tbuckley/cabot-search huggingface dataset:
Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma
Authors: Shannon Coy, Rumana Rashid, Jia-Ren Lin, Ziming Du, Andrew M Donson, Todd C Hankinson, Nicholas K Foreman, Peter E Manley, Mark W Kieran, David A Reardon, Peter K Sorger, Sandro Santagata
Journal: Neuro-Oncology (2018)

Craniopharyngiomas are neoplasms of the sellar/parasellar region that are classified into adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) subtypes. Surgical resection of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible to BRAF/MEK inhibitors, but effective targeted therapies are needed for ACP. We explored the feasibility of targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway in ACP and PCP.We mapped and quantified PD-L1 and PD-1 expression in ACP and PCP resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. We used tissue-based cyclic immunofluorescence to map the spatial distribution of immune cells and characterize cell cycle and signaling pathways in ACP tumor cells which intrinsically express PD-1.All ACP (15 ± 14% of cells, n = 23, average ± SD) and PCP (35 ± 22% of cells, n = 18) resections expressed PD-L1. In ACP, PD-L1 was predominantly expressed by tumor cells comprising the cyst lining. In PCP, PD-L1 was highly expressed by tumor cells surrounding the stromal fibrovascular cores. ACP also exhibited tumor cell-intrinsic PD-1 expression in whorled epithelial cells with nuclear-localized beta-catenin. These cells exhibited evidence of elevated mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling. Profiling of immune populations in ACP and PCP showed a modest density of CD8+ T cells.ACP exhibit PD-L1 expression in the tumor cyst lining and intrinsic PD-1 expression in cells proposed to comprise an oncogenic stem-like population. In PCP, proliferative tumor cells express PD-L1 in a continuous band at the stromal-epithelial interface. Targeting PD-L1 and/or PD-1 in both subtypes of craniopharyngioma might therefore be an effective therapeutic strategy.
GP recruitment opens for third round
Authors: Abi Rimmer
Journal: BMJ (2015)

General practice recruitment in England has been opened for a third round, Health Education England (HEE) has announced.

Normally two rounds of GP recruitment take place, but in 2014 HEE opened an unprecedented third round to boost uptake. Despite this step, around 12% of GP training posts in England were unfilled last year.1

After the first round of recruitment this year, figures published by the General Practice National …
I have been out of a job for some time now and am still searching. There is a big gap in my employment history although I have been doing exams during this period to get registered with the GMC because I am from overseas; how do I account for this period on my CV to boost my chances of getting a job?
Authors: John Adsett
Journal: BMJ (2007)

Have a career related problem that needs answering? Can9t find the person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site <b>www.bmjcareers.com/advicezone</b>
The role of PTRF/Cavin1 as a biomarker in both glioma and serum exosomes
Authors: Kai Huang, Chuan Fang, Kaikai Yi, Xing Liu, Hongzhao Qi, Yanli Tan, Junhu Zhou, Ying Li, Mingyang Liu, Yuqing Zhang, Jingxuan Yang, Jianning Zhang, Min Li, Chunsheng Kang
Journal: Theranostics (2018)

Exosomes play critical roles in intercellular communication in both nearby and distant cells in individuals and organs.Polymerase I and transcript release factor (PTRF), also known as Cavin1, has previously been described as a critical factor in caveola formation, and aberrant PTRF expression has been reported in various malignancies.However, the function of PTRF in tumor progression remains controversial, and its role in glioma is poorly understood.In this study, we report that PTRF is associated with malignancy grade and poor prognosis in glioma patients.Our previous study using two proteomics methods, tandem mass tag (TMT) and data-independent acquisition (DIA), showed that EGFRvIII overexpression increased PTRF expression at the protein level.In contrast, blocking PI3K and AKT using LY294002 and MK-2206, respectively, decreased PTRF expression, showing that PTRF is regulated in the EGFR/PI3K/AKT pathway.ChIP-PCR analysis showed that PTRF is transcriptionally regulated by the H3K4me3 and H3K27me3 modifications.Furthermore, PTRF overexpression increased exosome secretion and induced cell growth in vitro.More importantly, overexpressing PTRF induced the malignancy of nearby cells in vivo, suggesting that PTRF alters the microenvironment through intercellular communication via exosomes.Furthermore, analysis of clinical samples showed a positive correlation between tumor grade and PTRF expression in both tumor tissues and exosomes isolated from blood harvested from glioma patients, and PTRF expression in exosomes isolated from the sera of GBM patients was decreased after surgery.In conclusion, PTRF serves as a promising biomarker in both tumor samples and serum exosomes, thus facilitating the detection of glioma and potentially serving as a therapeutic target for glioblastoma multiforme.
Abstract PD1-05: Transgenerational epigenetic silencing of <i>BRCA1</i> due to a germline variant unmasks a new mechanism for familial breast and ovarian cancer
Authors: EM van Veen, MJ Smith, HJ Byers, AJ Wallace, FI Lalloo, WG Newman, DGR Evans
Journal: Cancer Research (2018)

