
Journal: Molecular Therapy (2015)

Hemophilia A (HA) is a bleeding disorder caused by factor VIII (FVIII) gene mutations.Somatic cells can be reprogrammed to generate autologous, disease-free iPSCs, then differentiated into cell targetsrelevant for gene and cell therapy. Our aim is to develop a novel HA treatment strategy generating FVIII-corrected patient-specific iPSCs from peripheral blood cells anddifferentiating them into functional endothelial cells (ECs), secreting FVIII after transplantation. Mononuclear (MNC) and CD34+ cells were isolated from peripheral blood of healthy and hemophilic donors and reprogrammed with a Cre-excisable polycistronic LV carrying OCT4, SOX2 and KLF4. iPSCs were characterized by Alkaline Phosphatase (AP), immunofluorescence staining, telomeres length, RT-PCR for stem cell markers in iPSCs and three germ layers markers in embryoid bodies (EBs). The differentiation potential was assessed by adipogenic, osteogenic and chondrogenic differentiation. iPSCs were differentiated in ECs using hVEGF-supplemented EB medium. Endothelial markers expression was evaluated by FACS and RT-PCR. ECs, transduced with LV carrying GFP under the control of endothelial-specific promoters: Flk-1, Tie2 and VEC, were transplanted in NSG-HA mice. Cells engraftment was analyzed by GFP-staining of liver sections. Reprogrammed MNC and CD34+ cells gave rise to ESC-like-iPSCs coloniespositivesfor AP staining and stem cell markers. EBs differentiated in osteogenic, chondrogenic and adipose tissues, and expressed three germ layers markers. Increased iPSCs telomeres length suggested telomerase reactivation and normal karyotype. RT-PCR on FVIII-corrected HA-iPSCs showed hBDD-FVIII expression, confirming HA-MNC genetic correction by LV transduction. iPSCs differentiated into ECs, acquiring endothelial-like morphology, expressing ECs markers and formed tubules when cultured in matrigel. Flk-1/Tie2/VEC-GFP-LV transduced ECs were transplanted in NSG-HA mice and detected in liver sections up to 6 weeks after transplantation. These results are instrumental to assess engraftment, proliferation and FVIII expression levels from differentiated, gene corrected and reprogramming factor-free iPSCs to confirm the suitability of this approach for HA gene-cell-therapy.
Essential role of p53 of stromal fibroblasts (fibs) in the reciprocal interaction between PC3 prostate cancer cells and stromal fibs.
Authors: M. Karamouzis, N. Dioufa, E. Farmaki, C. Piperi, H. Kiaris, A. Papavassiliou
Journal: Journal of Clinical Oncology (2011)

e21009 Background: The p53/p21 regulatory network is frequently deregulated in stromal cells and aberrant expression of p53/p21 has been reported in stromal fibs in various cancers. Methods: In order to provide hints regarding the mode of the paracrine interaction between p53 in stromal fibs and cancer cells (ccs), primary fibs from mice differing in the status of p53 were cultured in the presence of conditioned media from PC3 human prostate ccs and the rate of cell growth was evaluated. In addition, in vitro wound healing assays were performed to assess motility and migration of ccs. Considering the effects of p53-deficient (p53d) fibs in the phenotype of PC3 cells, we also searched if this paracrine stimulatory mechanism also affects viability of PC3 cells bearing stem cell-like properties by flow-cytometry. Therefore, PC3 cells that is CD44(hi)/CD44(low) were assessed in cells co-cultured with wild-type or p53d fibs. Results: We showed that p53d fibs acquire proliferative advantage when cultured in the presence of PC3 media, an observation likely related to the predominance of cells bearing this alteration in the microenvironment. The reverse experiment, i.e. the culture of PC3 cells in the presence of conditioned media from wild-type or p53-null fibs indicated that the latter stimulate the proliferation of ccs establishing a paracrine reciprocal stimulatory network that facilitates tumor growth. In vitro wound healing assays revealed that media from p53d cells significantly stimulated PC3 cell migration that reflects the degree of cellular motility which is associated with the metastatic potential of ccs. Flow-cytometry demonstrated that although wild fibs reduced the fraction of CD44(hi)/CD44(low) cells compared to that of PC3 cells cultured alone, the presence of p53d fibs restored the CD44(hi)/CD44(low) cell content to levels similar to those of the controls. Conclusions: Our findings pose that deregulated expression and mutations in p53 and/or p21 in stromal fibs are causatively linked to tumor growth, affecting not only cellular proliferation but also migration and stem-cell content. Therefore, modulation of p53/p21 activity in stromal fibs merits further investigation.
Elementary Medical Statistics: The Principles of Quantitative Medicine.
Journal: JAMA (1952)

