tbuckley/cabot-search huggingface dataset:
TAS3681, a novel type of AR antagonist with AR downregulating activity, as a new targeted therapy for aberrant AR-driven prostate cancer.
Authors: Masanao Seki, Kazuhisa Minamiguchi, Daisuke Kajiwara, Hiroya Mizutani, Shohei Yoshida, Eiji Sasaki, Teruhiro Utsugi, Yoshikazu Iwasawa
Journal: Journal of Clinical Oncology (2018)

298 Background: Recent reports suggest that AR aberrations are involved in the development of metastatic castration-resistant prostate cancer and in resistance to AR-targeted therapies. These aberrations include point mutations, copy number gain, and alternatively spliced AR forms. TAS3681 has demonstrated activity as a pure AR antagonist against several AR mutations and has shown an antitumor effect in an AR-v7 positive xenograft model. In order to further characterize the properties of TAS3681, we investigated its effects in cell-based AR overexpression/stabilization models and assessed the subcellular localization of FL-AR and AR-v7 in enzalutamide (Enz) -resistant cells. Methods: The Nano-bit assay was performed to analyze dimerization of FL-AR and AR-v7 proteins. Prostate cancer (PCa) cells expressing AR-v7 were treated with TAS3681, and nuclear and cytoplasmic fractions were prepared. Then the levels of FL-AR and AR-v7 protein in each fraction were determined by western blotting. AR-overexpressing PCa cells transfected with a wild-type AR expression vector were treated with TAS3681 in the presence of androgen. AR-stabilized PCa cells were transfected with a Speckle-type POZ protein (SPOP) mutant expression vector and then were treated with TAS3681. Results: AR antagonism by TAS3681 caused dose-dependent inhibition of FL-AR homodimerization (HD) and FL-AR/AR-v7 heterodimer formation in the presence of androgen. TAS3681 had no direct inhibitory effect on HD of AR-v7. However, AR downregulation by TAS3681 reduced nuclear AR-v7 protein in Enz-resistant cells under castration conditions. In AR-overexpressing PCa cells, TAS3681 reduced the AR protein and effectively suppressed both AR transactivation and cell proliferation. In contrast to Enz, TAS3681 also effectively reduced the AR protein in AR-stabilized PCa cells harboring SPOP mutation. Conclusions: TAS3681 suppresses aberrant AR activation, including AR overexpression and expression of constitutively active nuclear localized AR-v7, via downregulation of AR/AR-v7. These findings suggest that TAS3681 has the potential to overcome resistance to current AR-targeted therapies.
A Rapamycin-Activated Caspase 9-Based Suicide Gene
Authors: Maria Stavrou, Brian Philip, Charlotte Traynor-White, Christopher G. Davis, Shimobi Onuoha, Shaun Cordoba, Simon Thomas, Martin Pule
Journal: Molecular Therapy (2018)

Engineered T cell therapies show considerable promise in the treatment of refractory malignancies. Given the ability of engineered T cells to engraft and persist for prolonged periods along with unpredicted toxicities, incorporation of a suicide gene to allow selective depletion after administration is desirable. Rapamycin is a safe and widely available immunosuppressive pharmaceutical that acts by heterodimerization of FKBP12 with the FRB fragment of mTOR. The apical caspase caspase 9 is activated by homodimerization through its CARD domain. We developed a rapamycin-induced caspase 9 suicide gene. First, we showed that caspase 9 could be activated by a two-protein format with replacement of the CARD domain with both FRB and FKBP12. We next identified an optimal compact single-protein rapamycin caspase 9 (rapaCasp9) by fusing both FRB and FKBP12 with the catalytic domain of caspase 9. Functionality of rapaCasp9 when co-expressed with a CD19 CAR was demonstrated in vitro and in vivo.
Point‐of‐Care Identification of Bacteria Using Protein‐Encapsulated Gold Nanoclusters
Authors: Haiwei Ji, Li Wu, Fang Pu, Jinsong Ren, Xiaogang Qu
Journal: Advanced Healthcare Materials (2018)

