tbuckley/cabot-search huggingface dataset:
A phase I dose escalation and cohort expansion study of T-cell redirecting bispecific antibody against Glypican 3 in patients with advanced solid tumors.
Authors: Kenji Hashimoto, Ayesh Perera, Yoshitaka Ogita, Mikiko Nakamura, Takahiro Ishiguro, Yuji Sano, Yasuko Kinoshita, Mika Kamata Sakurai, Werner Frings, Shun-ichiro Komatsu, Akihisa Kaneko, Masamichi Ueda, Shohei Kishishita, Athos Gianella-Borradori
Journal: Journal of Clinical Oncology (2016)

TPS2592 Background: Despite recent advance of immunotherapy, not all patient benefit. Reasons for the limited therapeutic effect include a low level of target protein expression or tumor immunogenicity. Bispecific antibodies to engage T-cells onto tumor are one approach to more active immunotherapy. However, management of on target/off tumor adverse effects including cytokine release can be a challenge. Glypican 3 (GPC3) is expressed across variety of solid tumors including hepatocellular carcinoma, while its expression in normal tissue is limited, making it an ideal target for a bispecific antibody. Our T-cell redirecting bispecific antibody against GPC3 is a fully humanised IgG4 bispecific antibody to recognise GPC3 on tumor with mutation to silence FcγR. Preclinical data show that this antibody is highly active against variety of GPC3-positive tumors, including poorly immunogenic models. Utilizing corticosteroids was effective in reducing cytokine release and widens the therapeutic window in preclinical study. Therefore, we designed a phase I dose escalation and cohort expansion study of this bispecific antibody in patients with GPC3-positive solid tumors. Methods: Approximately 50 patients with GPC3-positive solid tumor will be treated with this antibody weekly in dose escalation phase, until disease progression, occurrence of dose limiting toxicities (DLT) or discontinuation for other reasons. Subsequently, preliminary anti-tumor efficacy will be evaluated in patients with selected GPC3-positive tumor in a cohort expansion phase. Accelerated titration dose escalation design is utilised until grade 2 drug related event is observed, followed by 3+3 design. Modified continuous reassessment method will guide the dose escalation after the first event of DLT. Starting dose was determined based on the NOAEL and MABEL approach set as 0.003 µg/kg.
Analysis of prognostic biomarkers of response in patients with metastatic castration-resistant prostate cancer treated with abiraterone: A. C. Camargo Cancer Center experience.
Authors: Pedro Henrique Ferraro Silveira, Marcelo Corassa, Aldo Lourenço Abbade Dettino, José Augusto Rinck, Thiago Bueno Oliveira, Luiza Damian Ribeiro Barbosa, Audrey Oliveira, Maria Nirvana Cruz Formiga
Journal: Journal of Clinical Oncology (2018)

335 Background: Despite therapeutic progress in the management of advanced prostate cancer during the past decade, metastatic castration-resistant prostate cancer (mCRPC) remains a disease that causes substantial morbidity and mortality worldwide. A greater understanding of biomarkers permits to guide personalized therapy and can inform clinical trials tailored to men most likely to derive benefit from a given therapy. We aimed to identify prognostic biomarker candidates of Abiraterone Acetate (AA) response in mCRPC patients. Methods: A retrospective clinical records analysis of mCRPC patients treated with AA at A. C. Camargo Cancer Center between January 2012 to December 2016 was realized. Baseline clinical parameters evaluated were: Age, ECOG performance status, metastatic disease at diagnosis, Gleason score, prostate-specific antigen (PSA), Neuroendocrine differentiation, duration of previous androgen-deprivation therapy (ADT), PSA doubling-time (PSAdt), Timing of AA (chemotherapy-naïve or not), PSA response and alkaline phosphatase (ALP) level. Data were analyzed in relation to progression free survival (PFS) stratified by each parameter. Results: We included 141 patients with mCRPC treated with AA to correlate prognostic biomarkers with PFS. Five risk factors individually were associated with poor prognosis and a high risk to progression during AA therapy and were included in the final model: ECOG ≥2 [Relative risk (RR) = 1.52]; PSAdt &lt; 3 months (RR = 2.7); PSA response ( &lt; 50% decline) (RR = 3.03); AA post docetaxel (RR = 1.63) and duration of previous ADT &lt; 12 months (RR = 1.52). The probability to progression free survival in patients receiving AA calculated in 1, 2 and 3 years, was 39,2%, 15,2% and 6,2%, respectively. Conclusions: This analysis identified five factors used to model survival in mCRPC patients treat with AA in our institutional series. Whereas no biomarker has been validated as a predictor of response to a therapy in mCRPC, these those potential clinical biomarkers may help clinicians in distinguishing patients with mCRPC who would obtain the best survival benefit from AA treatment.
Consultants’ contracts don’t allow for sufficient supporting professional activities, college warns
Authors: Abi Rimmer
Journal: BMJ (2013)

