tbuckley/cabot-search huggingface dataset:
Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity
Authors: Nicola Amodio, Maria Angelica Stamato, Giada Juli, Eugenio Morelli, Mariateresa Fulciniti, Martina Manzoni, Elisa Taiana, Luca Agnelli, Maria Eugenia Gallo Cantafio, Enrica Romeo, Lavinia Raimondi, Daniele Caracciolo, Valeria Zuccalà, Marco Rossi, Antonino Neri, Nikhil C. Munshi, Pierosandro Tagliaferri, Pierfrancesco Tassone
Journal: Leukemia (2018)

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still to be investigated. Here, we studied the functional significance and the druggability of the oncogenic lncRNA MALAT1 in MM. Targeting MALAT1 by novel LNA-gapmeR antisense oligonucleotide antagonized MM cell proliferation and triggered apoptosis both in vitro and in vivo in a murine xenograft model of human MM. Of note, antagonism of MALAT1 downmodulated the two major transcriptional activators of proteasome subunit genes, namely NRF1 and NRF2, and resulted in reduced trypsin, chymotrypsin and caspase-like proteasome activities and in accumulation of polyubiquitinated proteins. NRF1 and NRF2 decrease upon MALAT1 targeting was due to transcriptional activation of their negative regulator KEAP1, and resulted in reduced expression of anti-oxidant genes and increased ROS levels. In turn, NRF1 promoted MALAT1 expression thus establishing a positive feedback loop. Our findings demonstrate a crucial role of MALAT1 in the regulation of the proteasome machinery, and provide proof-of-concept that its targeting is a novel powerful option for the treatment of MM.
Relationship between ethnicity and overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib (S).
Authors: Daniel E. Meyers, Richard M. Lee-Ying, Mohammed Abdullah Alghamdi, Winson Y. Cheung, Haider Samawi, Vincent C. Tam
Journal: Journal of Clinical Oncology (2018)

248 Background: The SHARP and Asia Pacific (AP) trials showed that S improves OS compared to placebo in advanced HCC. However, OS was worse in the AP trial which included predominantly Asian patients. It is unclear if ethnicity, or perhaps Hepatitis B (HBV) infection, is a poor prognostic factor for these patients. The purpose of this study was to determine whether ethnicity affects OS in patients with advanced HCC being treated with S. Methods: All patients treated with S for HCC in Alberta, Canada from 01/2008 to 07/2016 were included. Patient demographics and clinical/pathological variables were retrospectively collected. Patients were dichotomized by ethnicity as either East Asian or not according to a validated list of surnames. Survival outcomes were assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox-proportional hazard model was constructed with ethnicity and relevant clinical/pathological characteristics to assess their impact on survival. Results: A total of 175 patients were included. Mean age was 64 years. 78% were men, 28% were East Asian, and 79% were Child-Pugh A at initiation of S. The most common etiologies of underlying liver disease were Hepatitis C (HCV) (31%), HBV (29%) and alcohol (21%). 42% had distant metastatic disease. The majority of patients had an ECOG performance status of 0 (26%) or 1 (64%). Median OS was 9.0 months in Asians and 9.5 months in non-Asians (p = 0.68). On multivariate analysis, ethnicity (HR 0.76, 95% CI 0.39 – 1.32, p = 0.33) was not a significant prognostic factor for OS. However, lack of distant metastases (HR 0.57 95% CI 0.40 - 0.82, p &lt; 0.01), initial AFP &lt; 400 (HR 0.54 95%CI 0.38 - 0.78, p &lt; 0.01) and 3+ localized treatments (HR 0.60 95% CI 0.39 - 0.92, p = 0.02) were associated with better OS. Further, HBV was associated with inferior OS when compared to HCV (HR 2.12, 95% CI 1.08 - 4.17, p = 0.03). Conclusions: When treated with S in one Canadian province, ethnicity does not appear to be a prognostic factor for OS. However, HCV infection, lack of distant metastases, initial AFP &lt; 400, and 3+ previous localized treatments were significant prognosticators of OS. We are validating these findings in a larger multi-centre Canadian dataset.
RIGHT VENTRICULAR PAPILLARY MUSCLES APPROXIMATION: INSIGHT FROM EX VIVO FUNCTIONAL TRUCISPID REGURGITATION MODEL
Authors: Michal Jaworek, Omar A. Pappalardo, Matteo Selmi, Guido Gelpi, Federico Lucherini, Claudia Romagnoni, Carlo Antona, Alberto Redaelli, Gianfranco B. Fiore, Emiliano Votta, Riccardo Vismara
Journal: Journal of the American College of Cardiology (2018)
Chemotherapeutic drug delivery by tumoral extracellular matrix targeting
Authors: René Raavé, Toin H. van Kuppevelt, Willeke F. Daamen
Journal: Journal of Controlled Release (2018)

