tbuckley/cabot-search huggingface dataset:
P016 Baseline levels of IL-17-producing CD4<sup>+</sup> T cells predict clinical response to abatacept in rheumatoid arthritis patients
Authors: P Goutakoli, G Papadaki, G Bertsias, A Repa, H Kampouraki, N Avgoustidis, N Kougas, P Verginis, P Sidiropoulos
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Rheumatoid arthritis (RA) develops upon aberrant activation of the immune system mainly due to failure of self-tolerance mechanisms.<sup>1</sup> Abatacept, approved for RA treatment, a recombinant fusion protein of the extracellular domain of human cytotoxic T lymphocyte antigen 4 (CTLA4), restricts T cell activation by blocking interaction of CD80/CD86 on dendritic cells (DCs) to CD28 on T cells.<sup>2</sup> In clinical practice, approximately 40–50% of RA patients treated with abatacept, respond to therapy in the first 6 months.<sup>3</sup> Development of a predictor of response is of clinical and immunological significance. <h3>Objectives</h3> Herein, we sought to investigate for early biomarkers of response to abatacept, based on a detailed immunological profile of peripheral blood cells and cytokines. <h3>Methods</h3> RA patients (ACR/EULAR 2010 criteria) who started abatacept due to highly active disease, were recruited to perform immunological studies at baseline, 3 and 6 months of therapy. Peripheral blood mononuclear cells (PBMCs) were isolated and pathogenic IL-17 and IFN-γ producing CD4+ T cells (Th1, Th17), regulatory (Tregs) T cell subsets as well as myeloid cell populations, like DCs and myeloid derived suppressor cells (MDSCs) were characterized using flow cytometry. Response to therapy (remission or low disease activity) was assessed based on the "Swollen joints" value. <h3>Results</h3> We studied 21 patients (mean age 60 years, 86% women, 48% rheumatoid factor or anti-citrullinated protein antibody positive). After 6 months of treatment, 45% of them attained remission or low disease activity. Notably, baseline levels of Th17 were statistically significant decreased in peripheral blood of patients in remission or low disease activity compared to those with active disease at 6 months of treatment (1.29±0.18% versus 2.44±0.41%, p=0.0482). Baseline levels of Th1 and Foxp3<sup>+</sup>Tregs were comparable between responders and non-responders. No significant differences in CD14<sup>int</sup>CD15<sup>+</sup>CD33<sup>+</sup> MDSCs or CD3<sup>-</sup>HLADR<sup>+</sup> DCs were observed. <h3>Conclusions</h3> In this cohort of RA patients treated with abatacept (CTLA4Ig), low levels of IL-17 producing CD4<sup>+</sup> T cells at baseline are associated with a better response to abatacept at 6 months. This novel finding (validation to a larger cohort in progress) may be used as an early biomarker to predict clinical responses to abatacept. <h3>References</h3> . McInnes, <i>et al</i>. <i>The Lancet</i> 2017. . Wing, <i>et al. Science</i> 2008. . Smolen, <i>et al. Arthritis Res Ther</i> 2015. <h3>Acknowledgements</h3> Project funded by BMS (Investigator initiated study, BMS PROTOCOL NUMBER: 2014-ORE-0033), "Pancretia" health organization.
Hybrid Strategy to Prevent Venous Thromboembolism after Joint Arthroplasty
Authors: David Garcia
Journal: New England Journal of Medicine (2018)

Total hip and total knee replacement procedures offer the potential to relieve pain and disability, but both surgeries expose patients to a substantial risk of venous thromboembolism. Most experts agree that postoperative pharmacologic prophylaxis is warranted, but different clinical practice guidelines encompass a relatively wide spectrum of strategies. Recommended approaches range from low-dose aspirin monotherapy at one extreme to the long-term use of an anticoagulant such as low-molecular-weight heparin at the other. These differences are partly explained by limitations of the available evidence and partly attributable to the degree to which different physicians prioritize the avoidance of bleeding versus the . . .
Editor’s Choice: Aspiration and achievement
Authors: Tom Moberly
Journal: BMJ (2015)

This week BMJ Careers focuses on the gap between aspiration and achievement: what doctors need to do to narrow this gap and how the government faces a widening gap in two areas.

