tbuckley/cabot-search huggingface dataset:
Apparent plasticity in the biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.
Authors: Roland Seiler, Ewan Gibb, Natalie Qiqi Wang, Htoo Zarni Oo, Hung-Ming Lam, Kim E.M van Kessel, Mandeep Takhar, Nicholas Erho, Brian Winters, James Douglas, Bas W.G. Van Rhijn, Gottfrid Sjödahl, Ellen C Zwarthoff, George N. Thalmann, Elai Davicioni, Joost L Boormans, Marc Dall'era, Michiel Simon Van Der Heijden, Jonathan L. Wright, Peter C. Black
Journal: Journal of Clinical Oncology (2018)

433 Background: After cisplatin-based neoadjuvant chemotherapy (NAC) almost two thirds of patients have residual muscle-invasive bladder cancer (MIBC) present at radical cystectomy (RC). The alterations induced by NAC in these cisplatin-resistant tumors remain largely unstudied. Here, we aim to investigate the characteristics of cisplatin-resistant tumors. Methods: RC samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. In addition, the tumor bed (scar tissue) of 21 post-NAC RC specimens with no residual tumor was profiled. Unsupervised consensus clustering (CC) was performed and the CC were investigated for their biological and clinical characteristics. H&amp;E and immunohistochemistry (KRT5/6, GATA3, KI67 and CD8) were used to confirm tissue sampling and gene expression analysis. Results: Unsupervised consensus clustering yielded four distinct consensus clusters (CC). Consistent basal-(CC1) and luminal-like (CC2) phenotype similar to pre-NAC subtyping was observed in 42% of cases. One third of cases became immune-infiltrated (CC3) in the post-NAC setting but lacked basal and luminal markers. These tumors expressed a strong T-cell signature, chemokine signaling and checkpoint molecules. Conversely, CC4 was associated with healing/scarring. This ‘scar-like’ character of CC4 was consistent with the scar samples. Despite being pathological non-responders, the relative risk of death for CC4 was 2.8 and 3 times less than CC2-Luminal (p = 0.038) and CC3-Infiltrated (p = 0.018), respectively. Luminal-like pre-NAC samples were more likely to adopt a scar-like character (CC4) in the post-NAC setting, while the basal-like tumors were more likely to develop luminal features (CC2). Conclusions: This study expands our knowledge of cisplatin-resistant MIBC by suggesting molecular subtypes to understand the biology of these tumors. Clinical trials are necessary to test the impact of these molecular subtypes with respect to selection of adjuvant and salvage treatments. Post-NAC immune infiltration could have implications for subsequent immunotherapy.
INCIDENCE, ETIOLOGY AND PREDICTORS OF 30-DAY READMISSION RATES AFTER PERCUTANEOUS CLOSURE OF LEFT ATRIAL APPENDAGE: ANALYSIS OF THE 2013-2014 NATIONWIDE READMISSION DATABASE
Authors: Mohamed A. Omer, Abdelrahman Aly, Kevin Kennedy, Siva Sagar Taduru, Shehabaldin Alqalyoobi, Islam Elgendy, Ahmed Mahmoud, Jonathan Enriquez, Sanjaya Gupta
Journal: Journal of the American College of Cardiology (2018)
Abstract P4-06-17: Expanded panel testing in patients with breast or ovarian cancer in a rural familial cancer program
Authors: DJ Hermel, WC McKinnon, L Colello, MS Greenblatt, ME Wood
Journal: Cancer Research (2018)