Consultant paediatricians are working in contracts that don’t allow enough time for supporting professional activities (SPAs), the Royal College of Paediatrics and Child Health has warned.

The college raised its concern after a survey of 339 holders of certificates of completion of training (CCTs) found that 18.4% had one SPA or no SPAs in their contract. …
CCG is told it can’t pull £600 000 from children’s respite centre
Authors: Clare Dyer
Journal: BMJ (2018)

Parents of disabled children who went to the High Court to try to stop a clinical commissioning group withdrawing funding from a respite centre for children with complex medical needs have won a reprieve.

Mr Justice Mostyn quashed a decision by Hertfordshire Valleys CCG last November to withdraw the £600 000 yearly funding necessary to keep Nascot Lawn centre in Watford, Hertfordshire, open.1

The CCG has been placed in financial turnaround, meaning that it is at risk of not meeting its financial plans, and has to make savings of £47m. A member of the investment committee that made the decision to discontinue the …
Determinants of psychological well-being in axial spondyloarthritis: an analysis based on linked claims and patient-reported survey data
Authors: Imke Redeker, Falk Hoffmann, Johanna Callhoff, Hildrun Haibel, Joachim Sieper, Angela Zink, Denis Poddubnyy
Journal: Annals of the Rheumatic Diseases (2018)

Objectives The aim of this study was to assess the psychological well-being and to analyse factors associated with depressive symptoms in axial spondyloarthritis (axSpA). Methods A stratified random sample of subjects with a diagnosis of axSpA (International Classification of Diseases, Tenth Revision, German Modification M45) was drawn from health insurance data in Germany. These persons received a postal questionnaire on disease-related, psychological and lifestyle factors as well as socioeconomic status. Additional information to verify the axSpA diagnosis was also collected. The psychological well-being was assessed by means of the 5-item WHO Well-Being Index (WHO-5), which is considered a screening tool for depression. The following established cut-offs on the WHO-5 were applied: &gt;50: good well-being, no depressive symptoms; 29–50: mild depressive symptoms; ≤28: moderate-to-severe depressive symptoms. Information on comorbidities, drug prescriptions and non-pharmacological treatment was retrieved from claims data and linked to the questionnaire data. Results A total of 1736 persons with a confirmed axSpA diagnosis were included. Using the cut-offs on the WHO-5, 533 persons (31%) were found to have moderate-to-severe depressive symptoms, 479 (28%) had mild depressive symptoms and 724 (42%) had a good well-being. Multivariable logistic regression revealed that higher disease activity, higher level of functional impairment, lower income, self-reported stress and lack of exercise, and younger age represent factors associated with moderate-to-severe depressive symptoms. Conclusions The prevalence of depressive symptoms in axSpA subjects is high and associated with disease-related parameters, socioeconomic status and lifestyle factors. These findings highlight the need for the careful evaluation of depressive symptoms as a part of the management strategy for axSpA.
LACK OF ATLS COURSES Advanced trauma life support can be studied overseas
Authors: Declan Fox
Journal: BMJ (2007)

We welcome your rapid responses, whether in direct response to an article in Career Focus or as a way of sharing your own ideas. As long as it isn9t libellous or offensive, we9ll post it on our website. We print a selection of rapid reponses here and the writer of the best each month wins an <i>Oxford Handbook</i> of their choice. Letter of the month prize is donated by OUP.
Pretreatment Cardiac Vagal Tone Predicts Dropout from and Residual Symptoms after Exposure Therapy in Patients with Panic Disorder and Agoraphobia
Authors: Julia Wendt, Alfons O. Hamm, Christiane A. Pané-Farré, Julian F. Thayer, Alexander  Gerlach, Andrew T. Gloster, Thomas Lang, Sylvia Helbig-Lang, Paul Pauli, Thomas Fydrich, Andreas Ströhle, Tilo Kircher, Volker Arolt, Jürgen Deckert, Hans-Ulrich Wittchen, Jan Richter
Journal: Psychotherapy and Psychosomatics (2018)
Ubiquitin‐Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice
Authors: Yichao Zhao, Fang Wang, Lingchen Gao, Longwei Xu, Renyang Tong, Nan Lin, Yuanyuan Su, Yang Yan, Yu Gao, Jie He, Lingcong Kong, Ancai Yuan, Ying Zhuge, Jun Pu
Journal: Hepatology (2018)

