tbuckley/cabot-search huggingface dataset:
Oncological and postoperative outcome of salvage PSMA-radioguided surgery in recurrent prostate cancer.
Authors: Thomas Horn, Isabel Rauscher, Matthias Eiber, Hans-Juergen Wester, Margret Schottelius, Matthias Michael Heck, Juergen E. Gschwend, Tobias Maurer
Journal: Journal of Clinical Oncology (2018)

270 Background: Positron-emission tomography (PET) directed against PSMA allows detection of even small metastatic prostate cancer (PC) lesions at low PSA values. In a subset of patients (pts) with recurrent PC salvage surgery might be beneficial. To facilitate removal during salvage surgery, we recently introduced PSMA-targeted radioguided surgery (PSMA-RGS). Methods: 121 consecutive patients with recurrent PC (PSA median: 1.13 ng/ml, range: 0.00 – 13.90 ng/ml; 9 pts under androgen-deprivation therapy) and soft-tissue lesions on 68 Ga-PSMA PET after radical prostatectomy underwent 111 In- or 99m Tc-based PSMA-RGS between April 2014 and May 2017. The rate of complete biochemical response (cBR; PSA &lt; 0.2ng/ml) was determined 6-16 weeks following PSMA-RGS. Biochemical recurrence-free survival (bRFS), PC-specific treatment-free survival and postoperative complications were evaluated. Results: Metastatic soft-tissue lesions from PC metastases could be removed in 120/121 pts (99.2%). One patient died six days postoperatively from a pulmonary embolism, five patients were lost to follow-up. Eleven pts suffered from Clavien grade III complications within 90d from surgery. In 75 out of 115 (65.2%) pts cBR was achieved. cBR was more likely in patients with a preoperative PSA level &lt; 1.13 (76.3% vs. 52.7%) or a single anatomical location of recurrence (71.9% vs. 58.8%). Median bRFS was 5.1 months. At the time of analysis, 15 pts exhibited an ongoing cBR for at least 12 months (range: 12-32 months). A significantly longer bRFS was achieved in pts with a preoperative PSA &lt; 1.13 ng/ml (median 14.9 vs 3.2 months, p = 0.02). In pts with a single compared to multiple location of recurrence we observed a trend towards a longer median bRFS (8.2 months vs. 3.5 months, p = 0.08). After one year of follow-up, 61.6 % of pts did not receive any further PC-directed treatment. Conclusions: PSMA-RGS is a promising tool to enhance intraoperative detection of metastatic lesions in PC with an acceptable complication rate. It leads to a high number of biochemical response with substantial duration in a subset of pts. Our data showed that bRFS was highest in patients with a low preoperative PSA and a single anatomical site of recurrence.
Hundreds of GP surgeries no longer offer extended opening hours
Authors: Helen Jaques
Journal: BMJ (2012)

The number of general practices in England offering evening and weekend appointments has dropped by 5.7% in 2011-12 from the 2010-11 figure, research by the Labour Party has found.

Of the 91 primary care trusts (PCTs) that responded to a request made under freedom of information legislation, more than half (56%) reported a decrease from 2010-11 in the number of surgeries that offered extended opening hours.

A total of 234 (5.7%) of the practices covered by these 91 trusts no longer offered extended opening hours …
Junior doctors must join BMA by 23 October to take part in ballot
Authors: Abi Rimmer
Journal: BMJ (2015)

Junior doctors wishing to take part in a ballot for industrial action in response to plans to impose a new contract must join the BMA by 23 October, the association has said.

The BMA said that around 5600 doctors had joined the association in the past few weeks, most of whom were juniors.

Junior …
Reverse Myocardial Remodeling Following Valve Replacement in Patients With Aortic Stenosis
Authors: Thomas A. Treibel, Rebecca Kozor, Rebecca Schofield, Giulia Benedetti, Marianna Fontana, Anish N. Bhuva, Amir Sheikh, Begoña López, Arantxa González, Charlotte Manisty, Guy Lloyd, Peter Kellman, Javier Díez, James C. Moon
Journal: Journal of the American College of Cardiology (2018)

