tbuckley/cabot-search huggingface dataset:
Effect of Perioperative Opioids on Cancer-Relevant Circulating Parameters: Mu Opioid Receptor and Toll-Like Receptor 4 Activation Potential, and Proteolytic Profile
Authors: Nan Xie, Nicholas Matigian, Tharindu Vithanage, Kye Gregory, Zeyad D. Nassar, Peter J. Cabot, Paul N. Shaw, Carl M.J. Kirkpatrick, Kim-Anh Lê Cao, David Sturgess, Marie-Odile Parat
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The purpose of this study is to investigate the potential interplay between opioid analgesia and tumor metastasis through modulation of μ-opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental Design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement preoperatively and at 3, 6, and 24 hours after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen cyclic AMP assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue hTLR4 were utilized to measure TLR4 activation. Circulating matrix metalloprotease and tissue inhibitor of matrix protease activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Postoperative plasma samples displayed the ability to activate MOR and to inhibit lipopolysaccharide (LPS)-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was correlated neither to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point. Clin Cancer Res; 24(10); 2319–27. ©2018 AACR.
Education Outcomes in a Duty-Hour Flexibility Trial in Internal Medicine
Authors: Sanjay V. Desai, David A. Asch, Lisa M. Bellini, Krisda H. Chaiyachati, Manqing Liu, Alice L. Sternberg, James Tonascia, Alyssa M. Yeager, Jeremy M. Asch, Joel T. Katz, Mathias Basner, David W. Bates, Karl Y. Bilimoria, David F. Dinges, Orit Even-Shoshan, David M. Shade, Jeffrey H. Silber, Dylan S. Small, Kevin G. Volpp, Judy A. Shea
Journal: New England Journal of Medicine (2018)

Concern persists that inflexible duty-hour rules in medical residency programs may adversely affect the training of physicians.We randomly assigned 63 internal medicine residency programs in the United States to be governed by standard duty-hour policies of the 2011 Accreditation Council for Graduate Medical Education (ACGME) or by more flexible policies that did not specify limits on shift length or mandatory time off between shifts. Measures of educational experience included observations of the activities of interns (first-year residents), surveys of trainees (both interns and residents) and faculty, and intern examination scores.There were no significant between-group differences in the mean percentages of time that interns spent in direct patient care and education nor in trainees' perceptions of an appropriate balance between clinical demands and education (primary outcome for trainee satisfaction with education; response rate, 91%) or in the assessments by program directors and faculty of whether trainees' workload exceeded their capacity (primary outcome for faculty satisfaction with education; response rate, 90%). Another survey of interns (response rate, 49%) revealed that those in flexible programs were more likely to report dissatisfaction with multiple aspects of training, including educational quality (odds ratio, 1.67; 95% confidence interval [CI], 1.02 to 2.73) and overall well-being (odds ratio, 2.47; 95% CI, 1.67 to 3.65). In contrast, directors of flexible programs were less likely to report dissatisfaction with multiple educational processes, including time for bedside teaching (response rate, 98%; odds ratio, 0.13; 95% CI, 0.03 to 0.49). Average scores (percent correct answers) on in-training examinations were 68.9% in flexible programs and 69.4% in standard programs; the difference did not meet the noninferiority margin of 2 percentage points (difference, -0.43; 95% CI, -2.38 to 1.52; P=0.06 for noninferiority). od Institute and the ACGME; iCOMPARE ClinicalTrials.gov number, NCT02274818 .).There was no significant difference in the proportion of time that medical interns spent on direct patient care and education between programs with standard duty-hour policies and programs with more flexible policies. Interns in flexible programs were less satisfied with their educational experience than were their peers in standard programs, but program directors were more satisfied. (Funded by the National Heart, Lung, and Blo
Financial incentives could attract GPs to Wales, says GPC
Authors: Abi Rimmer
Journal: BMJ (2014)

GP trainees could be attracted to Wales by incentives such as payments towards student loans or exam fees, said the chairwoman of the BMA’s General Practitioners Committee for Wales.

