tbuckley/cabot-search huggingface dataset:
Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis
Authors: Mandy O J Grootaert, Manon Moulis, Lynn Roth, Wim Martinet, Cécile Vindis, Martin R Bennett, Guido R Y De Meyer
Journal: Cardiovascular Research (2018)

In the present review, we describe the causes and consequences of loss of vascular smooth muscle cells (VSMCs) or their function in advanced atherosclerotic plaques and discuss possible mechanisms such as cell death or senescence, and induction of autophagy to promote cell survival. We also highlight the potential use of pharmacological modulators of these processes to limit plaque progression and/or improve plaque stability. VSMCs play a pivotal role in atherogenesis. Loss of VSMCs via initiation of cell death leads to fibrous cap thinning and promotes necrotic core formation and calcification. VSMC apoptosis is induced by pro-inflammatory cytokines, oxidized low density lipoprotein, high levels of nitric oxide and mechanical injury. Apoptotic VSMCs are characterized by a thickened basal lamina surrounding the cytoplasmic remnants of the VSMC. Inefficient clearance of apoptotic VSMCs results in secondary necrosis and subsequent inflammation. A critical determinant in the VSMC stress response and phenotypic switching is autophagy, which is activated by various stimuli, including reactive oxygen and lipid species, cytokines, growth factors and metabolic stress. Successful autophagy stimulates VSMC survival, whereas reduced autophagy promotes age-related changes in the vasculature. Recently, an interesting link between autophagy and VSMC senescence has been uncovered. Defective VSMC autophagy accelerates not only the development of stress-induced premature senescence but also atherogenesis, albeit without worsening plaque stability. VSMC senescence in atherosclerosis is likely a result of replicative senescence and/or stress-induced premature senescence in response to DNA damaging and/or oxidative stress-inducing stimuli. The finding that VSMC senescence can promote atherosclerosis further illustrates that normal, adequate VSMC function is crucial in protecting the vessel wall against atherosclerosis.
Polygenic Risk Scores in Clinical Psychology: Bridging Genomic Risk to Individual Differences
Authors: Ryan Bogdan, David A.A. Baranger, Arpana Agrawal
Journal: Annual Review of Clinical Psychology (2018)

Genomewide association studies (GWASs) across psychiatric phenotypes have shown that common genetic variants generally confer risk with small effect sizes (odds ratio < 1.1) that additively contribute to polygenic risk. Summary statistics derived from large discovery GWASs can be used to generate polygenic risk scores (PRS) in independent, target data sets to examine correlates of polygenic disorder liability (e.g., does genetic liability to schizophrenia predict cognition?). The intuitive appeal and generalizability of PRS have led to their widespread use and new insights into mechanisms of polygenic liability. However, when currently applied across traits they account for small amounts of variance (<3%), are relatively uninformative for clinical treatment, and, in isolation, provide no insight into molecular mechanisms. Larger GWASs are needed to increase the precision of PRS, and novel approaches integrating various data sources (e.g., multitrait analysis of GWASs) may improve the utility of current PRS.
Doctors will need to show generic skills such as communication to complete training
Authors: Abi Rimmer
Journal: BMJ (2015)

Doctors will need to show that they have generic professional skills such as good communication skills before they can complete their training, the General Medical Council has proposed.

The GMC and the Academy of Medical Royal Colleges have published a consultation on their proposals for a “framework for generic professional capabilities.”1 Generic professional capabilities include the ability to communicate effectively, the ability to work as part …
Treatment modification with sunitinib in first-line (1L) metastatic renal cell carcinoma (mRCC): An analysis of the STAR-TOR registry.
Authors: Martin Boegemann, Marcus Hubbe, Despina Thomaidou, Stuart Blackburn, Nawal Bent-Ennakhil, Robert Wood, Danielle Bargo
Journal: Journal of Clinical Oncology (2018)

