tbuckley/cabot-search huggingface dataset:
Examining inhibition of VEGFR and EGFR signaling in MMTV-neu transgenic mice with well-established tumors: an immunohistochemical and oncogenomic analysis of AZD2171, vandetanib and gefitinib treatment
Authors: Stephen Wedge, Teresa Klinowska, Neil Smith, Helen Brown, Paul Farrington, Kai-Ming Chang, Marie South, Alex Graham, Lynsey Womersley, Peter Hall, Sharon Barnett, Donald Ogilvie
Journal: Cancer Research (2007)

2122  MMTV-neu transgenic mice express an activated form of the rat neu (erbB2) gene under the control of the MMTV promoter (Muller et al. Cell 1988:54;105) and spontaneously develop mammary gland tumors. This study examined mice bearing a tumor of ≥0.4 cm3 volume and treated with once-daily oral administration of vascular endothelial growth factor receptor (VEGFR) and/or epidermal growth factor receptor (EGFR) signaling inhibitors: AZD2171 (6 mg/kg/day; a highly potent inhibitor of VEGFR tyrosine kinases); gefitinib (100 mg/kg/day; an inhibitor of EGFR tyrosine kinase); or vandetanib (ZD6474; 100 mg/kg/day; an inhibitor of both VEGFR and EGFR tyrosine kinases). AZD2171 induced profound and durable regression of tumors and comparable tumor regression was observed following vandetanib treatment. Gefitinib inhibited tumor growth significantly compared with tumors from vehicle-treated mice. Analysis of tumor blood vessels (CD31 staining) indicated that 1-3 days of treatment with AZD2171 induced a progressive reduction in vessel density and area (56% and 81% reduction, respectively, by day 3) and similar reductions in vessel density and area were evident following 5 days of vandetanib treatment. Gefitinib treatment had no effect on vessel parameters over a 5-day period. A high proportion (86%) of CD31-positive vessels within MMTV-neu tumors were associated with cells that stained positive for α-smooth muscle actin (α-SMA), although some heterogeneity was observed in the extent of endothelial-mural cell contact. Co-staining verified that following 3 days of AZD2171 treatment the mean number of α-SMA/CD-31-positive structures was reduced by 88%. Tumors treated with AZD2171 (for 4 days), vandetanib or gefitinib (both for 5 days) were analyzed at a genomic level. Following removal of probe sets of low expression (which reduced the total number from 45,000 to 12,000), remaining probe sets from treated samples were assigned significance using a cut-off of P
Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia
Authors: Nicholas C. P. Cross, Yvette Hoade, William J. Tapper, Gonzalo Carreno-Tarragona, Tiziana Fanelli, Mohamad Jawhar, Nicole Naumann, Iwo Pieniak, Johannes Lübke, Sahra Ali, Kaljit Bhuller, Sonja Burgstaller, Catherine Cargo, Jamie Cavenagh, Andrew S. Duncombe, Emma Das-Gupta, Paul Evans, Peter Forsyth, Philip George, Charlotte Grimley, Fergus Jack, Laura Munro, Varun Mehra, Kavita Patel, Ali Rismani, Gabriela Sciuccati, Rowena Thomas-Dewing, Patrick Thornton, Andres Virchis, Simon Watt, Louise Wallis, Alastair Whiteway, Kris Zegocki, Barbara J. Bain, Andreas Reiter, Andrew Chase
Journal: Leukemia (2018)

Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0–4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy.
Response to: ‘Role of linoleic acid in autoimmune disorders: aMendelian randomisation study’ by Lee <i>et al</i>
Authors: Jie V Zhao, C Mary Schooling
Journal: Annals of the Rheumatic Diseases (2018)

We are pleased that our article on the role of linoleic acid (LA) in autoimmune disorders is of interest to readers. However, regarding the methodological issues raised by Lee,1 several points need to be considered and clarified.