Abstract Objective: We sought to investigate our center's experience with multi-gene panel testing in breast and ovarian cancer patients from a largely rural catchment area. Our goal was to identify predictors of pathogenic variants and assess indicators for expanded genetic testing. Methods: We conducted a retrospective review of breast and ovarian cancer patients who underwent panel testing between May 2011 and April 2016. A variety of commercial gene panels were used with variant classification determined by the individual laboratory. Differences in patient demographics, age of first cancer diagnosis, number of genes tested and tumor characteristics including hormone/HER2 status, histology, differentiation, tumor size and AJCC staging classification were analyzed among pathogenic variant positive, negative, and VUS patient subsets with a chi-square test and one-way ANOVA. Results: We identified 215 patients who underwent panel testing: the average age of patients was 52.9 ± 12 with first cancer onset at 47 ± 12; 27% of patients had undergone prior single-gene testing; 7% of patients had ovarian cancer and 93% of patients had breast cancer. VUS were detected in 18.1% of patients and pathogenic variants were detected in 9.3% of patients. Of the 20 pathogenic variants identified, 1 was detected in BARD1, 2 in BRIP1, 3 in MUTYH, 5 in CHECK2, 2 in BRCA1, 2 in BRCA2, 3 in ATM, 1 in PALB2 and 1 in PMS2. In our breast cancer cohort, there was a statistical difference (p=.03) between patients with VUS, pathogenic variants and negative testing in respect to hormone and HER2 status. Most pathogenic variants (75%) were in patients who were HER2 negative, with the majority of VUS detected in patients who were hormone receptor positive (66%). Between the groups, there were no differences in histology, tumor differentiation, size or AJCC stage classification. However, individuals with pathogenic variants tended to have a younger age of first cancer diagnosis, have higher grade disease and have triple negative tumors. Conclusions: Specific tumor patterns (that is, HER2 negative or triple negative pathology) may be important indicators for genetic testing in breast cancer patients. Expanded panel testing should be considered in patients with a younger age of cancer diagnosis, higher grade disease and triple negative tumors. Citation Format: Hermel DJ, McKinnon WC, Colello L, Greenblatt MS, Wood ME. Expanded panel testing in patients with breast or ovarian cancer in a rural familial cancer program [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 P4-06-17.
Lupus Regulator Peptide P140 Represses B Cell Differentiation by Reducing HLA Class II Molecule Overexpression
Authors: Maud Wilhelm, Fengjuan Wang, Nicolas Schall, Jean‐François Kleinmann, Michael Faludi, Emil Pablo Nashi, Jean Sibilia, Thierry Martin, Evelyne Schaeffer, Sylviane Muller
Journal: Arthritis & Rheumatology (2018)

Phosphopeptide P140 (Lupuzor) is an inhibitor of autophagy currently being evaluated in late-stage clinical trials for the treatment of lupus. This study was undertaken to investigate the effect of P140 ex vivo on human T and B cells.Human B cells, T cells, and dendritic cells were analyzed by flow cytometry and cellular assays. The expression of autophagy markers was evaluated by immunoblotting and flow cytometry. The levels of B cell receptor (BCR) signaling markers and HLA molecules were assessed by flow cytometry. Toll-like receptor ligands were screened using an assay with transfected HEK 293 cells. P140 cell entry and trafficking were measured by immunofluorescence in the presence of various inhibitors of endosomal pathways.As was previously observed after intravenous injection of the peptide in a mouse model of lupus, P140 entered human B cells by a clathrin coat-dependent endocytosis process and homed into lysosomes. The peptide displayed no direct effect on BCR signaling of memory, naive mature, transitional, and B1 cells. However, it strongly reduced the overexpression of HLA class II molecules on lupus B cells that were acting as antigen-presenting cells, down-regulated the maturation and differentiation of B cells into plasma cells, and decreased IgG secretion.These findings show that P140 down-regulates HLA class II overexpression in human lupus B cells, and also that P140 hampers the differentiation of B cells into autoantibody-secreting plasma cells, likely due to the resulting lack of T cell signaling and activation. This mechanism appears to switch off the downstream events leading to secretion of pathogenic autoantibodies, thus explaining the highly promising results obtained in clinical trials of P140 (Lupuzor) for the treatment of lupus.
Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines
Authors: Jason Miska, Jen Bon Lui, Kevin H. Toomer, Priyadharshini Devarajan, Xiaodong Cai, JeanMarie Houghton, Diana M. Lopez, Maria T. Abreu, Gaofeng Wang, Zhibin Chen
Journal: The Journal of Experimental Medicine (2018)

