tbuckley/cabot-search huggingface dataset:
Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment
Authors: Sarah A. Best, David P. De Souza, Ariena Kersbergen, Antonia N. Policheni, Saravanan Dayalan, Dedreia Tull, Vivek Rathi, Daniel H. Gray, Matthew E. Ritchie, Malcolm J. McConville, Kate D. Sutherland
Journal: Cell Metabolism (2018)
Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study
Authors: Björn Pasternak, Malin Inghammar, Henrik Svanström
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To investigate whether oral fluoroquinolone use is associated with an increased risk of aortic aneurysm or dissection. <h3>Design</h3> Nationwide historical cohort study using linked register data on patient characteristics, filled prescriptions, and cases of aortic aneurysm or dissection. <h3>Setting</h3> Sweden, July 2006 to December 2013. <h3>Participants</h3> 360 088 treatment episodes of fluoroquinolone use (78%<b></b>ciprofloxacin) and propensity score matched comparator episodes of amoxicillin use (n=360 088). <h3>Main outcome measures</h3> Cox regression was used to estimate hazard ratios for a first diagnosis of aortic aneurysm or dissection, defined as admission to hospital or emergency department for, or death due to, aortic aneurysm or dissection, within 60 days from start of treatment. <h3>Results</h3> Within the 60 day risk period, the rate of aortic aneurysm or dissection was 1.2 cases per 1000 person years among fluoroquinolone users and 0.7 cases per 1000 person years among amoxicillin users. Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection (hazard ratio 1.66 (95% confidence interval 1.12 to 2.46)), with an estimated absolute difference of 82 (95% confidence interval 15 to 181) cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes. In a secondary analysis, the hazard ratio for the association with fluoroquinolone use was 1.90 (1.22 to 2.96) for aortic aneurysm and 0.93 (0.38 to 2.29) for aortic dissection. <h3>Conclusions</h3> In a propensity score matched cohort, fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection. This association appeared to be largely driven by aortic aneurysm.
Peanut Oral Immunotherapy Threshold Dose for Reactivity: What is the Upper Limit?
Authors: Carla M. Davis, Aikaterini Anagnostou, Sridevi Devaraj, Daisy Tran, Avina Nguyen, Kathy Pitts, Charles Minard, Danielle Guffey, Jordan S. Orange, Sara Anvari
Journal: Journal of Allergy and Clinical Immunology (2018)
Osteoclast-secreted SLIT3 coordinates bone resorption and formation
Authors: Beom-Jun Kim, Young-Sun Lee, Sun-Young Lee, Wook-Young Baek, Young Jin Choi, Sung Ah Moon, Seung Hun Lee, Jung-Eun Kim, Eun-Ju Chang, Eun-Young Kim, Jin Yoon, Seung-Whan Kim, Sung Ho Ryu, Sun-Kyeong Lee, Joseph A. Lorenzo, Seong Hee Ahn, Hyeonmok Kim, Ki-Up Lee, Ghi Su Kim, Jung-Min Koh
Journal: Journal of Clinical Investigation (2018)

Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating β-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.
I passed my MRCPCH clinical exam recently and have worked in paediatrics as an SHO for 2.5 years and as a senior SHO for six months. Is this degree recognised in other countries for further studies such as fellowships?
Authors: Elitham Turya
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 (www.bmjcareers.com/advicezone) 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.
If I leave a medical rotation after a month in order to take up a post in accident and emergency in January 2005, will it jeopardise my chances in that same region?
Authors: Stephen Hearns
Journal: BMJ (2004)

<i>Got 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 (www.bmjcareers.com/advicezone) 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.</i>
I have recently seen in the immigration status section of a job application that there is a special clause for the doctors who were allowed to enter the UK as doctors before 1 April 1991. Is this true?
Authors: Shaaz Mahboob
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>
Abstract ES8-2: Exosome analysis in breast cancer: Clinical translation
Authors: JF Bromberg
Journal: Cancer Research (2018)