Left ventricular (LV) hypertrophy, a key process in human cardiac disease, results from cellular (hypertrophy) and extracellular matrix expansion (interstitial fibrosis). This study sought to investigate whether human myocardial interstitial fibrosis in aortic stenosis (AS) is plastic and can regress. Patients with symptomatic, severe AS (n = 181; aortic valve area index 0.4 ± 0.1 cm2/m2) were assessed pre–aortic valve replacement (AVR) by echocardiography (AS severity, diastology), cardiovascular magnetic resonance (CMR) (for volumes, function, and focal or diffuse fibrosis), biomarkers (N-terminal pro–B-type natriuretic peptide and high-sensitivity troponin T), and the 6-min walk test. CMR was used to measure the extracellular volume fraction (ECV), thereby deriving matrix volume (LV mass × ECV) and cell volume (LV mass × [1 − ECV]). Biopsy excluded occult bystander disease. Assessment was repeated at 1 year post-AVR. At 1 year post-AVR in 116 pacemaker-free survivors (age 70 ± 10 years; 54% male), mean valve gradient had improved (48 ± 16 mm Hg to 12 ± 6 mm Hg; p < 0.001), and indexed LV mass had regressed by 19% (88 ± 26 g/m2 to 71 ± 19 g/m2; p < 0.001). Focal fibrosis by CMR late gadolinium enhancement did not change, but ECV increased (28.2 ± 2.9% to 29.9 ± 4.0%; p < 0.001): this was the result of a 16% reduction in matrix volume (25 ± 9 ml/m2 to 21 ± 7 ml/m2; p < 0.001) but a proportionally greater 22% reduction in cell volume (64 ± 18 ml/m2 to 50 ± 13 ml/m2; p < 0.001). These changes were accompanied by improvement in diastolic function, N-terminal pro–B-type natriuretic peptide, 6-min walk test results, and New York Heart Association functional class. Post-AVR, focal fibrosis does not resolve, but diffuse fibrosis and myocardial cellular hypertrophy regress. Regression is accompanied by structural and functional improvements suggesting that human diffuse fibrosis is plastic, measurable by CMR and a potential therapeutic target. (Regression of Myocardial Fibrosis After Aortic Valve Replacement; NCT02174471)
Edinburgh FOCUS course: foundation course in ophthalmology
Authors: Sonali Nagendran
Journal: BMJ (2009)

Eyes tend to be a mystery to many non-specialists, particularly given the minimal exposure to ophthalmology at medical school. Eye problems are common, however, and a basic knowledge of ophthalmology is useful in many settings. This course aims to give a practical introduction to the assessment and management of common eye problems.

The course is aimed primarily at doctors preparing for their first job in ophthalmology, but it is useful for all non-specialists who deal with eye problems on a regular basis. The course I attended had a good mix of accident and emergency doctors, general practice trainees, …
Intralesional anti-PD1 treatment in patients with metastatic melanoma: The pilot study.
Authors: Igor Samoylenko, Olga V. Korotkova, Tatiana Zabotina, Lev V. Demidov
Journal: Journal of Clinical Oncology (2018)