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis (HS), insulin resistance (IR), and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here, we report that USP4 expression was dramatically down-regulated in livers from NAFLD patients and different NAFLD mouse models induced by high-fat diet (HFD) or genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes. Hepatocyte-specific USP4 depletion exacerbated HS, IR, and inflammatory response in HFD-induced NAFLD mice. Conversely, hepatic USP4 overexpression notably alleviated the pathological alterations in two different NAFLD models. Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-β activated kinase 1 (TAK1), leading to a suppression of the activation of downstream nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) cascades, which, in turn, reversed the disruption of insulin receptor substrate/protein kinase B/glycogen synthase kinase 3 beta (IRS-AKT-GSK3β) signaling. In addition, USP4-TAK1 interaction and subsequent TAK1 deubiquitination were required for amelioration of metabolic dysfunctions. Conclusion: Collectively, the present study provides evidence that USP4 functions as a pivotal suppressor in NAFLD and related metabolic disorders. (Hepatology 2018; 00:000-000).
GETTING TO AN IMPROVED UNDERSTANDING OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL AND DYSLIPIDEMIA MANAGEMENT (GOULD): A REGISTRY OF HIGH CARDIOVASCULAR RISK PATIENTS IN THE UNITED STATES
Authors: Christopher P. Cannon, James de Lemos, Robert Rosenson, Christie Ballantyne, Brian Boatman, Larisa Yedigarova, Katherine Mues, Hui-Chun Hsu, Deepak Bhatt, Mikhail Kosiborod
Journal: Journal of the American College of Cardiology (2018)
Impact of 2012 USPSTF prostate cancer screening recommendations on prostate cancer detection and presentation at Kaiser Permanente Northern California (KPNC).
Authors: Joe Presti, Brandon Horton, Stacey Alexeeff, Stephanie Prausnitz, Andy Avins
Journal: Journal of Clinical Oncology (2018)

37 Background: In 2012, the USPSTF gave a “D” grade to PSA-based prostate cancer screening stating “the benefits of PSA-based screening for prostate cancer do not outweigh the harms”. The impact on prostate cancer screening, detection and presentation are unknown. Methods: A retrospective cohort design encompassing the years 2010 to 2015. In screen-eligible, KPNC members (African American men ages 45-69 and all other men ages 50-69), the annual rates of PSA testing, prostate biopsy and the grade and stage of all prostate cancers at presentation were compared between the pre-guideline period, 2010/2011; and the post-guideline period , 2014/2015. Results: The rate of screening declined substantially from the pre-guideline period to the post-guideline period, from a rate of 42.7% of eligible men screened per year during 2010/2011 to a rate of 32.5% of eligible men screened per year during 2014/2015; the relative rate and 95% confidence interval (CI) was 0.762 (0.759-0.765). Comparing the same time periods, the rates of prostate biopsy and overall prostate cancer detection declined even more sharply, with relative rates of 0.391 (95%CI 0.375-0.407) and 0.455 (95%CI 0.436-0.475) respectively. There was a modest increase in the rate of metastatic disease between these two time periods, with a relative rate of 1.29 (95%CI 1.11-1.48). Conclusions: Following the 2012 USPSTF statement, significant declines in PSA testing, prostate biopsy and overall cancer detection rates were seen along with a significant increase in the rate of patients presenting with metastatic disease. [Table: see text]
Meaning and significance of low density area (LDA) of renal cell carcinoma (RCC) on computed tomography (CT).
Authors: Keita Shibayama, Go Kimura, Tatsuro Hayashi, Jun Akatsuka, Ryoji Kimata, Kazutaka Horiuchi, Tsutomu Hamasaki, Yukihiro Kondo
Journal: Journal of Clinical Oncology (2018)