Abstract The rapid, simple, and reliable identification of the most prevalent pathogens is essential for clinical diagnostics, biology, and food safety. Herein, four protein‐encapsulated gold nanoclusters (protein–AuNCs) are designed and prepared as a sensor array for rapid identification of bacteria. The discrimination of six kinds of bacteria, including two kinds of drug‐resistant bacteria, is successfully realized by the as‐fabricated sensor array. The strategy presented here shows the advantages of easy synthesis and convenient to use. Furthermore, 100% classification accuracy is achieved by the sensor array consisting of two protein–AuNCs probes, demonstrating the design with sufficient diagnostic capacity. Taken together, the developed sensor array holds great promise for facile diagnosis of bacterial infection in resource‐limited settings.
Neutrophil-to-lymphocyte ratio as a prognostic marker for metastatic pancreatic cancer.
Authors: Jasmin Radhika Desai, Bradley Scott Colton, Hongkun Wang, John Marshall, Sunnie S. Kim, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2018)

251 Background: Metastatic pancreatic cancer is a deadly disease, with a median survival that remains less than 12 months. However, more patients than ever before are surviving for more than 1 year, though it has been difficult to determine which patients have a better or worse prognosis. In the MPACT trial of gemcitabine + nab-paclitaxel vs gemcitabine alone, the neutrophil-to-lymphocyte ratio (NLR) prior to treatment was found to be a promising prognostic marker. However, the significance of NLR has not been confirmed. We examined our institutional experience with assessing the prognostic value of the NLR for patients with metastatic pancreatic cancer treated with standard chemotherapies. Methods: We performed an IRB approved retrospective chart review of patients with metastatic pancreatic adenocarcinoma. Patients were eligible if a routine blood count from which an NLR would be calculated was available prior to initiating any chemotherapy. 41 patients were identified who were treated with either FOLFOX (n = 9), FOLFIRINOX (n = 8) or gemcitabine + nab-paclitaxel (n = 24). Patients were stratified into two groups: NLR &lt; 5 and NLR &gt; 5. The median progression free survival and overall survival were determined, and statistical analyses performed to observe any correlation to NLR. Results: In this review, patients with an elevated NLR (NLR &gt; 5) had an improved PFS and OS when compared with patients with a decreased NLR (NLR &lt; 5). OS was 12.2 months in NLR &gt; 5 and 11.0 months in NLR &lt; 5. PFS was 4.7 months and 3.6 months, respectively. When comparing patients that were treated with 5-FU based regimens, the overall survival was similar with the NLR &gt; 5 of 11.5 months and the NLR &lt; 5 group of 11.0 months. However, those patients treated with gemcitabine and abraxane had more of a difference; patients with an NLR &gt; 5 had an OS of 16.0 months and NLR &lt; 5, the OS was 11.5 months. Conclusions: Our single institution experience suggests that NLR could be a marker for prognosis for metastatic pancreatic cancer. However, our data contradicts the results of the MPACT trial where an increased NLR was associated with a worsened overall survival. Therefore, additional confirmatory studies will need to be performed to find the true prognostic value of the NLR.
107. α2, 3 and α2,6 N-Linked Sialic Acid Facilitate Efficient Binding and Transduction by Adeno-Associated Virus Type 1 and 6
Authors: Zhijian Wu, R. Jude Samulski
Journal: Molecular Therapy (2006)

Recombinant adeno-associated viruses (AAV) are promising vectors in the field of gene therapy. Different AAV serotypes display distinct tissue tropism, believed to be associated with distribution of their receptors on target cells. Of the eleven well -characterized AAV serotypes, heparan sulfate proteoglycan and sialic acid have been suggested to be the attachment receptors for AAV type 2 and 4 & 5 respectively. In this report, we identify primary attachment molecules for the two closely related serotypes, AAV1 and AAV6. First we demonstrate use of similar receptor for AAV 1 & 6 through competition experiments after co-infection. Second, similar to removal of heparin sulfate for AAV2, enzymatic or genetic removal of sialic acid significantly reduced AAV1 and AAV6 binding and transduction. Third, contrasting AAV5, which uses only |[alpha]|2,3 sialic acid as the major attachment factor for transduction, lectin staining and lectin competition assay identified both |[alpha]|2,3-linked and |[alpha]|2,6-linked sialic acid for efficient AAV 1 & 6 transduction. Inhibitor of O-linked glycosylation did not block transduction, however, significantly reduction was observed on N-glycan deficient Lec1 cells, indicating that N-linked, but not O-linked sialic acid is required for AAV1 and AAV6 transduction. This was confirmed by resialylation experiment using sialic acid deficient Lec2 cells. Furthermore, mucin which binds to O-linked sialic acid and inhibits AAV4 transduction had no inhibition effect on AAV1 and AAV6 transduction. Finally, proteinase K treatment compared to glycolipid inhibitor treatment supports sialic acid modification of glycoproteins rather than glycolipids with respect to AAV1 and AAV6 transduction. Taken together, the data support a glycoprotein with N-linked |[alpha]|2,3 and /or |[alpha]| 2,6 sialic acid serving as a primary attachment molecule for AAV1 and AAV6 transduction.
Prenatal Primary Prevention of Mental Illness by Micronutrient Supplements in Pregnancy
Authors: Robert Freedman, Sharon K. Hunter, M. Camille Hoffman
Journal: American Journal of Psychiatry (2018)

