tbuckley/cabot-search huggingface dataset:
Abstract 10826: GBT1118, a Potent Allosteric Modifier of Hemoglobin Oxygen Affinity Increases Tolerance to Hypoxia in Mice
Authors: Pedro Cabrales, Kobina Dufu, Athiwat Hutchaleelala, Qing Xu, Josh Lehrer-Graiwer, Uma Sinha
Journal: Circulation (2015)

Introduction: Adaptation to hypoxia involves several mechanisms that influence oxygen (O2) transport and utilization, including a reduction in hemoglobin (Hb) O2 affinity to favor the release of O2 to tissues. Paradoxically, increased Hb O2 affinity has been observed to have beneficial effects during severe hypoxia. Hypothesis: This study was designed to test the hypothesis that pharmacologically increasing Hb O2 affinity with GBT1118 can augment O2 transport during severe hypoxia (10 and 5% O2). Method: Mice were orally dosed with GBT1118 (70 or 140 mg/kg) or only vehicle (Control), and Hb O2 affinity was determined by hemoximetry. During hypoxia, changes in systemic and microvascular hemodynamics, tissue partial pressure of O2 (PO2) and tissue hypoxia were evaluated. At each timepoint, mice with adequate systolic blood pressure (BP) were counted as survived and mice with severe hypotension (BP ≤60 mmHg) were counted as non-survived and were euthanized. Results: Similar trends were observed at 10 and 5% O2 hypoxia. GBT1118 at 70 and 140 mg/kg decreased the P50 (PO2 at which blood is 50% saturated with O2) by 29 and 35 mmHg, respectively. During 5% O2 hypoxia, GBT1118 at 70 and 140 mg/kg increased SaO2 from 40% (Control) to 57% (70mg/kg) and 80% (140mg/kg), respectively. Moreover, mean BP and heart rate (HR) decreased to 50 mmHg and 375 bpm in control mice, whereas GBT1118-dosed mice sustained higher mean BP and HR in a dose-dependent fashion and improved survival (Figure 1). In addition, GBT1118 preserved microvascular blood flow and tissue oxygenation; consequently, GBT1118 reduced heart and brain hypoxic areas compared with control groups during hypoxia. Conclusion: Under severe hypoxia, GBT1118-mediated increase in Hb O2 affinity increases SaO2. At the tissue level, local milieu allows for efficient O2 extraction leading to improved oxygenation as measured by decreased lactic acidosis, improved cardiovascular function and ultimately, survival.
GPR56/ADGRG1 regulates development and maintenance of peripheral myelin
Authors: Sarah D. Ackerman, Rong Luo, Yannick Poitelon, Amit Mogha, Breanne L. Harty, Mitchell D’Rozario, Nicholas E. Sanchez, Asvin K.K. Lakkaraju, Paul Gamble, Jun Li, Jun Qu, Matthew R. MacEwan, Wilson Zachary Ray, Adriano Aguzzi, M. Laura Feltri, Xianhua Piao, Kelly R. Monk
Journal: The Journal of Experimental Medicine (2018)

Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADGRG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin—a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed “plectinopathies”—as a novel interacting partner of GPR56. Finally, we show that Gpr56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define Gpr56 as a new regulator in the development and maintenance of peripheral myelin.
The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling
Authors: Gaia Botteri, Laia Salvadó, Anna Gumà, D. Lee Hamilton, Paul J. Meakin, Gemma Montagut, Michael L.J. Ashford, Victoria Ceperuelo-Mallafré, Sonia Fernández-Veledo, Joan Vendrell, María Calderón-Dominguez, Dolors Serra, Laura Herrero, Javier Pizarro, Emma Barroso, Xavier Palomer, Manuel Vázquez-Carrera
Journal: Metabolism (2018)
Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer
Authors: R.J. Hartmaier, S.E. Trabucco, N. Priedigkeit, J.H. Chung, C.A. Parachoniak, P. Vanden Borre, S. Morley, M. Rosenzweig, L.M. Gay, M.E. Goldberg, J. Suh, S.M. Ali, J. Ross, B. Leyland-Jones, B. Young, C. Williams, B. Park, M. Tsai, B. Haley, J. Peguero, R.D. Callahan, I. Sachelarie, J. Cho, J.M. Atkinson, A. Bahreini, A.M. Nagle, S.L. Puhalla, R.J. Watters, Z. Erdogan-Yildirim, L. Cao, S. Oesterreich, A. Mathew, P.C. Lucas, N.E. Davidson, A.M. Brufsky, G.M. Frampton, P.J. Stephens, J. Chmielecki, A.V. Lee
Journal: Annals of Oncology (2018)

BackgroundEstrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer.Patients and methodsTo identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287–395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots.ResultsWe identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3′ partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations.ConclusionsCollectively, these data indicate that N-terminal ESR1 fusions involving exons 6–7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.
I would like to do an MD in any medical specialty to increase my chances of getting into type 1 specialist registrar training. How do I go about getting this degree? I have just completed my MRCP in medicine and will be completing my two year basic specialist training in August this year.
Authors: Justin Stebbing
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>
E-Cigarettes and the Harm-Reduction Continuum
Authors: Amy L. Fairchild, Ju Sung Lee, Ronald Bayer, James Curran
Journal: New England Journal of Medicine (2018)

In recent years, there has been a trend of acknowledging the importance of a harm-reduction approach in policy discussions about e-cigarettes. But some proposed strategies might well limit, if not entirely undermine, the population benefits associated with e-cigarettes.
The Findings on Bone Scintigraphy in Patients With Suspected Tumor-Induced Osteomalacia Should Not Be Overlooked
Authors: Ling Wang, Shu Zhang, Hongli Jing, Libo Chen, Zhenghua Wang, Fang Li
Journal: Clinical Nuclear Medicine (2018)

Tumor-induced osteomalacia (TIO) is a chronic, devastating disease. The causative tumor is usually a small benign one that is very difficult to localize. Because the presenting symptoms include diffuse bone pain, a bone scintigraphy is commonly performed to determine the cause of the pain before TIO is suspected. In this retrospective investigation, we tried to assess whether bone scintigraphy acquired will be helpful in the eventual identification of the culprit tumor.The images of bone scan and clinical charts of total 91 patients with confirmed TIO were retrospectively reviewed. The image findings were compared with the results of other imaging studies, surgical notes, histopathologic examinations and clinical follow-ups.In 76.9% (70 of 91) of the patients, the findings of bone scintigraphy did not correspond to the sites of the causative tumors, which were subsequently located. However, in 23.1% of the patients (21 of 91), the sites of the causative tumors corresponded to one of the abnormal technetium 99m-methyl diphosphonate activity on bone scintigraphy. More importantly, 6 tumors corresponded to the dominant activity on bone scintigraphy.Although findings of whole-body scintigraphy are nonspecific in patients with TIO, careful evaluation of bone scintigraphy results can be helpful in guiding further evaluation in some patients.
East Asia may have a better 1‐year survival following an acute heart failure episode compared with Europe: results from an international observational cohort
Authors: Eiichi Akiyama, Lucas N L Van Aelst, Mattia Arrigo, Johan Lassus, Òscar Miró, Jelena Čelutkienė, Dong-Ju Choi, Alain Cohen-Solal, Shiro Ishihara, Katsuya Kajimoto, Said Laribi, Aldo Pietro Maggioni, Justina Motiejunaite, Christian Mueller, Jiri Parenica, Jin Joo Park, Naoki Sato, Jindrich Spinar, Jian Zhang, Yuhui Zhang, Kazuo Kimura, Kouichi Tamura, Etienne Gayat, Alexandre Mebazaa
Journal: European Journal of Heart Failure (2018)
Commuting by bike
Authors: Maire Cooney
Journal: BMJ (2005)

Cycling is good for you, your wallet, and the environment. In cities, you'll get there faster. Here's how to do it well.

