tbuckley/cabot-search huggingface dataset:
Magnitude and Pattern of Placebo Response in Clinical Trials of Oral Antihyperglycemic Agents: Data From the U.S. Food and Drug Administration, 1999–2015
Authors: Arif Khan, Kaysee Fahl Mar, Joshua Schilling, Walter A. Brown
Journal: Diabetes Care (2018)

OBJECTIVE To evaluate the magnitude of placebo response and treatment response patterns in clinical trials of investigational oral antihyperglycemics over time. RESEARCH DESIGN AND METHODS We examined the U.S. Food and Drug Administration medical and statistical reviews for 19 oral antihyperglycemic agents (23,438 patients, 50 trials, and 96 treatment arms) approved between 1999 and 2015. Placebo and medication treatment response (HbA1c reduction) and effect sizes were examined over time (year of approval). Exclusively placebo-controlled and augmented/adjunctive placebo-controlled trials were analyzed separately, and differences were compared. Potential effects of trial and patient characteristics were explored. RESULTS In more recent trials, augmented placebo-controlled arms reduced HbA1c by 0.2% on average and more frequently lowered HbA1c from baseline compared with exclusively placebo-controlled arms (63 vs. 18%; χ2 = 9.93; P = 0.002). In exclusively placebo-controlled trials, placebo response increased significantly over time (β = 0.035; R2 = 0.31; P = 0.0013), reaching ∼0% average change in HbA1c, whereas drug response also increased significantly (β = 0.017; R2 = 0.076; P = 0.0498). In augmented placebo-controlled trials, placebo response (β = 0.33; R2 = 0.407; P &amp;lt; 0.001) showed the same pattern, whereas the growth in drug response was not significant (R2 = 0.031; P = 0.207). Placebo response in both groups increased by 0.5% HbA1c reduction over time, whereas effect sizes remained stable with high success rates (100%; 96 out of 96). Drug response and effect size were not significantly predicted by patient or trial characteristics, but follow-up analysis suggested an inverse relationship of placebo baseline HbA1c with placebo response. CONCLUSIONS Remarkably, placebo-treated patients with diabetes commonly experienced reduction in HbA1c, more markedly in augmented compared with exclusively placebo-controlled treatment arms. Placebo response increased significantly over time without impacting efficacy outcomes. Nonpharmacologic effects measured in the placebo response appear stronger when used with active medication than when implemented in isolation and may be related to the level of HbA1c at baseline.
Pazopanib to suppress MET signaling in patients with refractory advanced solid tumors.
Authors: Apurva K. Srivastava, Jeevan P Govindharajulu, Sook Ryun Park, Tony Navas, Katherine V. Ferry-Galow, Robert J. Kinders, Young H. Lee, Donald P. Bottaro, John Joseph Wright, Melinda G. Hollingshead, Alice P. Chen, Ralph E. Parchment, Shivaani Kummar, James H. Doroshow
Journal: Journal of Clinical Oncology (2016)

2553 Background: Activation of MET signaling has been proposed as an adaptive response to pharmacological inhibition of VEGFR. We compared MET and phospho-MET levels in paired biopsies collected before and after pazopanib treatment of patients (pts) with advanced solid tumors enrolled in this single-agent arm of the Phase I trial of a pazopanib/tivantinib combination (NCT01468922). Methods: Eligible pts had histologically confirmed refractory cancers; ≥18 years old; and adequate bone marrow, hepatic, and renal function. Pts underwent pre-treatment tumor biopsy, received 7 days of pazopanib (800 mg/d, po) followed by post-treatment biopsy on day 8. The biopsies were flash frozen and one core processed into total cell lysates for MET analysis by validated ELISA (Srivastava et al, JCO 2011). Results: Paired biopsies were evaluable in 8 pts (age 19-59 yrs), and levels of full length MET (total) were measurable in 6 biopsy pairs, ranging from 3.1 - 626.3 fmol/mg protein (Table). Pazopanib treatment decreased total MET levels in 5 out of 6 pts; similarly, it decreased pMET levels in 3 of 3 pts. This decrease in MET levels did not appear to be related to sampling variability, based on H&E staining of the second pass biopsies. In vitro experiments using MET/VEGFR2 expressing cell lines confirmed decreased MET and pMET levels following pazopanib treatment. Conclusions: Pazopanib-associated decline in MET levels were contrary to the hypothesis of the trial that blockade of VEGFR would result in activation of MET. Pazopanib is known to inhibit multiple kinases including MET (MET IC50 6uM), so establishing a link between VEGFR blockade and MET response will need further study in clinical trials of VEGFR-targeted agents with greater target selectivity than pazopanib. Funded by NCI Contract No HHSN261200800001E. Clinical trial information: NCT01468922.Patient # Cancer Type Biopsy Time Total MET (fmol/mg Pr) pY1234-35MET (fmol/mg Pr) pY1356MET (fmol/mg Pr) 25 RCC Pre 73.5 <LLQ Post 54.0 <LLQ 26 CUP Pre 5.2 <LLQ Post 12.1 <LLQ 28 Ovarian Pre 626.3 177.7 63.8 Post 120.7 19.0 <LLQ 29 NSLC Pre 3.1 <LLQ Post <LLQ <LLQ 30 Esophageal Pre 434.7 168.1 72.4 Post 132.8 66.2 19.7 32 Colon Pre 135.8 1.7 Post 8.6 <LLQ LLQ, limit of quantitation
Language testing of EU doctors is a step closer after legislative proposals pass first hurdle
Authors: Helen Jaques
Journal: BMJ (2013)