188 Background: Systemic anti-PD1 treatment is major advantage for metastatic melanoma patients over the last five years. Nevertheless up to the moment there are no solid predictive factors discovered. On the other hand immune related adverse events develop quite frequent and sometimes could be dangerous. Methods: Patient with advanced cutaneous melanoma with known BRAF status and at least one superficial lesion (suitable for injection) are eligible. One of two commercially available anti-PD1 drugs (nivolumab or pembrolizumab) is administered intralesionaly to patients every 2 weeks with total daily dose not more than 50 mg (5 ml) using a scale-base approach depending on lesions size. Clinical and immunological outcomes assessed every 12 weeks. For assessing lymphoid infiltrate tumor biopsy performed before treatment and on week 12. To detect a systemic objective response rate of 50% with sensitivity of 80% and error type alfa 5% at least 25 patients to be included. Interim analysis was preplanned when 3 (25%) of events occurred. Results: Among 7 pts OR was detected in 4 (54.7%), PD in 3 (42.9%). Bystander effect was seen in 2 of 4 patients (50%). Among 3 non-responders 2 failed to salvage systemic anti-PD1 treatment and one is now on anti-CTLA4. The most common adverse event was injection site pain, which was self-limiting. Baseline immune phenotype of tumor infiltrating lymphocytes (TILs) was available for 5 of 7 pts included. Baseline percent of TILs, CD3+CD8+ and CD8+CD279+ was higher in responders vs non-responders (3.6±4.08% vs 0.8±0, NS, 75.1±20.6% vs 54.8±1.13, NS; 36.75±18.7% vs 42.8±13.1, NS respectively ). Baseline difference in CD11b+CD28- between responders (7.06±7.768) and non-responders (25.0 ±0.00) was statistically significant. Conclusions: these results demonstrates feasibility, tolerability and potential clinical efficacy of intralesional anti-PD1 in melanoma patients. Further study are needed to determine if unsuccessful intralesional administration could predict failure to systemic treatment as well as TILs phenotype could predict intralesional or systemic anti-PD1 clincal benefit Clinical trial information: MEL004IL.
Chronic Obstructive Pulmonary Disease as a Risk Factor for Cardiovascular Disease. A View from the SUMMIT
Authors: John R. Hurst, Don D. Sin
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Although the importance of CVDs in COPD has been well established, COPD as a risk factor for CVDs is less well known. Not surprisingly, most major CVD consensus guidelines do not list COPD as an important risk factor for CVDs (5). Although some CVD risk prediction tools, such as QRISK (https://qrisk.org), include selected chronic inflammatory conditions such as rheumatoid arthritis, COPD is not included (6). Although previous studies have shown that reduced lung function is associated with a future risk of CV events, including myocardial infarction (MI), heart failure, and sudden death, even among lifetime nonsmokers, how (and why) this occurs is largely unknown (7). As described in this issue of the Journal, Kunisaki and colleagues (pp. 51–57) performed a secondary analysis of the SUMMIT (Study to Understand Mortality and Morbidity) trial to fill in some critical gaps in our knowledge regarding the relationship between COPD and CVDs (8). They showed that CVD events occurred mostly during periods of acute exacerbations (AECOPDs), with the highest risk occurring within the first 30 days after an AECOPD (relative risk, 3.8) and the risk returning to baseline levels at 1 year after the AECOPD. The risk was particularly notable when the presentation of the AECOPD event—a composite of the severity of the underlying COPD and the trigger—was severe enough to warrant a hospitalization. Remarkably, with these serious AECOPDs, the relative risk of a CV event was 10-fold higher in the first 30 days after hospitalization.
Basolateral CD147 induces hepatocyte polarity loss by E‐cadherin ubiquitination and degradation in hepatocellular carcinoma progress
Authors: Meng Lu, Jiao Wu, Zhi‐Wei Hao, Yu‐Kui Shang, Jing Xu, Gang Nan, Xia Li, Zhi‐Nan Chen, Huijie Bian
Journal: Hepatology (2018)

Hepatocytes are epithelial cells with highly specialized polarity. The disorder and loss of hepatocyte polarity leads to a weakness of cell adhesion and connection, the induction of epithelial–mesenchymal transition, and eventually the occurrence of hepatocellular carcinoma (HCC). Cluster of differentiation 147 (CD147), a tumor‐related glycoprotein, promotes epithelial–mesenchymal transition and the invasion of HCC. However, the function of CD147 in hepatocyte depolarization is unknown. Here we identified that CD147 was basolaterally polarized in hepatocyte membrane of liver tissues and HepG2 cells. CD147 not only promoted transforming growth factor‐β1–mediated hepatocyte polarity loss but also directly induced endocytosis and down‐regulation of E‐cadherin which contributed to hepatocyte depolarization. Overexpression of CD147 induced Src activation and subsequently recruited ubiquitin ligase Hakai for E‐cadherin ubiquitination and lysosomal degradation, leading to decreases of partitioning defective 3 expression and β‐catenin nuclear translocation. This signal transduction was initiated by competitive binding of CD147 with integrin β1 that interrupted the interaction between the Arg‐Gly‐Asp motif of fibronectin and integrin β1. The specific antibodies targeting integrin α5 and β1 reversed the decrease of E‐cadherin and partitioning defective 3 levels induced by CD147 overexpression. In human liver tissues, CD147 polarity rates significantly declined from liver cirrhosis (71.4%) to HCC (10.4%). CD147‐polarized localization negatively correlated with Child‐Pugh scores in human liver cirrhosis (r = –0.6092, P < 0.0001) and positively correlated with differentiation grades in HCC (r = 0.2060, P = 0.004). HCC patients with CD147‐polarized localization had significantly better overall survival than patients with CD147 nonpolarity (P = 0.021). Conclusion: The ectopic CD147‐polarized distribution on basolateral membrane promotes hepatocyte depolarization by activation of the CD147–integrin α5β1–E‐cadherin ubiquitination–partitioning defective 3 decrease and β‐catenin translocation signaling cascade, replenishing a molecular pathway in hepatic carcinogenesis. (Hepatology 2018;68:317‐332).
The north east flap course
Authors: Niroshan Sivathasan
Journal: BMJ (2010)

Flaps are a method of covering defects and are part of the standard reconstructive armamentarium of plastic and maxillofacial surgeons. There are two main courses in the United Kingdom covering flap surgery: the north east flap course, based in Newcastle; and the Canniesburn practical course on the use of flaps in reconstructive microsurgery, based in Glasgow.