First, Mendelian randomisation (MR) requires stringent assumptions, that is, the genetic instruments are associated with the exposure, are not linked with the outcomes other than via effects on the exposure and no confounders of the associations of the genetic instruments with the outcome exist.2 We agree that weak instruments which violate these assumptions would lead to biased associations. As such, we are very cautious in the selection of genetic instruments. Specifically, we used the most significant three uncorrelated (r2<0.01) single-nucleotide polymorphisms (SNPs) from a genome-wide association …
Potential Harms of HIPAA
Authors: Charles G. Kels, Lori H. Kels
Journal: JAMA (2018)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
CD47 Expression Defines the Efficacy of Rituximab in Non-Germinal Center B-Cell (non-GCB) Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Tom Van Meerten, Renee Bouwstra, Yuan He, de Boer Janneke, Hilde Kooistra, Rudolf Fehrmann, Emanuele Ammatuna, Gerwin Huls, Edwin Bremer
Journal: Blood (2018)
Abstract 2868: Long-Term Prognostic Predictors of Isolated Significant Tricuspid Regurgitation
Authors: Jeong-Woo Lee, Jong-Min Song, Jae Won Lee, Myung-Zoon Yi, Eun Sun Jin, Duk-Hyun Kang, Jae-Kwan Song
Journal: Circulation (2008)

Background: Long-term outcomes of isolated significant tricuspid regurgitation (TR) without significant left-side heart disease remain to be clearly demonstrated. Methods: We enrolled 547 consecutive patients (age: 64 ± 14 years) with isolated significant TR. The patients with atrial septal defect, significant pulmonary or pulmonary vascular disease, right ventricular dysplasia and constrictive pericarditis were excluded. Initial clinical and echocardiographic characteristics and clinical outcomes were analyzed for 5.6 ± 2.1 years. Results: Survival rate was not different between 39 patients who underwent tricuspid valve (TV) surgery and 508 patients who did not (p=0.48). Of 508 patients without TV surgery, 32 patients (6.3%) died with cardiac cause during the follow-up period. Those patients were older (71 ± 16 vs. 64 ± 13 years, p&lt;0.05) and showed initial larger TR jet area (15 ± 7 vs. 12 ± 4 cm 2 , p&lt;0.05), and higher pulmonary artery systolic pressure (PASP, 46 ± 22 vs. 39 ± 16 mmHg, p&lt;0.05). By adjusting other baseline characteristics using Cox proportional hazard model, age (HR; 1.045, 95% CI: 1.013 – 1.078), initial TR jet area (HR; 1.110, 95% CI; 1.061 – 1.160), and PASP (HR; 1.025, 95% CI; 1.009 – 1.042) were independent predictors of cardiac mortality. Mortality rates did not differ between patients with organic and functional TR. Initial TR jet area ≥12 cm 2 and PASP ≥36 mmHg were best cut-off values for predicting cardiac mortality (Figure ). Conclusions: Severity of TR and pulmonary hypertension are prognostic factors independent of age in medically-managed patients with isolated significant TR. The results may suggest an optimal surgical timing in these patients.
The UK's pandemic influenza research portfolio: a model for future research on emerging infections
Authors: Colin R Simpson, Dan Beever, Kirsty Challen, Daniela De Angelis, Ellen Fragaszy, Steve Goodacre, Andrew Hayward, Wei Shen Lim, G James Rubin, Malcolm G Semple, Marian Knight
Journal: The Lancet Infectious Diseases (2019)
Abstract 19353: Genome Wide Association Studies of Heart Failure With Reduced and Preserved Ejection Fraction Point to Different Genetic Architectures
Authors: Rebecca T Levinson, Eric Farber-Eger, Christian M Shaffer, Jonathan D Mosley, Dan M Roden, Quinn S Wells
Journal: Circulation (2017)

Introduction: Heart failure (HF) is commonly subgrouped into HF with preserved and reduced ejection fraction (HFpEF and HFrEF). Genome-wide association studies (GWAS) of all-HF have identified few ...
An investigation into the effects of prior irradiation to the tumour mass on murine TIL expansion
Authors: A. Azizi, E. Cheadle, A. Popple, T. Illidge
Journal: Annals of Oncology (2018)