Abstract There is a growing appreciation that tumor secreted factors can function by orchestrating the cross-talk between cancer, stromal and immune cells. Tumors constitutively release membrane-derived extracellular vesicles (EVs) or exosomes that are readily detected in body fluids and have been appreciated to play important roles in signaling, immunomodulation and metastasis. We examined the role of circulating and stromal-derived EVs in hormonal therapy resistant breast cancer. We identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal-therapy resistant metastatic breast cancer. We generated xenograft models of hormonal therapy-resistant (HTR) metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HT-resistant cells had acquired host-derived (murine) mtDNA promoting ER-independent metabolic proficiency. Functional studies identified cancer associated fibroblasts (CAF)-derived EVs (from patients and xenograft models) laden with the complete mitochondrial genome as a mediator of this phenotype. Specifically, the treatment of HT-naïve cells or HT-treated metabolically dormant populations with CAF-derived mtDNAhi EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV-mtDNA especially in cancer stem-like cells, expression of EV-mtRNA and restoration of metabolic activity. In addition to mtDNA, we also identified miR-221 in CAF derived EVs as a driver of HTR disease. Specifically, EV-mediated transfer of miR-221 to cancer cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi cancer stem like cells. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221hi CAF EVs. Our results illuminate how EV-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Citation Format: Bromberg JF. Exosome analysis in breast cancer: Clinical translation [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 ES8-2.
Punctate palmoplantar keratoderma: an unusual mutation causing an unusual phenotype
Authors: D. Vodo, O. Sarig, D. Jeddah, N. Malchin, M. Eskin-Schwarz, J. Mohamad, T. Rabinowitz, I. Goldberg, N. Shomron, Z. Khamaysi, R. Bergman, E. Sprecher
Journal: British Journal of Dermatology (2018)
Transoceanic Dispersal and Plate Tectonics Shaped Global Cockroach Distributions: Evidence from Mitochondrial Phylogenomics
Authors: Thomas Bourguignon, Qian Tang, Simon Y W Ho, Frantisek Juna, Zongqing Wang, Daej A Arab, Stephen L Cameron, James Walker, David Rentz, Theodore A Evans, Nathan Lo
Journal: Molecular Biology and Evolution (2018)

Following the acceptance of plate tectonics theory in the latter half of the 20th century, vicariance became the dominant explanation for the distributions of many plant and animal groups. In recent years, however, molecular-clock analyses have challenged a number of well-accepted hypotheses of vicariance. As a widespread group of insects with a fossil record dating back 300 My, cockroaches provide an ideal model for testing hypotheses of vicariance through plate tectonics versus transoceanic dispersal. However, their evolutionary history remains poorly understood, in part due to unresolved relationships among the nine recognized families. Here, we present a phylogenetic estimate of all extant cockroach families, as well as a timescale for their evolution, based on the complete mitochondrial genomes of 119 cockroach species. Divergence dating analyses indicated that the last common ancestor of all extant cockroaches appeared ∼235 Ma, ∼95 My prior to the appearance of fossils that can be assigned to extant families, and before the breakup of Pangaea began. We reconstructed the geographic ranges of ancestral cockroaches and found tentative support for vicariance through plate tectonics within and between several major lineages. We also found evidence of transoceanic dispersal in lineages found across the Australian, Indo-Malayan, African, and Madagascan regions. Our analyses provide evidence that both vicariance and dispersal have played important roles in shaping the distribution and diversity of these insects.
Where can I find statistics on the number of applicants for each specialist registrar post in the various specialties? I am interested mainly in neurosurgery and orthopaedics.
Authors: Ramesh Chelvarajah
Journal: BMJ (2004)

<i>Got 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 (www.bmjcareers.com/advicezone) 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.</i>
The Trade-offs When Focusing on the Mortality Benefit
Authors: Albert Liu, Gregory Curfman
Journal: JAMA Internal Medicine (2018)

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Abstract 11991: Intraluminal and Intrawall Hyperintense Plaques Identified by Noncontrast T1-Weighted Magnetic Resonance Imaging Showed Different Vulnerable Plaque Morphology Assessed by Optical Coherence Tomography
Authors: Kenji Matsumoto, Shoichi Ehara, Takao Hasegawa, Mikumo Sakaguchi, Hitoshi Inanami, Kenichiro Otsuka, Takanori Yamazaki, Tomokazu Iguchi, Kenei Shimada, Minoru Yoshiyama
Journal: Circulation (2013)