Genetically predisposed CTLA4 insufficiency in humans is associated with gastric cancer development, which is paradoxical to the prototypical role of CTLA4 in suppressing antitumor immunity. CTLA4 is a critical immune checkpoint against autoimmune disorders. Autoimmunity has been implicated in protumor or antitumor activities. Here, we show that CTLA4 insufficiency initiates de novo tumorigenesis in the mouse stomach through inflammation triggered by host-intrinsic immune dysregulation rather than microbiota, with age-associated progression to malignancy accompanied by epigenetic dysregulation. The inflammatory tumorigenesis required CD4 T cells, but not the TH1 or TH17 subsets. Deficiencies in IL-4 and IL-13 or IL-4 receptor α broke the link between inflammation and initiation of tumorigenesis. This study establishes the causality of CTLA4 insufficiency in gastric cancer and uncovers a role of type 2 inflammation in initiating gastric epithelial transformation. These findings suggest possible improvement of immune therapies by blocking tumorigenic type 2 inflammation while preserving antitumor type 1 immunity.
E2F1 Suppresses Oxidative Metabolism and Endothelial Differentiation of Bone Marrow Progenitor Cells
Authors: Shiyue Xu, Jun Tao, Liu Yang, Eric Zhang, Chan Boriboun, Junlan Zhou, Tianjiao Sun, Min Cheng, Kai Huang, Jiawei Shi, Nianguo Dong, Qinghua Liu, Ting C. Zhao, Hongyu Qiu, Robert A. Harris, Navdeep S. Chandel, Douglas W. Losordo, Gangjian Qin
Journal: Circulation Research (2018)

The majority of current cardiovascular cell therapy trials use bone marrow progenitor cells (BM PCs) and achieve only modest efficacy; the limited potential of these cells to differentiate into endothelial-lineage cells is one of the major barriers to the success of this promising therapy. We have previously reported that the E2F transcription factor 1 (E2F1) is a repressor of revascularization after ischemic injury.We sought to define the role of E2F1 in the regulation of BM PC function.Ablation of E2F1 (E2F1 deficient) in mouse BM PCs increases oxidative metabolism and reduces lactate production, resulting in enhanced endothelial differentiation. The metabolic switch in E2F1-deficient BM PCs is mediated by a reduction in the expression of pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase kinase 2; overexpression of pyruvate dehydrogenase kinase 4 reverses the enhancement of oxidative metabolism and endothelial differentiation. Deletion of E2F1 in the BM increases the amount of PC-derived endothelial cells in the ischemic myocardium, enhances vascular growth, reduces infarct size, and improves cardiac function after myocardial infarction.Our results suggest a novel mechanism by which E2F1 mediates the metabolic control of BM PC differentiation, and strategies that inhibit E2F1 or enhance oxidative metabolism in BM PCs may improve the effectiveness of cell therapy.
Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment
Authors: Jessica Wagner, C. Leah Kline, Lanlan Zhou, Kerry S. Campbell, Alexander W. MacFarlane, Anthony J. Olszanski, Kathy Q. Cai, Harvey H. Hensley, Eric A. Ross, Marie D. Ralff, Andrew Zloza, Charles B. Chesson, Jenna H. Newman, Howard Kaufman, Joseph Bertino, Mark Stein, Wafik S. El-Deiry
Journal: Journal of Clinical Investigation (2018)

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax–/– tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti–PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.
New insights in the antitumor effects of β-caryophyllene in breast cancer cells: The role of cannabinoid and adrenergic systems
Authors: A. Di Sotto, D. Romaniello, G. Freddoni, L. Abete, R. Cocchiola, S. Di Giacomo, F. Altieri, G. Mazzanti, M. Eufemi
Journal: Annals of Oncology (2018)
NHS Employers recommends extending doctors’ pay freeze
Authors: Caroline White
Journal: BMJ (2012)

NHS Employers has recommended that the Doctors and Dentists Review Body (DDRB) should extend the freeze on doctors’ pay for another year, a move that has angered the BMA.

The association, which will be submitting its own evidence to the DDRB later this week, said that this was yet another blow to doctors’ morale in the wake of changes to their pensions.

In its annual submission to the DDRB, which will issue its recommendations early next year, NHS Employers said that extending the pay freeze would help organisations maintain the quality of NHS patients’ care while plugging the “unprecedented” financial shortfall and keeping job losses to a minimum. …
Number of clinical academics up nearly 5% in five years
Authors: Helen Jaques
Journal: BMJ (2013)

The number of medical clinical academics in the UK has risen by nearly 5% over the past five years, an annual staffing survey shows.1

As at 31 July 2012 there were 3167 full time equivalent (FTE) medical clinical academic posts in UK medical schools, a rise of 4.5% since 2008. However, the number was 11% lower than in 2000, when there were 3549 FTE medical clinical academic posts. In …
Shp2 deletion in hepatocytes suppresses hepatocarcinogenesis driven by oncogenic β-Catenin, PIK3CA and MET
Authors: Jacey J. Liu, Yanjie Li, Wendy S. Chen, Yan Liang, Gaowei Wang, Min Zong, Kota Kaneko, Ruiyun Xu, Michael Karin, Gen-Sheng Feng
Journal: Journal of Hepatology (2018)
National variation in payment for GP commissioning responsibilities
Authors: Helen Jaques
Journal: BMJ (2012)

The funding general practitioners receive towards their responsibilities in clinical commissioning groups (CCGs) varies widely across England.