Fiona Tasker looks at how doctors should approach the preparation of a personal development plan (http://careers.bmj.com/careers/advice/How\_to\_prepare\_a\_personal\_development\_plan). Such …
Abstract P1-02-01: NMR metabolomic signatures reveal predictive plasma metabolites associated with long-term risk of developing breast cancer
Authors: L Lécuyer, A Victor Bala, M Deschasaux, N Bouchemal, M Nawfal Triba, M-P Vasson, A Rossary, A Demidem, P Galan, S Hercberg, V Partula, L Le Moyec, B Srour, T Fiolet, P Latino-Martel, E Kesse-Guyot, L Zelek, P Savarin, M Touvier
Journal: Cancer Research (2018)

Abstract Background: Combination of metabolomics and epidemiological approaches opens new perspectives for ground-breaking discoveries. The aim of the present study was to investigate for the first time whether plasma non-targeted metabolomic profiles, established from a simple blood draw from healthy women, could contribute to predict the risk of developing breast cancer within the following decade and to better understand the etiology of this complex disease. Methods: A prospective nested case-control study was set up in the SU.VI.MAX cohort, including 206 breast cancer cases diagnosed during a 13y follow-up, and 396 matched controls. Non-targeted NMR metabolomic profiles were established from baseline plasma samples. Multivariable conditional logistic regression models were computed for each individual NMR variable and for combinations of variables derived by principal component analysis. Results: Several metabolomic variables from 1D NMR spectroscopy were associated with breast cancer risk. Women characterized by higher fasting plasma levels of valine, lysine, arginine, glutamine, creatine, creatinine, and glucose and lower plasma levels of lipoproteins, lipids, glycoproteins, acetone, glycerol-derived compounds and unsaturated lipids had a higher risk of developing breast cancer. P-values ranged from 0.00007 (ORT3vsT1=0.37[0.23-0.61] for glycerol-derived compounds) to 0.04 (ORT3vsT1=1.61[1.02-2.55] for glutamine). Conclusion: This study highlighted associations between baseline NMR plasma metabolomic signatures and long-term breast cancer risk. These results provide interesting insights to better understand complex mechanisms involved in breast carcinogenesis and evoke plasma metabolic disorders favorable for carcinogenesis initiation. This study may contribute to develop screening strategies for the identification of at-risk women for breast cancer well before symptoms appear. Citation Format: Lécuyer L, Victor Bala A, Deschasaux M, Bouchemal N, Nawfal Triba M, Vasson M-P, Rossary A, Demidem A, Galan P, Hercberg S, Partula V, Le Moyec L, Srour B, Fiolet T, Latino-Martel P, Kesse-Guyot E, Zelek L, Savarin P, Touvier M. NMR metabolomic signatures reveal predictive plasma metabolites associated with long-term risk of developing breast cancer [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 P1-02-01.
In DMARD and steroid naïve early rheumatoid arthritis patients D-vitamin metabolites at baseline correlated inversely with 'the number of tender joints', VAS pain, DAS28, HAQ and CRP levels (the CIMESTRA-cohort)
Authors: M. Herly, K. Stengaard-Pedersen, P. Vestergaard, Merete Lund Hetland, K. Hørslev-Petersen, T. Ellingsen
Journal: Annals of the Rheumatic Diseases (2011)
Association between objective responses (OR) and overall survival (OS) in patients (pts) with metastatic Merkel cell carcinoma (mMCC) treated with avelumab.
Authors: Sandra P. D'Angelo, Matthias Hunger, Michael Schlichting, Meliessa G. Hennessy, Murtuza Bharmal
Journal: Journal of Clinical Oncology (2018)