Backgrounds:  Many studies have suggested that the onset of clinical symptoms are related to thrombosis and intraplaque hemorrhage in patients with acute coronary syndrome. Recently, magnetic resonance T1-weighted imaging (T1WI) enables assessment of vulnerable morphology of carotid and coronary atherosclerotic plaques as hyperintense plaque (HIP). However, the association between localization of HIPs and plaque morphology was not investigated in previous studies. The aim of this study was to investigate the characteristics of coronary intraluminal or intrawall HIP on noncontrast T1WI compared with plaque morphology assessed by optical coherence tomography (OCT).   Methods and Results:  A total of 80 lesions from 78 patients with either stable or unstable angina pectoris were included and divided into 3 groups according to the presence and the localization of HIPs. First, the plaques with the signal intensity of coronary plaque to cardiac muscle ratio (PMR) ≤1.0 were classified into non-HIPs (n=33). Then, HIPs with PMR >1.0 were classified into 2 types using the cross-sectional coronary images (Figure): intraluminal HIP was defined as one occupied the lumen and the lumen was not identified (n=19), and intrawall HIP was defined as one was localized within the coronary wall and the lumen was identified as black hole (n=28). Regarding plaque characterization detected by OCT, there were significant differences in the frequency of lipid rich plaque, calcification, thin-cap fibroatheroma, thrombus, macrophage infiltrations, and microchannels in the 3 groups. Multivariate analysis revealed that intrawall HIPs were related to macrophage infiltrations (P=0.006) and the absence of calcification (P=0.001). In contrary, intraluminal HIPs were associated with thrombus (P=0.005) and microchannels (P=0.007).   Conclusions:  This study suggests that the intraluminal and intrawall HIPs on T1WI show different types of vulnerable plaque morphology assessed by OCT imaging.
Doctors are reluctant to disclose mental health problems to employers
Authors: Tom Moberly
Journal: BMJ (2014)

Doctors are often reluctant to disclose their own mental health problems to employers, and many do so only if this is a condition of employment, researchers have found.

A team led by Debbie Cohen, senior medical research fellow at Cardiff University, used an online questionnaire to survey doctors across England, Scotland, and Wales. The work was funded by the Wales Deanery, and the questionnaire was disseminated through deaneries, royal colleges, and other organisations. In total, 1946 doctors responded to the survey, and …
Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland
Authors: Charlotte Warren-Gash, Ruth Blackburn, Heather Whitaker, Jim McMenamin, Andrew C. Hayward
Journal: European Respiratory Journal (2018)

While acute respiratory tract infections can trigger cardiovascular events, the differential effect of specific organisms is unknown. This is important to guide vaccine policy. Using national infection surveillance data linked to the Scottish Morbidity Record, we identified adults with a first myocardial infarction or stroke from January 1, 2004 to December 31, 2014 and a record of laboratory-confirmed respiratory infection during this period. Using self-controlled case series analysis, we generated age- and season-adjusted incidence ratios (IRs) for myocardial infarction (n=1227) or stroke (n=762) after infections compared with baseline time. We found substantially increased myocardial infarction rates in the week after Streptococcus pneumoniae and influenza virus infection: adjusted IRs for days 1–3 were 5.98 (95% CI 2.47–14.4) and 9.80 (95% CI 2.37–40.5), respectively. Rates of stroke after infection were similarly high and remained elevated to 28 days: day 1–3 adjusted IRs 12.3 (95% CI 5.48–27.7) and 7.82 (95% CI 1.07–56.9) for S. pneumoniae and influenza virus, respectively. Although other respiratory viruses were associated with raised point estimates for both outcomes, only the day 4–7 estimate for stroke reached statistical significance. We showed a marked cardiovascular triggering effect of S. pneumoniae and influenza virus, which highlights the need for adequate pneumococcal and influenza vaccine uptake. Further research is needed into vascular effects of noninfluenza respiratory viruses.
Diploma in pharmaceutical medicine (DipPharmMed)
Authors: Amanda McCormick
Journal: BMJ (2005)

A Mc: Doctors working in the pharmaceutical industry or for regulatory agencies.

NS : Medical graduates who are working in pharmaceutical medicine and who have received supervised and structured training. The diploma is part of higher medical training in pharmaceutical medicine, leading to specialist registration.

A Mc: In November 2004, three years after I joined GlaxoSmithKline.

NS : I took the exam in November 2004, three years after I started working in the pharmaceutical industry.

NS : For personal development and to expand my knowledge, especially in areas of pharmaceutical medicine which I don't cover day to day. There's also a slight chance that holding the diploma might help my career progression.

A Mc : I wanted to understand how the industry works, getting a total overview. Course modules explain how drugs are discovered, tested, registered, and marketed. After I started, a certificate of the completion of …
Evaluating cell cycle progression score as a prognostic marker for non-muscle invasive bladder cancer (NMIBC).
Authors: Christopher J. Weight, Paari J Murugan, David Chesla, Resha Tejpaul, Ayman Soubra, William Boshoven, Zaina Sangale, Saradha Rajamani, Steven Stone, Brian R. Lane
Journal: Journal of Clinical Oncology (2018)

