tbuckley/cabot-search huggingface dataset:
Exosome-Based Detection of <i>EGFR</i> T790M in Plasma from Non–Small Cell Lung Cancer Patients
Authors: Elena Castellanos-Rizaldos, Dominik G. Grimm, Vasisht Tadigotla, James Hurley, John Healy, Patricia L. Neal, Mia Sher, Raajdeep Venkatesan, Chris Karlovich, Mitch Raponi, Anne Krug, Mikkel Noerholm, Jihane Tannous, Bakhos A. Tannous, Luis E. Raez, Johan K. Skog
Journal: Clinical Cancer Research (2018)

Abstract Purpose: About 60% of non–small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third-generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a noninvasive option to detect the mutation; however, sensitivity is low as many patients have too few detectable copies in circulation. Here, we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele-specific qPCR. Experimental Design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a Clinical Laboratory Improvement Amendment laboratory. Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging. Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared with historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing. Clin Cancer Res; 24(12); 2944–50. ©2018 AACR.
MicroRNA (miR)‐433 and miR‐22 dysregulations induce histone‐deacetylase‐6 overexpression and ciliary loss in cholangiocarcinoma
Authors: Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz‐Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. LaRusso, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
Journal: Hepatology (2018)

Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a posttranscriptional regulation, possibly involving microRNAs (miRNAs). Here, we describe that at least two HDAC6‐targeting miRNAs, miR‐433 and miR‐22, are down‐regulated in CCA both in vitro and in vivo . Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin‐5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin‐5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, short hairpin RNA (shRNA) depletion of Exportin‐5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. Conclusion : These data suggest that down‐regulated Exportin‐5 impairs the nuclear export of miR‐433 and miR‐22 precursor forms, causing a decrease in levels of mature miR‐433 and miR‐22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. (H epatology 2018).
Electronic coordination of palliative care and its effect on primary and community care
Authors: Khyati Bakhai, Ruth Branford, Julia Riley
Journal: BMJ (2013)

To respond better to patients’ wishes, palliative care must be efficiently and effectively coordinated across hospital, primary, and community care. <b>Khyati Bakhai and colleagues</b> look at the implications of an electronic care coordination system for patients and staff workloads.
Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events—a meta-analysis
Authors: J.C. Trone, E. Ollier, C. Chapelle, L. Bertoletti, M. Cucherat, P. Mismetti, N. Magné, S. Laporte
Journal: Annals of Oncology (2018)
Preclinical development of tumor-infiltrating lymphocyte therapy for metastatic colorectal cancer.
Authors: Donastas Sakellariou-Thompson, Marie-Andree Forget, Jason Roszik, Kyle R Jackson, Young Uk Kim, Shadarra Crosby, Mark W Hurd, Ji Wu, Zhi-Qin Jiang, Patrick Hwu, Gregory Lizee, David Menter, Scott Kopetz, Michael J. Overman, Cara L. Haymaker, Chantale Bernatchez
Journal: Journal of Clinical Oncology (2018)

95 Background: Immunotherapy has become an effective cancer therapy, particularly in the case of checkpoint blockade and adoptive T-cell therapy (ACT). ACT exploits the presence of tumor-infiltrating lymphocytes (TIL) by exponentially expanding their numbers ex vivo and re-infusing them into the patient in an autologous setting. With the effectiveness of TIL therapy already well established in multiple phase II studies in melanoma, there is a push to translate it to other cancers in need of improved therapies. Colorectal cancer (CRC) is a cancer where the presence of TIL has been strongly correlated with increased survival. Metastatic CRC (mCRC) has a poor outcome with median overall survival of less than 3 years. At present anti-PD1 therapy is only active in the small subset of mCRC patients (4%) that are MSI-high. We sought to evaluate the ability to generate and characterize TIL from patients with mCRC to provide a rationale for future TIL therapy in this disease. Methods: To assess the feasibility of utilizing TIL ACT for this patient population, we characterized the immune infiltrate of mCRC, TIL growth from tumor fragments (n = 24), as well as the TIL repertoire (n = 4) and anti-tumor potential in samples with available autologous tumor target. Results: Flow cytometry analysis detected a CD4-rich T-cell infiltration at the tumor site as well as a scarce yet activated CD8 + TIL population. The outgrowth of CD8 + TIL from tumor fragments in media containing IL-2 was potentiated by the addition of an agonistic 4-1BB antibody (Urelumab, BMS). Additionally, the use of a 4-1BB mAb improved the likelihood of growing TIL (63% [14/24] to 83% [20/24]) and increased the total yield of TIL grown. T-cell receptor sequencing showed enrichment in the tumor of CD8 + T-cell clones shared between the blood and tumor, suggesting selective expansion at the tumor site. Using IFNγ ELISPOT, CD8 + TIL from one patient with an MSS tumor were found to be reactive against a peptide derived from mutated TP53 R116W restricted to HLA-B*39:01. Conclusions: It is possible to expand CD8 + T cells from microsatellite stable (MSS) mCRC that are able to target tumor antigens. Although preliminary, the initial data suggest the feasibility of TIL therapy for mCRC.
Autophagy in dendritic cells
Authors: Ghita Ghislat, Toby Lawrence
Journal: Cellular and Molecular Immunology (2018)