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
L3MBTL1: A Polycomb Protein At the Node of Crosstalk Between the BMP4 and Hippo Signaling Pathways in Erythropoiesis.
Authors: Fabiana Perna, Ly P. Vu, Maria Themeli, Ruben Hoya-Arias, Fan Liu, Lan Wang, Nadia Gurvich, Todd Hricik, Eirini P. Papapetrou, Malcolm A.S. AS Moore, Ross L. Levine, Michel Sadelain, Stephen Nimer
Journal: Blood (2012)
Zika Virus —10 Public Health Achievements in 2016 and Future Priorities
Authors: Nadia L. Oussayef, Satish K. Pillai, Margaret A. Honein, C. Ben Beard, Beth Bell, Coleen A. Boyle, Lars M. Eisen, Katrin Kohl, Matthew J. Kuehnert, Eva Lathrop, Stacey W. Martin, Rebecca Martin, Janet C. McAllister, Elizabeth Pantino McClune, Paul Mead, Dana Meaney-Delman, Brett Petersen, Lyle R. Petersen, Kara N.D. Polen, Ann M. Powers, Stephen C. Redd, James J. Sejvar, Tyler Sharp, Julie Villanueva, Denise J. Jamieson
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

The introduction of Zika virus into the Region of the Americas (Americas) and the subsequent increase in cases of congenital microcephaly resulted in activation of CDC's Emergency Operations Center on January 22, 2016, to ensure a coordinated response and timely dissemination of information, and led the World Health Organization to declare a Public Health Emergency of International Concern on February 1, 2016. During the past year, public health agencies and researchers worldwide have collaborated to protect pregnant women, inform clinicians and the public, and advance knowledge about Zika virus (Figure 1). This report summarizes 10 important contributions toward addressing the threat posed by Zika virus in 2016. To protect pregnant women and their fetuses and infants from the effects of Zika virus infection during pregnancy, public health activities must focus on preventing mosquito-borne transmission through vector control and personal protective practices, preventing sexual transmission by advising abstention from sex or consistent and correct use of condoms, and preventing unintended pregnancies by reducing barriers to access to highly effective reversible contraception.
MicroRNA-206 prevents hepatosteatosis and hyperglycemia by facilitating insulin signaling and impairing lipogenesis
Authors: Heng Wu, Tianpeng Zhang, Fei Pan, Clifford J. Steer, Zhuoyu Li, Xin Chen, Guisheng Song
Journal: Journal of Hepatology (2016)

