tbuckley/cabot-search huggingface dataset:
Interpreting Genetic Variants in Titin in Patients With Muscle Disorders
Authors: Marco Savarese, Lorenzo Maggi, Anna Vihola, Per Harald Jonson, Giorgio Tasca, Lucia Ruggiero, Luca Bello, Francesca Magri, Teresa Giugliano, Annalaura Torella, Anni Evilä, Giuseppina Di Fruscio, Olivier Vanakker, Sara Gibertini, Liliana Vercelli, Alessandra Ruggieri, Carlo Antozzi, Helena Luque, Sandra Janssens, Maria Barbara Pasanisi, Chiara Fiorillo, Monika Raimondi, Manuela Ergoli, Luisa Politano, Claudio Bruno, Anna Rubegni, Marika Pane, Filippo M. Santorelli, Carlo Minetti, Corrado Angelini, Jan De Bleecker, Maurizio Moggio, Tiziana Mongini, Giacomo Pietro Comi, Lucio Santoro, Eugenio Mercuri, Elena Pegoraro, Marina Mora, Peter Hackman, Bjarne Udd, Vincenzo Nigro
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Mutations in the titin gene (<i>TTN</i>) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in<i>TTN</i>is a difficult challenge given its large size. <h3>Objective</h3> To identify genetic variants in titin in a cohort of patients with muscle disorders. <h3>Design, Setting, and Participants</h3> In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in<i>TTN</i>were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. <h3>Main Outcomes and Measures</h3> The identification of novel mutations in the<i>TTN</i>gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the<i>TTN</i>gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. <h3>Results</h3> Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing<i>TTN</i>variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. <h3>Conclusions and Relevance</h3> The interpretation of<i>TTN</i>variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.
Physiology-Guided Management of Serial Coronary Artery Disease
Authors: Bhavik N. Modi, Kalpa De Silva, Ronak Rajani, Nick Curzen, Divaka Perera
Journal: JAMA Cardiology (2018)

Ischemia-guided revascularization is the cornerstone of contemporary management of coronary artery disease and has evolved from noninvasive functional evaluation to real-time assessment with invasive physiological indices during diagnostic catheterization. However, serial/diffuse disease is common, and revascularization decisions often need to be made about individual lesions within the same vessel. It is unclear whether current physiological techniques, such as fractional flow reserve, can be reliably used to discern the individual contribution of lesions within a serially diseased vessel with erroneous measurements, potentially leading to suboptimal revascularization decisions. This review addresses the application of physiological techniques to serial coronary disease, highlighting challenges and potential solutions.
Schoolchildren are enlisted to help recruit GPs
Authors: Abi Rimmer
Journal: BMJ (2014)

A community in Cumbria has enlisted the help of local schoolchildren to recruit GPs to the area. Residents from the town of Millom in southwest Cumbria have created a short film featuring 12 primary school children to help recruit GPs. The local general practice has struggled to recruit GPs after partners retired and is in need of 1.5 full time equivalent GPs.

The video (https://www.youtube.com/watch?v=8rky8n7Co5U) was created by Millom Health Action Group, which represents the local community within the Millom Alliance, …
Development of novel modified aptamers to target Axl receptor in ovarian cancer
Authors: P. Amero, C. Rodriguez-Aguayo, G.L.R. Lokesh, E. Bayraktar, C. Ivan, R.R. Chaudhari, S. Zhang, D.E. Volk, A.K. Sood, G. Lopez-Berestein
Journal: Annals of Oncology (2018)
Cell-free DNA (cfDNA) analysis and evaluation of BRAF amplifications and mutations in metastatic castration-resistant prostate cancer.
Authors: Peter Steinwald, Elisa Ledet, Bryce Raymon Christensen, Marcus Marie Moses, Lynne Chapman, Ashkan Shahbandi, Patrick Cotogno, Joshua Schiff, Jodi Lyn Layton, Brian E. Lewis, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2018)