Background: Tumour infiltrating lymphocyte (TIL) therapy extracts CD8+ and CD4+ T cells from a tumour mass, expands and re-infuses them back into the patient. TIL therapy can lead to substantial complete, durable responses, particularly in refractory melanoma. TIL therapy is more effective if more T cells are infused, if they are less differentiated and if they target tumour antigen. Radiotherapy (RT) prior to TIL extraction may have immunostimulatory effects and so increase T cell infiltration into tumours, alter the T cell phenotype or increase number of tumour specific T cells in the expanded TIL. Methods: Two murine melanoma models (B16 and 4434) were grown in CD57Bl/6 mice. Treated tumours were irradiated with single dose (8 Gray) local radiotherapy, harvested 72 hours later and TIL were enriched. TIL were expanded for 9-10 days ex vivo using the allosensitised allogeneic lymphocyte expansion protocol (AEP), which uses soluble growth factors and allogeneic feeder cells to stimulate T cell growth. Live expanded TIL were counted using a haemocytometer, phenotyped using fluorescence-activated cell sorting and assayed for tumour reactivity by interferon gamma production. Results: CD8 + (≤ 61 fold) and CD4 + (≤ 16 fold) murine T cells expanded using the AEP in both murine tumour lines. 4434-derived and B16-derived TIL expanded to similar numbers with (n = 4) and without (n = 4) prior RT to tumour mass. When B16-derived TIL were analysed further, there were no changes in differentiation status or in the tumour reactivity (p = 0.48) of TIL from RT treated tumours. However, B16-derived TIL expanded from RT treated tumours had significantly greater expression of PD1 (as measured by percentage positive cells (p = 0.020) and geometric mean fluorescence intensity (p = 0.030)). Conclusions: This is the first study to expand murine or human TIL treated with prior RT. The AEP expanded tumour reactive murine melanoma TIL to numbers (1-5 x 106 cells) which might effectively treat in vivo murine models. Increased PD1 expression on TIL from RT-treated tumours might predict increased in vivo effectiveness, particularly if combined with PD1 inhibitors. The effect of different RT regimens on TIL expansion and effectiveness could be investigated with this approach. Legal entity responsible for the study: The University of Manchester. Funding: The University of Manchester. Disclosure: All authors have declared no conflicts of interest.
Abstract 19414: Hypochloridemia as a Prognostic Marker in Pulmonary Arterial Hypertension
Authors: Rajat Kalra, Kurt Prins, Lauren Rose, Marc Pritzker, Thenappan Thenappan
Journal: Circulation (2017)

Introduction: Right ventricular (RV) dysfunction identifies pulmonary arterial hypertension (PAH) patients at increased risk of mortality. Currently, few widely available biomarkers are associated with RV dysfunction in PAH. Serum chloride, a commonly measured laboratory value, is used to prognosticate left ventricular systolic heart failure patients, but the link between serum chloride, RV dysfunction, exercise capacity, and mortality in PAH patients is unexplored. Methods: We performed a longitudinal observational study of 203 PAH patients to determine if hypochloridemia is associated with markers of RV function, exercise capacity, and survival in PAH. Serum chloride levels were measured at the time of referral. Hypochloridemia was defined as the lowest quartile of chloride levels in our study cohort. Data on clinical characteristics, six-minute walk distance (6MWD), hemodynamics, and cardiovascular mortality were collected. Results: Hypochloridemia was significantly associated with higher right atrial ...
Genotype‐phenotype correlations in Brazilian patients with hereditary angioedema due to C1 inhibitor deficiency
Authors: Luana S. M. Maia, Adriana S. Moreno, Mariana P. L. Ferriani, Fernanda Leonel Nunes, Maria Fernanda Ferraro, Marina M. Dias, Persio Roxo‐Junior, Fabrício César Dias, Solange O. R. Valle, Soloni Levy, Maria Luiza Oliva Alonso, Alfeu T. França, Faradiba Sarquis Serpa, Antonio Abílio Motta, Felipe G. M. Maia, Davi Casale Aragon, Willy Sarti, Wilson Araújo Silva, Sven Cichon, Konrad Bork, L. Karla Arruda
Journal: Allergy (2018)
Abstract 17900: Medical Therapy Influences Outcome Of PCI Vs CABG Comparison Studies
Authors: Paul Kurlansky, Morley Herbert, Syma Prince, Michael Mack
Journal: Circulation (2015)