All you need is a bike, lights, and a good lock. A good secondhand bike costs around £150 ($280; €220). New bikes under £200 are often heavy. A light waterproof jacket, comfy trousers, and panniers make it a nicer …
MULTILAYER LEFT VENTRICULAR GLOBAL LONGITUDINAL STRAIN AND LEFT VENTRICULAR REMODELLING IN PATIENTS AFTER ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION
Authors: Rachid Abou, Laurien Goedemans, Edgard Prihadi, Martin Schalij, Nina Ajmone Marsan, Jeroen J. Bax, Victoria Delgado
Journal: Journal of the American College of Cardiology (2018)
Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up
Authors: Robert J. Kreitman, Martin S. Tallman, Tadeusz Robak, Steven Coutre, Wyndham H. Wilson, Maryalice Stetler-Stevenson, David J. FitzGerald, Linda Santiago, Guozhi Gao, Mark C. Lanasa, Ira Pastan
Journal: Blood (2018)
Nitric Oxide Production by PBMC from IgE+ Allergic Adults Varies with Time of Day and Correlates with Total Serum IgE and Exhaled Breath NO
Authors: Adam El Sehamy, Maja Nowakowski, Charles J. Kim, Telcan Ali Kizi, Helen G. Durkin, Rauno O. Joks
Journal: Journal of Allergy and Clinical Immunology (2018)
PREVALENCE OF CARDIOVASCULAR RISK FACTORS AND PROGNOSTIC SIGNIFICANCE OF CORONARY ARTERY CALCIUM IN INDIVIDUALS WITH LDL-C ≥190 MG/DL: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS
Authors: Pratik Sandesara, Wesley O’Neal, Heval Mohamed Kelli, Vasanth Sathiyakumar, Seth Martin, Michael Blaha, Roger Blumenthal, Laurence Sperling
Journal: Journal of the American College of Cardiology (2018)
Surgical re-excision vs. observation for histologically dysplastic naevi: a systematic review of associated clinical outcomes
Authors: K.T. Vuong, J. Walker, H.B. Powell, N.E. Thomas, D.E. Jonas, A.S. Adamson
Journal: British Journal of Dermatology (2018)

BackgroundThe management of histologically dysplastic naevi (HDN) with re‐excision vs. observation remains controversial because of lack of evidence about associated melanoma outcomes.
Addressing Potential Conflicts of Interest in Dermatology Clinical Practice Guidelines
Authors: Henry W. Lim, Craig A. Elmets, Wendy Smith Begolka
Journal: JAMA Dermatology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Ten treatments to avoid in patients with lower limb tendon pain
Authors: Jill L Cook
Journal: British Journal of Sports Medicine (2018)

Tendon pain and dysfunction are the presenting clinical features of tendinopathy. Research has investigated many treatment options, but consistent, positive, clinical outcomes remain elusive. We know that treatment should be active (eg, exercise-based), and that a consistent and ongoing investment in rehabilitation is required. It is important to maximise this investment by understanding (and conveying to patients) treatments that do not help. The following 10 points highlight treatment approaches to avoid as they do not improve lower limb tendinopathy.

1. Don’t rest completely. 

Rest decreases the load tolerance of tendon, and complete rest decreases tendon stiffness within 2 weeks.1 It also decreases strength and power in the muscle attached to the tendon and the function of the kinetic chain,2 and likely changes the motor cortex, leaving the person less able to tolerate load at multiple levels. Treatment should initially reduce painful, high tendon load (point 2) and introduce beneficial loads (eg, isometrics3). Once pain is low and stable (consistent …
Working shifts of 12 hours or more linked to burnout risk, researchers say
Authors: Abi Rimmer
Journal: BMJ (2015)

Working shifts of 12 hours or more is linked to a heightened risk of burnout and job dissatisfaction, researchers have found.

The study, published in the online journal BMJ Open , also found that hospital nurses who worked shifts of 12 hours or longer were more likely to want to leave their jobs.1

The researchers surveyed 31 627 registered hospital nurses, excluding those in intensive or …
Just 4% of UK doctors come from working class backgrounds
Authors: Caroline White
Journal: BMJ (2016)

Just 4% of UK doctors come from working class backgrounds, a report by the Social Mobility Commission has found.1

The commission’s fourth annual report found that 4% of doctors were from working class backgrounds, a proportion that was even lower than that of two other enclaves of privilege—law (6%) and journalism (11%).