476 Background: Accurate grading and staging from transurethral resection of bladder tumors (TURBT) is vital for appropriate clinical management. Non-muscle-invasive bladder cancer (NMIBC) can recur progress with higher grade and or stage progression to MIBC, requiring radical intervention with poorer prognosis. Further, grade and stage may change in 20-50% of TURBTs following re-review by expert GU pathologists Objective measures of stage and grade might offer additional and/or improved risk stratification; therefore we evaluated a molecular RNA signature as a prognostic marker for NMIBC. Methods: Patients were diagnosed with NMIBC at the University of Minnesota (UM)or Spectrum Health System(SHS) from 2005-2012. A Cell Cycle Progression (CCP) score was determined from the average expression of 36 CCP genes for patients with available FFPE diagnostic TURBT. The combined cohort consisted of 293 patients (UM n = 152, SHS n = 141). Study outcome was time from NMIBC diagnosis to progression to MIBC. Median follow-up for patients who did not experience an event was 4.4 years for UM and 6.9 for SHS. Association with outcomes was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. All analyses were stratified by cohort. Results: CCP score was associated with progression to MIBC in univariable analysis [hazard ratio 1.42 (95% CI 1.19, 1.68), p = 4.3x10 -5 ]. Tumor grade and stage were also highly prognostic. CCP score was strongly associated with stage (T1 vs Ta, p &lt; 10 -6 ) and grade (high vs low, p &lt; 10 -14 ) in both cohorts. As a result, CCP score did not provide independent prognostic information in multivariable analysis after adjusting for stage and grade (p = 0.32). There was a significant interaction between stage and CCP score (p = 0.0017), justifying an exploratory analysis of CCP score in Ta disease. In this subset, CCP score trended toward (p = 0.056) after adjusting for grade. Conclusions: In NMIBC, CCP score was highly correlated with tumor stage and grade and could serve as a quantitative measure of clinical parameters. The score may also provide prognostic information regarding risk of progression to MIBC, particularly in patients with Ta disease, but requires additional validation.
Next generation sequencing of urothelial bladder cancer: Memorial Sloan Kettering Cancer Center experience in 454 patients.
Authors: Sumit Isharwal, Francois Audenet, Esther N. Drill, Irina Ostrovnaya, Eugene J. Pietzak, Hikmat Al-Ahmadie, Eugene K. Cha, Timothy F. Donahue, Min Yuen Teo, Samuel Funt, Maria E. Arcila, Michael F. Berger, Jonathan E. Rosenberg, Dean F. Bajorin, Jonathan Coleman, Guido Dalbagni, Bernard H. Bochner, David B. Solit, Gopa Iyer
Journal: Journal of Clinical Oncology (2018)

469 Background: Genomic characterization of urothelial bladder cancer (UBC) may help to identify alterations associated with tumor stage, novel therapeutic targets and biomarkers to predict outcomes. Methods: 454 UBC patients were sequenced using next generation sequencing assay (MSK−IMPACT). 264 patients (123 NMIBC, 112 MIBC and 29 metastatic) were chemotherapy naïve primary tumors. Results: Patients whose primary tumors harbored TP53, RB1, TP53/MDM2, and cell cycle pathway alterations more frequently presented with advanced disease whereas those with tumors containing FGFR3, and RTK/RAS/RAF pathway alterations generally presented with NMIBC (all FDR &lt; 0.001). TP53, RB1, TP53/MDM2, and cell cycle pathway alterations were associated with worse overall and metastasis free survival whereas FGFR3 alterations were associated with more favorable overall and metastasis free survival (all FDR &lt; 0.05). RTK/RAS/RAF pathway alterations were associated with more favorable metastasis free survival (FDR = 0.01). MIBC with no DDR alterations, DDR alterations of unknown significance and DDR deleterious alterations had pathologic downstaging rates of 37%, 48% and 81% with platinum-based neoadjuvant chemotherapy (p = 0.013). Patients with ERCC2 mutations had significantly higher pathologic downstaging with platinum-based neoadjuvant chemotherapy compared to patients without ERCC2 mutations (p = 0.025). MIBC with DDR alterations had better overall survival with neoadjuvant chemotherapy compared to MIBC without DDR alterations (p = 0.04). Of note, MIBC cases with and without DDR alterations have similar overall survival in the absence of neoadjuvant chemotherapy (p = 0.78). Conclusions: TP53, RB1 and FGFR3 alterations as well as TP53/MDM2, cell cycle and RTK/RAS/RAF pathway alterations showed an association with tumor stage and patient outcomes. MIBC with DDR alterations had higher pathological downstaging as well as better overall survival compared to MIBC without DDR alterations with platinum−based neoadjuvant chemotherapy. In absence of neoadjuvant chemotherapy, MIBC with and without DDR alterations have similar patient outcomes.