602 Background: The standard dosing schedule for administration of Sunitinib is 50mg once daily for a 4-week period followed by 2 weeks off. However, in clinical practice, many patients require schedule or dose reductions to mitigate toxicity. We aimed to assess if these treatment modifications result in improved outcomes in mRCC patients. Methods: Data were drawn from STAR-TOR, a German, multi-centre, real-world, prospective registry to report outcomes of mRCC patients who received Sunitinib in 1L. Patients were categorised into 2 treatment groups: 1) Sunitinib initiated at standard schedule/dose with subsequent schedule/dose modification (SM), 2) Sunitinib as per standard schedule/dosage (SS). Kaplan-Meier survival analysis was used to determine time on treatment (TT) of Sunitinib and progression-free survival (PFS). Differences between groups were assessed using log-rank tests. Results: In total 297 patients were identified initiating 1L Sunitinib. Schedule or dose reductions occurred in 33% of patients. Significant differences between groups at baseline are noted in Table 1. Median TT was greater in SM vs. SS (15.1 vs. 3.9 months (m), p &lt; 0.0001). Median PFS was improved in SM vs. SS (15.1 vs. 6.0 m, p &lt; 0.0001). Fatigue (31/14%), hand-foot syndrome (HFS) (28/10%), diarrhea (35/19%) and stomatitis (20/6%) were more frequently reported in SM vs. SS since initiation of Sunitinib. Incidence of adverse events, (excluding diarrhea) was reduced following schedule/ dose modification of sunitinib; fatigue (before SM/ after SM) (18/7%), HFS (21/8%) and stomatitis (8/4%). Conclusions: Modifying Sunitinib schedule or individualizing the dose represent therapy management strategies that are associated with improved tolerability, prolonged treatment duration and significant improvement in PFS in a real life setting. These data suggest that effective management of toxicity of Sunitinib can optimize patient outcomes. [Table: see text]
After the amendment made by the visa office what is the chance of getting a specialist job in this field after finishing two years of an SHO job in the UK?
Authors: Sunder R Gopaul
Journal: BMJ (2006)

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>
Concordance of ETS fusion status of matched metastatic castration-resistant prostate cancer and primary prostate cancer: Data from NCI 9012, a randomized ETS fusion-stratified phase II trial.
Authors: Lakshmi Priya Kunju, Nallasivam Palanisamy, Stephanie Daignault, Rohit Mehra, Javed Siddiqui, Shannon Lea Carskadon, Przemyslaw Twardowski, Mark N. Stein, Noah M. Hahn, Walter Michael Stadler, Jon Jacobson, Matthew S. Davenport, Scott A. Tomlins, Arul M. Chinnaiyan, Felix Yi-Chung Feng, Maha Hussain
Journal: Journal of Clinical Oncology (2014)

5019 Background: Fusions of androgen-regulated genes with ETS transcription family members have been reported in 50% of localized pPCa patients (pts), with TMPRSS2-ERG fusions being the most common. ETS fusion products functionally depend upon Poly (ADP-ribose) polymerase 1 (PARP1), and its inhibition is preferentially cytotoxic to ETS translocation positive disease in preclinical models. We hypothesized that targeting ETS gene fusions will improve response rate in pts with these molecular subtypes and in pts with ETS fusion positive tumors, targeting the promoter and transcription factor of ETS fusion is more effective than targeting a single aspect of the fusion. Methods: Eligible mCRPC pts undergo a metastatic site biopsy to determine ETS fusion status by immunohistochemistry (ERG), fluorescent in-situ hybridization and/or RNA in-situ hybridization (ETV1) and sequencing (ETV4). Pts are stratified by ETS status and randomized to abiraterone (ABI) +/- the PARP inhibitor veliparib. Soft tissue biopsies are done using 18-gauge needle: 1-cm core (≥ 6 specimens), 2-cm core (≥4 specimens). For bone biopsy: 2-8 cores. We report interim results on rates of positive biopsy, ETS status/type and concordance between primary PCa and metastasis. Results: To date, 86 pts (Caucasians: 80%, African Americans 14%) with a median age 70 years and a median PSA 36.3 ng/ml have been enrolled. Of the 86 pts, 1 had an unreachable bone lesion, 36 had soft tissue and 49 had bone biopsies; all soft tissue and 36/49 (73%) bone biopsies were evaluable for analysis (13 had no tumor), ETS fusion status is positive in 36% pts: ERG positive (31%), ETV1 positive (4%), ETV4 positive (1%). Concordance of ETS status between primary PCa and metastatic site was found in 30/31 pts (97 % [95% CI: 83-99.9%]. Conclusions: This trial represents one of the first prospective predictive biomarker-driven trials in mCRPC. Results indicate feasibility of real time biopsy (adequate tissue yield including from bone) and biomarker determination, and demonstrates significant concordance of ETS status between primary PCa and metastasis in the subset analyzed to date. Clinical trial information: NCT01576172.
Prostate-Specific Membrane Antigen PET/CT Incidental Finding of a Schwannoma
Authors: André H. Dias, Kirsten Bouchelouche
Journal: Clinical Nuclear Medicine (2018)

