tbuckley/cabot-search huggingface dataset:
The transcription factor PPAR (Peroxisome Proliferator-activated Receptor) alpha is overexpressed and is associated with a favourable prognosis in IDH-wildtype primary glioblastoma
Authors: Harry Haynes, Paul White, Kelly Hares, Julia Redondo, Kevin Kemp, Will Singleton, Clare Killick-Cole, Jonathan Stevens, Krishnakumar Garadi, Sam Guglani, Alistair Wilkins, Kathreena Kurian
Journal: Neuro-Oncology (2018)

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors governing lipid, carbohydrate and amino-acid metabolism. PPARα agonists such as fenofibrate is in current clinical use as a hypolipidaemic agents. We investigated PPARα in a cohort of primary glioblastoma and the expression of PPARα in large-scale glioblastoma data sets. The clinicopathological features and PPARα expression was examined by immunohistochemistry IHC in primary glioblastoma-IDH wild-type (n=100) and semiquantitively scored by 2 independent pathologists. Total RNA was extracted from macro-dissected regions of glioblastoma (n=48; x10 5µm FFPE unstained sections) and control tissue (temporal lobe epilepsy / healthy brain tissue) (n=17; x10 5µm FFPE unstained sections) using the Omega EZNA. Real time quantitative PCR was performed using a Taqman® Fast Gene Expression Mastermix. PPARα protein expression was examined in post-mortem GM and WM control tissue samples (n=4 GM; n=4 WM) and glioblastoma (IDH1-wildtype) patient samples (n=28). PPARα IHC scores were high in 60/100 and low in 40/100 glioblastoma samples. There was no significant association between PPARα IHC score and patient sex, patient age, Karnofsky Performance Score (KPS), tumour location and MGMT promoter methylation status (p>0.05 for all covariates). RT-qPCR showed a 2.03 fold increase in PPARA mRNA expression in the glioblastoma samples compared to controls (p=0.005) PPARα protein expression was found to be significantly overexpressed in glioblastoma compared to control brain tissue (p=0.032). Within the TCGA data set multivariate analyses identified PPARA gene expression as an independent prognostic marker for overall survival (p=0.042). Hierarchical clustering revealed novel, significant associations between high PPARA expression and a putative set of glioblastoma molecular mediators including EMX2, AQP4 and NTRK2. Conclusions: PPARα protein is overexpressed in primary glioblastoma and high PPARAα gene expression functions as an independent prognostic marker in the glioblastoma TCGA data set.
Etiology and Pharmacology of Neuropathic Pain
Authors: Sascha R. A. Alles, Peter A. Smith
Journal: Pharmacological Reviews (2018)

Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this "disease of pain." Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system. This leads to central sensitization and aberrant processing such that tactile and innocuous thermal information is perceived as pain (allodynia). Processes involved in the onset of neuropathic pain differ from those involved in its long-term maintenance. Opioids display limited effectiveness, and less than 35% of patients derive meaningful benefit from other therapeutic approaches. We thus review promising therapeutic targets that have emerged over the last 20 years, including Na<sup>+</sup>, K<sup>+</sup>, Ca<sup>2+</sup>, hyperpolarization-activated cyclic nucleotide–gated channels, transient receptor potential channel type V1 channels, and adenosine A3 receptors. Despite this progress, the gabapentinoids retain their status as first-line treatments, yet their mechanism of action is poorly understood. We outline recent progress in understanding the etiology of neuropathic pain and show how this has provided insights into the cellular actions of pregabalin and gabapentin. Interactions of gabapentinoids with the <i>α</i>2<i>δ</i>-1 subunit of voltage-gated Ca<sup>2+</sup> channels produce multiple and neuron type-specific actions in spinal cord and higher centers. We suggest that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development.
IMPACT OF LEFT VENTRICULAR EJECTION FRACTION BETWEEN 50 AND 60% VERSUS ≥60% ON MORTALITY AFTER AORTIC VALVE REPLACEMENT FOR SEVERE AORTIC STENOSIS
Authors: Saki Ito, William Miranda, Jeremy Thaden, Vuyisile Nkomo, Heidi Connolly, Sorin Pislaru, Kevin Greason, Patricia Pellikka, Bradley Lewis, Jae Oh
Journal: Journal of the American College of Cardiology (2018)
Single agent and combination checkpoint inhibitors therapy: A post marketing safety analysis.
Authors: Rawad Elias, Jennifer Rider, Xainming Tan, Osama E. Rahma
Journal: Journal of Clinical Oncology (2018)