The report said that an unfair education system was hampering efforts to widen participation from early childhood onwards, a disadvantage that economic and employment factors then compound.

Just 5% of children eligible for free school meals gained five A grades at GCSE. Poor careers advice and work experience opportunities meant that, even with the same GCSE results, one third more …
SINGLE CENTER EXPERIENCE: COMPARISON OF ONE YEAR SURVIVAL OF MORE THAN 120 PATIENTS WITH HEARTMATE 3 AND HEARTWARE HVAD
Authors: Marcus Müller, Gregor Richter, Christoph Hoermandinger, Felix Schoenrath, Volkmar Falk, Evgenij Potapov, Thomas Krabatsch
Journal: Journal of the American College of Cardiology (2018)
Multivitamin use and risk of prostate cancer recurrence: Data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE).
Authors: Erin Van Blarigan, Stacey A. Kenfield, Benjamin E Cedars, Jenny Broering, Janet E. Cowan, Peter Carroll, June M. Chan
Journal: Journal of Clinical Oncology (2018)

70 Background: Multivitamin (MV) use is common among men with prostate cancer (PCa). Yet, data on MV use and risk of PCa recurrence are limited. Methods: We conducted a prospective study among 1,373 men with non-metastatic PCa to examine whether MV use after diagnosis was associated with risk of recurrence. Participants completed a comprehensive lifestyle survey a median of 2 y after diagnosis and were followed through 2016. We defined an event of recurrence as the first of the following: PCa death, bone metastasis from PCa, biochemical recurrence, or initiation of secondary treatment. Multivariate Cox Proportional Hazards regression models were used to calculate hazards ratios (HRs) and 95% confidence intervals (CI) for the association between MV use and PCa recurrence. We adjusted for time between diagnosis and the survey, age at diagnosis, Gleason grade, clinical T-stage, PSA at diagnosis, smoking, BMI, walking pace, and primary treatment. We also explored whether age at diagnosis, BMI, time since diagnosis, smoking, or clinical features (grade, stage, treatment) modified the association between MV use and recurrence. Results: We observed 142 events of PCa recurrence over a median follow-up of 10 y; 858 (62%) men were current MV users, 216 (16%) were past users, and 299 (22%) were never users. Overall, MV use was not associated with risk of PCa recurrence (current vs. never HR: 0.69; 95% CI: 0.45, 1.07; p-trend: 0.09). However, long-term MV users (≥10 y; n = 396) had a 56% lower risk of PCa recurrence compared to never users (HR: 0.44; 95% CI: 0.25, 0.78; p-trend: 0.006). Additionally, treatment modified the association between MV use and risk of PCa recurrence ( p-interaction: 0.02). Among the 845 men who had a radical prostatectomy (RP), current MV users had a 44% lower risk of PCa recurrence compared to past/never users (HR: 0.56; 95% CI: 0.34, 0.91; p-value: 0.02). MV use was not associated with risk of PCa recurrence among the 441 men who did not have a RP. Conclusions: Long-term MV use may be associated with lower risk of PCa recurrence.
Effectiveness of Particle Radiotherapy in Various Stages of Hepatocellular Carcinoma: A Pilot Study
Authors: Yushi Sorin, Kenji Ikeda, Yusuke Kawamura, Shunichiro Fujiyama, Masahiro Kobayashi, Tetsuya Hosaka, Hitomi Sezaki, Norio Akuta, Satoshi Saitoh, Fumitaka Suzuki, Yoshiyuki Suzuki, Yasuji Arase, Hiromitsu Kumada
Journal: Liver Cancer (2018)