The north east flap course is run by the Department of Anatomy at the University of Newcastle in conjunction with surgeons from the University Hospital of North Durham and the James Cook University Hospital, Middlesbrough. The course director is Matt Erdmann, a consultant hand and plastic surgeon, and the faculty consists of other senior plastic surgeons.

I attended the 2009 course at the Department of Anatomy and Clinical Skills Centre in the University of Newcastle Medical School, adjacent to the Royal Victoria Infirmary. 

I feel that one must have adequate operating experience to benefit fully from this course—that is, be at registrar level or …
What is the role of microRNA-301A expression as a diagnostic and predictive marker of biochemical recurrence for prostate cancer?
Authors: Adnan Dervishi, Samarpit Rai, Kristy Doan Nguyen, Thomas Michael FitzGibbon, Paul Knoll, Saad Shaheen, Chendil Damodaran, Murali Ankem
Journal: Journal of Clinical Oncology (2018)

19 Background: Prostate specific antigen (PSA) screening for prostate cancer (PCa) remains controversial, due to its association with an increase in overdiagnosis of clinically insignificant PCa, and overtreatment. Hence, the need for more specific biomarkers to detect PCa and determine its prognosis. MicroRNA expression has previously been demonstrated as a biomarker to detect several malignancies. Studies suggest that microRNA-301a (miR-301a) inhibits the pro-apoptotic function of RUNX3, a transcription factor, and consequently activates ROCK1-mediated survival signaling in PCa. This study establishes the role of miR-301a as a reliable biomarker that can distinguish between patients with benign prostate hyperplasia (BPH) and PCa, and predict biochemical recurrence (BCR) after definitive treatment of PCa. Methods: Serum samples and tissue from prostate biopsies were collected from patients with an elevated PSA prospectively. The expression of miR- 301a was measured via reverse transcriptase-polymerase chain reaction. Additionally, miR-301a expression was retrospectively evaluated in prostatic tissue of 50 patients with PCa, including benign tissue, and correlated with clinico-pathological characteristics to predict BCR. Immunohistochemistry was performed to confirm the molecular target of miR-301a in cancerous tissue. Results: miR-301a demonstrated a significantly higher expression (p = 0.013) in both PCa tissue (Gleason 6 &amp; 7 PCa) and serum samples (p = 0.011) when compared to BPH. Expression of miR-301a in Gleason 6 &amp; 7 prostatectomy specimens positively correlated with patients who developed BCR when compared to patients who did not. When compared to the current nomogram for the prediction of PCa (i.e., PSA, age, race, Gleason score, and family history), incorporation of miR-301a was associated with a superior prediction of BCR at three years post-prostatectomy. Conclusions: miR-301a expression is a valuable tool for diagnosing PCa in patients with an elevated PSA. Combining miR-301a with PSA is associated with better risk stratification of PCa patients, and may help facilitate clinical decision making.
Trajectories and Early Determinants of Circulating CC16 from Birth to Age 32 Years
Authors: Jing Zhai, Debra A. Stern, Duane L. Sherrill, Amber L. Spangenberg, Anne L. Wright, Wayne J. Morgan, Marilyn Halonen, Fernando D. Martinez, Stefano Guerra
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

symptoms, future risk for exacerbations, and death.These data suggest that for individuals with known COPD, a CT with 5% or more emphysema should signal the clinician that this individual is at greater risk for poor outcomes, and directed therapy would be indicated if it has not already been initiated.For individuals without a prior COPD diagnosis, the presence of 5% or more emphysema suggests spirometry should be considered, as presence of airflow obstruction identifies a subgroup of patients with COPD at higher risk for poor outcomes.
Abstract P5-11-01: The accuracy of nomograms based on large dataset using clinico-pathologic variables for prediction of oncotype DX breast cancer recurrence score
Authors: J-M Kim, JM Ryu, I Kim, HJ Choi, SJ Nam, SW Kim, J Yu, SK Lee, JE Lee
Journal: Cancer Research (2018)