628 Background: LDA in solid RCC on CT is often interpreted as ‘central necrosis’ in routine clinical practice. However, the details of clinicopathological (CP) features of LDA of RCC on CT and their prognostic significance have not been shown. We retrospectively investigated LDA of RCC to clarify the CP features and prognostic significance. Methods: Of 428 surgically treated patients for RCC between January 2007 and March 2017 at Nippon Medical School hospital, we found 267 cases who had dynamic CT performed before operation. Among them, we selected and analyzed 199 consecutive cases whose tumor had low density area and whose cancer status resulted in no evidence of disease after surgery. We first examined pathological features of LDA. Then, we examined the correlation between pathological features of LDA and CP parameters and prognosis. The differences of values between the three groups were examined with the Kruskal-Wallis test. Recurrence free survival (RFS) was examined with the Kaplan-Meyer curves and the log-rank test. Results: The histology of LDA was divided into two groups: central necrosis (+) or (-: NN). Central necrosis (+) group was further divided into two subgroups: with neutrophilic infiltration (NI+) and without NI (NI-). This means that, in the end, there were three groups according to microscopic findings: group A (NI+, n = 20, 10%), B (NI-, n = 55, 28%), C (NN, n = 124, 62%). The pathological features of the NN group were composed of hyaline degeneration, hydropic degeneration, fibrosis, scars, and so on. The results of the comparison between CP parameters among the three groups were as follows: C-reactive protein, WBC, platelet, and alkaline phosphatase are statistically higher, and hemoglobin, triglyceride, and albumin were statistically lower in group A. CT value was statistically lower in group A and B. Median follow-up was 35months, and 3-year RFS (group A, B, C, p value) was (49.8%, 77.9%, 94.3%, p &lt; 0.0001). Conclusions: In RCC patients only about one-third of LDA on CT was shown to be central necrosis. Necrosis with NI was clinically most closely associated with poor prognosis. Central necrosis may be predictive from lower CT values compared to non-necrotic tissues.
Asthmatic Exacerbation as a Cause of False-Positive Whole-Body Iodine Scan in a Patient With Treated Papillary Thyroid Carcinoma
Authors: Guillaume Chaussé, Tina Kader, Gad Abikhzer, Stephan Probst
Journal: Clinical Nuclear Medicine (2018)

Abstract A 44-year-old woman was found to have new diffuse lung uptake on a follow-up whole-body 131 I scan 1 year after being treated with surgery and radioactive iodine for papillary thyroid cancer. However, subsequent CT thorax and thyroglobulin levels were both unremarkable. Shortly after, she presented with respiratory symptoms, exhibiting end-expiratory wheezing on auscultation. Metacholine challenge test confirmed asthma. Symptoms improved under inhaled corticosteroids and beta-2 agonists. Resolution of lung uptake was confirmed on a second 131 I imaging 6 months later.
Lung Recruitment and Positive End-Expiratory Pressure Titration in Patients With Acute Respiratory Distress Syndrome—Reply
Authors: Alexandre Biasi Cavalcanti, Marcelo Britto Passos Amato, Carlos Roberto Ribeiro de Carvalho
Journal: JAMA (2018)

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<i>Do I need to have the MRCGP to work as a GP?</i>
Authors: Rodger Charlton
Journal: BMJ (2004)