125 Background: Immune Checkpoint Inhibitors (ICIs) are used to treat patients with a wide spectrum of malignancies. Individuals enrolled in clinical trials are usually more fit compared to patients seen in everyday practice. Therefore, it is important to evaluate the safety profile of these agents in real-world data. In addition, it is not clear if the safety of these agents is similar across all age groups. Methods: We reviewed the FDA Adverse Event Reporting System (FAERS) for adverse events associated with the use of PD-1 inhibitors (nivolumab and pembrolizumab); PD-L1 inhibitor (atezolizumab); and CTLA-4 inhibitor (ipilimumab). Our analysis was restricted to reports that included only an ICI as a suspect agent. For each agent, we performed a descriptive analysis of hospitalization (HO) and death (DE) outcomes, as well as select adverse events of special interest (AESI). We compared the distribution of each outcome within age groups ( &lt; 65 years; 67-75; &gt; 75) using Mantel-Haenszel chi -quare test for trend. Results: A total of 23,586 safety reports were included in our analysis. 415 for atezolizumab, 10,026 for nivolumab, 4,808 for pembrolizumab, 6,339 for ipilimumab, and 1,988 for the combination nivolumab plus ipilimumab. Increased age was associated with a statistically significant trend of more hospitalizations for all drugs except for the combination nivolumab plus ipilimumab where hospitalization rate was high ( &gt; 80%) but similar across all age groups. Prevalence of any of the AESI was higher as age increased for all drugs (p &lt; 0.0001) except for atezolizumab (p 0.12) and combination nivolumab plus ipilimumab (p 0.488). Proportion of older patients who experienced death was higher for pembrolizumab (p &lt; 0.001), ipilimumab (p 0.002), and combination nivolumab plus ipilimumab (p &lt; 0.001). Conclusions: Our analysis suggests that among patients treated with ICI, older individuals receiving pembrolizumab, Nivolumab or ipilimumab were more likely to develop immune related AEs, and to be hospitalized. An increased rate of death with higher age was seen with the use of pembrolizumab, ipilimumab, and combination nivolumab + ipilimumab. Older patients treated with ICIs should be monitored carefully for treatment-related AEs.
Intracellular distribution and internalization pathways of guanidinylated bioresponsive poly(amido amine)s in gene delivery
Authors: Jinmin Zhang, Chunxi Wang, Mei Lu, Haonan Xing, Tianzhi Yang, Cuifang Cai, Xiaoyun Zhao, Minjie Wei, Jiankun Yu, Pingtian Ding
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Guanidinylated bioresponsive poly(amido amine)s polymers, CAR-CBA and CHL-CBA, were synthesized by Michael-type addition reaction between guanidine hydrochloride (CAR) or chlorhexidine (CHL) and N,N′-cystaminebisacrylamide (CBA). Previous studies have shown that both polymers had high transfection efficiencies as gene delivery carriers. In this study, we investigated the nucleolus localization abilities and cellular internalization pathways of these two polymers in gene delivery. Each polymer condensed plasmid DNA (pDNA) and formed nanoparticle complexes, and then their transfection studies were performed in MCF-7 cells. Both complexes were found enriched in nucleolus after cellular transfection, and their transfection efficiencies were significantly improved when transfection was performed on MCF-7 cells arrested at M phase. The transfection efficiency of CAR-CBA-pDNA was inhibited by chlorpromazine, and cell endosomes were disrupted after being exposed to CAR-CBA-pDNA. In regards to CHL-CBA-pDNA, its transfection efficiency was not affected by three types of endocytosis inhibitors used in the study, and CHL-CBA-pDNA showed no effect on endosomes. Cellular lactate dehydrogenase release and membrane morphology were changed after cells were transfected by the two complexes. The results indicated that both CAR-CBA and CHL-CBA polymers demonstrated good nucleolus localization abilities. It was beneficial for transfection when cells were arrested at M phase. CAR-CBA-pDNA cellular internalization was involved with clathrin-mediated endocytosis pathway, and escaping from endosomal entrapment, while the cellular uptake of CHL-CBA-pDNA occurs via clathrin- and caveolae-independent mechanism.
Risk factors for developing post-operative seizures following meningioma resection
Authors: Arousa Ali, Ananyo Bagchi, Samantha Mills, David Giraldi, Emmanuel Chavredakis, Andrew Brodbelt, Michael Jenkinson
Journal: Neuro-Oncology (2018)