Genes, infection, malnutrition, and other factors affecting fetal brain development are a major component of risk for a child's emotional development and later mental illnesses, including schizophrenia, bipolar disorder, and autism. Prenatal interventions to ameliorate that risk have yet to be established for clinical use. A systematic review of prenatal nutrients and childhood emotional development and later mental illness was performed. Randomized trials of folic acid, phosphatidylcholine, and omega-3 fatty acid supplements assess effects of doses beyond those adequate to remedy deficiencies to promote normal fetal development despite genetic and environmental risks. Folic acid to prevent neural tube defects is an example. Vitamins A and D are currently recommended at maximum levels, but women's incomplete compliance permits observational studies of their effects. Folic acid and phosphatidylcholine supplements have shown evidence for improving childhood emotional development associated with later mental illnesses. Vitamins A and D decreased the risk for schizophrenia and autism in retrospective observations. Omega-3 fatty acid supplementation during early pregnancy increased the risk for schizophrenia and increased symptoms of attention deficit hyperactivity disorder, but in later pregnancy it decreased childhood wheezing and premature birth. Studies are complicated by the length of time between birth and the emergence of mental illnesses like schizophrenia, compared with anomalies like facial clefts identified at birth. As part of comprehensive maternal and fetal care, prenatal nutrient interventions should be further considered as uniquely effective first steps in decreasing risk for future psychiatric and other illnesses in newborn children. [AJP at 175: Remembering Our Past As We Envision Our Future July 1959: Longitudinal Observations of Biological Deviations in a Schizophrenic Infant Barbara Fish described the course of an infant born with fluctuating motor problems who developed schizophrenia. (Am J Psychiatry 1959; 116:25-31 )].
NHS doctors face racism, exclusion, and discrimination, report finds
Authors: Matthew Limb
Journal: BMJ (2014)

The NHS, with its highly ethnically diverse workforce and a specific focus on people’s health, ought to be an exemplar for staff wellbeing, but this is far from the case, a study has found.1

Experiences of racism, exclusion, and discrimination contribute to low levels of wellbeing among black and other minority ethnic (BME) groups, including staff in the NHS, the study report said. A decade on since the NHS Race Equality Plan, “there is little evidence of progress in achieving its goals,” the report said. Far from being an exemplar, “the NHS helps to illuminate the impact and consequences of lower wellbeing as well as specific drivers for differences in wellbeing between different ethnic groups.”

The report, published last month, was written by Mala Rao, professor of international health at East London University, and Jacqui Stevenson, an expert in gender equity and human rights. “The need to address racism and discrimination within the NHS is incontrovertible,” they said.

Their research examined a range of literature on ethnic disparities in wellbeing and included interviews with NHS staff, clinicians, and senior leaders and a summary of a roundtable discussion. It highlighted ethnic discrimination in the NHS recruitment process and cited research by BMJ Careers showing that white doctors were almost three times as likely to be successful in applying for hospital jobs as doctors from ethnic minorities.2

The research by BMJ Careers showed that black or black British applicants were the ethnic group least likely to …
Prediction of overall survival for metastatic pancreatic cancer treated with gemcitabine monotherapy: Development and external validation of a prognostic nomogram with open clinical trial data.
Authors: Junjie Hang, Lixia Wu, Jiadi Du, Hua Jiang, Kequn Xu
Journal: Journal of Clinical Oncology (2018)