A committee of the European parliament has approved plans that would allow the General Medical Council to test the language skills of doctors from other European Union countries who sought work in the United Kingdom.

Members of the parliament’s Internal Market and Consumer Protection Committee voted in favour of a motion to allow employers and regulatory bodies to test the language skills of healthcare professionals from elsewhere in the EU.

The committee agreed that language controls should be “reasonable and necessary” for the job in question, should not constitute grounds for excluding professionals from the labour market, and should be free of charge for the professional concerned.

The General Medical …
I am interested in gastroenterology. Would doing an MSc in it be beneficial for me?
Authors: Alan R Watson
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>
Naphthalene-based fluorescent probes for glutathione and their applications in living cells and patients with sepsis
Authors: Jun Li, Younghee Kwon, Kyung Soo Chung, Chang Su Lim, Dayoung Lee, Yongkang Yue, Jisoo Yoon, Gyoungmi Kim, Sang-Jip Nam, Youn Wokk Chung, Hwan Myung Kim, Caixia Yin, Ji-Hwan Ryu, Juyoung Yoon
Journal: Theranostics (2018)

Among the biothiols-related diseases, sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and can result in severe oxidative stress and damage to multiple organs. In this study, we aimed to develop a fluorescence chemosensor that can both detect GSH and further predict sepsis.
Mobilization of hematopoietic stem cells as a result of innate immunity-mediated sterile inflammation in the bone marrow microenvironment—the involvement of extracellular nucleotides and purinergic signaling
Authors: Mariusz Z Ratajczak, Mateusz Adamiak, Monika Plonka, Ahmed Abdel-Latif, Janina Ratajczak
Journal: Leukemia (2018)

Hematopoietic stem/progenitor cells (HSPCs) circulate in peripheral blood (PB) under normal conditions and their number increases in response to stress, inflammation, tissue/organ injury, and may increase up to 100-fold after administration of mobilization-inducing drugs. Mounting evidence suggests that mobilizing agent-induced mobilization of HSPCs from bone marrow into PB is a result of innate immunity-mediated sterile inflammation in the bone marrow (BM) microenvironment. A critical initiating role in this process is played by tissue/organ injury-mediated or pharmacologically induced release from bone marrow-residing granulocytes and monocytes of (i) danger-associated molecular patterns (DAMPs), (ii) reactive oxygen species (ROS), and (iii) proteolytic and lipolytic enzymes. All these factors together trigger activation of the complement and coagulation cascades, both of which orchestrate egress of HSPCs into BM sinusoids and lymphatics. Recent evidence also indicates that, in addition to attenuation of the SDF-1–CXCR4 and VLA-4–VCAM-1 retention axes in the BM microenvironment and the presence of a mobilization-directing phosphosphingolipid gradient in PB, an important role in the mobilization process is played by extracellular nucleotides and purinergic signaling. In particular, a new finding by our laboratory is that, while extracellular ATP promotes mobilization of HSPCs, its derivative, adenosine, has the opposite (inhibitory) effect.
Promises and Challenges in the Use of Consumer-Grade Devices for Sleep Monitoring
Authors: Sirinthip Roomkham, David Lovell, Joseph Cheung, Dimitri Perrin
Journal: IEEE Reviews in Biomedical Engineering (2018)

