tbuckley/cabot-search huggingface dataset:
Patient-Derived Xenograft Models: An Emerging Platform forTranslational Cancer Research
Authors: Manuel Hidalgo, Frederic Amant, Andrew V. Biankin, Eva Budinská, Annete T. Byrne, Carlos Caldas, Robert B. Clarke, Steven de Jong, Jos Jonkers, Gundhild Mari Maelandsmo, Sergio Roman-Roman, Joan Seoane, Livio Trusolino, Alberto Villanueva
Journal: Cancer Discovery (2014)

Recently, there has been an increasing interest in the
development and characterization of patient-derived tumor
xenograft (PDX) models for cancer research. PDX models mostly
retain the principal histologic and genetic characteristics of
their donor tumor and remain stable across passages. These
models have been shown to be predictive of clinical outcomes
and are being used for preclinical drug evaluation, biomarker
identification, biologic studies, and personalized medicine
strategies. This article summarizes the current state of the
art in this field, including methodologic issues, available
collections, practical applications, challenges and
shortcomings, and future directions, and introduces a European
consortium of PDX models. Significance: PDX models are
increasingly used in translational cancer research. These
models are useful for drug screening, biomarker development,
and the preclinical evaluation of personalized medicine
strategies. This review provides a timely overview of the key
characteristics of PDX models and a detailed discussion of
future directions in the field.
Abstract 324: Knockout of the Pro-apoptotic Er-stress Gene Chac1 in Mice Results in Embryonic Lethality and Activation of the Notch Pathway
Authors: Imran Mungrue, Eugenia T Prescott, Charity F Sylvester, Rebecca R Crawford
Journal: Circulation Research (2015)

The ER-stress pathway is activated by oxidized phospholipids in human aortic endothelial cells (HAECs), and may play a role in the development of atherosclerosis. Systems genetics screens of transcriptome wide RNA co-expression in populations of human cells can broadly define novel functional gene-gene relationships. Using this method, we predicted a role for the human CHAC1 gene downstream of ATF4 in the ER-stress pathway in HAECs. Targeted cell culture and genetic perturbations refined the ATF4 dependent ER-stress induction of CHAC1 and a role in regulating apoptosis. Herein we report the generation of a mouse model with the Chac1 gene deleted (Chac1-KO), and heterozygous insufficiency (Chac1-Het). We obtained transgene positive C57BL6 founders that were bred to subsequent generations producing Chac1-Het mice. Intercrossing Chac1-Het mice revealed embryonic lethality, as no Chac1-KO progeny were generated from 25 litters. Chac1-KO embryos were produced at 13 days post coitus and used to make Mouse Embryonic Fibroblasts (MEFs), and the absence of Chac1 expression in these cells was validated. Since Chac1 is an ER-stress inducible gene activated by ATF4, we examined the expression of this pathway in Chac1-KO MEFs, versus controls. We noted increased basal and ER-stress induced expression of ATF4 and its target CHOP accompanying Chac1 knockout, highlighting a novel role for Chac1 in feedback regulation of the ATF4 branch of the ER-stress pathway. We also noted increased expressions of Parp1 and Caspase3, in Chac1-KO MEFs, supporting a role in the regulation of apoptosis pathways. Additionally, Chac1 cells had a higher proliferation rate, displayed a distinct morphology, and grew to a higher density. Since recent reports show a role for Chac1 in blocking Notch maturation, we examined expression of the Notch pathway in Chac1-KO MEFs, versus controls. We noted increased expression of the Notch target gene Hes1 in Chac1-KO MEFs at baseline. Following treatment with the proteasome inhibitor MG132, Chac1-KO MEFs had increased expressions of Hes1, Hey2 and Nrarp, target genes of the Notch pathway. These data reveal activation of the Notch pathway in Chac1-KO cells treated with MG132, a hyper proliferative phenotype and embryonic lethality at dpc 13.
Abstract P318: Vasoprotective Effects of an Apo A-I Mimetic Peptide
Authors: C White, Geeta Datta, Dale Parks, G Anantharamaiah
Journal: Circulation Research (2011)