255 Background: Cell-free DNA (cfDNA) is an accessible method for characterizing tumoral alterations. We report cfDNA screenings of prostate cancer pts positive for BRAF amplifications/mutations in pts with metastatic CRPC. Methods: Guardant360 testing (Guardant Health, Inc.) assesses cell-free DNA analysis using sequencing to identify genomic alterations in 73 cancer-related genes in circulation. A total of 133 metastatic castrate resistant prostate cancer (mCRPC) pts in various stages of therapy had Guardant cfDNA analyses. Treatment histories prior to testing and concurrent cfDNA alterations were analyzed. Results: BRAF amplifications were detected in 32 (24%) mCRPC pts; 5 pts had concurrent BRAF mutations. Of the mutations detected, only one (K601E, n = 2) was a known activating mutation while all others were variants of unknown significance (VUS). One K601E mutation pt had no other cfDNA alterations. Additionally, 4 pts without BRAF amplification had VUS BRAF mutations. BRAF amplification pts had ≥ 2 concurrent gene amplifications/alterations with the median being 8. The most common recurrent amplifications/alterations were AR (75%), p53 (59%), CDK6 (53%), MET (50%), and MYC (50%). Abiraterone (Abi) and/or Enzalutamide (Enza) resistance was associated with BRAF amplification (p = 0.0042). Non-Abi/Enza resistance pts were less likely to have BRAF amplification. The 2 pts with BRAF K601E mutation were treated with targeted protocol therapy without success however one K601E pts was subsequently treated with cabazitaxel+carboplatin which produced a positive clinical response and a 99.79% reduction in PSA. Conclusions: Pts resistant to Abi/Enza have an increased risk of developing BRAF amplifications. BRAF amplifications arise in the context of multiple additional detectable cfDNA alterations. Identification of actionable mutations, such as BRAF K601E, illustrates the potential for cfDNA testing to direct pt treatment. As cfDNA profiling continues to expand, the ability translate alterations into clinically actionable strategies is critical.
Abstract P6-09-03: Gene expression patterns in younger versus older HR+ breast cancer patients: An age-related analysis of HoxB13/IL17BR (H/I), proliferation status, and quantitative hormone receptor expression
Authors: M Melisko, AJ Chien, GM Poage, M Salganik, CA Schnabel, KJ Ruddy, K Blackwell
Journal: Cancer Research (2018)

Abstract Background: HR+ breast cancer in younger vs older patients may have distinct biological features. The Breast Cancer Index (BCI) is a gene expression-based assay that includes two component biomarkers: the HoxB13/IL17BR (H/I ratio), an endocrine response biomarker; and the molecular grade index (MGI), a set of proliferation-related genes. The objective of this study was to assess age-related associations with endocrine sensitivity (H/I), proliferative status (MGI), and quantitative expression of ER and PR. Methods: Data were extracted from the BCI Clinical Database for Correlative Studies, an IRB-approved de-identified database containing clinicopathologic and molecular variables from clinical cases submitted for BCI testing. Molecular results from H/I, MGI, and quantitative (qPCR–based) ER and PR were analyzed across age groups. Chi-squared tests and ANOVA were used to compare the results between age groups (&amp;lt;40y, 40-49y, 50-59y, 60-69y, and ≥70y). Results: Analyses included 19,126 patients (median age at diagnosis 58.6y; 4.5% &amp;lt;40y, 20.6% 40-49y, 28.9% 50-59y, 32.5% 60-69y, and 13.6% ≥70y). Proliferation status (MGI) was significantly higher in patients &amp;lt;40y and 40-49y compared to older groups (P&amp;lt;.0001).H/I analysis indicated a similar distribution of high versus low endocrine responsiveness across all groups (P=.94), except the 40-49y group, in which fewer patients had high H/I (44.2% in &amp;lt;40y, 39.4% in 40-49y, 43.7% in 50-59y, 43.7% in 60-69y, and 43.1% in ≥70y; P=.0001). Median qER increased with age (P&amp;lt;0.0001), while qPR was similar across all age groups except for the 40-49y group (P=.57), in which expression was higher (P&amp;lt;.0001). Conclusion: Results from &amp;gt;19,000 patients with early-stage HR+ breast cancer and BCI testing showed a broad distribution in all variables. Tumors from the youngest patients (&amp;lt;40y) had the highest expression of proliferative genes and the lowest quantitative ER expression. However, endocrine response, according to the H/I biomarker, does not appear to be strongly linked to age. Citation Format: Melisko M, Chien AJ, Poage GM, Salganik M, Schnabel CA, Ruddy KJ, Blackwell K. Gene expression patterns in younger versus older HR+ breast cancer patients: An age-related analysis of HoxB13/IL17BR (H/I), proliferation status, and quantitative hormone receptor expression [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 P6-09-03.
Metamodeling of late rectal bleeding in patients undergoing radiotherapy for prostate cancer.
Authors: Alessandro Cicchetti, Federica Palorini, Tiziana Rancati, Claudio Fiorino, Cesare Cozzarini, Barbara Avuzzi, Vittorio Vavassori, Giovanni Fellin, Claudio Stucchi, Giuseppe Procopio, Martin Ebert, Angel Kennedy, James William Denham, David John Joseph, Pietro Gabriele, Claudio Degli Esposti, Riccardo Valdagni
Journal: Journal of Clinical Oncology (2018)