Charlotte Jones said that workforce recruitment and retention were among the main concerns raised by GPs at the Welsh local medical committees’ conference in Newport last weekend, as practices in the country were struggling to recruit GPs.

Speaking to BMJ Careers after the conference, she said, “We need to look at mechanisms that will attract GPs to Wales, such as the environment in which they …
A single-arm, phase II study assessing the efficacy of pembrolizumab (pembro) plus radiotherapy (RT) in metastatic triple negative breast cancer (mTNBC).
Authors: Heather L. McArthur, Christopher Andrew Barker, Ayca Gucalp, Lizza Lebron-Zapata, Yong Hannah Wen, Anh Phung, Micaela Rodine, Brittany Arnold, Zhigang Zhang, Alice Ho
Journal: Journal of Clinical Oncology (2018)

14 Background: Overall response rates of 13-19% have been reported with checkpoint inhibitor monotherapy in chemotherapy-resistant, PD-L1-positive mTNBC. RT is frequently used to enhance local control in mTNBC and has been reported to induce distant (abscopal) tumor responses when combined with immunotherapy. In this study, we evaluate the safety and efficacy of RT combined with a programmed cell death protein 1 (PD-1) inhibitor, pembro, in a single-arm, two-stage, phase II study in mTNBC. Methods: Eligible women had biopsy-proven mTNBC, ECOG performance status 0-2, and ≥2 measurable sites of metastatic disease with at least one site requiring RT. A total RT dose of 3000 cGy was delivered in 5 daily fractions. Pembro 200 mg was given intravenously within 3 days of first RT fraction, then every 3 weeks +/-3 days until disease progression. The primary endpoint was overall response rate at week 13 in the non-irradiated lesions by RECIST v1.1. Secondary endpoints included safety and overall survival. Tumor biopsies were obtained at baseline and at week 7. PD-L1 expression was not required for study entry. Results: Of the 17 women enrolled, the median age was 52 y (range 37-73y). and the median number of prior chemotherapies received for metastatic disease was 3 (range 0 to 8). Of the 8 women not evaluable at 13 weeks: 5 died secondary to disease-related complications (at weeks 2, 6, 7, 8, and 9) and 3 came off study due to disease progression prior to week 13. Of the 9 women evaluable at week 13, 3 (33%) had a partial response, 1 (11%) had stable disease and 5 (56%) had disease progression. The 3 partial responses represented 60%, 54%, and 34% decreases in tumor burden by RECIST v1.1 and were durable for 31, 21, and ongoing at 22 weeks, respectively. The stable disease response was durable for 22 weeks. Common toxicities were mild and included fatigue, myalgia and nausea. Conclusions: The combination of pembro and RT is well-tolerated. This is a poor prognosis population with 5/17 (29%) of patients dying within 12 weeks of study entry. However, durable responses were observed outside of the RT field in 3/9 (33%) patients who were unselected for PD-L1 expression and evaluable at 13 weeks. Clinical trial information: NCT02730130.
Polyamine-Targeting Gefitinib Prodrug and its Near-Infrared Fluorescent Theranostic Derivative for Monitoring Drug Delivery and Lung Cancer Therapy
Authors: Xinyu Song, Xiaoyue Han, Fabiao Yu, Xiaoyu Zhang, Lingxin Chen, Changjun Lv
Journal: Theranostics (2018)