Hepatic ischemia/reperfusion (I/R) injury is associated with several pathologic states and contributes to the development of systemic vascular complications. High density lipoprotein (HDL) and apolipoprotein (apo) A-1 possess antioxidant and anti-inflammatory properties and reduce tissue injury in several models of I/R. In the current study, we tested the hypothesis that the synthetic apoA-I mimetic peptide 4F, similar to HDL and apoA-I, exerts cytoprotective effects in a murine model of hepatic I/R injury. C57BL/6 mice were randomized to receive 4F (5 mg/kg, IP) or an equivalent volume of saline vehicle. Mice were then subjected to 45 min of segmental hepatic ischemia, followed by 24 hr reperfusion. Sham-operated mice served as a control. Hepatic I/R injury was associated with an increase in alanine transaminase (ALT: 980±95U/mL) and xanthine oxidase (XO: 700±100U/mL) release compared to sham-operated controls (ALT=27±8U/mL; XO=100±10U/mL). Endothelium-dependent relaxation was impaired in aortae of I/R mice (R max =20%) compared to controls (R max =72%). This response was associated with a decrease in eNOS protein and an increase in iNOS and plasma levels of nitric oxide metabolites (NOx). Further, immunohistochemical studies revealed an increase in the nitration (3-NT) and chlorination (3-CT) of protein tyrosine residues in aortic sections from I/R mice that was associated with an increase in tissue myeloperoxidase (MPO) content. 4F treatment significantly improved the relaxation response in the aorta of I/R mice (R max =60%), prevented the upregulation of iNOS and NOx and reduced tissue protein nitration/chlorination. 4F treatment was further associated with a reduction in hepatocellular injury in I/R mice, as revealed by a decrease in ALT (110±15U/mL) and XO (270±50U/mL) release. Collectively, these data suggest that 4F reduces systemic vascular injury via cytoprotective effects at the level of the liver. ApoA-I mimetic peptide-based therapies may be effective in reducing vascular complications associated with clinical procedures such as transplantation.
Induction of New Autoimmune Diseases After Alemtuzumab Therapy for Multiple Sclerosis
Authors: Lawrence Steinman
Journal: JAMA Neurology (2017)

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 Neurology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Neurology journal
Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense
Authors: Miwa Sasai, Naoya Sakaguchi, Ji Su Ma, Shuhei Nakamura, Tsuyoshi Kawabata, Hironori Bando, Youngae Lee, Tatsuya Saitoh, Shizuo Akira, Akiko Iwasaki, Daron M Standley, Tamotsu Yoshimori, Masahiro Yamamoto
Journal: Nature Immunology (2017)
ПРОБЛЕМИ ХВОРОБ ОРГАНІВ ТРАВЛЕННЯ В НАУКОВИХ ДОСЛІДЖЕННЯХ
Authors: Yu.M. Stepanov, V.V. Rodionova, I.Yu. Skyrda
Journal: GASTROENTEROLOGY (2013)

Проведено аналіз 49 дисертаційних робіт, захищених за спеціальністю 14.01.36 — «гастроентерологія». Із них 40 % докторських дисертацій присвячено проблемам хвороб кишечника, 40 % — виразковій хворобі та 20 % — хронічному панкреатиту. У структурі дисертацій на здобуття наукового ступеня кандидата наук 29,5 % захищені за тематикою виразкової хвороби, 22,7 % — хвороб кишечника, 18,2 % — гастроезофагеальна рефлюксна хвороба, 13,6 % — біліарної патології, 6,8 % — гастриту та 9,1 % — хвороб печінки. Більшість робот присвячені питанням консервативного лікування хворих із патологією органів травлення, їх реабілітації, досягненню комплайєнсу в терапії. Поряд із цим у дисертаційних дослідженнях висвітлюються питання патофізіології хвороб органів травлення, а також вплив захворювань інших органів на травну систему.
Tongxie Formula Reduces Symptoms of Irritable Bowel Syndrome
Authors: Heng Fan, Liang Zheng, Yaoliang Lai, Weimin Lu, Zhixiang Yan, Qi Xiao, Baiwen Li, Min Tang, Dawei Huang, Yuanyuan Wang, Zhen Li, Yuwei Mei, Zhengyan Jiang, Xingxing Liu, Qing Tang, Dongmei Zuo, Jingyi Ye, Yongqiang Yang, Huisuo Huang, Zongxiang Tang, Jun Xiao
Journal: Clinical Gastroenterology and Hepatology (2017)
Magnetic resonance imaging assessed inflammation in the wrist is associated with patient-reported physical impairment, global assessment of disease activity and pain in early rheumatoid arthritis: longitudinal results from two randomised controlled trials
Authors: Daniel Glinatsi, Joshua F Baker, Merete L Hetland, Kim Hørslev-Petersen, Bo J Ejbjerg, Kristian Stengaard-Pedersen, Peter Junker, Torkell Ellingsen, Hanne M Lindegaard, Ib Hansen, Tine Lottenburger, Jakob M Møller, Lykke Ørnbjerg, Aage Vestergaard, Anne Grethe Jurik, Henrik S Thomsen, Trine Torfing, Signe Møller-Bisgaard, Mette B Axelsen, Mikkel Østergaard
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs). <h3>Methods</h3> Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman’s correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests. <h3>Results</h3> MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p&lt;0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs. <h3>Conclusions</h3> MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand. <h3>Trial registration number</h3> NCT00660647.
Alloimmune T cells in transplantation
Authors: Susan DeWolf, Megan Sykes
Journal: Journal of Clinical Investigation (2017)