Systemic chemotherapy is a primary strategy in the treatment of cancer, but comes with a number of limitations such as toxicity and unfavorable biodistribution. To overcome these issues, numerous targeting systems for specific delivery of chemotherapeutics to tumor cells have been designed and evaluated. Such strategies generally address subsets of tumor cells, still allowing the progressive growth of tumor cells not expressing the target. Moreover, tumor stem cells and tumor supportive cells, such as cancer associated fibroblasts and cancer associated macrophages, are left unaffected by this approach. In this review, we discuss an alternative targeting strategy aimed at delivery of anti-tumor drugs to the tumoral extracellular matrix with the potential to eliminate all cell types. The extracellular matrix of tumors is vastly different from that of healthy tissue and offers hooks for targeted drug delivery. It is concluded that matrix targeting is promising, but that clinical studies are required to evaluate translation.
DNA repair gene panel mutations in young onset prostate cancer cases in the.
Authors: Ros A. Eeles, Daniel Leongamornlert, Ed Saunders, Sarah Wakerell, Ian Whitmore, Tokhir Dadaev, Clara Cieza Borrella, Koveela Govindasami, Mark Brook, Artitaya Lophatananon, Kenneth Muir, David V Conti, Zsofia Kote-Jarai
Journal: Journal of Clinical Oncology (2018)

18 Background: Prostate cancer (PrCa) is the most common solid tumour in men in the Western world. There is substantial evidence that PrCa predisposition is due both to common and rare germline variation. Methods: We screened 167 genes from DNA damage response and repair pathways, within a UK based cohort of young onset cases (diagnosed at &lt; 65 years) and controls. Samples were sequenced using a custom Agilent SureSelectXT bait library and Illumina HiSeq technology and processed using a BWA/GATK 2.8 pipeline. Following sample QC, data were analysed from 1,285 PrCa cases and 1,163 controls. Results: We identified 5,086 single nucleotide variants (SNVs) and 175 indels; 233 unique protein truncating variants (PTVs) with MAF &lt; 0.5% in controls were found in 97 genes of the screening panel. The total proportion of PTV carriers in cases was higher than in controls (14.5% vs. 11.6%, P = 0.036; OR = 1.29, 95% CI 1.01-1.64). This enrichment was greater within the previously reported BROCA gene set of 22 tumour suppressor genes (4.5% vs 2.2%, P = 2.5x10 -3 ; OR = 2.07, 95% CI 1.28-3.34). To identify genes which best to distinguish PrCa cases from controls, we applied the adaptive combination of P values algorithm, ADA, for genes with at least 2 carriers of PTVs. This analysis selected 10 genes, (OR = 3.37, 95% CI 2.05-5.66, P ADA = 5.99x10 -3 ); men with PTVs in these were about 3.4-fold more likely to have PrCa (5.8% vs. 1.8%). We subsequently compared aggressive cases (Gleason score ≥ 8, n = 204) with non-aggressive cases (Gleason score ≤ 7, n = 1049) and lethal PrCa cases (cause of death PrCa, n = 183) with indolent cases (Gleason score ≤ 6, n = 563) to evaluate genes associated with poor clinical prognosis. Using ADA, 4 genes were selected for aggressive PrCa ( P ADA = 0.006) and 2 of these also for lethal PrCa ( P ADA = 0.057). Conclusions: These gene sets provide an 11 gene panel which could be used for clinical testing and will help to facilitate the development of a PrCa specific sequencing panel with both predictive and prognostic potential.
I am working as a registrar in orthopaedic surgery in Saudi Arabia. My total orthopaedic experience is 13 years. I would like to come to the UK as an orthopaedic SHO. How should I go about this?
Authors: Kuntal Patel
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>
Recently Evolved Tumor Suppressor Transcript TP73-AS1 Functions as Sponge of Human-Specific miR-941
Authors: Haiyang Hu, Jian-Mei Liu, Zhenyu Hu, Xi Jiang, Xiaode Yang, Jiangxia Li, Yao Zhang, Haijing Yu, Philipp Khaitovich
Journal: Molecular Biology and Evolution (2018)

