tbuckley/cabot-search huggingface dataset:
Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis
Authors: Pierre-Simon Bellaye, Chiko Shimbori, Toyoshi Yanagihara, David A. Carlson, Philip Hughes, Chandak Upagupta, Seidai Sato, Nolan Wheildon, Timothy Haystead, Kjetil Ask, Martin Kolb
Journal: European Respiratory Journal (2018)

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity through worsening dyspnoea and overall functional decline. IPF is characterised by apoptosis-resistant myofibroblasts, which are a major source for the excessive production of extracellular matrix (ECM) overtaking normal lung tissue. We sought to study the role of heat shock protein (HSP) isoforms HSP90α and HSP90β, whose distinct roles in lung fibrogenesis remain elusive. We determined the level of circulating HSP90α in IPF patients (n=31) and age-matched healthy controls (n=9) by ELISA. The release of HSP90α and HSP90β was evaluated in vitro in primary IPF and control lung fibroblasts and ex vivo after mechanical stretch on fibrotic lung slices from rats receiving adenovector-mediated transforming growth factor-β1. We demonstrate that circulating HSP90α is upregulated in IPF patients in correlation with disease severity. The release of HSP90α is enhanced by the increase in mechanical stress of the fibrotic ECM. This increase in extracellular HSP90α signals through low-density lipoprotein receptor-related protein 1 (LRP1) to promote myofibroblast differentiation and persistence. In parallel, we demonstrate that the intracellular form of HSP90β stabilises LRP1, thus amplifying HSP90α extracellular action. We believe that the specific inhibition of extracellular HSP90α is a promising therapeutic strategy to reduce pro-fibrotic signalling in IPF.
Association of Preoperatively Diagnosed Patent Foramen Ovale With Perioperative Ischemic Stroke
Authors: Pauline Y. Ng, Andrew K.-Y. Ng, Balachundhar Subramaniam, Sara M. Burns, Fanny Herisson, Fanny P. Timm, Cand Med, Maira I. Rudolph, Cand Med, Flora Scheffenbichler, Cand Med, Sabine Friedrich, Cand Med, Timothy T. Houle, Deepak L. Bhatt, Matthias Eikermann
Journal: JAMA (2018)

<h3>Importance</h3> Perioperative stroke is a major complication for patients undergoing surgery. Patent foramen ovale (PFO) represents a possible anatomical link between venous thrombosis and stroke. <h3>Objective</h3> To determine whether a preoperatively diagnosed PFO is associated with increased risk of perioperative ischemic stroke. <h3>Design, Setting, and Participants</h3> Retrospective cohort study from Massachusetts General Hospital and 2 affiliated community hospitals between January 1, 2007, and December 31, 2015. Participants were 182 393 consecutive adults undergoing noncardiac surgery with general anesthesia. <h3>Exposures</h3> Preoperatively diagnosed PFO. <h3>Main Outcomes and Measures</h3> Perioperative ischemic stroke occurring within 30 days of surgery; stroke subtype by Oxfordshire Community Stroke Project classification and stroke severity by National Institute of Health Stroke Scale (NIHSS). <h3>Results</h3> Among the 150 198 patient cases analyzed (median [SD] age, 55 [16] years), 1540 (1.0%) had a diagnosis of PFO before surgery. A total of 850 (0.6%) ischemic strokes occurred within 30 days of surgery (49 [3.2%] among patients with PFO and 801 [0.5%] among patients without PFO). In adjusted analyses, patients with PFO had an increased risk of ischemic stroke compared with patients without PFO (odds ratio, 2.66 [95% CI, 1.96-3.63];<i>P</i> &lt; <i>.</i>001). The estimated risks of stroke were 5.9 for every 1000 patients with PFO and 2.2 for every 1000 patients without PFO (adjusted absolute risk difference, 0.4% [95% CI, 0.2%-0.6%). Patients with PFO also had an increased risk of large vessel territory stroke (relative risk ratio, 3.14 [95% CI, 2.21-4.48];<i>P</i> &lt; <i>.</i>001) and a more severe stroke-related neurologic deficit measured by NIHSS (median, 4 [interquartile range {IQR}, 2-10] vs median, 3 [IQR, 1-6] for those without PFO;<i>P</i> = <i>.</i>02). <h3>Conclusions and Relevance</h3> Among adult patients undergoing noncardiac surgery at 3 hospitals, having a preoperatively diagnosed PFO was significantly associated with increased risk of perioperative ischemic stroke within 30 days after surgery. Further research is needed to confirm these findings and to determine whether interventions would decrease this risk.
Outcomes with chemotherapies and molecular characteristics of <i>HER2</i>-mutant lung cancers.
Authors: Juliana Eng, Bob T. Li, Meier Hsu, Jamie E. Chaft, Maria E. Arcila, Mark G. Kris
Journal: Journal of Clinical Oncology (2015)