193 Background: Response rates are key efficacy endpoints in oncology trials, yet correlations with OS are not universal across cancer types. MCC is a rare and aggressive skin carcinoma, although it is chemo sensitive with high response rates, responses are of short duration with no demonstrated benefit to OS. This study explores the association between OR and OS in mMCC pts treated with the anti-PD-L1 avelumab. Methods: Efficacy data with ≥ 18 months of follow-up from Part A of the phase II avelumab trial (NCT02155647) were analyzed. Pts had prior progression on or after chemotherapy and received avelumab 10 mg/kg IV Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed for OR every 6 weeks (RECIST v1.1). Using conditional landmark analyses, OS was compared between pts with and without an independently confirmed OR up to day 47. Only pts alive at the landmark (day 47) are included in this analysis. In a sensitivity analysis, a landmark of 89 days was used. A Cox model including OR as a covariate was fit (unadjusted, controlling for age, visceral disease, and number of previous therapies). Results: 20 pts had an initial OR reported up to day 47, with 7 further pts having an OR between day 48 and day 89, and 2 pts having an OR after day 89, including 10 complete responses (CRs). 5 pts died and 1 withdrew consent before day 47 (all without OR). Survival probabilities 18 months after treatment initiation were 0.900 (95%CI: 0.656; 0.974) for pts with OR up to day 47 vs. 0.262 (95% CI 0.157; 0.378) for pts without OR but alive up to day 47. Similar results were observed for the 89-day landmark. In the unadjusted Cox model, OR was associated with a 94% risk reduction of death (hazard ratio: 0.064 [95% CI: 0.022; 0.181]). The hazard ratio in the adjusted model was 0.052 (95% CI: 0.018; 0.152). Conclusions: Avelumab therapy for previously treated mMCC pts demonstrated a clinically relevant and high survival impact. For avelumab, OR was associated with long-term survival, likely driven by the rapid time to response, substantial tumor reductions including CRs and sustained durable responses not reported in the chemotherapy literature for mMCC. Clinical trial information: NCT02155647.
First line gemcitabine and nab-paclitaxel chemotherapy for localized pancreatic ductal adenocarcinoma.
Authors: Pat Gulhati, Laura Prakash, Matthew H. G. Katz, Xuemei Wang, Milind M. Javle, Rachna T. Shroff, David R. Fogelman, Jeffrey Edwin Lee, Ching-Wei David Tzeng, Jeffrey H Lee, Brian Weston, Eric P. Tamm, Priya Bhosale, Eugene Jon Koay, Anirban Maitra, Huamin Wang, Robert A. Wolff, Gauri R. Varadhachary
Journal: Journal of Clinical Oncology (2018)

369 Background: Chemotherapy is widely used as a component of treatment of localized pancreatic ductal adenocarcinoma (PDAC). Pre-operative chemotherapy is associated with early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy. For locally advanced (LA) PDAC, induction chemotherapy is standard of care. We evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy in localized PDAC. Methods: Records of pts with localized PDAC who initiated Gem/nab-P at a single institution from 2013-2015 were retrospectively reviewed. Clinicopathologic features, dose and outcomes were evaluated. Pts were staged using our previously published criteria: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR-C (co-morbidities requiring medical optimization), and LA. Co-morbidities were classified using adult comorbidity evaluation-27 score. Overall survival (OS) was analyzed using Kaplan Meier method. Results:99 pts [M/F: 50/49; median age: 70 yrs (range 30-85); PR/BR/LA: 45/14/40] were treated with Gem/nab-P. Clinical staging showed PR+BR-A/BR-B+C: 20/39. BR-B+C included one or more of the following factors: age ≥80 yrs [13%], ECOG PS ≥2 [13%], moderate/severe co-morbidities [55%], CA19-9≥1000 [28%], suspicion for metastatic disease [21%]. Majority of pts received biweekly Gem/nab-P dosing [standard/biweekly/other: 10/80/9] with minimal grade 4 toxicity. 45/99 pts received chemoradiation after Gem/nab-P [30Gy/50.4Gy: 15/30]. 12/20 (60%) PR+BR-A, 2/39 (5%) BR-B+C and 1/40 (3%) LA pts underwent pancreatectomy. 13/15 resected pts received adjuvant chemotherapy. At median follow-up of 26 mo, median OS was 18 (95% CI: 15.6-20.5) mo for all, 17 (95% CI: 14.6-19.5) mo for unresected and not reached for resected pts (p = 0.03). Conclusions: A significant number of pts with resectable PDAC albeit aggressive biology (BR-B) and/or medically inoperable disease (BR-C) received first-line Gem/nab-P; resection rates were lower compared to PR/BR-A pts. Biweekly dosing is being used in localized PDAC and is well tolerated.
A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail
Authors: Allison K. Simi, Alişya A. Anlaş, Melody Stallings-Mann, Sherry Zhang, Tiffaney Hsia, Magdalena Cichon, Derek C. Radisky, Celeste M. Nelson
Journal: Cancer Research (2018)