Alloimmune T cells are central mediators of rejection and graft-versus-host disease in both solid organ and hematopoietic stem cell transplantation. Unique among immune responses in terms of its strength and diversity, the T cell alloresponse reflects extensive genetic polymorphisms between allogeneic donors and recipients, most prominently within the major histocompatibility complex (MHC), which encodes human leukocyte antigens (HLAs) in humans. The repertoire of alloreactive T cell clones is distinct for every donor-recipient pair and includes potentially thousands of unique HLA/peptide specificities. The extraordinary magnitude of the primary alloresponse and diversity of the T cell population mediating it have presented technical challenges to its study in humans. High-throughput T cell receptor sequencing approaches have opened up new possibilities for tackling many fundamental questions about this important immunologic phenomenon.
Selective Sensitization of murine tumors to chemotherapy by a novel class of non-toxic small molecule inhibitors of MRP1
Authors: Catherine A. Burkhart, Fujiko Watt, Marina Pajic, Jayne Murray, Chengyuan Xue, Claudia Flemming, Janice Smith, Glenn M. Marshall, Michelle Haber, Murray D. Norris, Andrei V. Gudkov
Journal: Cancer Research (2006)

594  Intrinsic or acquired multidrug resistance (MDR) is one of the major causes of treatment failure in human malignancies. Such drug resistance can be conferred by overexpression of members of the ABC superfamily of transporters. Included in this superfamily are P-glycoprotein and the multidrug resistance associated protein (MRP) family. Of all the MRP family members, MRP1 has been the most closely linked to the development of clinical MDR for several types of cancer, most notably neuroblastoma, the most common solid tumor of infancy. MRP1 overexpression in this disease is strongly associated with poor survival making MRP1 a plausible target for therapeutic intervention. While first generation P-glycoprotein inhibitors failed clinically due to nonspecific toxicities, second and third generation inhibitors are showing greater selectivity and less toxicity. However, most have little or no effect on MRP1 and currently available MRP1 inhibitors have yet to make it to clinical trials. Thus, novel inhibitors are greatly needed. Screening of a focused small molecule chemical library using a cell-based readout system has led to the discovery of several potent inhibitors of MRP1-mediated drug transport that do not appear to be related to other known MRP1 inhibitors. Treatment of MRP1 overexpressing cells with these molecules greatly sensitized these cells to conventional chemotherapeutic agents that are known MRP1 substrates (vincristine and VP-16) in vitro. CBLC-4H10, the best compound among the “hits”, was found to be as good or better than known MRP1 inhibitors. More importantly, this compound increased the in vivo efficacy of both vincristine and VP-16 in a systemic murine neuroblastoma model as well as a human neuroblastoma xenograft model. This increased efficacy occurred in the absence of increased toxicity either from CBLC4H10 itself or from increased sensitivity to vincristine at the doses used for the efficacy studies. As demonstrated by 3H-vincristine biodistribution experiments, this lack of non-specific toxicity may be the result of increased uptake/retention of 3H-vincristine in tumor compared to normal tissues. This phenomenon has not been observed with 3H-vincristine alone or in combination with the MRP1 inhibitor difloxacin. Therefore, we have identified a new class of non-toxic MRP1 inhibitors, which may be clinically useful for the treatment of neuroblastoma by increasing the sensitivity of these drug refractory tumors to conventional chemotherapeutic agents.
Abstract 17347: De novo Ceramide Synthesis is Upregulated by Cardiac Ischemia and is Associated With Cardiomyocyte Apoptosis and Mitochondrial Dysfunction
Authors: Ruiping Ji, Xianghai Liao, Xiaokan Zhang, Hongfeng Jiang, Konstantinos Drosatos, Peter J Kennel, Estibaliz Castillero, Jennifer Y Chang, Shunichi Homma, Ira Goldberg, Paul Christian Schulze
Journal: Circulation (2015)