Introduction: Multiple studies have compared coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) to determine the optimal strategy for coronary revascularization (CR). Very few have evaluated the impact of medication history on the relative outcomes. Hypothesis: Evidence-based medical therapy influences outcomes of CABG vs. PCI Methods: All non-STEMI patients (N=3871 PCI, 1181 CABG) undergoing isolated CR in eight community-based hospitals were enrolled. Follow-up (63.5±27.9, median 79.7 months) was obtained at 12, 18 and &gt;60 months by patient/physician contact and Social Security Death Index. Kaplan-Meier curves were used to compare survival free of MACE (nonfatal myocardial infarction, PCI, CABG, mortality) between groups,. Results: Compliance with appropriate anti-platelet therapy improved long-term freedom from MACE in both PCI and CABG patients (Figure 1). Similarly, lipid-lowering therapy improved MACE-free survival in both PCI and CABG patients (Figure 2). Interestingly, treatment with beta blockers appeared to have either a negative (PCI) or marginal (CABG) impact.(Figure 3), most likely representing patient selection. Conclusion: Medication history has a dramatic impact on the long-term outcomes of both PCI and CABG patients and therefore must be included in the evaluation of comparative strategies for revascularization.
Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma
Authors: Aline Talhouk, Heather Derocher, Pascal Schmidt, Samuel Leung, Katy Milne, C. Blake Gilks, Michael S. Anglesio, Brad H. Nelson, Jessica N. McAlpine
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Tumors with high mutation load are thought to engender stronger immune responses, which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TILs) and immunosuppressive factors across the 4 molecular subtypes of endometrial cancer, which have characteristic mutation rates ranging from low to ultra-high. Experimental Design: A total of 460 endometrial cancers were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into 4 molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wild-type (p53wt). Immune markers (CD3, CD8, CD79a, CD138, PD-1, PD-L1, FoxP3, IDO-1) were quantified by multiplex IHC and tested for associations with ProMisE subtype, survival, and other clinicopathologic parameters. Results: Two major TIL patterns were observed. TILhigh tumors harbored dense T- and B-lineage infiltrates and multiple immunosuppressive features and were common in molecular subtypes associated with high mutation load (MMRd and POLE); however, equally strong responses were seen in significant numbers of p53abn and p53wt tumors, which have characteristically low mutation loads. TILlow tumors were generally devoid of immunologic features and were more prevalent in p53abn and p53wt endometrial cancers, yet were also seen in MMRd and POLE subtypes. In multivariable models involving ProMisE subtype, T-cell markers, and TIL clusters, only ProMisE showed independent prognostic significance. Conclusions: Immune response correlates with endometrial cancer molecular subtype but does not carry independent prognostic significance. Profound variation in immune response is seen across and within endometrial cancer molecular subtypes, suggesting that assessment of immune response rather than molecular subtype may better predict response to immunotherapy. See related commentary by Mullen and Mutch, p. 2366
Scaling up an early childhood development programme through a national multisectoral approach to social protection: lessons from Chile Crece Contigo
Authors: Helia Molina Milman, Claudio A Castillo, Andrea Torres Sansotta, Paula Valenzuela Delpiano, John Murray
Journal: BMJ (2018)