Abstract In families with multiple affected individuals with early-onset breast/ovarian cancer pathogenic variants in BRCA1 or BRCA2 are identified in approximately 20% of the cases. Extensive efforts have been made to identify additional highly penetrant breast cancer genes or alternative mutational mechanisms affecting BRCA1 and BRCA2 to explain the missing heritability. It has been proposed that part of the missing heritability may be explained by gene silencing due to promoter methylation of cancer associated genes, as described in colorectal cancer (MLH1 and MSH2). Here, for the first time, we report two independent families with multiple individuals affected by breast and ovarian cancer with transgenerational promoter methylation of BRCA1. RNA analysis of BRCA1 in the germline of breast/ovarian families, previously found to be BRCA1/2 mutation negative by Sanger sequencing and copy number analysis, identified two families with allelic loss of expression. To investigate the mechanism of transcriptional silencing, a total of 14 affected and unaffected family members from these two families were tested for BRCA1 promoter methylation by pyrosequencing in blood, buccal, and hair follicle cells. Allele specific methylation was determined by clonal bisulphite sequencing. BRCA1 promoter methylation in all three germ layers was present in 11 of 14 family members. Of the 7 women with promoter methylation five were affected with grade 3 breast/high grade serous ovarian cancer. The four males with BRCA1 promoter methylation had no history of cancer. Methylation levels were ˜50%, consistent with the silencing of one allele detected in RNA in these family members. Clonal bisulphite sequencing of an affected family member of each family confirmed that the alternative allele was specifically methylated. Interestingly, in both families the methylation pattern of the BRCA1 promoter segregated with the same novel heterozygous variant in the 5'UTR of BRCA1. These results indicate a novel mechanism for familial breast/ovarian cancer, caused by epigenetic silencing of one allele by transgenerational hypermethylation of the BRCA1 promoter, secondary to a variant in cis of BRCA1. We propose that methylation analyses are indicated in all families affected by early onset breast/ovarian cancer where standard mutation screening of BRCA1/2 has not identified a causative variant. Citation Format: van Veen EM, Smith MJ, Byers HJ, Wallace AJ, Lalloo FI, Newman WG, Evans DGR. Transgenerational epigenetic silencing of BRCA1 due to a germline variant unmasks a new mechanism for familial breast and ovarian cancer [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 PD1-05.
Should UK medical students be guaranteed a job on leaving medical school? No
Authors: Helen Macdonald
Journal: BMJ (2011)

<b>Helen Macdonald</b> believes that the NHS is not obliged to provide medical students with a job when they leave medical school, but <b>Oliver Ellis</b> (http://careers.bmj.com/careers/advice/view-article.html?id=20002743) argues that it makes financial sense to ensure that students are guaranteed a place
Online petition launched to push government to reopen negotiations on NHS pensions
Authors: Ingrid Torjesen
Journal: BMJ (2012)

The BMA has set up an online petition demanding the government reopen “meaningful” negotiations on pensions following the breakdown of talks with health secretary, Andrew Lansley.

BMA chairman Dr Hamish Meldrum met Mr Lansley last week to discuss the proposed changes to the NHS pension scheme, which most doctors consider unacceptable, in an effort to avoid industrial action by the medical profession.