We describe a case of a 73-year-old man with newly diagnosed prostate cancer referred to Ga-PSMA PET/CT for staging. A focal uptake of PSMA was visualized in the prostate compatible with primary prostate cancer. Outside the prostate, a PSMA-avid paravertebral soft tissue mass was observed. Further investigation with MRI of the same region showed signs compatible with schwannoma. This case shows the importance of including schwannoma in the differential diagnostic evaluation of patients with Ga-PSMA-positive foci in paravertebral locations, as schwannomas may show avid PSMA uptake and may potentially lead to an incorrect diagnosis of metastasis.
Ultrasonography in psoriatic arthritis: which sites should we scan?
Authors: Alen Zabotti, Matteo Piga, Marco Canzoni, Garifallia Sakellariou, Annamaria Iagnocco, Carlo Alberto Scirè
Journal: Annals of the Rheumatic Diseases (2018)

In psoriatic arthritis (PsA), ultrasonography (US) plays a growing role in the differential diagnosis and in monitoring treatment response.1 PsA is a heterogeneous disease with different domains and peculiar sites involved.2 Therefore, a dedicated US composite score is needed to monitor disease activity and to identify structural damage progression. A recently published Systematic Literature Review (SLR) identified only two US scores specifically developed for PsA (ie, 5TPD and PsA-Son) and, although these had a good sensitivity to detect inflammation and a good feasibility, they have not been validated in other series.1 3 4 Recently, the Study Group for US of the Italian Society of Rheumatology promoted the Ultrasound in PSoriatic Arthritis TREAtMent (UPSTREAM) study (registered at ClinicalTrial.gov, NCT03330769). UPSTREAM is a multicentre observational prospective cohort study and it represents the first …
Phase 3, randomized, double-blind trial of pembrolizumab in the adjuvant treatment of renal cell carcinoma (RCC): KEYNOTE-564.
Authors: David I. Quinn, Tian Zhang, Howard Gurney, Gurjyot K. Doshi, Patrick Wayne Cobb, Francis Parnis, Jae-Lyun Lee, Se Hoon Park, Andrey Semenov, Wayne Yen-Hwa Chang, Thomas Powles, Shuyan (Sabrina) Wan, Christian Heinrich Poehlein, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2018)