MicroRNA (miRNA) sponges are vital components of posttranscriptional gene regulation. Yet, only a limited number of miRNA sponges have been identified. Here, we show that the recently evolved noncoding tumor suppressor transcript, antisense RNA to TP73 gene (TP73-AS1), functions as a natural sponge of human-specific miRNA miR-941. We find unusually nine high-affinity miR-941 binding sites clustering within 1 kb region on TP73-AS1, which forms miR-941 sponge region. This sponge region displays increased sequence constraint only in humans, and its formation can be traced to the tandem expansion of a 71-nt-long sequence containing a single miR-941 binding site in old world monkeys. We further confirm TP73-AS1 functions as an efficient miR-941 sponge based on massive transcriptome data analyses, wound-healing assay, and Argonaute protein immunoprecipitation experiments conducted in cell lines. The expression of miR-941 and its sponge correlate inversely across multiple healthy and cancerous tissues, with miR-941 being highly expressed in tumors and preferentially repressing tumor suppressors. Thus, the TP73-AS1 and miR-941 duo represents an unusual case of the extremely rapid evolution of noncoding regulators controlling cell migration, proliferation, and tumorigenesis.
Targeting CD38 to improve anti-PD-1/CTLA-4 combination therapy in lung cancer.
Authors: Limo Chen, Yanli Li, Xiaohui Yi, Don Lynn Gibbons
Journal: Journal of Clinical Oncology (2018)