The therapy of non-small-cell lung cancer (NSCLC) is challenging because of poor prognosis.There are urgent demands for targeting anti-tumor drugs with reliable efficacy and clear pharmacokinetics.Methods: We designed and synthesized an active tumor-targeting prodrug for the precision therapy of NSCLC.The prodrug polyamine analog Gefitinib (PPG) was derived from the conjugation between a tumor-targeting ligand polyamine analog (PA) and an epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib via a cleavable disulfide linker.Furthermore, the integration of the near-infrared azo-BODIPY fluorophore into the structure of the prodrug PPG yielded an activatable fluorescent theranostics (TPG), which could be used to monitor the in real-time delivery of prodrug PPG and initiate precise medicine in vivo.Results: PPG efficiently delivered the anti-tumor drug to cancer cells and reduced the serious side effects of the drug to normal cells, thereby increasing the potent of the anti-tumor drug.PPG was not only efficacious for killing Gefitinib-sensitive PC9 cells, but also for inhibiting the growth of Gefitinib-resistant H1650 cells.We provided a new evidence that the tumor-targeting PA ligand could inhibit the Akt pathway in H1650 cells, and had a synergistic effect with Gefitinib for anticancer efficacy.The in vivo results on nude mice bearing tumors of NSCLC cell lines demonstrated that PPG could target tumor lesions and had the expected therapeutic effects.Finally, we used TPG for fluorescent labeling of transbronchial lung biopsy (TBLB) specimens.The results indicated that TPG could provide rapid diagnosis for lung cancer within 4 h.Conclusion: Our work had identified that PPG could be effectively used for the treatment of Gefitinib-resistance NSCLC in cells and in mice models.The theranostic TPG emerged as a promising fluorescent imaging tool for the application in the therapy and diagnosis of NSCLC.
Genetic landscape of hepatitis B virus–associated diffuse large B-cell lymphoma
Authors: Weicheng Ren, Xiaofei Ye, Hong Su, Wei Li, Dongbing Liu, Mohammad Pirmoradian, Xianhuo Wang, Bo Zhang, Qiang Zhang, Longyun Chen, Man Nie, Yao Liu, Bin Meng, Huiqiang Huang, Wenqi Jiang, Yixin Zeng, Wenyu Li, Kui Wu, Yong Hou, Klas G. Wiman, Zhiming Li, Huilai Zhang, Roujun Peng, Shida Zhu, Qiang Pan-Hammarström
Journal: Blood (2018)
Advertising and Youth
Authors: Megan A Moreno
Journal: JAMA Pediatrics (2018)

John P. Pierce, PhD; James D. Sargent, MD; David B. Portnoy, PhD; Martha White, MS; Madison Noble, MPH; Sheila Kealey, MPH; Nicolette Borek, PhD; Charles Carusi, PhD; Kelvin Choi, PhD; Victoria R. Green, BA; Annette R. Kaufman, PhD; Eric Leas, MPH; M. Jane Lewis, DrPH; Katherine A. Margolis, PhD; Karen Messer, PhD; Yuyan Shi, PhD; Marushka L. Silveira, BDS, PhD; Kimberly Snyder, MPH; Cassandra A. Stanton, PhD; Susanne E. Tanski, MD; Maansi Bansal-Travers, PhD; Dennis Trinidad, PhD; Andrew Hyland, PhD
SEATTLE ANGINA QUESTIONNAIRE AND PROGNOSIS IN CORONARY VASCULAR DYSFUNCTION: RESULTS FROM THE WOMEN'S ISCHEMIA SYNDROME EVALUATION-CORONARY VASCULAR DYSFUNCTION (WISE-CVD)
Authors: Romana Herscovici, Janet Wei, Chrisandra Shufelt, Puja Mehta, Galen Weins-Cook, Reddy Sailaja Marpuri, Eileen Handberg, Carl Pepine, C. Noel Bairey Merz
Journal: Journal of the American College of Cardiology (2018)
I have been off work for two long periods with an autoimmune condition. Through various self help means I have got back to work and have had little sick leave in the past two years. Because of some challenging symptoms I would like to have complementary treatment over two to three weeks. My medical advisers are happy with this. Would I have to take this as annual leave?
Authors: Caron Grainger
Journal: BMJ (2006)

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>
Should UK medical students be guaranteed a job on leaving medical school? Yes
Authors: Oliver Ellis
Journal: BMJ (2011)

<b>Helen Macdonald</b> (http://careers.bmj.com/careers/advice/view-article.html?id=20002742) believes that the NHS is not obliged to provide medical students with a job when they leave medical school, but <b>Oliver Ellis </b>argues that it makes financial sense to ensure that students are guaranteed a place
Phase I Study of LY2940680, a Smo Antagonist, in Patients with Advanced Cancer Including Treatment-Naïve and Previously Treated Basal Cell Carcinoma
Authors: Johanna Bendell, Valerie Andre, Alan Ho, Ragini Kudchadkar, Michael Migden, Jeffrey Infante, Ramon V. Tiu, Celine Pitou, Trevor Tucker, Les Brail, Daniel Von Hoff
Journal: Clinical Cancer Research (2018)

