tbuckley/cabot-search huggingface dataset:
Loss of Sirt3 accelerates arterial thrombosis by increasing formation of neutrophil extracellular traps and plasma tissue factor activity
Authors: Daniel S Gaul, Julien Weber, Lambertus J van Tits, Susanna Sluka, Lisa Pasterk, Martin F Reiner, Natacha Calatayud, Christine Lohmann, Roland Klingenberg, Jürgen Pahla, Daria Vdovenko, Felix C Tanner, Giovanni G Camici, Urs Eriksson, Johan Auwerx, François Mach, Stephan Windecker, Nicolas Rodondi, Thomas F Lüscher, Stephan Winnik, Christian M Matter
Journal: Cardiovascular Research (2018)

Abstract Aims Sirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI). Methods and results Using a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3−/− mice (n = 6) was reduced by half compared to Sirt3+/+ wild-type (n = 8, P &lt; 0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry revealed accelerated clot formation and increased clot stability in Sirt3−/− compared to wild-type blood. rotational thromboelastometry of cell-depleted plasma showed accelerated clotting initiation in Sirt3−/− mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap formation was increased in Sirt3−/− bone marrow-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3−/− mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in bone marrow -derived Sirt3−/− neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, P &lt; 0.01). Conclusions Sirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of neutrophil extracellular traps and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore, enhancing SIRT3 activity by pan-sirtuin activating NAD+-boosters may provide a novel therapeutic target to prevent or treat thrombotic arterial occlusion in myocardial infarction or stroke.
“What’s my risk of sustaining an ACL injury while playing sports?” A systematic review with meta-analysis
Authors: Alicia M Montalvo, Daniel K Schneider, Laura Yut, Kate E Webster, Bruce Beynnon, Mininder S Kocher, Gregory D Myer
Journal: British Journal of Sports Medicine (2018)

Objective To estimate the incidence proportion (IP) and incidence rate (IR) for ACL injury in athletes. Design Systematic review with meta-analysis Data sources The PubMed, CINAHL and SPORTDiscus electronic databases were searched from inception to 20 January 2017. Eligibility criteria for selecting studies Studies were included if they reported total number of participants/population by sex, total number of ACL injuries by sex and total person-time by sex. Results Fifty-eight studies were included. The IP and IR of ACL injury in female athletes were 3.5% (1 out of every 29 athletes) and 1.5/10 000 athlete-exposures over a period of 1 season-25 years. The IP and IR of ACL injury in male athletes were 2.0% (1 out of every 50 athletes) and 0.9/10 000 athlete-exposures over a period of 1–25 years. Female athletes had a higher relative risk (RR) for ACL injury compared with males (RR=1.5; 95% CI 1.2 to 1.9; P&lt;0.01) and a higher incidence rate ratio (IRR) of ACL injury compared with males over 1 season–25 years (IRR=1.7; 95% CI 1.4 to 2.2; P&lt;0.010). When accounting for participation level, the disparity in the IR between female and male athletes was highest for amateur athletes compared with intermediate and elite athletes (IRR=2.1; 95% CI 1.3 to 3.4; P&lt;0.01; I²=82%). Amateur female athletes remained at higher risk of ACL injury than did with amateur male athletes. In studies where follow-up length was &lt;1 year, female athletes had a higher IR of ACL injury than did to males (IRR=1.7; 95% CI 1.3 to 2.2; P&lt;0.01). Where follow-up was 1 year and beyond, there was no sex difference in the IR of ACL injury (IRR=2.1; 95% CI 0.9 to 4.8; P=0.06; I²=65%). Summary/conclusions One in 29 female athletes and 1 in 50 male athletes ruptured their ACL in a window that spanned from 1season to 25 years. The IR of ACL injury among female athletes in a season was 1.7 times higher than the IR of ACL injury among male athletes and the IP of ACL injury among female athletes was 1.5 times higher than the IP of ACL injury among male athletes. The reported sex disparity in ACL injury rates is independent of participation level and length of follow-up.
Know Yourself—the individual's guide to career development in healthcare
Authors: Sheila Dawson
Journal: BMJ (2006)

Anita Houghton

Radcliffe, £23.50, 184 pages

ISBN 1 85775 714 9

Rating: ★★★★/5



If you pick up this book and focus on the subtitle, The individual's guide to career development in healthcare, and block out the main title, Know Yourself , you may find this superb book too “touchy feely.” It's a phrase Anita Houghton uses in the text.