144 Background: The combination of anti-PD-1 and anti-CTLA-4 is a promising strategy that is being clinically explored to treat a variety of cancer types. Some patients display primary resistance to this combination treatment, while others relapse after treatment. Although some cancer patients have long-term durable responses to the combination therapy of anti-PD-1 and anti-CTLA-4, physicians have been looking for biomarkers that predict response. Methods: Using multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the mechanisms of resistance to anti-PD-1/CTLA-4 combination therapy by evaluating the molecular and cellular immune profiles of the tumor microenvironment. Antibody-mediated cell depletion assays were also conducted to validate the mechanisms. Lastly, to determine the applicability to patients, we analyzed 791 lung cancer patients’ specimens with immunohistochemistry staining and mined many immune markers in multiple large independent patient databases (~1900 tumors). Results: We observed that tumor bearing mice treated with combined PD-1 and CTLA-4 blocking antibodies developed resistance through the up-regulation of CD38, and that targeting CD38 abolished the resistance in a manner dependent on B7-costimulation. Additionally, combined PD-1 and CTLA-4 blockade eradicates CD38-deficient tumors in mice. Further study revealed that control of tumors by triple blockade of CD38, PD-1, and CTLA-4 depended on improved functionality of CD4+/CD8+ TILs, which were reactivated by enriched CD103+ dendritic cells in the tumor microenvironment. Pathologic analysis revealed positive immunohistochemical staining for CD38 on tumor cells in 15-23% of cases and bioinformatic analyses revealed a strong correlation between CD38 expression and an immune inflammatory signature. Conclusions: Targeting CD38 improves the efficacy of anti-PD-1/CTLA-4 combination therapy in lung cancer. CD38 on tumor cells could potentially serve as a novel biomarker of resistance for immune checkpoint inhibition.
RELATIONSHIP BETWEEN LEFT VENTRICULAR STRUCTURAL AND FUNCTIONAL PARAMETERS AND PEAK EXERCISE PERFORMANCE: A THREE-DIMENSIONAL ECHOCARDIOGRAPHIC STUDY IN YOUNG ATHLETES
Authors: Bálint Lakatos, Orsolya Kiss, Máté Babity, Csaba Bognár, Carmen Bátorfi, Mónika Szilágyi, Nora Sydo, Timea Kovats, Attila Kovács, Bela Merkely
Journal: Journal of the American College of Cardiology (2018)
Molecular and histopathologic correlates of imaging and biological responses to neoadjuvant GnRH agonist plus enzalutamide for high risk prostate cancer.
Authors: Adam G. Sowalsky, Scott Wilkinson, Huihui Ye, David James VanderWeele, Baris Turkbey, S. Thomas Hennigan, Rayann Atway, Shana Y. Trostel, Ross Lake, Fatima Karzai, Stephanie Harmon, Guinevere Chun, Kathleen Kelly, Peter A. Pinto, Peter L. Choyke, William L. Dahut
Journal: Journal of Clinical Oncology (2018)

34 Background: AR directed therapies are standard of care for metastatic prostate cancer, and their use for high-risk localized disease may improve survival. Previous trials showed low rates of complete pathologic responses to neoadjuvant ADT. The underlying biology and molecular features of tumors that fail to respond remain unknown. Methods: Men with localized prostate cancer with high risk features received 6 months of GnRH agonist plus enzalutamide. mpMRI was performed at baseline and prior to RP. MRI-US fusion guided biopsies were performed at study enrollment. RP specimens were sectioned in the same plane as mpMRI. Imaging and anatomical landmarks on pre- and post-treatment mpMRI were used to match targeted biopsies to RPs. IHC stains including AR, GR, and SYP were performed to guide laser capture microdissection (LCM) and characterization of residual disease. DNA was extracted from LCM biopsy and RP tissues. Whole exome sequencing with somatic mutation calling and copy number analysis was performed. Results: Most patients showed incomplete pathologic responses despite reductions in tumor volume. Several patients harbored multiple tumor clones prior to treatment, distinguished by distinct copy number alterations and mutations in biopsies. Alignment of biopsies to pre- and post-treatment mpMRI correlated with imaging response and histopathology of matched RP sections. Minimal genomic divergence from untreated clones on biopsy suggested intrinsic resistance, while extensive divergence indicated selection for pre-existing subclones. Most residual tumor was AR- and GR-positive adenocarcinoma, with some regions of AR-negative Panneth cell-like differentiation positive for synaptophysin. AR-V7 was rare in residual tumor and &lt; 1% cells were positive for KI-67. The most common alteration in all samples was single-copy loss of chromosome 16q overlapping with ZFHX3. Conclusions: Our approach of repeated sampling by matching targeted biopsies to mpMRI demonstrates feasibility in comparing mpMRI response, pathologic treatment response, and the underlying genomic features that drive tumor development versus treatment resistance. Clinical trial information: NCT02430480.
Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis
Authors: Xin Cui, Renee-Tyler Tan Morales, Weiyi Qian, Haoyu Wang, Jean-Pierre Gagner, Igor Dolgalev, Dimitris Placantonakis, David Zagzag, Luisa Cimmino, Matija Snuderl, Raymond H.W. Lam, Weiqiang Chen
Journal: Biomaterials (2018)
GP workload is a barrier to collaboration, BMA survey finds
Authors: Abi Rimmer
Journal: BMJ (2014)

More than two thirds of general practitioners believe that their workloads stop them from forming networks, a BMA survey has found.1

Of the 1555 respondents who completed the BMA’s GP Practice Collaboration Survey , 69% said that workload pressure was a barrier to establishing a network or federation. Similarly, 66.5% said that a lack of time prevented them from collaborating with others.

