tbuckley/cabot-search huggingface dataset:
Dual-energy CT: a new imaging modality for bone marrow oedema in rheumatoid arthritis
Authors: Lennart Jans, Isabelle De Kock, Nele Herregods, Koenraad Verstraete, Filip Van den Bosch, Philippe Carron, Edwin H Oei, Dirk Elewaut, Peggy Jacques
Journal: Annals of the Rheumatic Diseases (2018)

Active joint inflammation is a key feature in rheumatoid arthritis (RA). Treatment guidelines for RA,1 including ‘Treat-to-Target’ strategies,2 stress the importance of abrogation of inflammation. MRI clearly demonstrates bone marrow oedema lesions (BMEL) as a sign of inflammation.3 Dual-energy CT (DECT) scanners could provide a new approach to visualise BME.4–7 We investigated if DECT could visualise BME of the hand and wrist in patients with active RA, with MRI-proven BME as a gold standard.

Institutional review board approval was obtained. Twenty consecutive patients with active clinical synovitis of a metacarpophalangeal, proximal interphalangeal or wrist joint provided written informed consent and were included; 9 men and 11 women with a mean age of 60.7 (±10.3) years. Thirteen patients were ACPA positive and 8 were ACPA and RF positive; mean tender joint count and swollen joint count were both 5.9. Mean DAS28 was 4.37 (±1.4). The mean disease duration was 6.6 (±6.1) years. Seventeen patients were treated with conventional disease-modifying antirheumatic drugs, 7 were also treated with biologicals.

DECT was performed on a dual-source CT, data were post-processed with SyngioVia ‘Bone Marrow Oedema’ application (see the online supplementary text). Images were presented as colour-coded maps. …
General practice is imploding, BMA warns
Authors: Abi Rimmer
Journal: BMJ (2014)

General practice is “imploding” and practices are in danger of closure, the BMA has warned. 

Speaking at the association’s annual representative meeting, Chaand Nagpaul, chairman of the BMA’s General Practitioners Committee, warned that general practice was in a “parlous” state. “NHS general practice has been systematically devalued, attacked, and defunded, leaving it in a parlous state, with the quadruple whammy of a crisis in workload, workforce, premises, …
Recombinant relaxin protects liver transplants from ischemia damage by hepatocyte glucocorticoid receptor: From bench‐to‐bedside
Authors: Shoichi Kageyama, Kojiro Nakamura, Takehiro Fujii, Bibo Ke, Rebecca A. Sosa, Elaine F. Reed, Nakul Datta, Ali Zarrinpar, Ronald W. Busuttil, Jerzy W. Kupiec‐Weglinski
Journal: Hepatology (2018)

Hepatic ischemia‐reperfusion injury (IRI) represents a major risk factor of early graft dysfunction and acute/chronic rejection as well as a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although glucocorticoid receptor (GR) signaling may enhance cytoprotective programs, clinical use of glucocorticoid is limited because of adverse effects, whereas clinical relevance of GR‐facilitated cytoprotection in OLT remains unknown. We aimed to evaluate the significance of hepatic GR in clinical OLT and verify the impact of recombinant human relaxin (rhRLX), which may function as a GR agonist in a tissue/disease‐specific manner. Fifty‐one OLT patients were recruited under an institutional research board (IRB) protocol. Liver biopsies were collected after cold storage (presurgery) and 2 hours postreperfusion (before abdominal closure), followed by western blotting–assisted hepatic analyses. Forty‐three percent of OLTs failed to increase GR perioperatively under surgical stress. Post‐/pre‐GR ratios at postoperative day 1 correlated negatively with serum aspartate aminotransferase (AST)/cleaved caspase‐3 and positively with B‐cell lymphoma‐extra large (Bcl‐xL)/B‐cell lymphoma 2 (Bcl‐2) levels. In a murine OLT model with extended (18‐hour) cold storage, treatment with rhRLX ameliorated ischemia‐reperfusion (IR) damage and improved survival while up‐regulating hepatocyte GR and Bcl‐xL/Bcl‐2 expression in OLT. rhRLX‐induced GR suppressed hepatocyte high‐mobility group box 1 (HMGB1) translocation/release, accompanied by decreased Toll‐like receptor 4 (TLR4)/receptor for advanced glycation end products (RAGE), suppressed interleukin 1 beta (IL1β), chemokine (C‐C motif) ligand 2 (CCL2), C‐X‐C motif chemokine (CXCL)10, tumor necrosis factor alpha (TNFα), CXCL1, and CXCL2 levels, and attenuated neutrophil/macrophage accumulation in OLT. Inhibition of GR in hepatocyte culture and in OLT diminished rhRLX‐mediated cytoprotection. Conclusion: This translational study underscores the role of rhRLX‐GR signaling as a regulator of hepatocellular protection against IR stress in OLT. In the context of a recent phase III clinical trial demonstrating positive outcomes of rhRLX in patients with acute heart failure, studies on rhRLX for the management of IRI in OLT recipients are warranted. (Hepatology 2018;68:258‐273).
Self-Management of an Inferior ST-Segment Elevation Myocardial Infarction
Authors: Felicity Lee, Paul Maggiore, Kevin Chung
Journal: New England Journal of Medicine (2018)