Got a career or related problem that needs answering? Can't find the right person to point you in the right direction? Log on to the Advice Zone ( www.bmjcareers.com/advicezone ) 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.
A NOVEL ENSEMBLE MACHINE LEARNING-BASED METHOD VERSUS CLINICAL RISK SCORING FOR DISCRIMINATION OF INDIVIDUALS WHO WILL VERSUS WILL NOT EXPERIENCE ACUTE CORONARY SYNDROME AFTER CORONARY COMPUTED TOMOGRAPHIC ANGIOGRAPHY: RESULTS FROM THE ICONIC STUDY
Authors: Subhi Al’Aref, Gabriel Maliakal, Michael Cheng, Kranthi Kolli, Gurpreet Singh, Mohit Pandey, Amit Kumar, Aeshita Dwivedi, Daniele Andreini, Filippo Cademartiri, Kavitha Chinnaiyan, Benjamin Chow, Ricardo Cury, Gudrun Feuchtner, Martin Hadamitzky, Yong-Jin Kim, Jonathon Leipsic, Hugo Marques, Gianluca Pontone, Todd Villines, Daniel Berman, Matthew Budoff, Jeroen J. Bax, Hyuk-Jae Chang, James K. Min
Journal: Journal of the American College of Cardiology (2018)
P044 Transglutaminase-2 in osteoarthritis: MMP-13 production through enhanced FOXO3A nuclear translocation
Authors: S Han, M-S Han, S-R Kwon
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Transglutamiase 2 (TG2) also known as tissue transglutamiase, is a calcium-dependent enzyme that has a variety of intracellular and extracellular substrates. It has been well known that TG2 increases in osteoarthritis (OA) tissue and can be used as a biomarker of OA. <h3>Objectives</h3> To elucidated the molecular mechanism of TG2 during the cartilage degradation in OA. <h3>Methods</h3> The surgical destabilisation of the medial meniscus (DMM) model is used to induce OA in 10-week-old male C57BL/6J mice. Primary chondrocytes were obtained from E15.5 long bones, and ZDON, a cell-permeable, peptide-based, irreversible inhibitor of TG2, was used to inhibit the function of TG2 and calcium ionophore to stimulate TG2. <h3>Results</h3> TG2 expression was increased in articular cartilage and growth plate in surgical OA model. When treated with various growth factors, only TGFβ1 increased TG2 expression of primary chondrocyte in a dose-dependent manner. Intra-articular injection of specific TG2 inhibitor, ZDON, ameliorated the severity and MMP-13 expression in surgically-induced OA. ZDON attenuated MMP-3 and MMP-13 expression in TGFβ- and calcium ionophore-treated chondrocytes in a Runx2-independent manner. TG2 activation by calcium ionophore induced phosphorylation of FoxO3a and ZDON decreased total FoxO3a as well as nuclear FoxO3a level. FoxO3a and TG2 were co-localised in primary chondrocytes and immunoprecipitation analysis revealed a direct interaction of FoxO3a and TG2, suggesting enhanced nuclear translocation of FoxO3a by TG2. <h3>Conclusions</h3> Our data provide an evidence of TG2 as an enhancer of FoxO3a-nuclear translocation which was responsible for the TG2-dependent MMP-13 expression. <h3>Disclosure of interest</h3> None declared
Reactive oxygen species-responsive nanoprodrug with quinone methides-mediated GSH depletion for improved chlorambucil breast cancers therapy
Authors: Cheng-Qiong Luo, Yu-Xin Zhou, Tian-Jiao Zhou, Lei Xing, Peng-Fei Cui, Minjie Sun, Liang Jin, Na Lu, Hu-Lin Jiang
Journal: Journal of Controlled Release (2018)
How do I get a postgraduate microbiology degree in the United Kingdom?
Authors: Andrew Wilson
Journal: BMJ (2004)

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Impact of comorbidities on functional recovery from partial nephrectomy.
Authors: Sudhir Isharwal, Wenda Ye, Alice Y. Wang, Joseph Abraham, Joseph Zabell, Wen Dong, Jitao Wu, Chalairat Suk-Ouichai, Elvis Caraballo, Tianming Gao, Steven C. Campbell
Journal: Journal of Clinical Oncology (2018)

612 Background: Preservation of parenchymal mass and ischemia type/duration can influence functional recovery after partial nephrectomy (PN). Some have hypothesized that relevant comorbidities may also impact functional recovery, but this has not been adequately investigated. Methods: 405 patients with PN at our center (2007-2015) had necessary data to determine function/parenchymal mass preserved within the ipsilateral kidney. All comorbidities potentially associated with renal functional status were reviewed. Multivariable linear regression assessed factors associated with functional recovery, defined as percent ipsilateral GFR preserved. Results: Median tumor size and R.E.N.A.L. score were 3.5cm and 8, respectively. Overall, 264 (65%) patients had warm ischemia and 141cold ischemia (median durations = 21/27 minutes, respectively). The median ipsilateral GFR preserved was 79%. Age, comorbidity index, hypertension, and proteinuria all associated with preoperative GFR (all p &lt; 0.01). Parenchymal mass preserved and ischemia characteristics significantly associated with functional recovery (all p &lt; 0.001). On univariable analysis of comorbidities, only hypertension associated significantly with functional recovery. However, on multivariate analysis, none of the analyzed comorbidities associated with functional recovery. Conclusions: Recovery of function after PN depends primarily on parenchymal mass preservation and ischemia characteristics, while comorbidities failed to associate with functional outcomes. Comorbidities can impact function leading into surgery and may influence long-term functional stability, yet our data suggest that they do not influence short-term recovery after PN. [Table: see text]