The market for smartphones, smartwatches, and wearable devices is booming. In recent years, individuals and researchers have used these devices as additional tools to monitor and track sleep, physical activity, and behavior. Their use in sleep research and clinical applications could address the difficulties in scaling up studies that rely on polysomnography, the gold-standard. However, the use of commercial devices for large-scale sleep studies is not without challenges. With this in mind, this paper presents an extensive review of sleep monitoring systems and the techniques used in their development. We also discuss their performance in terms of reliability and validity, and consider the needs and expectations of users, whether they are experts, patients, or the general public. Through this review, we highlight a number of challenges with current studies: a lack of standard evaluation methods for consumer-grade devices (e.g., reliability and validity assessment); limitations in the populations studied; consumer expectations of monitoring devices; constraints on the resources of consumer-grade devices (e.g., power consumption).
How easy is it for UK graduates to work in the USA?
Authors: Matthew J Thompson
Journal: BMJ (2004)

<i>Got 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 (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</i>
Breaking down barriers
Authors: Tom Moberly
Journal: BMJ (2014)

The need to tackle cultural barriers in different areas of medical careers is examined in two recent articles in BMJ Careers. Matthew Limb (http://careers.bmj.com/careers/advice/view-article.html?id=20017245) looks at the obstacles that prevent doctors from taking on senior management and leadership roles, while Clare Gerada and Richard Jones (http://careers.bmj.com/careers/advice/view-article.html?id=20017282) consider the issues that put surgeons off seeking help for mental health problems. …
MPhil in medical law
Authors: Christopher Danbury
Journal: BMJ (2006)

Further information 

Professor Sheila McLean, Institute of Law and Ethics in Medicine, The School of Law, 5-8 The Square, University of Glasgow, Glasgow G12 8QQ; 0141 330 3528.



Anyone interested in medical law, including doctors, nurses, and lawyers. The tutors try to keep the intake varied to promote discussion.

I did it between 2001 and 2004. I started it as a final year specialist registrar and completed it as a consultant. Other than a first degree there are no fixed prerequisites, and people on my course varied between those who were very junior …
Generic instructor course
Authors: Jonathan W Brand
Journal: BMJ (2008)

The generic instructor course (GIC) is designed to train potential candidates in how to teach on courses for providers of life support. It is a course overseen by the Resuscitation Council (UK) and the Advanced Life Support Group, and it focuses on the acquisition of practical skills in teaching and assessment as applied to the life support courses offered by the two groups.

The course is available for any life support provider who performed exceptionally well in their parent course and was recommended for training as an instructor by their faculty. The criterion for recommendation varies according to provider course. There are many eligible provider courses—for example, the advanced life support course, the newborn life support course, and the advanced paediatric life support course.

I completed the GIC as a potential instructor for advanced life support four months after my original provider …
Overcoming resistance to antiandrogens with a TGF-β RI inhibitor in preclinical mouse model of PCa.
Authors: Channing Judith Paller, Hong Pu, Diane Begemann, Mary Nakazawa, Natasha Kyprianou
Journal: Journal of Clinical Oncology (2018)

288 Background: Epithelial-mesenchymal transition (EMT) is a significant contributor to PCa metastatic progression and therapeutic resistance in patients treated with the androgen receptor (AR) directed therapies. We previously demonstrated that aberrant TGF-β signaling accelerates prostate tumor progression in the TRAMP mouse model of tumorigenesis via selective effects on EMT. Methods: We hypothesize that the combination of the TGF-β receptor inhibitor, galunisertib (G), and enzalutamide (E) will perturb the interactive signaling between TGF-β and AR signaling affecting the phenotypic landscape of EMT. This perturbation may be exploited in our mouse model, towards enhanced anti-tumor efficacy in advanced castration-resistant PCa (CRPC). We treated 2-week old mice for two weeks with the G (75mg/kg) and/or E (30mg/kg) in combination and as single agents. Results: Treatment with G alone or in combination with E resulted in a significant reduction in prostate tumor weight without affecting total body weight. Immunohistochemical (IHC) and Western blot analysis showed that, while treatment with the G alone led to increased apoptosis and decreased cell proliferation, combination of G and E had significantly higher efficacy in inducing apoptosis and inhibiting cell proliferation than either E or G alone. As expected treatment with the G decreased the levels of nuclear Smad4 protein; the combination of G and E further decreased nuclear Smad4 expression. Furthermore the combination of G and E reversed phenotypic EMT to MET (mesenchymal-epithelial-transition), as assessed by the increase in E-cadherin among the prostate tumor cell populations. IHC and Western blot analysis also revealed that the combined treatment of G and E led to a significant decrease in nuclear AR levels compared to E-only-treated or vehicle-control tumors. Conclusions: These results provide significant insights as to the therapeutic impact of G to effectively impair the TGF-β signaling and overcome resistance of PCa patients to E by reversing EMT to potentially sensitize tumors to the antiandrogen effect. This study has major translational relevance; the combination of G and E may lead to synergistic anti-tumor impact in patients with CRPC.
Cholangioscopy Is Safe and Feasible in Elderly Patients
Authors: Jessica Bernica, Sherif Elhanafi, Neeharika Kalakota, Yi Jia, Christopher Dodoo, Alok Dwivedi, Robert J. Sealock, Kalpesh Patel, Isaac Raijman, Marc J. Zuckerman, Mohamed O. Othman
Journal: Clinical Gastroenterology and Hepatology (2018)
GPs to hold hospitals to account for transparency on patient safety
Authors: Helen Jaques
Journal: BMJ (2012)