If, however, you are a person who is open to self reflection, have enjoyed Houghton's pieces in Career Focus, or …
Impact of lung and heart dose on survival after radiotherapy for esophageal cancer.
Authors: Patrick Oh, Minsi Zhang, Paul Brady, Ellen Yorke, Elizabeth Won, Karyn A. Goodman, Abraham Jing-Ching Wu
Journal: Journal of Clinical Oncology (2018)

3 Background: Chemoradiation is an essential tool in treatment of localized esophageal cancer. Recent data indicates that cardiac dose is an independent predictor of survival after chemoradiation for locally advanced lung cancer. However, the impact of normal tissue dose in esophageal cancer has not been well characterized. We investigated cardiac and pulmonary dose-volume histogram (DVH) metrics as potential predictors of overall survival (OS) after chemoradiation for esophageal cancer. Methods: We reviewed 453 consecutive patients with stage I-III esophageal cancer treated with definitive or preoperative chemoradiation (median dose 50.4 Gy in 28 fractions) between 2007 and 2015 at our center. Most (n = 442) received intensity-modulated radiation therapy. Radiation plans were reviewed and multiple DVH metrics for heart (max and mean dose, V 5Gy , V 10Gy , V 20Gy , V 30Gy , and V 40Gy ) and lung (mean dose, V 5Gy , and V 20Gy ) were extracted for analysis. Other clinical covariates (surgery, performance status, stage, and histology) were recorded. Cox univariate (UVA) and multivariate (MVA) regression was used to analyze the association of these factors with overall survival. Results: Median follow-up for surviving patients was 28.4 months. On UVA, older age, lower performance status, Stage III disease, lack of surgery, heart V 40Gy , lung V 5Gy , lung V 20Gy , and lung mean dose were significantly associated with decreased survival. On MVA, surgery (p = 0.008), stage III disease (p &lt; 0.0002) and lung V 20Gy (p = 0.0389) remained significant, while heart V 40Gy did not (p = 0.211). Patients with lung V 20Gy &lt; 20% had a median survival of 44.0 months, compared to 24.0 months for patients with lung V 20Gy ≥20%. Conclusions: This comprehensive dosimetric analysis of heart and lung dose in a large cohort of esophageal cancer patients suggests that lung dose is a significant independent predictor of survival. Cardiac dose was not independently predictive after adjusting for lung dose and other clinical factors. This data suggests that esophageal cancer outcomes may be improved by minimizing lung dose, particularly the volume receiving 20Gy or more, and provides further rationale for pursuing new techniques to reduce lung dose, such as proton therapy.
Geographical variations in the use of cancer treatments are associated with survival of lung cancer patients
Authors: Henrik Møller, Victoria H Coupland, Daniela Tataru, Michael D Peake, Anders Mellemgaard, Thomas Round, David R Baldwin, Matthew E J Callister, Erik Jakobsen, Peter Vedsted, Richard Sullivan, James Spicer
Journal: Thorax (2018)

Introduction Lung cancer outcomes in England are inferior to comparable countries. Patient or disease characteristics, healthcare-seeking behaviour, diagnostic pathways, and oncology service provision may contribute. We aimed to quantify associations between geographic variations in treatment and survival of patients in England. Methods We retrieved detailed cancer registration data to analyse the variation in survival of 176,225 lung cancer patients, diagnosed 2010-2014. We used Kaplan-Meier analysis and Cox proportional hazards regression to investigate survival in the two-year period following diagnosis. Results Survival improved over the period studied. The use of active treatment varied between geographical areas, with inter-quintile ranges of 9%–17% for surgical resection, 4%–13% for radical radiotherapy, and 22%–35% for chemotherapy. At 2 years, there were 188 potentially avoidable deaths annually for surgical resection, and 373 for radical radiotherapy, if all treated proportions were the same as in the highest quintiles. At the 6 month time-point, 318 deaths per year could be postponed if chemotherapy use for all patients was as in the highest quintile. The results were robust to statistical adjustments for age, sex, socio-economic status, performance status and co-morbidity. Conclusion The extent of use of different treatment modalities varies between geographical areas in England. These variations are not attributable to measurable patient and tumour characteristics, and more likely reflect differences in clinical management between local multi-disciplinary teams. The data suggest improvement over time, but there is potential for further survival gains if the use of active treatments in all areas could be increased towards the highest current regional rates.
Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review
Authors: D. Arnold, G.W. Prager, A. Quintela, A. Stein, S. Moreno Vera, N. Mounedji, J. Taieb
Journal: Annals of Oncology (2018)

The optimal chemotherapeutic regimen for use beyond the second line for patients with metastatic colorectal cancer (mCRC) remains unclear.
A phase 2 trial of CRS-207 and pembrolizumab in adults with recurrence of metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinomas.
Authors: Ronan Joseph Kelly, Thomas Adam Abrams, Daniel V.T. Catenacci, Zev A. Wainberg, Bruce Shih-Li Lin, Amanda Enstrom, Chan C. Whiting, Prieya Wason, Aimee Murphy, Dirk G. Brockstedt, Anne Moon, Jackie Walling, Rose Lai, Geoffrey Yuyat Ku
Journal: Journal of Clinical Oncology (2018)