Dr Meldrum urged Mr Lansley to commit to further talks on the issue, but so far the government has not seemed willing to return to …
A modified HLA-A*0201-restricted CTL epitope from human oncoprotein (hPEBP4) induces more efficient antitumor responses
Authors: Weihong Sun, Junyi Shi, Jian Wu, Junchu Zhang, Huabiao Chen, Yuanyuan Li, Shuxun Liu, Yanfeng Wu, Zhigang Tian, Xuetao Cao, Nan Li
Journal: Cellular and Molecular Immunology (2018)
Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells
Authors: Mohamed Rahmani, Jewel Nkwocha, Elisa Hawkins, Xinyan Pei, Rebecca E. Parker, Maciej Kmieciak, Joel D. Leverson, Deepak Sampath, Andrea Ferreira-Gonzalez, Steven Grant
Journal: Cancer Research (2018)

Abstract Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38−/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment–associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK−/− cells and failed to induce apoptosis in BAX−/− and BAX−/−BAK−/− cells, whereas BIM−/− cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML. Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075–86. ©2018 AACR.
REDUCING CARDIOVASCULAR RISK IN THE MEDICARE MILLION HEARTS RISK REDUCTION MODEL
Authors: William Borden, Jingyan Wang, Philip Jones, Johanna Contreras, Stacie L. Daugherty, Nihar Desai, Steven A. Farmer, Salim Virani, Jason Wasfy, Thomas M. Maddox
Journal: Journal of the American College of Cardiology (2018)
Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
Authors: Antonio Cuadrado, Gina Manda, Ahmed Hassan, María José Alcaraz, Coral Barbas, Andreas Daiber, Pietro Ghezzi, Rafael León, Manuela G López, Baldo Oliva, Marta Pajares, Ana I Rojo, Natalia Robledinos-Antón, Angela M Valverde, Emre Guney, Harald H H W Schmidt
Journal: Pharmacological Reviews (2018)

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)–like 2 (NRF2) by cross-validating its position in a protein–protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein–protein or DNA–protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases.
CHARACTERISTICS OF CORONARY ARTERY ANEURYSMS CAUSED BY ATHEROSCLEROSIS VERSUS KAWASAKI DISEASE
Authors: Sherif Rizk Youssef Rizk, Wasseem Gobran, Karim Said, Hala Hamza, Jane Burns, John Gordon, Lori B. Daniels, Ryan Reeves, Galal El Said, Kasr El Aini
Journal: Journal of the American College of Cardiology (2018)
Antiestrogen Therapy Increases Plasticity and Cancer Stemness of Prolactin-Induced ERα+ Mammary Carcinomas
Authors: Michael P. Shea, Kathleen A. O'Leary, Saja A. Fakhraldeen, Vincent Goffin, Andreas Friedl, Kari B. Wisinski, Caroline M. Alexander, Linda A. Schuler
Journal: Cancer Research (2018)

Abstract Although antiestrogen therapies are successful in many patients with estrogen receptor alpha-positive (ERα+) breast cancer, 25% to 40% fail to respond. Although multiple mechanisms underlie evasion of these treatments, including tumor heterogeneity and drug-resistant cancer stem cells (CSC), further investigations have been limited by the paucity of preclinical ERα+ tumor models. Here, we examined a mouse model of prolactin-induced aggressive ERα+ breast cancer, which mimics the epidemiologic link between prolactin exposure and increased risk for metastatic ERα+ tumors. Like a subset of ERα+ patient cancers, the prolactin-induced adenocarcinomas contained two major tumor subpopulations that expressed markers of normal luminal and basal epithelial cells. CSC activity was distributed equally across these two tumor subpopulations. Treatment with the selective estrogen receptor downregulator (SERD), ICI 182,780 (ICI), did not slow tumor growth, but induced adaptive responses in CSC activity, increased markers of plasticity including target gene reporters of Wnt/Notch signaling and epithelial–mesenchymal transition, and increased double-positive (K8/K5) cells. In primary tumorsphere cultures, ICI stimulated CSC self-renewal and was able to overcome the dependence of self-renewal upon Wnt or Notch signaling individually, but not together. Our findings demonstrate that treatment of aggressive mixed lineage ERα+ breast cancers with a SERD does not inhibit growth, but rather evokes tumor cell plasticity and regenerative CSC activity, predicting likely negative impacts on patient tumors with these characteristics. Significance: This study suggests that treatment of a subset of ERα+ breast cancers with antiestrogen therapies may not only fail to slow growth but also promote aggressive behavior by evoking tumor cell plasticity and regenerative CSC activity. Cancer Res; 78(7); 1672–84. ©2018 AACR.
Clinical supervisors need tools to teach patient safety, say researchers
Authors: Abi Rimmer
Journal: BMJ (2015)