Pay per hour to GPs for CCG board or advisory meetings varies from £48 to £80 an hour in Country Durham to £115 an hour in Hertfordshire, according to data provided by 54 primary care trusts in England obtained under a freedom of information request by the Labour party.

Annual sums paid to GPs with commissioning responsibilities ranges from £8000 a …
Fibroblast growth factor receptor 3 (FGFR3), peroxisome proliferator-activated receptor gamma (PPARg), and outcomes with nivolumab (nivo) in metastatic urothelial cancer (UC).
Authors: Matt D. Galsky, Abdel Saci, Peter Szabo, Li Wang, Jun Zhu, Alex Azrilevich, Bruce S. Fischer, Andrea Necchi, Arlene O. Siefker-Radtke, Padmanee Sharma
Journal: Journal of Clinical Oncology (2018)

511 Background: Prior studies have correlated FGFR3 mutations (mut) and increased PPARg expression with decreased T-cell infiltration raising the possibility that these might represent mediators of PD-1/PD-L1 blockade resistance in luminal UC and targets for combination strategies. The causality of these associations remains unclear and the clinical relevance in PD-1/PD-L1 blockade treated patients has been underexplored. Methods: Archival tumor specimens from patients enrolled on CheckMate 275, a phase 2 trial of nivo in patients with platinum-resistant metastatic UC, underwent whole exome sequencing (WES) and gene expression profiling (HTG EdgeSeq). CD8 expression was determined by immunohistochemistry. Results: WES and gene expression data was available for 139 and 217 patients, respectively; the baseline characteristics and outcomes of both cohorts were similar to the full CheckMate 275 cohort. FGFR3mut were detected in 15 patients (11%) and correlated with higher FGFR3 gene expression. Neither FGFR3mut nor FGFR gene expression correlated with CD8 expression (Pearson's r -0.13; p=0.16) or with response rate (RR), progression-free survival (PFS), or overall survival (OS); RR in FGFRmut vs. FGFRwt = 20% vs 20%. PPARg gene expression was inversely correlated with CD8 (Pearson’s r -0.44; P &lt;0.001) and IFNg gene expression (Pearson’s r -0.52; P &lt;0.001). Higher PPARg gene expression was associated with inferior outcomes (Table); RR in PPARg highest vs lowest tertile = 15% vs 24%. Conclusions: FGFR3 alterations (mut/increased expression) do not preclude response to nivo and were not associated with decreased CD8. Higher PPARg expression was associated with decreased CD8, lower RR to nivo, and significantly shorter PFS and OS. These data support exploring therapeutic modulation of PPARg or downstream mediators in an effort to overcome resistance to PD-1/PD-L1 blockade. Cox proportional hazards model. [Table: see text]
LOW EICOSAPENTAENOIC ACID TO ARACHIDONIC ACID RATIO MAY BE ASSOCIATED WITH VULNERABLE PLAQUES ASSESSED BY INTRAVASCULAR ULTRASOUND IN YOUNGER PATIENTS WITH ACUTE CORONARY SYNDROME
Authors: Yumi Katsume, Kazunori Horie, Yukiko Mizutani, Akiko Tanaka, Norichika Osai, Takashi Matsumoto, Tsuyoshi Isawa, Norio Tada, Mie Sakurai, Masato Munehisa, Taku Honda, Tatsushi Ootomo, Naoto Inoue
Journal: Journal of the American College of Cardiology (2018)
IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell/IL-13/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis
Authors: Yuejin Liang, Panpan Yi, Denley Ming Kee Yuan, Zuliang Jie, Zakari Kwota, Lynn Soong, Yingzi Cong, Jiaren Sun
Journal: Cellular and Molecular Immunology (2018)
FLUORINE-18 LMI1195 POSITRON EMISSION TOMOGRAPHY PROVIDES ACCURATE MEASURE OF CARDIAC SYMPATHETIC INNERVATION COMPARED TO CARBON-11 HYDROXYEPHEDRINE
Authors: Jason Zelt, Jennifer Renaud, Lisa Mielniczuk, Linda Garrard, Olga Walter, Ann Guo, Robert deKemp, Rob Beanlands
Journal: Journal of the American College of Cardiology (2018)
Three quarters of senior paediatricians concerned about service sustainability, survey finds
Authors: Caroline White
Journal: BMJ (2013)