Meningiomas are benign primary tumours treated by surgical resection. Following surgery patients may develop postoperative seizures. The aim of this study was to investigate the risk factors associated with developing postoperative seizures and determine whether prophylactic antiepileptic drugs (AED) should be prescribed. Retrospective analysis of patients undergoing surgical resection of meningioma between 2010–2015. The following clinical factors were assessed: tumour location, grade, Simpson resection, post-operative haemorrhage/infection and use of AED prophylaxis. MRI parameters were assessed including: tumour volume, adjacent parenchymal T2 signal change, midline shift. Logistical regression was performed. 285 patients were identified with a median age of 60 years (range: 16–83 years). 68 (24%) had pre-operative seizures of which 62 were on AEDs and post-operatively 48 (17%) had seizures. 217 (76%) were seizure naïve, 19 were given prophylactic AEDs and post-operatively 5 had seizures. Of the 198 patients who did not receive prophylactic AED, 43 had post-operative seizures (22%). Prophylactic AED did not reduce the risk of seizures compared to no use (OR = 1.85, p= 0.260). Clinical risk factors for developing post-operative seizures were non-skull base location (n= 207, OR = 0.35, p= 0.010) and presence of post-operative haemorrhage/infection (n= 25, OR = 1.69, p= 0.002). MRI factors associated with developing post-operative seizures were presence of T2 signal intensity change greater than 66% of tumour volume (n= 81, OR = 4.71, p= 0.000). Risk factors associated with postoperative seizure development were the non-skull base tumour location and post-operative haemorrhage/infection. The role of prophylactic AED could not be determined in this study due to insufficient sample size. Randomized control trials are required.
A phase 2 trial of ODM-201 maintenance therapy in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a AR targeting agent and non-progressive on a second line taxane (SAKK 08/16).
Authors: Silke Gillessen, Stefanie Hayoz, Andrea Corinne Fuhrer, Christine Biaggi, Augusto Pedrazzini, Giuseppe Procopio, Richard Cathomas
Journal: Journal of Clinical Oncology (2018)

TPS393 Background: Treatment with the AR targeting agents abiraterone or enzalutamide followed by a taxane is currently the most used treatment for men with mCRPC. Further treatment after response to chemotherapy is only indicated in case of disease progression, with limited treatment options available. ODM-201 (Darolutamide) is a second-generation oral androgen receptor antagonist which has demonstrated a good safety profile and antitumor activity in mCRPC. This trial evaluates whether the immediate use of darolutamide after successful chemotherapy can prolong radiographic progression-free survival (rPFS) compared with watchful waiting in patients with mCRPC. Methods: This is a multicenter, randomized, double-blind, placebo-controlled phase 2 trial (NCT02933801) conducted in approximately 19 sites in Switzerland and Italy. Patients with mCRPC are required to have been previously treated with abiraterone or enzalutamide and have no evidence of disease progression on docetaxel or cabazitaxel. Patients (N = 88) will be randomized 1:1 to receive 600 mg darolutamide BID or placebo BID, both with best supportive care, until disease progression. Patients will be stratified by country, WHO performance status (0, 1 vs 2), presence/absence of visceral metastases, enzalutamide vs abiraterone prior to chemotherapy, and planned start of trial treatment after last taxane dose ( &lt; 35 days vs ≥35 days). The primary endpoint is rPFS at 12 weeks after treatment initiation. The secondary endpoints are rPFS, time to PSA progression, time to symptomatic/clinical progression, event-free survival, overall survival, PSA response (30%, 50%, 90%, and best), duration of PSA response (50%), adverse events, and fatigue. The rPFS rate at 12 weeks after treatment initiation will be compared between the two treatment arms using a one-sided test statistic using the Kaplan–Meier method. Recruitment is ongoing, with the first patient randomized on 20.04.2017. Clinical trial information: NCT02933801.
On average, a professional rugby union player is more likely than not to sustain a concussion after 25 matches
Authors: James Rafferty, Craig Ranson, Giles Oatley, Mohamed Mostafa, Prabhat Mathema, Tom Crick, Isabel S Moore
Journal: British Journal of Sports Medicine (2018)