One in five respondents …
Transparency of Shape of Training review process questioned by information tribunal
Authors: Abi Rimmer
Journal: BMJ (2015)

The transparency of the process through which the Shape of Training review of postgraduate medical education and training was developed has been questioned by an information tribunal.

Documents released by the General Medical Council show that meetings took place between David Greenaway, the chair of the Shape of Training review, and senior civil servants and politicians. The meetings, which took place during the review’s call for evidence in 2013, were not referenced in the final report.

The GMC initially refused a request made under the Freedom of Information Act to release the minutes …
I am a Canadian orthopaedic surgeon with more than 20 years' experience in a busy Canadian community practice. I am also qualified to work in the United States. I would like to spend a year in the United Kingdom, either working locums or attached to a training facility. I do have a right of abode. Is it possible to do something like this?
Authors: Christopher Liao
Journal: BMJ (2005)

<h3>AIMS</h3> To assess the reproducibility and validity of a new instrument for grading nuclear cataract—the laser slit lamp, by comparison with an established method of lens grading—the Lens Opacities Classification System III (LOCS III). <h3>METHODS</h3> 62 volunteers (113 eyes) were examined on two occasions. At each visit, a video image of the anterior segment was captured with the laser slit lamp and stored digitally. A measure of lens opacity for each laser slit lamp image was calculated using image analysis software. Each lens was also photographed on both visits for LOCS III grading of nuclear colour and nuclear opalescence. <h3>RESULTS</h3> There was a linear increasing relation between the laser slit lamp measure of nuclear lens opacity and the LOCS III nuclear opalescence scores. The overall reproducibility of the laser slit lamp measurement was comparable with LOCS III (intraclass correlation coefficient of 95% (95% CI 92.9–96.5) for the laser slit lamp method; 97% (95% CI 95.6–97.9) for the LOCS III method). However, among healthy subjects, the reproducibility was lower (intraclass correlation for the laser slit lamp of 38.6% (95% CI 12.9–59.2) and 76.1% (95% CI 62.3–85.4) for LOCS III. <h3>CONCLUSION</h3> The laser slit lamp appears to give a valid measurement of nuclear cataract. The reproducibility of the instrument was high and similar to that of LOCS III. Modifications to the design would have to be made to improve its reproducibility among healthy subjects. It is simpler than other objective instruments, and could be useful in large scale studies of cataract.
THE IMPACT OF VALVULOARTERIAL IMPEDANCE ON THE LEFT VENTRICULAR MYOCARDIAL REGRESSION AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT: A COMPARISON WITH TRANSVALVULAR MEAN PRESSURE GRADIENT
Authors: Satoshi Yamaguchi, Yuka Otaki, Balaji Tamarappoo, Atsushi Hayashi, Takafumi Nagaura, Jun Yoshida, Tetsuo Kamiyama, Tarun Chakravarty, Raj Makkar, John Friedman, Daniel Berman, Florian Rader, Robert Siegel, Takahiro Shiota
Journal: Journal of the American College of Cardiology (2018)
VORAPAXAR PHARMACODYNAMICS: EFFECTS ON THROMBOGENICITY, ENDOTHELIAL FUNCTION, AND INTERACTIONS WITH CLOPIDOGREL AND ASPIRIN
Authors: Paul A. Gurbel, Kevin Bliden, Rachel Bell, Hamid Taheri, Behnam Tehrani, Tenzin Dechen, Katherine Armstrong, Udaya Tantry
Journal: Journal of the American College of Cardiology (2018)
Cost-effectiveness of omalizumab for the treatment of chronic spontaneous urticaria
Authors: T.A. Kanters, H.B. Thio, L. Hakkaart
Journal: British Journal of Dermatology (2018)