<b>Helia Molina Milman and colleagues</b> describe how intersectoral collaboration between health, social protection, and education sectors enabled Chile Grows with You (Chile Crece Contigo) to help all children reach their full developmental potential
Abstract 18143: Impact of FMO3 Gene Loss-of-Function Variants on Coronary Artery Disease in Japanese
Authors: Atsushi Nohara, Satoko Okazaki, Mie Yoshida, Mika Mori, Chiaki Nakanishi, Hayato Tada, Masa-aki Kawashiri, Kunimasa Yagi, Akihiro Inazu, Masakazu Yamagishi, Hiroshi Mabuchi
Journal: Circulation (2014)

High-fat foods are rich in the lipid phosphatidylcholine, which is converted to trimethylamine by intestinal bacteria and then processed to harmful metabolite, trimethylamine N-oxide (TMAO), by key...
l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Authors: Robert A. Koeth, Betzabe Rachel Lam-Galvez, Jennifer Kirsop, Zeneng Wang, Bruce S. Levison, Xiaodong Gu, Matthew F. Copeland, David Bartlett, David B. Cody, Hong J. Dai, Miranda K. Culley, Xinmin S. Li, Xiaoming Fu, Yuping Wu, Lin Li, Joseph A. DiDonato, W.H. Wilson Tang, Jose Carlos Garcia-Garcia, Stanley L. Hazen
Journal: Journal of Clinical Investigation (2018)

l-Carnitine, an abundant nutrient in red meat, accelerates atherosclerosis in mice via gut microbiota-dependent formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) via a multistep pathway involving an atherogenic intermediate, γ-butyrobetaine (γBB). The contribution of γBB in gut microbiota-dependent l-carnitine metabolism in humans is unknown.Omnivores and vegans/vegetarians ingested deuterium-labeled l-carnitine (d3-l-carnitine) or γBB (d9-γBB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic (≥2 months) l-carnitine supplementation. Human fecal commensals capable of performing each step of the l-carnitine→γBB→TMA transformation were identified.Studies with oral d3-l-carnitine or d9-γBB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal l-carnitine→γBB→TMA→TMAO pathway in subjects. Moreover, a striking increase in d3-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral d3-l-carnitine ingestion, whereas fasting endogenous plasma l-carnitine and γBB levels were similar in vegans/vegetarians (n = 32) versus omnivores (n = 40). Fecal metabolic transformation studies, and oral isotope tracer studies before versus after chronic l-carnitine supplementation, revealed that omnivores and vegans/vegetarians alike rapidly converted carnitine to γBB, whereas the second gut microbial transformation, γBB→TMA, was diet inducible (l-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of l-carnitine→TMA transformation, multiple community members that converted l-carnitine to γBB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted γBB to TMA. In coculture, E. timonensis promoted the complete l-carnitine→TMA transformation.In humans, dietary l-carnitine is converted into the atherosclerosis- and thrombosis-promoting metabolite TMAO via 2 sequential gut microbiota-dependent transformations: (a) initial rapid generation of the atherogenic intermediate γBB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota γBB→TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic l-carnitine exposure.ClinicalTrials.gov NCT01731236.NIH and Office of Dietary Supplements grants HL103866, HL126827, and DK106000, and the Leducq Foundation.
Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers
Authors: Matthias G. Pauthner, Joseph P. Nkolola, Colin Havenar-Daughton, Ben Murrell, Samantha M. Reiss, Raiza Bastidas, Jérémie Prévost, Rebecca Nedellec, Benjamin von Bredow, Peter Abbink, Christopher A. Cottrell, Daniel W. Kulp, Talar Tokatlian, Bartek Nogal, Matteo Bianchi, Hui Li, Jeong Hyun Lee, Salvatore T. Butera, David T. Evans, Lars Hangartner, Andrés Finzi, Ian A. Wilson, Richard T. Wyatt, Darrell J. Irvine, William R. Schief, Andrew B. Ward, Rogier W. Sanders, Shane Crotty, George M. Shaw, Dan H. Barouch, Dennis R. Burton
Journal: Immunity (2018)