TPS712 Background: Most patients with intermediate- to high-risk advanced renal cell carcinoma (RCC) will progress within 3 years following nephrectomy. Novel treatments in the adjuvant setting are needed to prevent disease recurrence in these higher-risk patients. Upregulation of the programmed death 1 (PD-1) pathway is associated with more aggressive disease and poor prognosis. PD-1 inhibitors have demonstrated activity in metastatic RCC, and PD-1 may represent a novel therapeutic target in the adjuvant setting. Pembrolizumab, a PD-1 inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Methods: KEYNOTE-564 (NCT03142334) is a randomized, double-blind, placebo-controlled phase 3 trial designed to evaluate the efficacy and safety of pembrolizumab as adjuvant therapy in patients with RCC. Eligibility criteria include age ≥18 years; intermediate- to high-risk (T2 grade 4, T3), high-risk (T4, T), or M1 NED RCC with a clear cell component; no prior systemic therapy for advanced RCC; disease free following complete or partial nephrectomy (and metastasectomy in patients with M1 NED) with negative surgical margins; Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1; and provision of a tumor sample for biomarker analyses. Patients will be randomly assigned (1:1) to pembrolizumab 200 mg administered intravenously every 3 weeks or placebo. Randomization will be stratified by metastasis stage (M0 vs M1 NED); within the M0 group, randomization will be further stratified by ECOG PS (0 vs 1) and region (US vs rest of world). Treatment will continue until disease recurrence, unacceptable toxicity, or the completion of 17 cycles (~1 year). Imaging will be performed every 12 weeks. The primary end point is disease-free survival (DFS) per investigator assessment. The key secondary end point is overall survival (OS). Other secondary objectives include safety, disease recurrence-specific survival, DFS and OS according to PD-L1 expression status, and patient-reported outcomes. Biomarkers that may be associated with response will be evaluated as an exploratory objective. Enrollment is ongoing and will continue until ~950 patients are enrolled. Clinical trial information: NCT03142334.
Pharmacogenetic-based area-under-curve model to predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma.
Authors: Yoshiaki Yamamoto, Ryouichi Tsunedomi, Yoshihisa Kawai, Hiroaki Matsumoto, Shoichi Hazama, Hiroaki Nagano, Hideyasu Matsuyama
Journal: Journal of Clinical Oncology (2018)

625 Background: Although titrated-dose axitinib offers a good objective response rate (ORR) for metastatic renal cell carcinoma (RCC), its optimal initial dose is unclear because its dosing regimen is based on a hypertensive reaction. We investigated whether axitinib pharmacogenetics were related to clinical efficacy/adverse events, and calculated a model to predict clinical efficacy and adverse events, using pharmacokinetic data based on gene polymorphisms in a phase 2 trial. Methods: We prospectively evaluated objective response and adverse events to establish a prediction model in 44 consecutive patients with advanced RCC, treated with axitinib between October 2013 and March 2017. Gene polymorphisms, including ABC transporters ( BCRP and MDR1) and UGT1A were analyzed by whole-exome sequencing, Sanger sequencing, and DNA chips. To construct the prediction model for area under curve (AUC), we used an exponential regression model with gene polymorphisms and dosage as covariates. To further validate this prediction model, we prospectively compared the calculated AUC in this model with actual AUCs in 13 additional consecutive patients. Results: Actual AUC was significantly correlated with the best ORR ( P = 0.0002), and adverse events (grade 2–3 hand–foot syndrome [ P = 0.0055]; grade 2 hypothyroidism [ P = 0.0381]); it was also significantly correlated with calculated AUC ( P &lt; 0.0001). Calculated AUC was also significantly associated with best ORR ( P = 0.0044), grade 2–3 hand–foot syndrome ( P = 0.0191) and grade 2 hypothyroidism ( P = 0.0082). Surprisingly, hypertension was associated with neither ORR nor AUC. In the validation study, calculated AUC before axitinib treatment precisely predicted actual AUC ( P = 0.0079) in 13 additional consecutive patients. Conclusions: Our pharmacogenetics-based AUC model may offer a more benign method to determine optimal initial axitinib doses than hypertension, and could contribute to more precise treatment of individuals with advanced RCC. Clinical trial information: UMIN000011147.
Diagnosis of Acute Osteomyelitis in Previously Irradiated Bone
Authors: Ali Mousavi, Hussein M. Abdel-Dayem
Journal: Clinical Nuclear Medicine (2009)