Chronic spontaneous urticaria (CSU) is a skin disease with itchy hives and/or angio-oedema that last for at least 6 weeks without an obvious external trigger.To determine the cost-effectiveness of omalizumab relative to standard of care (SoC; up to four times the daily dose of H1 -antihistamines) in the Netherlands from a societal perspective.The Markov model used consisted of five health states based on Urticaria Activity Score over 7 days. Model settings and characteristics of the Dutch patient population were based on an online survey among clinical experts and were validated during an expert committee meeting. Transition probabilities were derived from the GLACIAL trial. Healthcare consumption, quality of life (using EuroQol-5D) and productivity losses were derived from a burden-of-illness study (ASSURE-CSU) among 93 Dutch patients. Healthcare consumption and productivity losses were evaluated using the Dutch costing manual. The comparator treatment was SoC, consisting of (updosed) antihistamines. A 10-year time horizon was used.The incremental cost-effectiveness ratio (ICER) of omalizumab vs. SoC was €17 502 per quality-adjusted life-year (QALY) gained. Productivity costs played an important role in the value of the ICER; discarding productivity costs resulted in an ICER of €85 310 per QALY.Omalizumab is cost-effective compared with SoC. The outcomes of this study were used to establish omalizumab as third-line therapy in the Dutch treatment guidelines for CSU.
Putting doctors through their paces
Authors: Norildin Al-Refaie, Ahmed Sabra
Journal: BMJ (2016)

The Membership of the Royal Coll­­­ege of Physicians part two examination can be daunting, particularly for those with little experience of the NHS. <b>Norildin Al-Refaie</b> and <b>Ahmed Sabra</b> give their tips for success
Four-Minute Bone SPECT Using Large-Field Cadmium-Zinc-Telluride Camera
Authors: Bastien Gregoire, Géraldine Pina-Jomir, Alexandre Bani-Sadr, Caroline Moreau-Triby, Marc Janier, Christian Scheiber
Journal: Clinical Nuclear Medicine (2018)

Purpose The aim of this study was to determine the minimum acquisition time without decreasing lesion detectability of bone SPECT using a whole-body cadmium-zinc-telluride camera. Methods Patients referred for bone SPECT were retrospectively included. SPECT of 30 patients were reframed from native data (16 s/projection) to produce 10-, 5-, and 3-s/projection data sets. A “critical” acquisition time/projection was defined as that below which the SPECT quality becomes insufficient for interpretation, as determined by 3 reviewers using a 4-point scale (0 = quality insufficient for interpretation, 1 = average, 2 = good, 3 = excellent). Three reviewers (blinded to the acquisition time) evaluated SPECT data sets (n = 79), native and reframed with “critical” acquisition times, in a randomized order. A lesion was defined as any uptake considered pathological by a reviewer. Lesion detectability equivalence between native SPECT and reframed SPECT was assessed by calculating a coefficient (κ) for each reviewer. Results Image quality of the first sample (n = 30) was significantly and progressively less well graded for the reframed data sets by all reviewers. Only 1 patient was graded 0 by each reviewer for the 5-s/projection data set. For the 3-s/projection data set, 3 patients were graded 0. No patients were graded 0 for 10-s/projection data set. The minimal acquisition time, for each projection, was defined as 5 s/projection. The coefficient κ, between native and reframed, with critical acquisition time/projection SPECT was greater than 0.9 for each reviewer. Conclusions The more contrasted images of the cadmium-zinc-telluride camera allow performance of 5-s/projection SPECT without loss of lesion detectability. This suggests the possibility of performing whole-body SPECT in a reasonable time or reducing injected doses, especially in pediatric patients.