More than seven in 10 senior paediatricians fear that staff shortages and working time regulation constraints will leave their services unable to cope with demand, a survey by the Royal College of Paediatrics and Child Health has found.1

The annual survey—the fourth consecutive study of its kind by the college—was completed by 180 clinical directors and clinical leads of general paediatric and neonatal units in 2012, representing 82% of all eligible units in the United Kingdom. 

Overall, one in five (19.8%) clinical directors said they were “very” concerned that their service would …
Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?
Authors: Edward L. Korn, Boris Freidlin
Journal: Clinical Cancer Research (2018)

Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints. Clin Cancer Res; 24(10); 2239-40. ©2018 AACRSee related article by Mushti et al., p. 2268.
Overseas doctors to face tougher GMC licensing exam
Authors: Tom Moberly
Journal: BMJ (2014)

International medical graduates will have to pass a tougher licensing examination if they wish to practise medicine in the UK, the General Medical Council has announced.

The GMC has accepted the recommendations of a panel that was established to review the Professional and Linguistic Assessment Board (PLAB) test.1 The test is a two part language and clinical competency examination for international medical graduates wishing to register with the GMC.

The panel, led by Ian Cumming, chief executive of Health Education England, recommended that the test include a broader assessment of ethical values, perhaps by using a situational judgment test. It also said …
Focused ultrasound therapy combined with pembrolizumab in metastatic breast cancer.
Authors: Patrick Michael Dillon, Bethany J Horton, Timothy Bullock, Christiana Brenin, David R. Brenin
Journal: Journal of Clinical Oncology (2018)

TPS19 Background: Focused ultrasound (FUS) is an ablative therapy which can heat tumors rapidly to cell damaging temperatures and simultaneously perturb the microenvironment, the microvasculature, and the lymphatics. At typical energy levels, FUS can induce controlled apoptotic cell death rather than liquefactive necrosis. FUS does not involve radiation. FUS is a partially ablative therapy using high energy ultrasound waves to induce heat shock proteins, cytokine release and cellular mediated mechanisms resulting in T cell activation and recognition of tumor antigens. FUS has been demonstrated to be an effective method for inducing tumor antigen exposure and presentation to dendritic cells, thus acting as an auto-vaccine. Pembrolizumab (PBZ) is a PD-1 targeted antibody used in multiple solid tumors to augment T cell activation. It is hypothesized that the combination of these two modalities will result in T cell infiltration into breast tumors as well as systemic immune responses. Methods: In this pilot study, we will examine PBZ therapy in combination with FUS to assess for immune stimulation and antitumor effects at local ablation sites, distant non-treated sites and in the blood. Biopsy before and after treatments will examine the tissue in the peripheral zone of ablation as well as at distant metastatic sites for CD8 and CD4 T cells, MDSC’s, T-regulatory cells and cytokine responses. Twelve patients will be randomized to receive either PBZ 14 days before or 7 days after a single time FUS partial tumor ablation on day 15. Biopsies will be on days 1, 22 and 64 and tumor imaging will be every 12 weeks. Patients must have metastatic or unresectable breast cancer, adequate organ function, and prior therapy in the metastatic setting. They must also have a tumor in the breast or axilla amenable to FUS and biopsy. Clinical trial information: NCT03237572.
GMC will review guidance on fitness to practise sanctions
Authors: Abi Rimmer
Journal: BMJ (2013)

The General Medical Council is to conduct a major review of its guidance on sanctions that can be placed on doctors after fitness to practise hearings.

Niall Dickson, the GMC’s chief executive, announced the move at the council’s conference on professionalism in Manchester on 12 December. 

“Next year we will conduct a major consultation on our sanctions guidance—the advice we give our decision makers and panels on the appropriate sanctions to protect the public and uphold the reputation of the profession,” he told the conference. The GMC’s sanctions guidance is used by the fitness …