GPs will be able to hold hospitals and other NHS organisations to account for their approach to patient safety incidents through a new duty of openness in contracts for commissioned services.

The government plans to introduce new regulations that will require the NHS Commissioning Board to include a contractual commitment to transparency in all commissioning contracts with NHS providers of acute care, ambulance, community, and mental healthcare services. 

All NHS standard contracts signed off after April 2013 must include a clause …
Natural Selection and Origin of a Melanistic Allele in North American Gray Wolves
Authors: Rena M Schweizer, Arun Durvasula, Joel Smith, Samuel H Vohr, Daniel R Stahler, Marco Galaverni, Olaf Thalmann, Douglas W Smith, Ettore Randi, Elaine A Ostrander, Richard E Green, Kirk E Lohmueller, John Novembre, Robert K Wayne
Journal: Molecular Biology and Evolution (2018)

Pigmentation is often used to understand how natural selection affects genetic variation in wild populations since it can have a simple genetic basis, and can affect a variety of fitness-related traits (e.g., camouflage, thermoregulation, and sexual display). In gray wolves, the K locus, a β-defensin gene, causes black coat color via a dominantly inherited KB allele. The allele is derived from dog-wolf hybridization and is at high frequency in North American wolf populations. We designed a DNA capture array to probe the geographic origin, age, and number of introgression events of the KB allele in a panel of 331 wolves and 20 dogs. We found low diversity in KB, but not ancestral ky, wolf haplotypes consistent with a selective sweep of the black haplotype across North America. Further, North American wolf KB haplotypes are monophyletic, suggesting that a single adaptive introgression from dogs to wolves most likely occurred in the Northwest Territories or Yukon. We use a new analytical approach to date the origin of the KB allele in Yukon wolves to between 1,598 and 7,248 years ago, suggesting that introgression with early Native American dogs was the source. Using population genetic simulations, we show that the K locus is undergoing natural selection in four wolf populations. We find evidence for balancing selection, specifically in Yellowstone wolves, which could be a result of selection for enhanced immunity in response to distemper. With these data, we demonstrate how the spread of an adaptive variant may have occurred across a species' geographic range.
CARDIAC TGFβ SIGNALING IS DECREASED IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY
Authors: Estibaliz Castillero, Catherine Wang, Adam Recht, Marcia Gailes, Karina Guaman, Michal Segall, Mathew Maurer, P. Christian Schulze, Hiroo Takayama, Paolo Colombo, Isaac George
Journal: Journal of the American College of Cardiology (2018)
Effects of apatinib dose interruptions on safety and efficacy in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction in third- or later-line setting.
Authors: Junsheng Wang, Shukui Qin, Jin Li, Wenying Deng, Lu Wen, Guifang Zhang, Haijun Zhong, Tongfu Jia, Jianwei Yang, Yuxian Bai, Xiaoyan Lin, Mei Wang, Lin Wang, Likun Liu, Yifu He, Min Tao, Congying Xie, Feng Ye, Xiang-yuan Wu, Yi Ba
Journal: Journal of Clinical Oncology (2018)