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGFβ, known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.Significance: These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Cancer Res; 78(9); 2277-89. ©2018 AACR.
ApoE facilitates the microglial response to amyloid plaque pathology
Authors: Jason D. Ulrich, Tyler K. Ulland, Thomas E. Mahan, Sofie Nyström, K. Peter Nilsson, Wilbur M. Song, Yingyue Zhou, Mariska Reinartz, Seulah Choi, Hong Jiang, Floy R. Stewart, Elise Anderson, Yaming Wang, Marco Colonna, David M. Holtzman
Journal: The Journal of Experimental Medicine (2018)

One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1ΔE9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.
Newshound: It's all academic to me
Authors: Woody Caan
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.
Abstract 19393: Role of Gut Microbiota and Short Chain Fatty Acids in Modulating Energy Harvest and Fat Partitioning in Youth
Authors: Martina Goffredo, Elizabeth Parks, David Wagner, Kendra Mass, Joerg Graf, Nicola Santoro
Journal: Circulation (2016)

Introduction:  Evidence for a role of the gut microbiota in the development of human obesity has been provided, but the mechanisms underlying this association remain unknown.   Hypothesis:  We hypothesize that gut microbiota promote fat accumulation in youth through the synthesis of short chain fatty acids (SCFA). In particular, in this study we aim at demonstrating that obese youth show a peculiar microbiome signature and that the degree of obesity is strongly associated with plasma levels of SCFA, which are the main product of carbohydrates oxidation from the gut flora. We also hypothesize that excessive production of SCFA can cause energy harvest by serving as substrates for hepatic de novo lipogenesis (DNL).   Methods:  We analyzed the gut microbiota of 84 youth in whom body fat distribution was measured by fast-MRI, DNL quantitated using deuterated water, and the capability of gut flora to ferment CHO was assessed by 13C-fructose treatment in vitro.   Results:  A significant association was found between the Firmicutes to Bacteroidetes ratio, and the abundance of Bacteroidetes and Actinobacteria with BMI, visceral and subcutaneous fat (all P    Conclusions:  These data demonstrate that obese youth show a different gut flora composition than lean and that SCFA are associated with body fat partitioning and DNL. Also, the gut flora of obese youth has a higher capability than the gut flora of lean to oxidize carbohydrates.
E-learning could enable millions more students worldwide to train as doctors and nurses
Authors: Matthew Limb
Journal: BMJ (2015)

Electronic learning could enable millions more students worldwide to train as doctors and nurses, says research commissioned by the World Health Organization.

A review of evidence by Imperial College London found that e-learning was likely to be at least as effective as traditional methods for teaching health professionals. But combining both methods would be more suitable than courses offering e-learning alone because of the need for people to develop practical skills, the review said.

The review was commissioned by WHO’s department of health workforce and department of knowledge, ethics, and research and was published by Imperial …
Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis
Authors: Cynthia A. Moylan, Manal F. Abdelmalek
Journal: Hepatology (2018)

Moylan, Cynthia A. M.D., M.H.S.1; Abdelmalek, Manal F. M.D., M.P.H.1 Author Information
Consultants’ contract has not increased productivity, study finds
Authors: Helen Jaques
Journal: BMJ (2012)

NHS consultants’ productivity did not rise after the introduction of their 2003 contract, a study has found.