Graphical abstractAbstractBackground & AimsThe paradox of selective hepatic insulin resistance, wherein the insulin-resistant liver fails to suppress glucose production but continues to produce lipids, has been central to the pathophysiology of hepatosteatosis and hyperglycemia. Our study was designed to investigate the mechanism(s) by which microRNA-206 alleviates the pathogenesis of hepatosteatosis and hyperglycemia.MethodsDietary obese mice induced by a high fat diet were used to study the role of microRNA-206 in the pathogenesis of hepatosteatosis and hyperglycemia. A mini-circle vector was used to deliver microRNA-206 into the livers of mice.ResultsLipid accumulation impaired biogenesis of microRNA-206 in fatty livers of dietary obese mice and human hepatocytes (p<0.01). Delivery of microRNA-206 into the livers of dietary obese mice resulted in the strong therapeutic effects on hepatosteatosis and hyperglycemia. Mechanistically, miR-206 interacted with the 3′ untranslated region of PTPN1 (protein tyrosine phosphatase, non-receptor type 1) and induced its degradation. By inhibiting PTPN1 expression, microRNA-206 facilitated insulin signaling by promoting phosphorylation of INSR (insulin receptor) and impaired hepatic lipogenesis by inhibiting Srebp1c transcription. By simultaneously modulating lipogenesis and insulin signaling, microRNA-206 reduced lipid (p=0.006) and glucose (p=0.018) production in human hepatocytes and livers of dietary obese mice (p<0.001 and p<0.01 respectively). Re-introduction of Ptpn1 into livers offset the inhibitory effects of microRNA-206, indicating that PTPN1 mediates the inhibitory effects of microRNA-206 on both hepatosteatosis and hyperglycemia.ConclusionsMicroRNA-206 is a potent inhibitor of lipid and glucose production by simultaneously facilitating insulin signaling and impairing hepatic lipogenesis. Our findings potentially provide a novel therapeutic agent for both hepatosteatosis and hyperglycemia.Lay summaryThe epidemic of obesity is causing a sharp rise in the incidence of insulin resistance and its major complications, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). However, there are no effective treatments because the mechanisms underlying both disorders are not well described. We identified microRNA-206 as a novel and effective inhibitor for both glucose and lipid production in liver and potentially provide a unique therapeutic drug for both hepatosteatosis and hyperglycemia.
PTH-010 Comparison of colorectal cancer diagnoses in bowel cancer screening and 2-week rule patients: Abstract PTH-010
Authors: S Ramamurthy, K Matthewson
Journal: Gut (2010)

<h3>Introduction</h3> The two most common pathways through which colorectal cancer (CRC) is diagnosed in 60–69-year-olds are the 2-week wait pathway or bowel cancer screenng. The 2-week wait system involves fast tracking patients with worrying symptoms such as rectal bleeding, change of bowel habit to loose stools or iron deficiency anaemia to colonoscopy. Bowel cancer screening patients are offered faecal occult blood (FOB) testing and then colonoscopy if they prove positive. We have compared the CRC diagnoses made via each pathway. <h3>Methods</h3> We identified all 60–69-year-olds who underwent colonoscopy between 1.4.08 and 31.3.09 in the Newcastle Hospitals as part of the Bowel Cancer Screening Programme or via the 2-week wait system from the endoscopy IT system. All patients with a colonoscopic diagnosis of CRC or of a polyp had their histology reviewed. All patients with confirmed CRC, after multidisciplinary team review and treatment were categorised as to the site and staging of the cancer and the two groups were compared. <h3>Results</h3> See Abstract 010. <h3>Conclusion</h3> Patients with bowel cancer diagnosed by bowel cancer screening are more likely to have their CRC in the sigmoid colon and to be diagnosed at an earlier stage than those referred through the 2-week pathway. There is a strong trend towards patients being diagnosed by BCS being male.
Reduced Paired Box 5 (PAX5) Expression Is Common In Childhood Pro-B Acute Lymphoblastic Leukemic Cells, However, Can Not Be Attributed to PAX5 Genetic Hemizygous Deletion Only
Authors: Sheng-Kai Chang, Yen-Ju Chen, Shiann-Tarng Jou, Yong-Li Yang, Shu-Wha Lin, Kuo-Sin Lin, Dong-Tsamn Lin, Chung-Yi Hu
Journal: Blood (2010)
705. Selective Advantage of Hepatocytes Expressing Wild-Type Alpha-1 Antitrypsin (AAT) in a Novel Human Liver Xenograft Model: A Model for Correction of a Gain-Of-Function Mutation
Authors: Qiushi Tang, Michael S. BrehmM, Terence R. Flotte, Darcy L. Reil, Leonard D. Shultz, Dale L. Greiner, Christian Mueller
Journal: Molecular Therapy (2015)