To the Editor: A 44-year-old man presented with severe chest pain and dizziness to the nursing post where he worked in Coral Bay, Australia, more than 1000 km from Perth and 150 km from the next nearest medical facility.He was the only nurse on duty when the symptoms occurred.Since no other medical personnel were available, he performed and emailed his own electrocardiograms to an emergency physician by means of the Emergency Telehealth Service (ETS).The first electrocardiogram showed complete heart block, right bundle-branch block, hyperacute T waves in the inferior leads, and reciprocal ST-segment depression in the anterolateral leads (Fig. 1A).The second electrocardiogram, obtained 50 minutes later, showed sinus tachycardia with 2 mm of inferior ST-segment elevation (Fig. 1B).He self-cannulated both antecubital fossae for intravenous access and self-administered aspirin, clopidogrel, sublingual nitroglycerin, intravenous
A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia
Authors: Timothy S. Pardee, Rebecca G. Anderson, Kristin M. Pladna, Scott Isom, Lais P. Ghiraldeli, Lance D. Miller, Jeff W. Chou, Guangxu Jin, Wei Zhang, Leslie R. Ellis, Dmitriy Berenzon, Dianna S. Howard, David D. Hurd, Megan Manuel, Sarah Dralle, Susan Lyerly, Bayard L. Powell
Journal: Clinical Cancer Research (2018)

Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060-73. ©2018 AACR.
Racial disparities in the presentation of hepatocellular carcinoma in the population 65+ years in the United States.
Authors: Michael Ross Kaufman, David J. Delgado, Stephanie Costa, Brandon George, Edith P. Mitchell
Journal: Journal of Clinical Oncology (2018)