We analyzed the effectiveness of external particle radiotherapy (PRT) as an alternative therapy for various stages of hepatocellular carcinoma (HCC).Eighty-three patients with HCC underwent PRT in our hospital from 2007 to 2015 (proton beam radiation in 58 patients and carbon ion radiation in 25 patients), including patients with early-stage HCC (single HCC measuring ≤3 cm, Barcelona Clinic Liver Cancer [BCLC] stage 0 or A) (group A, n = 30), those with intermediate-stage HCC (HCCs measuring ≥3 cm but inoperable or multinodular and transcatheter arterial embolization [TACE]-refractory, BCLC stage B) (group B, n = 31), and those with advanced-stage HCC (HCC with portal invasion or extrahepatic metastasis) (group C, n = 22). The median radiation dose was 72.6 GyE (range 50-74) for proton beam radiation and 45.0 GyE (range 45-52.8) for carbon beam radiation. Local control ability was defined as continuous shrinkage of the tumor size without development of new lesions for ≥6 months after PRT.The rates of local control of the target tumor at 6 months, 1 year, and 2 years were 91.9, 86.3, and 84.8%, respectively. The overall survival rates at 1, 2, and 3 years were 83.0, 65.6, and 55.1%, respectively. Patients in group A showed the best survival rates (100.0% at 1 year and 85.9% at 2 years). The 1-year survival rate was poor in group C (63.6%) despite a good local tumor control rate of 74.7%. The overall survival rates were significantly better in groups A and B than in group C.The local control rates after PRT were sufficiently high compared to TACE or sorafenib. Thus, PRT should be adopted for patients with difficult-to-treat HCC in the early and intermediate stages.
Junior doctors take trust to court for denying them breaks every four hours
Authors: Clare Dyer
Journal: BMJ (2018)

A junior doctor has accused her former employer of breaching her contract by not allowing breaks every four hours, in a High Court test case with reverberations throughout the NHS.

Sarah Hallett is acting on behalf of herself and another 20 junior doctors who trained with Royal Derby Hospitals NHS Foundation Trust in 2013-14, when she was in her foundation year. In a case supported by the BMA they argue that they did not receive …
Studying the Effect of Vitamin D Supplementation on Vascular Function in CKD: A Work in Progress
Authors: Nnamdi Kelechi Nwaohiri
Journal: Journal of the American Society of Nephrology (2018)

I read with great interest the article “A randomized trial of vitamin D supplementation on vascular function in CKD” published by Kumar et al.1 in the Journal of the American Society of Nephrology. The study provided a clear demonstration of a beneficial effect of vitamin D supplementation on flow-mediated dilation (FMD).1 As the authors noted, this may mitigate the cardiovascular disease risk in CKD. However, I think the jury is still out about the consistency of the positive results shown in this study. For example, in contrast to the results of this study, a randomized clinical trial by Kendrick et al.2 showed no evidence of change in FMD in the brachial artery after 6 months of daily supplementation with cholecalciferol. Although the trial by Kendrick et al.2 did not compare cholecalciferol supplementation with a placebo group, the absence of dilation in response to either choleciferol or calcitriol was telling. I should also point out that there was a higher number of smokers in the trial by Kendrick et al.2 (approximately 49%) than in the trial by Kumar et al.1 (approximately 9%). Smoking is a known risk factor for arterial stiffness and cardiovascular disease.3 The Cardiovascular Health Study that investigated 5808 patients who were >65 years of age and had CKD revealed that traditional risk factors, including smoking, were associated with the largest absolute increases in risks for cardiovascular deaths among patients with CKD.3 I concur with the authors that the exclusion of patients with diabetes was a limitation of the study. This, of course, limits the generalizability to other populations, particularly because type 2 diabetes mellitus is the most common cause of CKD and ESRD worldwide.4 Incidentally, although the study by Kendrick et al.2 did include a high percentage of patients with diabetes (38%), there was no difference in the response of vitamin D on FMD by diabetes status. In conclusion, the finding of this study is important, because it may bring us closer to decreasing the scourge of cardiovascular morbidity and mortality frequently observed in patients with CKD. A broader and more diverse patient population will need to be studied to give us a more complete understanding of the effect of vitamin D on cardiovascular health in patients with CKD. Disclosures None.