Retrospective analysis of hospital episode statistics showed that monthly finished consultant inpatient episodes decreased in England between 1999 and 2009, even after adjustment for case mix.1

In 2003 the government introduced a new contract for NHS consultants that split doctors’ working time into four hour sessions. Most full time hospital consultants are contracted to work 10 sessions a week. Some are paid for 11 or 12 sessions if they work more than 40 hours a week.

Between …
Effectiveness of transurethral resection (TUR) plus systemic chemotherapy as definitive treatment for muscle-invasive bladder cancer (MIBC).
Authors: François Audenet, Nikhil Waingankar, Bart Ferket, Scot Anthony Niglio, Kathryn E. Marqueen, Reza Mehrazin, John Sfakianos, Matt D. Galsky
Journal: Journal of Clinical Oncology (2018)

481 Background: TUR + neoadjuvant cisplatin-based chemotherapy achieves a pathologic complete response in 30-40% of patients with MIBC. Prior studies have demonstrated that long-term survival is possible for a subset of patients with MIBC treated with TUR plus chemotherapy alone, but such analyses have been limited by small sample sizes and poor generalizability. The objective of our study was to describe the characteristics and outcomes of patients managed with this approach using a large national registry. Methods: Within the National Cancer Database (2004-2012), we identified 1,003 patients who were treated with TUR + multi-agent systemic chemotherapy, without radiation, as definitive treatment for cT2-T4aN0M0 urothelial carcinoma of the bladder. Baseline characteristics were compared relative to those of 12,138 patients treated during the same period of time with radical cystectomy ± perioperative chemotherapy. Treatment outcomes were assessed using Kaplan-Meier analysis. Results: Compared to patients who were treated with cystectomy ± perioperative chemotherapy, patients treated with TUR + chemotherapy alone were significantly older (≥75 years old 37% vs. 30%; p &lt; 0.0001), had a higher clinical T stage (cT3: 14% vs. 12%; cT4: 12% vs 7%; p &lt; 0.0001) and were more frequently treated in non-academic facilities (66% vs. 49%; p &lt; 0.0001). There were no significant differences between groups regarding gender, Charlson comorbidity index, insurance type or income/education level. The 30-day and 90-day mortality with TUR + chemotherapy was 0.2% and 4%, respectively. The 5-year survival rate for all patients treated with TUR + chemotherapy was 30.5% (95% CI 26.8, 34.2), and limited to patients with cT2 disease was 33.1% (95% CI 28.7, 37.5). Conclusions: This large real-world cohort representing the continuum of practice settings in the United States confirms that long-term survival is achievable in a subset of patients treated with TUR + chemotherapy alone for MIBC. Refinement of this bladder-sparing approach integrating putative predictive biomarkers of pathologic complete response is now the focus of recently initiated prospective clinical trials.
Functional endoscopic sinus surgery course
Authors: Amit Parmar
Journal: BMJ (2010)

The annual Bristol functional endoscopic sinus surgery course is aimed at surgical trainees involved in sinus or skull base surgery. The course is mainly for ear, nose, and throat surgeons in training, but it will also appeal to neurosurgeons and maxillofacial surgeons. This year delegates came from Southampton, London, Manchester, Preston, and Bristol.

I went on this course at specialty training year 3 level, although doing it at an early stage would have allowed me to start sinus surgery sooner. Other attendees included specialty trainees years 3 to 6, clinical fellows, and associate specialists. 

It is not mandatory to go on a sinus surgery course, but consultants are increasingly keen for their junior doctors to attend such a course before doing any type of sinus surgery. Attendance at a course like the functional endoscopic sinus surgery course also helps to form part of the annual review of competence progression and record of in-training assessment that takes place for surgical trainees each year.

Aside from the formal reasons for attendance, most importantly this course allows trainees to gain confidence when operating close …