142 Background: Apatinib, a small molecule VEGFR TKI, has been approved in the treatment of advanced gastric cancer in China. Due to toxicity, many pts underwent temporary interruptions during treatment. We analyzed the data from a phase IV clinical trial of Ahead-G201 to evaluate the relationship between dose interruption, drug safety and efficacy. Methods: At the cutoff date of Jul 10, 2017, Ahead-G201 study enrolled 1037 pts. The adverse events (AEs) and clinical efficacy were evaluated for pts with no, 1, 2 and ≥3 dose interruptions. Results: 336 of 1037 pts underwent dose interruptions during apatinib treatment: 1 interruption in 183 pts; 2 interruptions in 67 pts; and ≥3 interruptions in 86 pts. The toxicity and efficacy for them were listed in Table. For safety, pts with no interruption had the lowest incidence of all AEs (59.3%) and grade 3-4 AEs (30.0%). Pts with ≥3 interruptions had the highest objective response rate (ORR, 20.3%) and disease control rate (DCR, 82.6%). Moreover, these pts got median progression-free survival (mPFS) of 6.6 mos and median overall survival (mOS) of 9.4 mos, which were the longest among 4 groups. Furthermore, multivariate analysis revealed that ≥3 interruptions of apatinib bring much more efficacy benefit both in mPFS (6.6 vs 3.8 mos: hazard ratio, 0.5, 95%CI, 0.3 to 0.7) and mOS (9.4 vs 6.6 mos: hazard ratio, 0.5, 95%CI, 0.3 to 0.8) for pts, than those with no interruption. Conclusions: Current results indicated that dose interruptions are required to manage toxicity and it is necessary to explore an optimal dosing pattern of apatinib in advanced gastric cancer. Clinical trial information: NCT02426034. [Table: see text]
Tumor infiltrating lymphocyte recruitment in patients with early stage breast cancer after intramammary IRX-2 cytokine immunotherapy.
Authors: David B. Page, Joanna Pucilowska, Neil Lorne Berinstein, James E. Egan
Journal: Journal of Clinical Oncology (2018)

7 Background: The IRX-2 biologic is an injectable immunotherapy containing cytokines derived from stimulated lymphocytes. In preclinical models, IRX-2 activates T-cells, natural killer (NK) cells, macrophages, and dendritic cells, and facilitates maturation of antigen-presenting cells. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved outcomes in early stage breast cancer (ESBC), and neoadjuvant IRX-2 increased TILs in a head/neck squamous cell carcinoma trial. We conducted a phase Ib trial to evaluate the feasibility/activity of IRX-2 in ESBC. Methods: Beginning 21 days prior to surgical resection, enrolled operable patients with stage I-III ESBC received the pre-operative IRX-2 regimen consisting of a single low dose of cyclophosphamide (300 mg/m 2 to facilitate T-regulatory cell depletion), followed by 10 days of subcutaneous peri-areolar injections of IRX-2 into the affected breast (1 mL × 2 at tumor axis and at 90°). Endpoints were feasibility (primary), sTIL count (secondary), and immune monitoring by flow cytometry and immune transcriptome analysis (Nanostring PanCancer Immune Panel). Results: As of October 2017, 12 patients are enrolled and evaluable. All patients received all planned injections with no treatment-related surgical delays, complications, or grade III/IV toxicities. Treatment was associated with a mean 52% relative increase in sTILs (range –25% to +166%, p = 0.02). RNA expression profiling revealed the greatest increases in Th1 cell signature (mean +28.5%, range -5.3% to +283%), but also increases in CD8+, NK, and DC signatures. PDL1 RNA expression increased in 10/12 patients (mean +131.5%, range –83% to +1112%). In blood, increases in T-cell activation markers (ICOS, HLADR, and CD38) and T-reg depletion were observed at 1-month follow-up. Conclusions: Peri-lymphatic IRX-2 was well tolerated with preliminary evidence of sTIL recruitment, PDL1 upregulation, and peripheral lymphocyte activation. Study enrollment is ongoing, including patients for a pre-neoadjuvant-chemotherapy triple-negative ESBC cohort. Clinical trial information: NCT02950259.
Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery
Authors: Shota Ichimizu, Hiroshi Watanabe, Hitoshi Maeda, Keisuke Hamasaki, Yuka Nakamura, Victor Tuan Giam Chuang, Ryo Kinoshita, Kento Nishida, Ryota Tanaka, Yuki Enoki, Yu Ishima, Akihiko Kuniyasu, Yoshihiro Kobashigawa, Hiroshi Morioka, Shiro Futaki, Masaki Otagiri, Toru Maruyama
Journal: Journal of Controlled Release (2018)
INFLUENCE OF CONCOMITANT CHRONIC TOTAL OCCLUSION AND COLLATERAL FLOW ON SINGLE CUTOFF INSTANTANEOUS WAVE-FREE RATIO ON INTERMEDIATE CORONARY LESIONS: RESULTS FROM A SINGLE-CENTER REGISTRY
Authors: Shunsuke Aoi, Neil Patel, Bora Toklu, Wonkyoung Lee, John Fox, Yumiko Kanei
Journal: Journal of the American College of Cardiology (2018)