Purpose: The purpose of this study was to determine a recommended phase II dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer.Experimental Design: This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naïve and previously hedgehog (Hh)-inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled.Results: Eighty-four patients were treated (dose escalation, n = 25; dose confirmation, n = 19; and BCC dose expansion, n = 40). Common treatment-emergent adverse events were dysgeusia [41 (48.8%)], fatigue [40 (47.6%)], nausea [38 (45.2%)], and muscle spasms [34 (40.5%)]. Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested that all doses were biologically active [inhibition median of 92.3% (80.9% to 95.7%)]. All clinical responses (per RECIST 1.1) were in patients with BCC (n = 47); the overall and estimated response rate was 46.8% (95% confidence interval, 32.1%-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh treatment-naïve (11/16) patients.Conclusions: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh treatment-naïve patients. Clin Cancer Res; 24(9); 2082-91. ©2018 AACR.
INDISCRIMINATE USE OF HYPOTHERMIA COULD BE DELETERIOUS IN HEART FAILURE PATIENTS WITH CARDIAC ARREST
Authors: Abhishek Dutta, John Azizian, Youssef Masmoudi, Malcom Mcdonald, Anthony Bleyer, Hanumantha Rao Jogu, Nikhil Patel, Andrew Mclean, Anurag Gaddam, Waqas Qureshi
Journal: Journal of the American College of Cardiology (2018)
Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia
Authors: Birgitt Gutbier, Anne-Kathrin Neuhauß, Katrin Reppe, Carolin Ehrler, Ansgar Santel, Jörg Kaufmann, Markus Scholz, Norbert Weissmann, Lars Morawietz, Timothy J. Mitchell, Stefano Aliberti, Stefan Hippenstiel, Norbert Suttorp, Martin Witzenrath
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: During pneumonia, pathogen–host interaction evokes inflammation and lung barrier dysfunction. Tie2 activation by angiopoietin-1 reduces, whereas Tie2 blockade by angiopoietin-2 increases, inflammation and permeability during sepsis. The role of angiopoietin-1/-2 in pneumonia remains unidentified.Objectives: To investigate the prognostic and pathogenic impact of angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia.Methods: Serum angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n = 148, n = 395). Human postmortem lung tissue, pneumolysin- or angiopoietin-2–stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated.Measurements and Main Results: In patients with pneumonia, decreased serum angiopoietin-1 and increased angiopoietin-2 levels were observed as compared with healthy subjects. Higher angiopoietin-2 serum levels were found in patients with community-acquired pneumonia who died within 28 days of diagnosis compared with survivors. Receiver operating characteristic analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment, and length of hospital stay if combined with angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial angiopoietin-2 release, angiopoietin-2 increased endothelial permeability, and angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with angiopoietin-2 knockdown showed reduced permeability on pneumolysin stimulation. Increased pulmonary angiopoietin-2 and reduced angiopoietin-1 mRNA expression were observed in Streptococcus pneumoniae–infected mice. Finally, angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia.Conclusions: These data suggest a central role of angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased angiopoietin-2 serum levels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.
P076 A bioassay to measure tgfΒ activity reveals decreased tgfΒ activity in systemic sclerosis serum
Authors: A van Caam, E Vitters, F van den Hoogen, M Vonk, P van der Kraan
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Systemic sclerosis (SSc) is a severe disease characterised by auto-immunity, vasculopathy and excessive fibrosis of connective tissues. The pathophysiology of SSc is still poorly understood, but its symptoms imply a role for dysregulated transforming growth factor β (TGFβ) signalling because this cytokine is known to regulate vascular and connective tissue biology. TGFβ circulates in blood in an inactive latent form bound to latency associated peptide and latent TGFβ binding proteins. This latent TGFβ has to be activated before it can become bioactive. With the use of a bioassay TGFβ's bioactivity can be measured in complex mixtures like serum. This is not possible with an ELISA because this technique does not take (cellular) activation processes into account. <h3>Objectives</h3> To determine the bioactivity of TGFβ in SSc serum compared to that of healthy control serum. <h3>Methods</h3> Serum was collected of 10 SSc patients and 10 age and sex matched healthy controls. Primary human fibroblasts of 3 donors were transduced with CAGA<sub>12</sub>-luc which produces luciferase in response to TGFβ/Smad3 or BRE-luc which produces luciferase in response to BMP/Smad1/5. These cells were treated with 10% serum for 16 hour and luciferase activity was measured. To activate all TGFβ, sera were treated with 4M HCl for 1 hour at RT, after which pH was normalised with 4M NaOH. Controls were treated with HCl and NaOH simultaneously. To verify that TGFβ signalling was measured in this reporter assay, sera were treated with anti-TGFβ1/2/3 for 1 hour at RT before use. <h3>Results</h3> Control sera significantly induced reporter activity by 4.5-fold. However, SSc sera only induced a 2.5-fold increase in luciferase activity, indicating significantly lower bioactivity of TGFβ (p&lt;0.0001). This difference was not due to a difference in total TGFβ levels; after activation of all TGFβ both HC and SSc sera induced a similar 6-fold increase in signal strength. These data show that in HC sera approximately 75% of all TGFβ is bioactive compared to only 42% in SSc. Addition of anti-TGFβ1/2/3 inhibited all CAGA<sub>12</sub>-luc reporter activity (p&lt;0.0001) of both HC and SSc serum, and of both acidified and not acidified sera (p&lt;0.0001), showing that our bioassay is indeed TGFβ-dependent. To investigate if reduced bioactivity is a more general phenomenon we measured BMP activity. BMP proteins are structurally closely related to TGFβ and also circulate in inactive form. Both HC and SSc sera induced a similar 8-fold increase in BRE-luc activity, and this activity was increased to a 16-fold induction after acidification for both groups. BMPs in SSc sera are thus not less bioactive. This illustrates the uniqueness of our observation on TGFβ bioactivity. <h3>Conclusions</h3> TGFβ in SSc serum is less bioactive than in control serum whereas BMPs are not less bioactive. <h3>Disclosure of interest</h3> None declared
Genetic Testing for Inherited Cardiac Diseases in Underserved Populations of Non-European Ancestry
Authors: Glenn S. Gerhard, Susan G. Fisher, Arthur M. Feldman
Journal: JAMA Cardiology (2018)