Autophagy and immunity share the property of being auto-protective for the organism. Autophagy is an important degradation pathway that buffers nutrient deprivation by recycling macromolecules in organisms from yeast to man. Perturbations in autophagy are associated with inflammation and cancer development. Emerging studies have characterized the molecular details regarding how autophagy is controlled by immune cells. Among these, dendritic cells (DCs) are one of the most potent professional antigen-presenting cells critical for the activation of naïve T cells to maintain immune tolerance and drive protective immunity to infection and cancer. DCs undergo functional maturation that can either lead to an immunostimulatory phenotype, as in the context of infection, or to a tolerogenic phenotype associated with immunosuppression to self-antigens, as well as to cancer. An increasing number of recent studies has characterized the involvement of autophagy in DC functions in various physiological and pathological contexts. Here, we provide a comprehensive review of these outcomes and discuss the limitation of the models used and the forefront of the knowledge concerning the crosstalk between autophagy and DC biology.
Impact of Intensive Lifestyle Intervention on Disability-Free Life Expectancy: The Look AHEAD Study
Authors: Edward W. Gregg, Ji Lin, Barbara Bardenheier, Haiying Chen, W. Jack Rejeski, Xiaohui Zhuo, Andrea L. Hergenroeder, Stephen B. Kritchevsky, Anne L. Peters, Lynne E. Wagenknecht, Edward H. Ip, Mark A. Espeland
Journal: Diabetes Care (2018)

OBJECTIVE The impact of weight loss intervention on disability-free life expectancy in adults with diabetes is unknown. We examined the impact of a long-term weight loss intervention on years spent with and without physical disability. RESEARCH DESIGN AND METHODS Overweight or obese adults with type 2 diabetes age 45–76 years (n = 5,145) were randomly assigned to a 10-year intensive lifestyle intervention (ILI) or diabetes support and education (DSE). Physical function was assessed annually for 12 years using the 36-Item Short Form Health Survey. Annual incidence of physical disability, mortality, and disability remission were incorporated into a Markov model to quantify years of life spent active and physically disabled. RESULTS Physical disability incidence was lower in the ILI group (6.0% per year) than in the DSE group (6.8% per year) (incidence rate ratio 0.88 [95% CI 0.81–0.96]), whereas rates of disability remission and mortality did not differ between groups. ILI participants had a significant delay in moderate or severe disability onset and an increase in number of nondisabled years (P &amp;lt; 0.05) compared with DSE participants. For a 60-year-old, this effect translates to 0.9 more disability-free years (12.0 years [95% CI 11.5–12.4] vs. 11.1 years [95% CI 10.6–11.7]) but no difference in total years of life. In stratified analyses, ILI increased disability-free years of life in women and participants without cardiovascular disease (CVD) but not in men or participants with CVD. CONCLUSIONS Long-term lifestyle interventions among overweight or obese adults with type 2 diabetes may reduce long-term disability, leading to an effect on disability-free life expectancy but not on total life expectancy.
Frequency and level of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond approvals of the US Food and Drug Administration: retrospective observational study
Authors: Jeffrey Wagner, John Marquart, Julia Ruby, Austin Lammers, Sham Mailankody, Victoria Kaestner, Vinay Prasad
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To determine the differences between recommendations by the National Comprehensive Cancer Network (NCNN) guidelines and Food and Drug Administration approvals of anticancer drugs, and the evidence cited by the NCCN to justify recommendations where differences exist. <h3>Design</h3> Retrospective observational study. <h3>Setting</h3> National Comprehensive Cancer Network and FDA. <h3>Participants</h3> 47 new molecular entities approved by the FDA between 2011 and 2015. <h3>Main outcome measures</h3> Comparison of all FDA approved indications (new and supplemental) with all NCCN recommendations as of 25 March 2016. When the NCCN made recommendations beyond the FDA’s approvals, the recommendation was classified and the cited evidence noted. <h3>Results</h3> 47 drugs initially approved by the FDA between 2011 and 2015 for adult hematologic or solid cancers were examined. These 47 drugs were authorized for 69 FDA approved indications, whereas the NCCN recommended these drugs for 113 indications, of which 69 (62%) overlapped with the 69 FDA approved indications and 44 (39%) were additional recommendations. The average number of recommendations beyond the FDA approved indications was 0.92. 23% (n=10) of the additional recommendations were based on evidence from randomized controlled trials, and 16% (n=7) were based on evidence from phase III studies. During 21 months of follow-up, the FDA granted approval to 14% (n=6) of the additional recommendations. <h3>Conclusion</h3> The NCCN frequently recommends beyond the FDA approved indications even for newer, branded drugs. The strength of the evidence cited by the NCCN supporting such recommendations is weak. Our findings raise concern that the NCCN justifies the coverage of costly, toxic cancer drugs based on weak evidence.
More female doctors must apply for excellence awards, says Medical Women’s Federation president
Authors: Abi Rimmer
Journal: BMJ (2015)