237 Background: There is a need for prognostic tools in metastatic pancreatic cancer (MPC) because they have the potential to optimize patients’ selection in clinical trail and guide treatment strategies. We address this issue by developing and validating a prognostic nomogram with open clinical trail data. Methods: Data from the comparator arm of three clinical trails (NCT00844649, NCT01124786 and NCT00574275) in MPC treated with gemcitabine as first-line chemotherapy were analyzed. The former two were taken as training cohort while NCT00574275 was used as validation cohort. Cox regression model was used to investigate prognostic factors from twenty-three baseline characteristics in training cohort. Based on these factors, a nomogram was developed and internally validated with Harrell’s Concordance index (C-index) and calibration plots. It was further externally validated in the validation cohort. Results: In the training cohort (n = 445), performance status, liver metastasis, CA19-9 log-value, neutrophil, platelet (PLT) and albumin were independent prognostic factors for overall survival (OS). A nomogram based on these factors was generated to predict OS and survival probabilities. The nomogram showed an acceptable discrimination ability (C-index: 0.683) and good calibration. The prognostic score based on nomogram could stratify patients into three-risk groups with median OS of 11.7, 7.0 and 3.7 months (P &lt; 0.001). The nomogram was further externally validated in validation cohort (n = 273, C-index: 0.699); median OS of 10.6, 7.3 and 4.0 months for the three-risk groups (P &lt; 0.001). Conclusions: The prognostic nomogram can accurately predict OS for MPC treated with gemcitabine as first-line chemotherapy. [Table: see text]
Consultant and junior doctor contract negotiations begin
Authors: Caroline White
Journal: BMJ (2013)

Contract negotiations for consultants and junior doctors began this week after NHS Employers announced that the government had given it a formal mandate to negotiate with the BMA.

The contract negotiations will apply to consultants working in the NHS in England and Northern Ireland, and to junior doctors across the United Kingdom. Consultants in Scotland and Wales already work under a different contract to that in place in England and Northern Ireland. The BMA’s consultants committees in Scotland and Wales have said that they do not believe that negotiations on a UK-wide contract would be in the best interests of their doctors.

The announcement follows months of preliminary discussions between the BMA and NHS Employers, and their …
Applications of gold nanoparticles in virus detection
Authors: Mohamed Shehata Draz, Hadi Shafiee
Journal: Theranostics (2018)

Viruses are the smallest known microbes, yet they cause the most significant losses in human health. Most of the time, the best-known cure for viruses is the innate immunological defense system of the host; otherwise, the initial prevention of viral infection is the only alternative. Therefore, diagnosis is the primary strategy toward the overarching goal of virus control and elimination. The introduction of a new class of nanoscale materials with multiple unique properties and functions has sparked a series of breakthrough applications. Gold nanoparticles (AuNPs) are widely reported to guide an impressive resurgence in biomedical and diagnostic applications. Here, we review the applications of AuNPs in virus testing and detection. The developed AuNP-based detection techniques are reported for various groups of clinically relevant viruses with a special focus on the applied types of bio-AuNP hybrid structures, virus detection targets, and assay modalities and formats. We pay particular attention to highlighting the functional role and activity of each core Au nanostructure and the resultant detection improvements in terms of sensitivity, detection range, and time. In addition, we provide a general summary of the contributions of AuNPs to the mainstream methods of virus detection, technical measures, and recommendations required in guidance toward commercial in-field applications.
Heart Disease and Stroke Statistics—2018 Update: A Report From the American Heart Association
Authors: Emelia J. Benjamin, Salim S. Virani, Clifton W. Callaway, Alanna M. Chamberlain, Alexander R. Chang, Susan Cheng, Stephanie E. Chiuve, Mary Cushman, Francesca N. Delling, Rajat Deo, Sarah D. de Ferranti, Jane F. Ferguson, Myriam Fornage, Cathleen Gillespie, Carmen R. Isasi, Monik C. Jiménez, Lori Chaffin Jordan, Suzanne E. Judd, Daniel Lackland, Judith H. Lichtman, Lynda Lisabeth, Simin Liu, Chris T. Longenecker, Pamela L. Lutsey, Jason S. Mackey, David B. Matchar, Kunihiro Matsushita, Michael E. Mussolino, Khurram Nasir, Martin O’Flaherty, Latha P. Palaniappan, Ambarish Pandey, Dilip K. Pandey, Mathew J. Reeves, Matthew D. Ritchey, Carlos J. Rodriguez, Gregory A. Roth, Wayne D. Rosamond, Uchechukwu K.A. Sampson, Gary M. Satou, Svati H. Shah, Nicole L. Spartano, David L. Tirschwell, Connie W. Tsao, Jenifer H. Voeks, Joshua Z. Willey, John T. Wilkins, Jason HY. Wu, Heather M. Alger, Sally S. Wong, Paul Muntner
Journal: Circulation (2018)

Each chapter listed in the Table of Contents (see next page) is a hyperlink to that chapter. The reader clicks the chapter name to access that chapter.