61 Background: Predictive models for late rectal bleeding (LRB) after radiotherapy (RT) for prostate cancer were established by several studies, with good performance on development population (POP). Nonetheless, they were found to be unsatisfactory in their generalization to independent validation cohorts. Aim of the study is to build a metamodel for grade 2-3 (G23) and grade 3 (G3) LRB (LENT/SOMA) starting from literature evidence and to validate it on a new POP. Methods: The metamodel was constituted by clinical/dosimetric features and by their coefficients. Available predictive models for LRB were selected by literature search. Models including rectal Equivalent Uniform Dose (EUD) with/without patient-related dose-modifying factors were retrieved. The process allowed identification of “evidence-based” clinical/dosimetric features associated to LRB. Coeff. for identified features were resolved by weighted mean of published values, using their standard deviation as weight and then inserted in a sigmoid-shaped logit-EUD model. The resulting metamodel was validated on a pooled POP of radically treated pts (3DCRT &amp; IMRT). Performance was assessed through calibration. Results: The search identified rectal EUD, previous abdominal surgery (SURG), hormone therapy (HT) and use of cardiovascular drugs (CARDIO) as relevant features (coeff. presented in table). Validation POP included 1591 pts with 240 (15%) LRBG23 and 98 (6.2%) LRBG3 pts. Calibration was very good: LRBG23 slope = 1.4 with R2 = 0.86; LRBG3 slope = 1.1 with R2 = 0.96. Conclusions: A metamodel for prediction of LRB has been developed from literature, including all currently available information on association between LRB and clinical/dosimetric factors. The model was successfully validated on a large POP, proving to be a valuable tool for predicting LRB before RT. [Table: see text]
RISK PREDICTION IN PATIENTS WITH VENOARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION FOR CARDIOPULMONARY SUPPORT: INSIGHTS FROM A EUROPEAN NATIONWIDE REGISTRY
Authors: Peter Moritz Becher, Christoph Sinning, Benedikt Schrage, Nina Fluschnik, Christoph Waldeyer, Moritz Seiffert, Alexander Bernhardt, Uwe Zeymer, Hermann Reichenspurner, Stefan Blankenberg, Raphael Twerenbold, Dirk Westermann
Journal: Journal of the American College of Cardiology (2018)
Reduced fetal movements
Authors: Adam D Jakes, Rebecca Whybrow, Clare Spencer, Lucy C Chappell
Journal: BMJ (2018)

### What you need to know

A 28 year old woman who is 32 weeks pregnant with her first baby tells you that, in the past 24 hours, she has not felt her baby move as much as usual. 

A reduction or change in fetal movements can be a warning sign for adverse outcomes in pregnancy. This article aims to help healthcare professionals become more familiar with how to assess, counsel, and decide when to refer a woman presenting with reduced fetal movements.

The perception of fetal movements is subjective. Most women become aware of fetal movements by around 18-20 weeks’ gestation, which may be felt as “a discrete kick, flutter, swish, or roll.”1 Nulliparous women may first become aware of fetal movements at a later gestation.2 Fetal movements usually increase in number up to 32 weeks’ gestation before reaching a plateau; fetal movements do not reduce in healthy late pregnancy and do not reduce before normal labour. They tend to become more frequent later in the day, and absent during fetal sleep cycles (lasting 20-40 minutes).13 Women will come to learn the normal pattern of their baby’s movements, which can vary considerably between women. A woman is said to have a reduction in fetal movements when there has been a decrease or change in her baby’s normal pattern of movements. The Royal College of Obstetricians and Gynaecologists (RCOG) guidelines from 2011 did not recommend formal daily counting of fetal movements or “kick-charts” as they had …
INSIGHTS INTO PERIPROCEDURAL NEUROLOGICAL EVENTS AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT: ANALYSIS OF STROKE AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT IN 1521 CONSECUTIVE PATIENTS FROM A SINGLE CENTER
Authors: Krishna Kandregula, Kesavan Sankaramangalam, Yash Jobanputra, Kinjal Banerjee, Kanza Qaiser, Prasanna Sengodan, Zoran Popovic, Maan Fares, Lars Svensson, Stephanie Mick, Jose Navia, Amar Krishnaswamy, E. Murat Tuzcu, Samir Kapadia
Journal: Journal of the American College of Cardiology (2018)
Abstract 9949: NADH/NAD+ Sensitive Protein Hyper-acetylation Links Mitochondrial Dysfunction to Cardiac Susceptibility to Stress
Authors: Chi Fung Lee, Lorena Garcia-Menendez, Yongseon Choi, Nathan D Roe, Juan D Chavez, Jim E Bruce, J S Edgar, Young Ah Goo, David R Goodlett, Rong Tian
Journal: Circulation (2015)