Clinical supervisors need tools to help them teach trainees non-technical patient safety skills, say Australian researchers.1

A team of researchers from the University of Sydney carried out a literature review of 14 publications that had looked at non-technical patient safety skills training for postgraduate trainees. 

The researchers found that trainees were more likely to incorporate patient safety skills into clinical work if these skills …
Organelle-Derived Acetyl-CoA Promotes Prostate Cancer Cell Survival, Migration, and Metastasis via Activation of Calmodulin Kinase II
Authors: Guoyu Yu, Chien-Jui Cheng, Song-Chang Lin, Yu-Chen Lee, Daniel E. Frigo, Li-Yuan Yu-Lee, Gary E. Gallick, Mark A. Titus, Leta K. Nutt, Sue-Hwa Lin
Journal: Cancer Research (2018)

Abstract Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer, its role in prostate cancer tumorigenesis is largely unknown. Here, we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes prostate cancer tumorigenesis. In human prostate cancer specimens, metastatic prostate cancer expressed higher levels of active CaMKII compared with localized prostate cancer. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of prostate cancer metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the β-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, whereas overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle β-oxidation and acetyl-CoA transport with cell survival, migration, and prostate cancer metastasis. Significance: This study identifies a cell metabolic pathway that promotes prostate cancer metastasis and suggests prostate cancer may be susceptible to β-oxidation inhibitors. Cancer Res; 78(10); 2490–502. ©2018 AACR.
Predictive role of peritumoral CD3+ infiltration and neutrophil to lymphocyte ratio on overall survial in pateints affected by colorectal liver metastases treated with chemotherapy and surgery.
Authors: Matteo Cimino, Matteo Donadon, Domenico Mavilio, Luca Di Tommaso, Massimo Roncalli, Kelly Hudspeth, Carlotta Sacerdote, Guido Torzilli
Journal: Journal of Clinical Oncology (2018)

27 Background: Systemic and local inflammation plays an important role in many cancers and colorectal liver metastases (CRLM). While the role of local immune response mediated by CD3+ tumour infiltrating lymphocyte is well established new evidence on systemic inflammation and cancer such as neutrophil–lymphocyte ratio (NLR) are emerging. The aim of the study is to associate these two markers of inflammation to predict overall survival (OS) in patients affected by CRLM. Methods: From January 2006 to January 2013 128 consecutive patients affected by CRLM treated with chemotherapy and surgery were included in the study. CD3+ peritumoral infiltration was defined as the ratio of intra-tumoural\invasive-margin CD3+ infiltration evaluated with immunohistochemistry on CRLM tumor slides. NLR was calculated as neutrophil absolute count divided by the absolute lymphocyte count on blood sample. ROC curves were used to calculate a cut-off for each bio-markers related to OS . Associating the bio-markers two risk groups were determined: low risk (LRG) two protective bio-markers; high risk (HRG) no protective bio-markers. Results: After a median follow-up of 45 months, median OS was 44 months.Twenty-nine patients (22.6%) belong to the LRG whereas 99 patients (77,4) belong to HRG. Adjusted Cox regression analysis showed a worse OS for HRG patients (HR 2.74 p = 0.003 95%CI 1.40-5.37). Median OS was 80.8 vs 42.5 months for LRG vs HRG respectively. Conclusions: High CD3+ peritumoural infiltration associated with low NRL are two protective factor on OS for patients affected by CRLM.