TPS200 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) strain with a mesothelin expression cassette inserted. CRS-207 has a well-established, manageable toxicity profile and can elicit mesothelin-specific cell-mediated immunity. Clinical activity of CRS-207 has been shown in a separate Phase 1 trial of mesothelioma. In gastroesophageal (GE) cancers, mesothelin expression is estimated between 30% – 50% and has been correlated with poor prognosis. Preclinical models suggest the combination of LADD-based immunotherapeutics and a PD1 inhibitor may induce more sustained anti-tumor responses than either LADD or PD1 inhibitor monotherapy. GE cancers are responsive to PD1 inhibitors in a subset of patients; this trial proposes to evaluate the efficacy of CRS-207 combined with pembrolizumab in patients with relapsed GE cancer, and to correlate clinical activity with mesothelin expression level. Methods: This Phase 2, open-label, single-arm, multicenter clinical study (NCT 03122548) will enroll approximately 79 subjects at 20 sites. Adults with histologically-confirmed, advanced gastric, GEJ, or esophageal adenocarcinomas are eligible. Subjects must have received 1 or 2 prior treatment regimens, which must have included a platinum and a fluoropyrimidine. Subjects must have disease progression with measurable tumors. A pre-treatment biopsy of either the primary tumor or metastatic site is required prior to dosing. Subjects with prior exposure to checkpoint inhibitors or other immunotherapies are excluded. From cycle 1 to 4 during the treatment and evaluation period, pembrolizumab (IV 200 mg) and CRS-207 (IV 1 x 10 9 CFU) are both administered in 3-week cycles. Afterward, pembrolizumab will be administered once every 3 weeks; CRS-207 will be given once every 6 weeks. CT scans will be performed every 6 weeks to monitor disease status. The primary endpoint is objective response rate defined by RECIST 1.1. Clinical trial information: NCT03122548.
Updated results of phase 1 study of DS-8201a in subjects with HER2-expressing gastric cancer.
Authors: Satoru Iwasa, Kohei Shitara, Shunji Takahashi, Haeseong Park, Shigenori Kadowaki, Shanu Modi, Yoshikane Nonagase, Kenji Tamura, Kensei Yamaguchi, Kei Muro, Junji Tsurutani, Javad Shahidi, Caleb C. Lee, Masahiro Sugihara, Yoshinori Kawaguchi, Toshihiko Doi
Journal: Journal of Clinical Oncology (2018)

118 Background: DS-8201a is a HER2 targeting antibody-drug conjugate of high drug to antibody ratio (7 to 8) with a novel linker and topoisomerase I inhibitor. In preclinical studies, DS-8201a demonstrated a broad antitumor spectrum including efficacy against low HER2 expressing cancers. Interim results of the first-in-human phase 1 trial reported an overall confirmed response rate of 40.2% across several tumor types including breast and gastric (data cutoff of May 11, 2017). Here, we present updated results focusing on HER2 expressing gastric cancer (GC) subjects as of August 1, 2017. Methods: The trial consists of part 1, dose-escalation, and part 2, dose expansion cohorts. Part 2 included the cohort for subjects with HER2 expressing GC previously treated with trastuzumab. HER2 status was determined by IHC, and/or FISH according to ASCO CAP guidelines. Results: Seven GC subjects were enrolled in Part 1and 41 subjects were enrolled in Part 2. The median number of prior anticancer treatment was 3. In Part 1, confirmed ORR across doses was 43% (3/7). One out of two subjects with HER2 low (IHC2+/ISH-) showed PR. In Part 2, confirmed ORR and DCR were 44% (16/36) and 78% (28/36), respectively with 83% of subjects experiencing tumor shrinkage. Currently, the median DoR and PFS are ≥31 weeks and 25 weeks, respectively. For subjects enrolled in part2b, the most common AEs of any grades were nausea (All 71%; ≥Gr3 2%), decreased appetite (All 61%; ≥Gr3 10%), vomiting (All 22%; ≥Gr3 0%) and platelet count decreased (All 32%; ≥Gr3 17%). Five subjects (10%) discontinued drug treatment due to AE. Conclusions: DS-8201a demonstrated promising antitumor activity in heavily pretreated subjects with HER2 expressing GC. Clinical trial information: NCT02564900.
Re: Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study
Authors: Yoshinaga Okugawa, Yuji Toiyama, Masato Kusunoki, Ajay Goel
Journal: Gut (2018)

In a recent issue of the journal, Choi1 and colleagues have assessed cumulative inflammatory burden (CIB) using endoscopic and histological findings from surveillance colonoscopy, and for the first time have revealed that CIB was significantly associated with the development of colorectal neoplasia (CRN) in patients with UC. This study is an elegant article and very meaningful from a clinical standpoint because the mean severity of microscopic inflammation derived from all surveillance procedures performed in the last decade has suggested it to be an important predictive biomarker for risk stratification of CRN in patients with UC. However, we would like to draw attention to a few important issues related to this very interesting article.