We are reporting a case of acute osteomyelitis in previously irradiated bone. In nonirradiated bone the diagnosis of acute osteomyelitis is established by the mismatch between focal indium-111 whole body scintigraphy (WBC) bone uptake and bone marrow replacement as seen on the Tc-99m sulfur colloid scans in areas of acute osteomyelitis. In previously irradiated bone, the bone marrow is absent due to radiation effects. Accordingly, the combination of indium-111 WBC and Tc-99m sulfur colloid mismatch cannot be implemented. In this case, we found that in spite of previous irradiation of the bone there is uptake in the bone matrix due to cortical and osteoblastic activity as seen on the Tc-99m MDP bone scan. For this reason we are recommending that for the diagnosis of acute osteomyelitis in previously irradiated bone, dual isotope imaging using indium-111 WBCs and Tc-99m MDP is more accurate than indium-111 WBCs and Tc-99m sulfur colloid.
Prevalence of Obesity Among Youths by Household Income and Education Level of Head of Household — United States 2011–2014
Authors: Cynthia L. Ogden, Margaret D. Carroll, Tala H. Fakhouri, Craig M. Hales, Cheryl D. Fryar, Xianfen Li, David S. Freedman
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Obesity prevalence varies by income and education level, although patterns might differ among adults and youths (1-3). Previous analyses of national data showed that the prevalence of childhood obesity by income and education of household head varied across race/Hispanic origin groups (4). CDC analyzed 2011-2014 data from the National Health and Nutrition Examination Survey (NHANES) to obtain estimates of childhood obesity prevalence by household income (≤130%, >130% to ≤350%, and >350% of the federal poverty level [FPL]) and head of household education level (high school graduate or less, some college, and college graduate). During 2011-2014 the prevalence of obesity among U.S. youths (persons aged 2-19 years) was 17.0%, and was lower in the highest income group (10.9%) than in the other groups (19.9% and 18.9%) and also lower in the highest education group (9.6%) than in the other groups (18.3% and 21.6%). Continued progress is needed to reduce disparities, a goal of Healthy People 2020. The overall Healthy People 2020 target for childhood obesity prevalence is <14.5% (5).
Abiraterone acetate plus prednisone (AAP) in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) and prior diethylstilbestrol (DES) therapy: Preliminary results.
Authors: Diogo Assed Bastos, Marcos Tobias Machado, Renato Panhoca, Giovani Thomaz Pioner, Gustavo Werutsky, Mariana Grings, Lizis Lopes, Francisco Gonzalez, Telma Murias Santos, Rosemarie Gidekel
Journal: Journal of Clinical Oncology (2018)

235 Background: AAP is approved for patients with chemotherapy-naïve mCRPC, but the population with previous use of DES was not studied before. DES is a commonly used hormone therapy for mCRPC in second and plus lines, especially in developing countries, due to lack of access to novel and efficacious therapies. The objective of this trial is to describe the efficacy and safety of AAP after DES treatment in patients who are chemotherapy-naïve, potentially affecting chemotherapy onset. This is the first and only prospective trial to show this data. Methods: This phase 2 multicenter, open-label single-arm study evaluated 46 patients receiving AA (1000 mg daily) + low-dose prednisone (P; 10 mg daily) and androgen deprivation therapy in patients with DES–refractory mCRPC enrolled from Oct 2014 to Oct 2015. The primary efficacy endpoint was time to prostate-specific antigen progression (PSAP) by Prostate Cancer Working Group (PCWG2) criteria. Secondary endpoints included PSA response (≥50% reduction), overall survival, and safety. Results: At baseline, median age was 69 years, median PSA was 40 ng/mL, there were no visceral metastases, 98% of patients had Eastern Cooperative Oncology Group Performance Status 0-1, and 44% had Gleason scores ≥7. Thirty two subjects (71.1%) had PSAP. PSA response was achieved by 47% of patients at week 12 and 56% at any time. Three patients remain on study drug and 4 are in follow-up. AA treatment continued until PSAP, clinical progression, consent withdrawal, or unacceptable toxicity. The median duration of study treatment was 8.6 months. The median time to PSAP was 7.4 months (95% CI = 5.6-9.4) and the median overall survival was 25.6 months (95% CI = 15.7-NE). Treatment-related adverse events included hypertension (19.6%), hyperglycemia (19.6%), fatigue (17.4%), and hypokalemia (4.5%); most grade 1-2. Conclusions: The present study confirmed that AAP provides PSA responses even in heavily treated patients, showing clinical benefit post-DES in chemotherapy-naive mCRPC patients. It also confirmed tolerability of AAP, with an easily manageable toxicity profile. Clinical trial information: NCT02217566.