To investigate concussion injury rates, the likelihood of sustaining concussion relative to the number of rugby union matches and the risk of subsequent injury following concussion.A four-season (2012/2013-2015/2016) prospective cohort study of injuries in professional level (club and international) rugby union. Incidence (injuries/1000 player-match-hours), severity (days lost per injury) and number of professional matches conferring a large risk of concussion were determined. The risk of injury following concussion was assessed using a survival model.Concussion incidence increased from 7.9 (95% CI 5.1 to 11.7) to 21.5 injuries/1000 player-match-hours (95% CI 16.4 to 27.6) over the four seasons for combined club and international rugby union. Concussion severity was unchanged over time (median: 9 days). Players were at a greater risk of sustaining a concussion than not after an exposure of 25 matches (95% CI 19 to 32). Injury risk (any injury) was 38% greater (HR 1.38; 95% CI 1.21 to 1.56) following concussion than after a non-concussive injury. Injuries to the head and neck (HR 1.34; 95% CI 1.06 to 1.70), upper limb (HR 1.59; 95% CI 1.19 to 2.12), pelvic region (HR 2.07; 95% CI 1.18 to 3.65) and the lower limb (HR 1.60; 95% CI 1.21 to 2.10) were more likely following concussion than after a non-concussive injury.Concussion incidence increased, while severity remained unchanged, during the 4 years of this study. Playing more than 25 matches in the 2015/2016 season meant that sustaining concussion was more likely than not sustaining concussion. The 38% greater injury risk after concussive injury (compared with non-concussive injury) suggests return to play protocols warrant investigation.
Effective teaching skills for doctors
Authors: James Hawken
Journal: BMJ (2012)

Effective teaching skills for doctors is a two day course run by Effective Professional Interactions. The aim of the course is to help doctors develop all aspects of their teaching skills, from tutorials and lectures to bedside teaching.

This course is relevant to all doctors, but particularly to junior doctors who are looking to develop their teaching skills. It emphasises techniques to consider when planning and delivering teaching sessions and gives attendees the opportunity to put theory and ideas into practice. Candidates on my course were foundation trainees, core trainees, and registrars. The number of attendees on the course varies between five and 10.

During my foundation year 2, before applying for core training.

The course was held at Croydon University Hospital, but it is also held in several other UK locations throughout the year.

Teaching in some capacity is expected from most doctors and …
Molecular characterization of intestinal (IS) and diffuse subtypes (DS) of gastric adenocarcinomas.
Authors: Mohamed E. Salem, Joanne Xiu, Alberto Puccini, Philip Agop Philip, Richard M. Goldberg, Jimmy J. Hwang, Birendra Kc, Wolfgang Michael Korn, Anthony Frank Shields, Heinz-Josef Lenz, John Marshall
Journal: Journal of Clinical Oncology (2018)

60 Background: Gastric adenocarcinomas are histologically categorized into IS and DS. TCGA categorization suggests that IS is more common in tumors arising via the chromosomal instability pathway and DS is more common in genomically stable tumors. However, molecular differences between these subtypes are not well understood. Methods: Gastric adenocarcinomas were examined using NextGen sequencing (MiSeq platform on 47 genes or NextSeq on 592 genes), protein expression, and gene amplification techniques. For tumors sequenced with NextSeq, tumor mutational load (TML) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated on known MSI loci in target regions. Chi-square and t-tests were used for comparative analyses. Results: In total, 268 gastric adenocarcinomas with annotated histology (DS [n = 144]; IS [n = 124]) were analyzed. Patients with DS were younger than those with IS (mean age: 27y [DS] vs. 65y [IS], p &lt; 0.0001). The majority of patients with DS were female (56% [DS] vs. 35% [IS], p = 0.0004). Most frequently mutated genes in DS were TP53 (44%), ARID1A (37%) , CDH1 (14%), BAP1 (8%), and PIK3CA (5%); whereas the most frequent mutations in IS were ARID1A (57%), TP53 (51%), CDKN2A (13%), MUTYH (13%), and PIK3CA (12%). IS had a higher rate of APC mutations (10% vs. 2%, p = 0.04), whereas DS had a higher rate of CDH1 (14% vs. 2%, p = 0.01). There was no difference in PD-L1 tumor expression (DS: 4%; IS: 8%). IS, when compared to DS, exhibited higher overexpression of TOP2A (90% vs 50%, p &lt; 0.0001), TS (58% vs 28%, p &lt; 0.0001), RRM1 (47% vs 22%, p = 0.0006), and Her2/neu (14% vs 1%, p &lt; 0.0001), and greater Her2 amplification (19% vs 2%, p &lt; 0.0001). Microsatellite instability was not detected in DS, and there was a trend toward a higher frequency of MSI-high in IS (6% [IS] vs. 0% [DS], p = 0.06), as well as a higher mean TML (10.3 vs. 6.6 mutation/megabase, p = 0.01). Conclusions: Significant molecular differences between IS and DS gastric adenocarcinomas were observed, a finding that indicates different carcinogenic pathways and biology, as well as potential differences in response to therapy. Low frequency mutations in several druggable genes may provide therapeutic options.
I have completed an MSc in transcultural mental health care, and I am eligible for GMC registration. But I am still struggling to get a job in psychiatry. Any tips?
Authors: Maire Cooney
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>
68-Ga-PSMA-PET in lymph node staging in PSA recurrent prostate cancer-does the primary influence the result?
Authors: David Pfister, Tobias Kohl, Daniel Porres-Knoblauch, Friederike Haidl, Axel Heidenreich
Journal: Journal of Clinical Oncology (2018)