This Viewpoint describes genetic testing for inherited cardiac conditions, the need to sequence many well-phenotyped cases and controls from diverse racial/ethnic and economic groups, and the financial assistance necessary to reduce disparities in access.
A Novel <scp>l</scp>-Asparaginase with low <scp>l</scp>-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias <i>In Vivo</i>
Authors: Hien Anh Nguyen, Ying Su, Jenny Y. Zhang, Aleksandar Antanasijevic, Michael Caffrey, Amanda M. Schalk, Li Liu, Damiano Rondelli, Annie Oh, Dolores L. Mahmud, Maarten C. Bosland, Andre Kajdacsy-Balla, Sofie Peirs, Tim Lammens, Veerle Mondelaers, Barbara De Moerloose, Steven Goossens, Michael J. Schlicht, Kasim K. Kabirov, Alexander V. Lyubimov, Bradley J. Merrill, Yogen Saunthararajah, Pieter Van Vlierberghe, Arnon Lavie
Journal: Cancer Research (2018)

Abstract Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug l-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine dependency of ALL cells. In addition to hydrolyzing the amino acid l-asparagine, all FDA-approved l-asparaginases also have significant l-glutaminase coactivity. Since several reports suggest that l-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced l-glutaminase coactivity might be clinically beneficial if their antileukemic activity would be preserved. Here we show that novel low l-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi l-asparaginase were highly efficacious against both T- and B-cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer l-asparaginases without l-glutaminase activity for the treatment of human ALL. Significance: A new l-asparaginase–based therapy is less toxic compared with FDA-approved high l-glutaminase enzymes Cancer Res; 78(6); 1549–60. ©2018 AACR.