Female doctors must apply for clinical excellence awards or they will lose out, the president of the Medical Women’s Federation has said.

Speaking in a panel discussion at the organisation’s spring conference in Manchester on Friday 15 May, Sally Davies called on more women to apply for excellence awards. “You don’t get in to the game unless you take part,” she said.

Figures show that in 2014 men received 85% of the national clinical excellence awards allocated in England and Wales.1

Two factors were preventing more women from gaining awards, Davies said: “One …
P111 Mesenchymal stem cell encapsulation in alginate micro-particles for intra-articular injection in osteoarthritis
Authors: A Smith, A Des Rieux, M Marquis, D Renard, C Vinatier, J Guicheux, C Le Visage
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Owing to their ability to secrete anti-inflammatory and immuno-modulatory factors Mesenchymal Stromal Cells (MSCs) are an attractive tool for the treatment of osteoarthritis. Considering cell death and the risk of cell leakage upon intra-articular injection, MSCs encapsulation therefore could protect cell from death, avoid cell effusion outside the articular space, and supply a suitable 3D microenvironment supporting the biological activity of MSCs. <h3>Objectives</h3> Our objective was to develop a method of MSC encapsulation compatible with their intra-articular injection through a 26G needle. <h3>Methods</h3> Human adipose-derived stem cells (hASCs) were encapsulated via a micromolding method. We first manufactured polydimethylsiloxane chips containing 1600 micromolds with a circular shape, 150 µm in diameter and 100 µm in depth. For cell encapsulation, a solution of 2% alginate (w/v) containing 3 million of hASCs per mL polymer was deposited onto the chips, loaded in the moulds either by sedimentation or centrifugation and crosslinked using an agarose gel charged with CaCl2. The number of encapsulated cells was evaluated by a CyQUANT assay immediately and 24 hour after encapsulation. The impact of encapsulation on metabolic activity was determined by a presto blue assay 24 hours after encapsulation and 24 hour after their injection through a 26G needle. <h3>Results</h3> We successfully obtained cylindrical alginate microparticles presenting a diameter of 103±0.7 µm. Using cell quantification, we determined that the centrifugation method allowed the encapsulation of 30 333 (±5552) cells within one chip versus 6056 (±2862) by sedimentation. Cell number and metabolic activity remained stable for 24 hours after encapsulation. We also demonstrated that injection through a 26G needle had no impact on the viability of encapsulated cells. <h3>Conclusions</h3> Our results show that micromolding allows hASCs encapsulation into alginate particles injectable through a 26 G needle without impacting cell viability. Future work will focus on evaluating <i>in vitro</i> long-term encapsulated cell survival and functionality. In case of success, we will then consider intra-articular injection in an animal model of osteoarthritis. <h3>Disclosure of interest</h3> None declared
I am about to apply for general practice training. Are there any deaneries not using assessment centres for recruitment— the sheer concept frightens me!
Authors: Anne Hastie
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right 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>
Presenting in Biomedicine: 500 Tips for Success
Authors: Georgios Lyratzopoulos
Journal: BMJ (2004)

S peaking in front of medical audiences is one of the things that doctors are meant simply to “pick up” as juniors and master as consultants. The results of this haphazard approach are there for everyone to see—in audit days, seminars, and conferences (and I have been responsible for several poorly prepared and delivered presentations myself).⇓



Jane Fraser and Richard Cave Radcliffe Medical Press, 2004 ISBN 1 85775 897 8

Rating: ★★★/5



The book includes a wide range of brief “speaking in …
Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice
Authors: Ya-Jie Lv, Yi Yang, Bing-Dong Sui, Cheng-Hu Hu, Pan Zhao, Li Liao, Ji Chen, Li-Qiang Zhang, Tong-Tao Yang, Shao-Feng Zhang, Yan Jin
Journal: Theranostics (2018)