Background: Serine palmitoyltransferase (SPT) is the rate-limiting enzyme of de novo ceramide formation.However, ceramides can be produced through various pathways. The role of de novo ceramide synthesis via SPT in cardiac ceramide synthesis in ischemic cardiomyopathy has not been conclusively studied. Hypothesis: Ceramide synthesis via SPT may be linked to myocardial infarction-induced mitochondrial dysfunction and cardiac remodeling. Methods: Left coronary artery ligation and sham surgery was performed in C57BL/6J (8 wks, n=69) and Sptlc2 gene deletion mice (8 wks, n=9). Echocardiography confirmed MI-related cardiomyopathy at 2 and 8 wks. Groups of mice were treated either with SPT inhibitor, myriocin (300 ug/kg/d) or placebo for 8 wks. Ceramides were analyzed by LC/MS lipidomics. Sptlc2 (p3xFLAG-CMv7) overexpression in AC16 human cardiomyocyte-like cells was assessed. Results: Post-MI, total cardiac ceramides and certain species increased (total: +19%; C16: +19%; C24: +39%; C24:1: +44%; all p&lt;0.05 vs sham), consistent with cardiac Sptlc2 protein levels (+68% vs sham; p&lt;0.05). Sptlc2 overexpression, in cells, also resulted in increased ceramides (total: +33%; p&lt;0.05), C14 (+66%; p&lt;0.001), C16 (+39%; p&lt;0.01), C16:1(+47%; p&lt;0.001) and C24:1 (+37%; p&lt;0.01), increased apoptosis (+64%; p&lt;0.01), decreased cellular respiration (-69%; p&lt;0.001) and lowered respiratory capacity (-36%; p&lt;0.001). Myriocin treatment resulted in reduced LV dilation (4.8±0.3 vs 5.9±0.3 mm in placebo; p&lt;0.05), improved fractional shortening (19.8±2.4% vs 13.4±2.2 in placebo; p&lt;0.05), decreased myocardial collagen (0.08% vs 0.7%, p&lt;0.05) and prevented the increase of ceramides, post-MI (+4% vs. +17% in placebo; p&lt;0.05). C16, C24:1, and C24 ceramides decreased by 19, 20, and 32%, respectively (all p&lt;0.05 vs placebo). Sptlc2 KO mice trended towards less progressive remodeling with reduced fractional shortening compared to WT post-MI (-7% vs -14%; p=0.06). Conclusion: Pharmacologic and genetic inhibition of de novo ceramide synthesis decreases cardiac ceramides and prevents cardiac remodeling post-MI. Increased ceramides induce apoptosis and mitochondrial dysfunction. Inhibition of ceramide synthesis can be a supplemental therapy for heart failure treatment.
Temporal trends in chronic disease among survivors of childhood cancer diagnosed across three decades: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Todd M. Gibson, Sogol Mostoufi-Moab, Kayla Stratton, Dana Barnea, Eric Jessen Chow, Sarah S. Donaldson, Rebecca M. Howell, Melissa M. Hudson, Wendy M. Leisenring, Anita Mahajan, Paul C. Nathan, Kirsten K. Ness, Charles A. Sklar, Emily S. Tonorezos, Christopher Bertero Weldon, Elizabeth M. Wells, Yutaka Yasui, Gregory T. Armstrong, Leslie L. Robison, Kevin C. Oeffinger
Journal: Journal of Clinical Oncology (2017)