249 Background: Insufficient evidence exists regarding the presentation and management of elderly patients with hepatocellular carcinoma (HCC). The purpose of this study was to describe racial differences in cancer staging of elderly (65+) patients with HCC diagnosed in the United States. Methods: A retrospective cohort study was conducted using the 1973-2014 Surveillance, Epidemiology and End Results Program (SEER) database of the National Cancer Institute. Patients with primary hepatocellular carcinoma, diagnosed between 2004 and 2014, and with complete information on race, gender, year of diagnosis, age, marital status, region and stage at diagnosis (Derived SEER Summary Stage 2000, and Derived American Joint Committee on Cancer (AJCC) Stage Group, 6 th Edition) were included. Descriptive statistics were used to compare sociodemographic and clinical variables with race. Univariate and multivariate logistic regressions were preformed to describe the association of race with the diagnosis of late stage HCC (Regional/Distant vs Localized Stage for SEER Summary Stage, and Stage III/IV vs Stage I/II for AJCC Stage Group). Results: The sample consisted of 19,902 HCC patients: 69.7% White, 9.2% Black, 20.2% API, 1.0% AI; 69.1% male; 45.1% diagnosed in 2004-2009; 56.2% age 65-74, 35.6% 75-84, and 8.2% 85 and older; 58.3% married; 7.4% Midwest, 12.4% Northeast, 17.0% Southeast, 63.2% Pacific West; 44.9% Regional/Distant Stage (SEER Summary Stage) and 41.2% Stage III/IV (AJCC Stage Group). After controlling for confounding variables, Asian/Pacific Islanders had a decreased odds of presenting with late stage disease relative to whites in both the SEER Summary Stage (OR: 0.867, CI:0.805-0.934) and AJCC Stage Group (OR: 0.904, CI:0.838-0.975). Conclusions: Racial disparities exist at the presentation of HCC in the 65+ population. Asian/Pacific Islanders are less likely to be diagnosed with late stage HCC compared to whites. There is a need to study further these relationships in subpopulations.
Genetic Mechanisms of Immune Evasion in Colorectal Cancer
Authors: Catherine S. Grasso, Marios Giannakis, Daniel K. Wells, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Michael Quist, Jonathan A. Nowak, Reiko Nishihara, Zhi Rong Qian, Kentaro Inamura, Teppei Morikawa, Katsuhiko Nosho, Gabriel Abril-Rodriguez, Charles Connolly, Helena Escuin-Ordinas, Milan S. Geybels, William M. Grady, Li Hsu, Siwen Hu-Lieskovan, Jeroen R. Huyghe, Yeon Joo Kim, Paige Krystofinski, Mark D.M. Leiserson, Dennis J. Montoya, Brian B. Nadel, Matteo Pellegrini, Colin C. Pritchard, Cristina Puig-Saus, Elleanor H. Quist, Ben J. Raphael, Stephen J. Salipante, Daniel Sanghoon Shin, Eve Shinbrot, Brian Shirts, Sachet Shukla, Janet L. Stanford, Wei Sun, Jennifer Tsoi, Alexander Upfill-Brown, David A. Wheeler, Catherine J. Wu, Ming Yu, Syed H. Zaidi, Jesse M. Zaretsky, Stacey B. Gabriel, Eric S. Lander, Levi A. Garraway, Thomas J. Hudson, Charles S. Fuchs, Antoni Ribas, Shuji Ogino, Ulrike Peters
Journal: Cancer Discovery (2018)

Abstract To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability–high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730–49. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663
Abstract P4-04-17: Elacestrant (RAD1901) demonstrates anti-tumor activity in a fulvestrant-resistant PDX model
Authors: H Arlt, F Garner, T Bihani
Journal: Cancer Research (2018)

Abstract Background: Breast cancer is subdivided into categories based on tumor receptor status, with estrogen-receptor positive (ER+) breast cancer making up approximately two-thirds of all breast cancers diagnosed. In advanced or metastatic disease, dependence on ER signaling is often retained even after multiple rounds of endocrine therapy, supporting the use of ER targeting agents for several lines of treatment prior to chemotherapy. Selective estrogen receptor degraders (SERDs) have gained recent attention as ER antagonists given their ability to target and degrade ER. Fulvestrant, the only approved SERD on the market, is currently used as a second-line therapy in the metastatic setting, however, the intramuscular route of administration and pharmacokinetic properties of fulvestrant have fueled the development of more potent and orally bioavailable SERDs. We have previously described elacestrant (RAD1901), a novel and orally bioavailable SERD, as an inhibitor of ER+ breast cancer growth in preclinical patient-derived xenograft (PDX) models, including those that are insensitive to fulvestrant. Here, we describe elacestrant activity in an ER+ PDX model that had been treated with multiple rounds of fulvestrant treatment. Methods: An ER+/PR+ PDX model, MAXF-713, derived from a treatment-naïve patient, was passaged multiple times in the presence of fulvestrant over the course of a year. After each round of fulvestrant treatment, elacestrant or fulvestrant were evaluated for anti-tumor activity. Pharmacodynamic endpoints including changes in ER and ER target gene expression were also evaluated. Results: Despite repeated exposure to fulvestrant, the PDX model retained sensitivity to elacestrant. In fact, regardless of the number of prior rounds of fulvestrant treatment, elacestrant produced consistent tumor growth inhibition within every passage, while the effects produced by fulvestrant exhibited a high degree of variability. Conclusions: Our data demonstrate that elacestrant is a SERD that can inhibit tumor growth in a fulvestrant-resistant preclinical setting and provides rationale for examining elacestrant in the clinical setting in patients that have progressed on fulvestrant treatment. Citation Format: Arlt H, Garner F, Bihani T. Elacestrant (RAD1901) demonstrates anti-tumor activity in a fulvestrant-resistant PDX model [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-17.
Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis
Authors: Dag Leonard, Elisabet Svenungsson, Johanna Dahlqvist, Andrei Alexsson, Lisbeth Ärlestig, Kimberly E Taylor, Johanna K Sandling, Christine Bengtsson, Martina Frodlund, Andreas Jönsen, Susanna Eketjäll, Kerstin Jensen-Urstad, Iva Gunnarsson, Christopher Sjöwall, Anders A Bengtsson, Maija-Leena Eloranta, Ann-Christine Syvänen, Solbritt Rantapää-Dahlqvist, Lindsey A Criswell, Lars Rönnblom
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA. Methods Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs). Results We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10 −5 ) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10 −3 ), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10 −7 ), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10 −5 ) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes. Conclusions The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.
Discretionary indemnity works
Authors: Stephanie Bown
Journal: BMJ (2009)