Mitochondrial dysfunction is a recognized player in heart failure progression although the underlying molecular mechanisms are largely unknown. Using a mouse model with Complex I-deficiency (cardiac Ndufs4-KO, cKO), we had shown that impairment of mitochondrial function led to increases in NADH/NAD+ ratio and inhibition of sirtuin activity. The resultant mitochondrial lysine acetylation (LysAc) sensitized the mitochondrial permeability transition pore (mPTP) opening and exacerbated heart failure progression. Here, we show that elevation of cardiac NAD+ levels pharmacologically or genetically normalized LysAc levels and rescued cardiac dysfunction in cKO mice under stresses. Furthermore, pressure overload in control mice also led to increases in cardiac NADH/NAD+ ratio, mitochondrial LysAc levels and mPTP sensitivity. All of them were normalized by increasing cardiac NAD+ levels. Together with the elevated LysAc levels in human failing hearts, these data support the roles of LysAc in human heart failure progression. Interestingly, proteomics analysis revealed increased LysAc of proteins in the mitochondria as well as in the cytosol and nucleus from cKO hearts without changes in the total protein amount. We identified LysAc of mitochondrial malate aspartate shuttle (MAS) as a mechanism for communicating elevated NADH/NAD+ ratio in the mitochondria to the cytosol, resulting in hyperacetylation of non-mitochondrial proteins. Furthermore, increased LysAc sensitized the mPTP to stress by promoting the binding of cyclophilin D (CypD) to the ATP synthase complex via increased interaction with oligomycin-sensitive conferring protein (OSCP). In silico docking calculation revealed an interaction interface between CypD and OSCP in ATP synthase complex, and their interaction can be facilitated via acetylation of the specific lysine residues identified by the acetylome analysis. This study unveils novel mechanisms by which mitochondrial dysfunction modulates protein modification and the propensity to cardiac dysfunction during stress. The results also identify NADH/NAD+ ratio as a therapeutic target for the progression of heart failure.
Relapsed acute lymphoblastic leukemia-specific mutations in NT5C2 cluster into hotspots driving intersubunit stimulation.
Authors: Ales Hnizda, Milan Fabry, Takaya Moriyama, Petr Pachl, Michael Kugler, Vitezslav Brinsa, David B Ascher, William L Carroll, Petr Novak, Marketa Zaliova, Jan Trka, Pavlina Rezacova, Jun J Yang, Vaclav Veverka
Journal: Leukemia (2018)
Richard Jolly: naval medical officer who was decorated by both sides in the Falklands
Authors: Anne Taylor
Journal: BMJ (2018)

At one point during his Royal Marine commando training in Lympstone in Devon in 1972 Rick Jolly felt totally defeated by the notoriously challenging assault course. After being encouraged by a younger fellow recruit he went on to complete the course and pass out with his coveted green beret.

In his book Doctor for Friend and Foe (first published as The Red and Green Life Machine ), a bestselling diary of the Falklands war, Jolly described how the training incident had provided him with a “very simple, but lifelong lesson: when you think you are beaten, and have nothing more to offer, you’ve only just scratched the surface of what you are really capable of.”

“Doc” Jolly was an eloquent, affable, larger than life character, known for always giving 100% to his men and patients. For his bravery and leadership in treating wounded personnel in the Falklands in 1982 he was awarded an OBE and the honorary naval rank of surgeon captain. Sixteen years after the conflict the Argentinian government awarded him the Order of May. He is thought to have been the only member of the armed services ever to be honoured by both sides in a conflict.