Rational: Senescence of mesenchymal stem cells (MSCs) and the related functional decline of osteogenesis have emerged as the critical pathogenesis of osteoporosis in aging.Resveratrol (RESV), a small molecular compound that safely mimics the effects of dietary restriction, has been well documented to extend lifespan in lower organisms and improve health in aging rodents.However, whether RESV promotes function of senescent stem cells in alleviating age-related phenotypes remains largely unknown.Here, we intend to investigate whether RESV counteracts senescence-associated bone loss via osteogenic improvement of MSCs and the underlying mechanism.Methods: MSCs derived from bone marrow (BMMSCs) and the bone-specific, senescence-accelerated, osteoblastogenesis/osteogenesis-defective mice (the SAMP6 strain) were used as experimental models.In vivo application of RESV was performed at 100 mg/kg intraperitoneally once every other day for 2 months, and in vitro application of RESV was performed at 10 μM.Bone mass, bone formation rates and osteogenic differentiation of BMMSCs were primarily evaluated.Metabolic statuses of BMMSCs and the mitochondrial activity, transcription and morphology were also examined.Mitofilin expression was assessed at both mRNA and protein levels, and short hairpin RNA (shRNA)-based gene knockdown was applied for mechanistic experiments.Results: Chronic intermittent application of RESV enhances bone formation and counteracts accelerated bone loss, with RESV improving osteogenic differentiation of senescent BMMSCs.Furthermore, in rescuing osteogenic decline under BMMSC senescence, RESV restores cellular metabolism through mitochondrial functional recovery via facilitating mitochondrial autonomous gene transcription.Molecularly, in alleviating senescence-associated mitochondrial disorders of BMMSCs, particularly the mitochondrial morphological alterations, RESV upregulates Mitofilin, also known as inner membrane protein of mitochondria (Immt) or Mic60, which is the core component of the mitochondrial contact site and cristae organizing system (MICOS).Moreover, Mitofilin is revealed to be indispensable for mitochondrial homeostasis and osteogenesis of BMMSCs, and that insufficiency of Mitofilin leads to BMMSC senescence and bone loss.More importantly, Mitofilin mediates resveratrol-induced mitochondrial and osteogenic improvements of BMMSCs in senescence.Conclusion: Our findings uncover osteogenic functional improvements of senescent MSCs as critical impacts in anti-osteoporotic practice of RESV, and unravel Mitofilin as a novel mechanism mediating RESV promotion on mitochondrial function in stem cell senescence.
The role of reference pathology to assess MRI-TRUS fusion prostate biopsies in a tertiary referral center.
Authors: Tobias Kohl, Melanie von Brandenstein, Timur H. Kuru, Nienke Hansen, Thorsten Persigehl, Daniel Porres-Knoblauch, David Pfister, Arndt Hartmann, Axel Heidenreich
Journal: Journal of Clinical Oncology (2018)

32 Background: Risk stratification for patients diagnosed with prostate cancer (PCa) through MR-TRUS fusion biopsy still relies on Gleason (GL) grading of the biopsy specimens. GL grading of the same sample can differ between pathologists. In our tertiary high-volume center GL grading of the biopsy specimens is crucial for further therapy planning. Methods: Reference pathology of 42 patients after transperineal MR-TURS fusion plus saturation biopsy was assessed by one specialized genitourinary pathologist. GL grading of the original pathology and the reference pathology for the saturation and targeted biopsy cores were compared. Risk groups for this study were set as GL 6 for low, GL 7a and GL 7b for intermediate and GL 8, GL 9 and GL 10 for high-risk. Results: In 42 patients 49 lesions were identified by mpMRI (PI-RADS 3-5) in which 150 biopsy cores were taken. In addition, 709 cores were taken as saturation biopsies. The highest GL grading per patient differed in 18 (43 %) of the cases. In 16 cases, there was a difference within the targeted biopsies but only in 8 cases there was a difference in the saturation biopsies. In 6 cases both saturation and fusion biopsies were different. Taking risk stratification into account there was a misclassification with low- and intermediate risk in 9 (21 %) cases, an intermediate- and high risk in 2 cases and a misclassification within the same risk group in 6 (14 %) cases. In 16 of the 18 differences there was an upgrading of the Gleason score by the reference pathologist whereas only in 2 cases there was a downgrading. Conclusions: The data shows that in times of mpMRIs and transperineal MRI-TRUS fusion biopsies it still is the GL score graded by the pathologist who accounts for many potential therapy plan mistakes. In this study 21 % of the patients were misclassified as GL 6 while reference pathology graded for GL 7a or GL 7b. The demonstrated data suggests that there should be a reference pathology at least for every GL 6 cancer and that the quality of GL grading should be monitored. Also this data again addresses the need for a better risk stratification irrespective of the GL score that can be done in a more objective way with less potential for misclassification.