Abstract Purpose The 21 gene expression assay, Oncotype DX (ODX) is costly (the current estimated cost is ˜$4000), and were tested in only approximately one-third of breast cancer patients who meet the inclusion criteria in the United States. Recent study of University of Tennessee Medical Center reported a novel nomogram for prediction of ODX recurrence score using clinico-pathologic data, which was based on a large dataset from the National Cancer Data Base (NCDB). The purpose of this study was to confirm that the nomogram could predict ODX score group accurately with Korean data, which is different from the NCDB in terms of ethnicity. Methods A retrospective review was performed with 218 patients who received breast-conserving surgery or mastectomy at Samsung Medical Center and were tested with the ODX from April 2011 to January 2017. An online nomogram calculator, provided by the University of Tennessee Medical Center on their website was used in order to calculate the probability of a low-risk or a high-risk ODX score for each patient. The cut-off value for predictive accuracy of the nomogram was set same as the original study. Results With the cut-off value as 90% for inspection of the commercial ODX score, high-risk group showed 33.3% positive predictive value (PPV) and low-risk group showed 68.7%. With the cut-off value as 86% for TAILORx score, PPV was 66.7% for high-risk group, and 38.9% for low-risk group. The sensitivity of the nomogram for the low-risk group commercial ODX score was 96.8%, and 33.3% for the TAILORx score. For the high-risk group, sensitivity was 20% for the commercial ODX score, and 16.7% for the TAILORx score. Conclusions Although the nomogram for prediction of ODX score was based on a large dataset of NCDB, it could not be generalized to patients in Asia. Further studies based on large data from different ethnicities should be performed to develop the nomogram for patients worldwide. Citation Format: Kim J-M, Ryu JM, Kim I, Choi HJ, Nam SJ, Kim SW, Yu J, Lee SK, Lee JE. The accuracy of nomograms based on large dataset using clinico-pathologic variables for prediction of oncotype DX breast cancer recurrence score [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 P5-11-01.
I wish to specialise in infectious diseases. When is the best time to do a PhD and will I get paid a salary?
Authors: Tim O'Dempsey
Journal: BMJ (2005)

<b>www.bmjcareers.com/advicezone</b> 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.
AMPHETAMINE ABUSE AND ACUTE MYOCARDIAL INFARCTION IN THE UNITED STATES
Authors: Prashant Patel, Sopan Lahewala, Nirali Patel, Shilpkumar Arora, Byomesh Tripathi, Abhishek Deshmukh, Apurva Badheka
Journal: Journal of the American College of Cardiology (2018)
The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression
Authors: Lu Huang, Shruti Malu, Jodi A. McKenzie, Miles C. Andrews, Amjad H. Talukder, Trang Tieu, Tatiana Karpinets, Cara Haymaker, Marie-Andrée Forget, Leila J. Williams, Zhe Wang, Rina M. Mbofung, Zhi-Qiang Wang, Richard Eric Davis, Roger S. Lo, Jennifer A. Wargo, Michael A. Davies, Chantale Bernatchez, Timothy Heffernan, Rodabe N. Amaria, Anil Korkut, Weiyi Peng, Jason Roszik, Gregory Lizée, Scott E. Woodman, Patrick Hwu
Journal: Clinical Cancer Research (2018)

Purpose: Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed to overcome resistance. The purpose of this study was to identify novel genes and understand the mechanisms that confer resistance to cancer immunotherapy.Experimental Design: To identify genes mediating resistance to T-cell killing, we performed an open reading frame (ORF) screen of a kinome library to study whether overexpression of a gene in patient-derived melanoma cells could inhibit their susceptibility to killing by autologous tumor-infiltrating lymphocytes (TIL).Results: The RNA-binding protein MEX3B was identified as a top candidate that decreased the susceptibility of melanoma cells to killing by TILs. Further analyses of anti-PD-1-treated melanoma patient tumor samples suggested that higher MEX3B expression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFNγ were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2. Consistent with this, we observed decreased HLA-A expression in MEX3B-overexpressing tumor cells. Finally, luciferase reporter assays and RNA-binding protein immunoprecipitation assays suggest that this is due to MEX3B binding to the 3' untranslated region (UTR) of HLA-A to destabilize the mRNA.Conclusions: MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR of HLA-A to destabilize the HLA-A mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells. Clin Cancer Res; 24(14); 3366-76. ©2018 AACRSee related commentary by Kalbasi and Ribas, p. 3239.
A people's peer and disability campaigner
Authors: John Bonner
Journal: BMJ (2005)

Nicky Chapman was one of the first babies with brittle bone disease to survive the trauma of childbirth; doctors believed she would be severely physically and mentally disabled throughout her expected short life span. But she has defied medical opinion and has gone on to become a respected teacher and peer of the realm. She led opposition to a government bill that in its original form she believed would have provided doctors and the relatives of disabled people with a “licence to kill”