Hepatocytes play a central role in energy metabolism and secretion of plasma proteins and represent an important target for gene therapy of single gene disorders. Alpha-1 antitrypsin (AAT) deficiency is one such disorder, in which one common missense mutation (E342K, known as the PI*Z allele) results in impaired secretion of AAT. In the majority of patients with AAT deficiency, this causes a lung disease due to a lack of the normal AAT-mediated protection of lung elastin from neutrophil elastase. In a subset of patients, accumulation of Z-mutant AAT protein triggers hepatocyte injury leading to inflammation and cirrhosis. As vector-mediated methods for correction of these two defects have been developed for both in vivo and ex vivo use, we sought to determine whether correction of the Z-mutant defect in hepatocytes might confer a selective advantage for repopulation of hepatocytes within an intact liver. To test this concept, a transgenic mouse strain expressing a human PI*Z allele was crossed with the NOD-SCID-gamma chain knockout (NSG) strain to create a recipient strain (PI*Z-NSG) for human hepatocyte xenotransplantation. Initial comparisons indicated that PI*Z-NSG recipients support more efficient engraftment of normal (wt-AAT) human primary hepatocytes as compared with NSG recipients. A number of procedures to optimize primary hepatocyte engraftment, and pretreatment of the recipient with monocrotaline further accentuated the level of engraftment. Finally, we propose to test the paradigm of using the selective advantage of wt-AAT hepatocytes to model gene and cell therapy of AAT deficiency, through the introduction of a dual-function lentivirus vector expressing both a myc-tagged wild-type AAT and a synthetic miRNA to knockdown the endogenous allele. The NSG-PI*Z recipient strain could be used as a platform for future studies of both cell-based and genetic therapies of AAT deficiency and further could predict a selective advantage of corrected cells in AAT deficient patients. In addition this new liver xenograft model provides a setting in which to easily a reproducibly repopulate a mouse liver with human hepatocytes.
473. The Significance of Academia-Industry Collaboration in Translational Research: A Survey of Over 300 PIs Who Have Received Industry Funding
Authors: Natasha L. Davie, Pavel Ovseiko, Steve Hyde, Richard Barker, Deborah Gill
Journal: Molecular Therapy (2015)

In the 24 years since the first gene therapy (GT) was administered to a human patient, the gene therapy field has advanced significantly. Recent clinical success in several diseases and the approval of Glybera (UniQure) in 2012 have heralded a new wave of investment from the private sector. This investment is evidenced by several
P214 The prevalence of respiratory symptoms and lung disease in a south london “lung health in addictions” service
Authors: CJ Jolley, A Healey, R Cole, R Baker-Wilding, B Tas, J Moxham, J Strang, M Kelleher
Journal: Thorax (2016)

<h3>Introduction and objectives</h3> Patients undergoing treatment for heroin addiction die on average 15 years earlier than the general population (Smyth <i>et al.,</i> 2006). Opioid-related deaths in England and Wales have increased by two-thirds since 2012 (Office for National Statistics 2015). Although smoking-related respiratory disease contributes to the excess mortality in drug and alcohol addiction, screening for lung disease is not routinely offered in community drug and alcohol treatment services (CDATs). We have established a “Lung Health Clinic” in our local CDAT (Brixton, Lambeth, SE London). Through this clinic we aimed to document the respiratory symptom burden, and COPD prevalence, in addicts accessing our local CDAT. <h3>Methods</h3> Assessments: handheld spirometry (FEV<sub>1</sub>, FVC, FEV<sub>1</sub>/FVC ratio) and pulse oximetry (SpO<sub>2</sub>%). We recorded breathlessness (mMRC Dyspnoea Scale), chronic cough and cigarette smoking status. <h3>Results</h3> 112 patients (88 male, mean(SD) age 46 (9) years) attended Jan–Dec 2015. Current/previous addictions included: smoked heroin 66.3%, intravenous heroin 32.5%, crack cocaine 68.2%, cannabis 60.0%. 81.3% were current cigarette smokers. Only 41% had accessed smoking cessation services despite these being offered in-house. 61.5% reported chronic cough. 20% reported significant breathlessness (mMRC Dyspnoea ≥ 2). 5% had a pre-existing COPD diagnosis, whereas spirometry [Figure 1] and clinical history were consistent with COPD in 36.4%. SpO<sub>2</sub> ≤ 95% in 12.8%. <h3>Conclusions</h3> There is a significant unmet burden of undiagnosed chronic lung disease, and respiratory symptoms, in our local CDAT, and a need to improve uptake of smoking cessation services. An economic model of expected gain in life expectancy and Quality Adjusted Life Expectancy (QALYs) from quitting is in development.