Each chapter listed here is a hyperlink. Click on the chapter name to be taken to that chapter. 

Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA’s My Life Check - Life’s Simple 7 (Figure1), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents …
WORSE ONE-YEAR HEART FAILURE OUTCOMES AFTER NON-ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION THAN ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION AND TREATMENT IMPLICATIONS IN A NATIONWIDE STUDY OF 36,333 UNSELECTED PATIENTS HOSPITALIZED FOR ACUTE MYOCARDIAL INFARCTION
Authors: Mark Y.Y. Chan, Huili Zheng, Derek Hausenloy, Terrance Chua, Huay-Cheem Tan, David Foo, Chee-Wan Lee, Khim-Leng Tong, Ling-Li Foo, A. Mark Richards
Journal: Journal of the American College of Cardiology (2018)
I have two years' experience in dermatology. After passing PLAB what are the job prospects in dermatology? Can I get an SHO job with my experience?
Authors: John Lear
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>
Under a fifth of CEA applicants in 2013 and 2014 were women
Authors: Abi Rimmer
Journal: BMJ (2015)

Women accounted for less than a fifth of all applicants for clinical excellence awards in 2013 and 2014. 

The figures were reported by Sally Davies, president of the Medical Women’s Federation, who has seen the data on applicants for the 2014 award round in England. She said that 270 (19.2%) of the 1404 doctors who applied for an award in 2014 were women. 

In total 300 clinical excellence awards were given out. Forty six (15%) went to women, giving a rate of success among women of 17%, …
Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins
Authors: Erik Laurini, Valentina Martinelli, Thomas Lanzicher, Luca Puzzi, Daniele Borin, Suet Nee Chen, Carlin S Long, Patrice Lee, Luisa Mestroni, Matthew R G Taylor, Orfeo Sbaizero, Sabrina Pricl
Journal: Cardiovascular Research (2018)

Given the clinical impact of LMNA cardiomyopathies, understanding lamin function will fulfill a clinical need and will lead to advancement in the treatment of heart failure. A multidisciplinary approach combining cell biology, atomic force microscopy (AFM), and molecular modeling was used to analyse the biomechanical properties of human lamin A/C gene (LMNA) mutations (E161K, D192G, N195K) using an in vitro neonatal rat ventricular myocyte model. The severity of biomechanical defects due to the three LMNA mutations correlated with the severity of the clinical phenotype. AFM and molecular modeling identified distinctive biomechanical and structural changes, with increasing severity from E161K to N195K and D192G, respectively. Additionally, the biomechanical defects were rescued with a p38 MAPK inhibitor. AFM and molecular modeling were able to quantify distinct biomechanical and structural defects in LMNA mutations E161K, D192G, and N195K and correlate the defects with clinical phenotypic severity. Improvements in cellular biomechanical phenotype was demonstrated and may represent a mechanism of action for p38 MAPK inhibition therapy that is now being used in human clinical trials to treat laminopathies.
HIGH CORONARY RESTENOSIS RATE WITH PERITONEAL DIALYSIS COMPARED TO HEMODIALYSIS AFTER PERCUTANEOUS CORONARY INTERVENTION IN PATIENTS WITH END-STAGE RENAL DISEASE
Authors: Yuko Yamamoto, Keisuke Yamamoto, Yoshitaka Isotani, Kazuyuki Uehara, Satoshi Hatsuse, Masataka Takizawa, Hiroki Uozumi, Hiroshi Ikenouchi
Journal: Journal of the American College of Cardiology (2018)
Improving staff experiences
Authors: Tom Moberly
Journal: BMJ (2014)

A great deal could be improved in the support given to doctors working, and those seeking to work, in the NHS. For doctors already employed in the NHS, changes to the structure of health services, and the context in which they are provided, have undermined the quality of working conditions, says Clare Gerada (http://careers.bmj.com/careers/advice/view-article.html?id=20018022). Support for the workforce is being …
PCSK9 INHIBITION: REAL WORLD APPLICATION AND CHALLENGES TO ACHIEVE UNMET CHOLESTEROL TARGETS IN CANADIAN ATHEROSCLEROTIC HEART DISEASE, THE PRACTICAL STUDY
Authors: Avinash Pandey, Harpreet Bajaj, Vinay Garg, Amritanshu Pandey, Subodh Verma
Journal: Journal of the American College of Cardiology (2018)