While the Medical Protection Society would prefer not to engage in what many readers will perceive as “playground politics,” it would be wrong not to respond to the groundless anxieties raised by the Medical Defence Union’s comments ( BMJ 2009;338:CR94, 28 March).

MPS has been providing discretionary indemnity successfully for over 115 years and now offers what we believe to be the gold standard of protection to more than 260 000 …
Binge watching TV linked to increased colon cancer risk
Authors: Jacqui Wise
Journal: BMJ (2018)

Men who watch four or more hours of television a day are more likely to develop colon cancer than men who spend less time watching TV, one of the largest studies to date investigating the link between sedentary behaviour and bowel cancer suggests.1

The research, published in the British Journal of Cancer , included 430 584 men and women enrolled in the UK Biobank study. After a median follow up time of 5.6 years there were 2391 cases of colorectal …
Association of the T-cell receptor landscape with survival in non-small cell lung cancer.
Authors: Alexandre Reuben, Rachel Gittelman, Jiexin Zhang, Kelly Quek, Luis M Vence, Carmen Behrens, Runzhe Chen, Junya Fujimoto, Chi-Wan Chow, Xifeng Wu, James Patrick Allison, Padmanee Sharma, Jianhua Zhang, J. Jack Lee, Boris Sepesi, Don Lynn Gibbons, John Heymach, Andrew Futreal, Ignacio Ivan Wistuba, Jianjun Zhang
Journal: Journal of Clinical Oncology (2018)

140 Background: Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types which respond best to immune checkpoint blockade, likely through its ability to enhance the anti-tumor T cell response. However, the lung is constantly exposed to the outside environment, which may result in a continuous state of inflammation targeting pathogens rather than tumor cells. Therefore, a greater understanding of the T cell receptor (TCR) landscape and phenotypes across normal lung and tumor is warranted. Methods: Here, we performed sequencing of the CDR3 variable region of the beta chain of the TCR as well as whole exome sequencing on peripheral blood, normal lung and tumor in 235 NSCLC patients. We further analyzed the immune microenvironment by Cytometry by Time-of-Flight (CyTOF) in 10 NSCLC patients with paired normal lung and tumor. Results: Comparison of the TCR repertoire showed 9% (up to 15%) of T cells were shared between normal lung and tumor, though the most dominant were generally shared (up to 95%). Interestingly, T cell clonality was higher in the normal lung than tumor in almost all patients (89%, p &lt; 0.0001) suggesting potential differences in the ongoing immune response in different regions of the lung. A substantial number of non-synonymous exonic mutations (NSEM) were detected in tumors (average = 566 NSEM) but also in the normal lung (average = 156 NSEM), with many shared (up to 45.6%). CyTOF confirmed marked differences in the immune microenvironment, including higher frequency of VISTA+ antigen-presenting cells in the tumor (p = 0.04). Finally, analysis of clinicopathological attributes revealed a greater T cell diversity in the periphery in patients with increased overall survival (OS, p = 0.001), while patients with a more similar normal lung/tumor T cell repertoire showed decreased OS (p = 0.028). Conclusions: These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be lung-resident T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes, which highlights differences in the ongoing antigenic response within the lung.
Health department made no plans for future training of 1500 extra medical students,<i>BMJ</i>finds
Authors: Abi Rimmer
Journal: BMJ (2018)

The Department of Health and Social Care did not consult the body in charge of foundation training before it announced the creation of 1500 extra medical school places in England, The BMJ has found.

A freedom of information request sent by The BMJ revealed that the department had no correspondence with the UK Foundation Programme Office (UKFPO) in 2016 or 2017 about “plans to examine, review, or …