First, the authors evaluated endoscopic and histological inflammatory scores from the most extreme degree …
Growing housing costs are forcing NHS staff to leave London
Authors: Matthew Limb
Journal: BMJ (2016)

Escalating housing and transport costs are forcing many NHS staff out of London posts, leaving trusts struggling to maintain safe care, it has been claimed.

The London NHS Partnership and NHS Employers urged candidates for the capital’s mayoral elections to prioritise affordable housing and transport for key workers in their campaigns.

An analysis of the postcodes of more than 100 000 NHS staff between 2010 and 2015 showed that more of them are moving …
Junior doctor contract plan is “appalling,” says Scotland’s health minister
Authors: Abi Rimmer
Journal: BMJ (2015)

Scotland’s cabinet secretary for health, wellbeing, and sport has said that she is appalled by the English health secretary’s planned changes to the junior doctor contract. 

Speaking at the Royal College of General Practitioners’ conference in Glasgow on Thursday, Shona Robison said that Scotland would not cut junior doctors’ pay.

She said that she was “appalled at the actions” …
Human arrogance and epidemics
Authors: Laurie Garrett
Journal: The Lancet (2018)

There was a time not so long ago, in the early 1990s, when warnings about emerging epidemics and infectious diseases were derided, the Cassandras were mocked, and the power of human ingenuity and countermeasures were hailed. Globalisation of HIV/AIDS, of course, curbed such hubris, but medical and public health leaders, including the top tiers of WHO, viewed HIV as an exception to the rule. And as Michael Merson and Stephen Inrig detail in their agonising account The AIDS Pandemic: Searching for a Global Response, that notion of AIDS exceptionalism spawned an international non-response that allowed the virus to sweep across the world, becoming the third largest pandemic in human history.
Randomised phase 3 trial of enzalutamide in androgen deprivation therapy (ADT) with radiation therapy for high risk, clinically localized prostate cancer: ENZARAD (ANZUP 1303).
Authors: Scott Williams, Ian D. Davis, Christopher Sweeney, Martin R. Stockler, Andrew James Martin, Wendy Hague, Xanthi Coskinas, Sonia Yip, Emily Tu, Nicola Jane Lawrence, Namrata Nayar, Ray McDermott, Paul Kelly, Olwyn Deignan, Simon Hughes, Valerie Fonteyne, Bertrand F. Tombal, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2018)

TPS156 Background: Adjuvant ADT with an LHRH analog (LHRHA) given before, during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide improves overall survival (OS) in castration-resistant, metastatic prostate cancer. We hypothesized that the addition of enzalutamide to adjuvant ADT and RT will improve outcomes. The aim is to determine the effects of enzalutamide versus a conventional non-steroidal anti-androgen (NSAA) as part of neoadjuvant and adjuvant ADT in men undergoing RT for high risk, localized PC. Methods: DESIGN: Open label, randomised, phase 3 trial including ANZ, USA, UK, Ireland and Europe. ENDPOINTS: OS (primary), cause-specific survival, PSA progression free survival (PFS), clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival (MFS), adverse events and health-related quality of life (HRQOL). CORRELATIVE OBJECTIVES: identification of prognostic/predictive biomarkers from archival tumour tissue and serial blood samples. SAMPLE SIZE: 800 participants with a minimum follow-up of 5.5 yrs is designed to give 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. TREATMENT: Enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. All participants receive LHRHA for 24 months, and RT starting about week 16 delivered as 78Gy in 39#, or 46Gy in 23# plus brachytherapy (nodal RT optional for N0, mandatory for N1). ASSESSMENTS: Baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. Imaging with CT/MRI and bone scan at baseline, PSA progression, then 6 monthly until re-initiation of ADT, when PCWG2 criteria for CRPC are met and then 3 monthly until evidence of metastases. 623 participants recruited from 61 sites as of 16 October 2017. ENZARAD is an investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funds and product from Astellas. Clinical trial information: NCT02446444.
Abstract 17220: First-in-human Single Ascending Dose Study of the Neprilysin Inhibitor TD-0714 Administered to Healthy Human Subjects
Authors: Michael Baldwin, Claire Sherman, Arthur Lo, Denise Wang, Jonathan Lee, Kenneth Colley, David L Bourdet
Journal: Circulation (2016)

Introduction: TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of a range of cardiorenal diseases including chronic heart fail...