LBA10500 Background: Modifications in childhood cancer treatments in recent decades have contributed to reductions in late mortality among 5-year survivors. We used the recently expanded CCSS cohort to investigate whether these changes have also reduced the incidence of chronic disease. Methods: We evaluated the incidence of severe, disabling/life-threatening, or fatal chronic health conditions (Common Terminology Criteria for Adverse Events, CTCAE grades 3-5) among 5-year survivors diagnosed prior to age 21 years from 1970 through 1999. We calculated the 15-year cumulative incidence of chronic health conditions by decade of cancer diagnosis and compared risk across decades using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 23,601 survivors, median age 28 years (range 5-63), 21 years from diagnosis (5-43), the 15-year cumulative incidence of grade 3-5 conditions decreased from 12.7% in survivors diagnosed in the 1970s to 10.1% and 8.8% in those diagnosed in the 1980s and 1990s (per 10 years, HR 0.84 [95% CI = 0.80-0.89]). The association with diagnosis decade was attenuated (HR 0.92 [0.85-1.00]) when detailed treatment data were included in the model, indicating that treatment reductions mediated risk. Adjusted for sex and attained age, significant reduction in risk over time was found among survivors of Wilms tumor (HR 0.57 [0.46-0.70]), Hodgkin lymphoma (HR 0.75 [0.65-0.85]), astrocytoma (HR 0.77 [0.64-0.92]), non-Hodgkin lymphoma (HR 0.79 [0.63-0.99]), and acute lymphoblastic leukemia (HR 0.86 [0.76-0.98]). Decreases were largely driven by a reduced incidence of endocrine conditions (1970s: 4.0% v. 1990s:1.6%; HR 0.66 [0.59-0.73]) and subsequent malignant neoplasms (1970s: 2.4% v. 1990s: 1.6%; HR 0.85 [0.76-0.96]). Significant reductions were also found for gastrointestinal (HR 0.80 [0.66-0.97]) and neurological conditions (HR 0.77 [0.65-0.91]), but not cardiac or pulmonary conditions. Conclusions: Changes in childhood cancer treatment protocols have not only extended lifespan for many survivors, but have also reduced the incidence of serious chronic morbidity in this population.
Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses
Authors: Shengduo Liu, Shasha Chen, Xinran Li, Shiying Wu, Qian Zhang, Qiuheng Jin, Lin Hu, Ruyuan Zhou, Zhengyang Yu, Fansen Meng, Siwen Wang, Yaowei Huang, Sheng Ye, Li Shen, Zongping Xia, Jian Zou, Xin-Hua Feng, Pinglong Xu
Journal: Cell Host & Microbe (2017)
Establishing a Nurse-Led Follow-Up Clinic for Colorectal Cancer Patients
Authors: S Ladds, N Manimaran, S Middleton
Journal: Endoscopy (2004)

Background: Following surgery for colorectal cancer, clinical follow-up had been thought to lead to earlier identification and management of recurrent disease in appropriate sub group of patients. Traditionally these patients are followed up in a consultant-led clinic. We describe the effectiveness of a nurse-led colorectal cancer follow-up clinic.
In vitro downregulated hypoxia transcriptome is associated with poor prognosis in breast cancer
Authors: Basel Abu-Jamous, Francesca M. Buffa, Adrian L. Harris, Asoke K. Nandi
Journal: Molecular Cancer (2017)

Hypoxia is a characteristic of breast tumours indicating poor prognosis. Based on the assumption that those genes which are up-regulated under hypoxia in cell-lines are expected to be predictors of poor prognosis in clinical data, many signatures of poor prognosis were identified. However, it was observed that cell line data do not always concur with clinical data, and therefore conclusions from cell line analysis should be considered with caution. As many transcriptomic cell-line datasets from hypoxia related contexts are available, integrative approaches which investigate these datasets collectively, while not ignoring clinical data, are required.
Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma.
Authors: Frank (Xiaohu) Fan, Wanhong Zhao, Jie Liu, Aili He, Yinxia Chen, Xingmei Cao, Nan Yang, Baiyan Wang, Pengyu Zhang, Yilin Zhang, Fangxia Wang, Bo Lei, Liufang Gu, Xugeng Wang, Qiuchuan Zhuang, Wanggang Zhang
Journal: Journal of Clinical Oncology (2017)

LBA3001 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Monday, June 5, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
David Burns Moffat
Authors: Bill Moffat
Journal: BMJ (2017)

David Burns Moffat was born in Swansea to non-medical parents (his father was a master tailor and sometime powerboat racer). He duly attended Swansea Grammar School before starting his medical studies at Barts in 1939. The 2nd MB course was then relocated to Queens’ College, Cambridge. Typically for the time, the course was greatly contracted—so 46 weeks of teaching was crammed into a single calendar year.

With wartime constraints and the desperate need for qualified doctors, the final conjoint exam was taken after just two and a half years of clinical training, so David qualified MRCP LRCP in April 1943, at the age …