210 Background: Prostate cancer is the most common cancer in western countries. 68Ga PSMA-PET is the most accurate tool to detect lymph node metastases even at low PSA values. Salvage lymph node dissection prolongs biochemical recurrent free survival, whereas salvage radical prostatectomy has the potential to achieve long term tumor control at least in node negative disease. We compared the diagnostic value of 68Ga-PSMA PET in patients with biochemical recurrence after radical prostatectomy an salvage radiotherapy (Group1) and in patients with local recurrence after radiotherapy (Group2) to evaluate the influence of the primary. Methods: We retrospectively reviewed 57 and 31 patients in Group I and II respectively. In Group I a salvage lymph node dissection was performed on the side of the positive PSMA-staining. In Group II an extended pelvic lymph node dissection was performed in addiction to a salvage radical prostatectomy. Sensitivity, Specificity, posisive and negative predictive value as well as accuracy of PSMA-PET was calculated per lesion. Results: A total of 649 (2-32) and 515 (3-29) lymph nodes had been dissected. In 39 (68%) and 11(35,5%) at least one positive lymph node could be found. Mean diameter of the metastases was 0,81 (0,1-2,6)cm and 0,8(0,1-2) cm respectively. Sensitivity, Specificity, pos and neg. predicitve value as well as accuracy in Group I and two are 85, 96, 77, 98, 94,6 and 40, 100, 100, 98, 97,6%. Conclusions: In salvage surgeries in PCA good diagnostic tools to identify lymph node metastases are mandatory. With the primary in situ there is a significant reduced sensitivity of only 40% to identify positive nodes. The specific role of the primary tumor is not yet known.
PROGNOSTIC VALUE OF ANATOMICAL AND CLINICAL SYNTAX SCORE IN VETERANS WITH LEFT MAIN OR THREE-VESSEL CORONARY ARTERY DISEASE
Authors: Naoki Misumida, Ahmed E. Ahmed, Mariah Pagath, Rachel Goodwin, Elliot Goodwin, Mohammad Mathbout, Ameer Musa, Ahmed Abdel-Latif, Khaled Ziada
Journal: Journal of the American College of Cardiology (2018)
Evolving M-protein pattern in patients with smoldering multiple myeloma: impact on early progression
Authors: Carlos Fernández de Larrea, Ignacio Isola, Arturo Pereira, Ma Teresa Cibeira, Laura Magnano, Natalia Tovar, Luis-Gerardo Rodríguez-Lobato, Xavier Calvo, Juan I. Aróstegui, Tania Díaz, Ester Lozano, María Rozman, Jordi Yagüe, Joan Bladé, Laura Rosiñol
Journal: Leukemia (2018)
Public health is threatened by “wholesale reductions” in staff and “dumbing down”
Authors: Gareth Iacobucci
Journal: BMJ (2015)

Public health medicine is under threat from the “wholesale reductions” in medically qualified jobs in local authorities and at Public Health England, the BMA has warned.

Amid claims that some local authorities were actively “dumbing down” by seeking to employ public health staff on lower pay grades, representatives at the BMA’s annual representative meeting in Liverpool this week backed a motion calling for …
BMA must resist separation of service and training, say junior doctors
Authors: Abi Rimmer
Journal: BMJ (2014)

The BMA’s Junior Doctors Committee (JDC) must resist any attempts to separate service and training, delegates at the BMA’s junior doctors conference have decided.

Delegates passed a motion stating that “service and training are inextricably linked and the JDC should actively resist any moves to separate them.” In March a report by an independent taskforce into the effects of the European Working Time Directive suggested that education and …
ABC to change your life: J, K, L
Authors: Susan E Kersley
Journal: BMJ (2004)

<i>Do you have to stay on the road you started on? How do you find out whether what you9re doing is right for you? And do you know how to really listen to others? Continuing her series on change,</i> Susan Kersley <i>explains that offering solutions is often not what others want</i>