Early in the war Jolly had saved two drowning men in an audacious rescue. He was in …
O-GlcNAcylation of RACK1 promotes hepatocellular carcinogenesis
Authors: Fangfang Duan, Hao Wu, Dongwei Jia, Weicheng Wu, Shifang Ren, Lan Wang, Shushu Song, Xinying Guo, Fenglin Liu, Yuanyuan Ruan, Jianxin Gu
Journal: Journal of Hepatology (2018)
Management and leadership for doctors
Authors: Masha Singh
Journal: BMJ (2012)

Currently in the NHS clinicians are encouraged to be clinical leaders and managers. The introduction of the NHS reforms and the new NHS clinical leadership competency framework supports this drive for doctors to develop skills in managing people and limited resources and to develop leadership skills.

The management and leadership for doctors course, run by ISC Medical, is designed to help clinicians to develop managerial skills and to teach them how to work together with medical managers to provide the best service for patients. It also covers techniques for clinicians to become more effective …
Abstract P1-02-05: The effect of obesity and metabolic factors on genomic assays for risk of recurrence
Authors: H Soliman, T Treece, W Audeh
Journal: Cancer Research (2018)

Abstract Background: Obesity and other factors contributing to metabolic syndrome (MS) have become increasingly prolific in today's population. They are also known risk factors or comorbidities in many disease states including breast cancer (BC). While obesity and MS are known to increase the risk of developing BC, the effect on the risk of distant recurrence is uncertain. This substudy evaluated the relationship of BMI, blood pressure, cholesterol, triglyceride, diabetic status, and MS on the risk of recurrence in early BC patients. Methods: The effect of these metabolic factors on MammaPrint (MP) and Oncotype DX (ODX) risk of recurrence assays was compared. Additionally, gene expression analysis was performed to elucidate the differences between obese patients who were MP high risk (HR) vs. low risk (LR), and MP HR patients who were obese vs. not-obese. This subanalysis included patients from the PROMIS (n=198) and IMPACt (n=382) studies for whom metabolic characteristics were captured with informed consent. From the IMPACt study, 98 patients also reported ODX results (RS range 0-69). Results: By BMI, 1% of patients were classified as underweight (BMI &amp;lt;18.5), 22% normal (18.5≤ BMI &amp;lt;25), 31% overweight (25≤ BMI &amp;lt;30), and 46% as obese (BMI ≥30). To be classified as having MS, the patient had to exhibit any 3 of the 5 metabolic factors. In the full cohort, having MS was significantly associated with ethnicity (p &amp;lt; 0.05) and menopausal status (p &amp;lt; 0.001), but not histopathological tumor type, histological grade, tumor stage, or lymph node status (p &amp;gt; 0.05). 36% (207/580) of patients were considered as having MS in the full cohort, similarly 36% (35/98) had MS in the ODX subset. Of the patients with MS, MP classified 52% (108/207) as HR. For the subset of ER-positive patients with an ODX result, ODX classified the 11% (4/35) as HR whereas MP classified 57% (20/35) of the same patients as HR. Conclusions: Patients with obesity as measured by BMI and with MS were more frequently classified as HR by MP, in contrast to ODX which classified nearly all patients as intermediate or LR, confirming previous findings by Robinson, et. al (SABCS 2012 and 2014). Understanding the biological foundation of how obesity and metabolic factors affect risk of recurrence in breast cancer will improve both the treatment and care of patients. Citation Format: Soliman H, Treece T, Audeh W, IMPACt Investigators Group I. The effect of obesity and metabolic factors on genomic assays for risk of recurrence [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 P1-02-05.
OUTCOME OF EN-BLOC COMBINED HEART AND LIVER TRANSPLANTATION IN THE ADULT FAILING FONTAN
Authors: Sumeet Vaikunth, Waldo Concepcion, Tami Daugherty, Michael Fowler, Glen Lutchman, Katsuhide Maeda, David Rosenthal, Jeffrey Teuteberg, Y. Joseph Woo, George K. Lui
Journal: Journal of the American College of Cardiology (2018)
Editor’s Choice: Is the grass any greener?
Authors: Tom Moberly
Journal: BMJ (2016)

Contract changes, rising workloads, staffing pressures, stagnant pay, increasing regulation, and political interference have all played their part in causing more doctors to talk about quitting the profession in recent months.

There are those who have daydreamed for years about pursuing ambitions outside medicine, others may have looked online for information about options …