8068 Background: Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations occur in 3% of lung adenocarcinomas and are increasingly being identified with the growing adoption of multiplex next-generation genotyping. HER2-mutant lung cancers impart a distinct natural history with a median overall survival from stage IV diagnosis of 1.6 years (Kris JAMA 2014). While case reports and series have shown activity of HER2-targeted agents in these patients, little is known about outcomes of systemic treatments. Methods: Patients with stage IV HER2-mutant lung cancers at Memorial Sloan Kettering were reviewed. Patient demographics, types of HER2 mutations, survival, and duration of systemic treatments were documented. Results: 37 patients with HER2-mutant lung cancers were identified: median age 62; majority were women (n = 24), never smokers (n = 21), and had adenocarcinomas (n = 36, 1 adenosquamous). A 12bp in-frame insertion in exon 20 (p.A775_G776insYVMA c.2324_2325ins12) was present in 23 (62%, 95% CI 45-78%) patients. In addition, there were four 9bp insertions, one 6bp insertion, and five 3bp insertions in exon 20, and four single base pair substitutions (3 exon 20, 1 exon 8). The median overall survival from date of diagnosis of stage IV disease was 2.3 years (95% CI 1.2-2.7). The median duration of all chemotherapy was 8 months (range 0.8-43 months). Median duration of treatment was 6 months for pemetrexed ±platinum/bevacizumab, 3 months for taxane ±platinum/bevacizumab, 4 months for gemcitabine, 4 months for vinorelbine, 5 months for mitomycin vinblastine. The median duration of targeted therapy was 3 months for trastuzumab, 4 months for small molecule HER2 tyrosine kinase inhibitors, 3 months for erlotinib. No objective responses were noted with trastuzumab (n = 2) or lapatinib (n = 4) alone. Conclusions: Most HER2-mutant lung tumors demonstrate an identical 12bp in-frame insertion (YVMA) in exon 20. In our cohort, the median duration of treatment with chemotherapy was double that of HER2-targeted therapies. Pemetrexed-containing regimens had the longest duration of treatment. As we search for better targeted therapies for patients with HER2-mutant lung cancers, chemotherapy remains an important component of care.
Junior doctors call for further strikes from September
Authors: Abi Rimmer
Journal: BMJ (2016)

The BMA’s Junior Doctors Committee is calling for escalated industrial action from September to resolve issues over the proposed new contract that the committee says the government has not dealt with.

In a letter sent to members on Thursday 11 August, Ellen McCourt, the committee’s chair, said that the committee had decided to reject the proposed new contract for junior doctors in England in full and to call for formal renegotiations https://twitter.com/McCourtEllen/status/763815538460065792. “In response to the government’s silence, the JDC [executive] has today made a formal request for a special meeting of BMA Council to authorise a rolling …
Avelumab in patients with previously treated metastatic melanoma: Phase 1b results from the JAVELIN Solid Tumor trial.
Authors: Ulrich Keilholz, Janice M. Mehnert, Sebastian Bauer, Hugues Pierre Bourgeois, Manish R. Patel, Donald Gravenor, John J. Nemunaitis, Matthew H. Taylor, Lucjan Wyrwicz, Keun-Wook Lee, Vijay Kasturi, Kevin M. Chin, Anja von Heydebreck, James L. Gulley
Journal: Journal of Clinical Oncology (2018)

191 Background: Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is approved for the treatment of metastatic Merkel cell carcinoma (US and EU) and advanced urothelial carcinoma progressed on platinum therapy (US). Here, we report phase 1b data for avelumab in a cohort of patients (pts) with previously treated metastatic melanoma. Methods: Pts with unresectable stage IIIC or IV melanoma progressed after ≥1 line of therapy for metastatic disease received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs; NCI CTCAE v4.0). Results: As of Dec 31, 2016, 51 pts were treated and followed for a median of 24.2 mo (range 16.1–31.5). Median age was 64 y (range 31–84). Site of primary tumor was cutaneous (n = 28, 54.9%), ocular (n = 16, 31.4%), mucosal (n = 2, 3.9%), or unknown (n = 5, 9.8%). Pts had received a median of 2 prior lines of therapy for advanced disease (range 0–4), including ipilimumab (n = 26, 51.0%). Confirmed ORR was 21.6% (95% CI 11.3–35.3), with complete response in 7.8% and partial response in 13.7%. In pts with cutaneous melanoma, ORR was 28.6% (95% CI 13.2–48.7). There were no objective responses in pts with ocular melanoma; however, 7 pts (43.8%) had stable disease. In pts with ≤1 (n = 25), 2 (n = 17), or ≥3 (n = 9) prior lines, ORR was 36.0% (95% CI 18.0–57.5), 11.8% (95% CI 1.5–36.4), and 0% (95% CI 0–33.6), respectively. Antitumor activity by PD-L1 status will be presented. Median duration of response was not estimable (NE) (95% CI 2.6 mo–NE). Median PFS was 3.1 mo (95% CI 1.4–6.3) and the 6-mo PFS rate was 39.2% (95% CI 25.2–52.9). Median OS was 18.5 mo (95% CI 9.3–NE) and the 12-mo OS rate was 62.3% (95% CI 46.9–74.4). 39 pts (76.5%) had a treatment-related (TR)AE, most commonly infusion-related reaction (25.5%), fatigue (17.6%), and chills (11.8%). 4 pts (7.8%) had a grade ≥3 TRAE. 5 pts (9.8%) had an immune-related AE; all were grade 1/2. No treatment-related deaths occurred. Conclusions: Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in pts with previously treated metastatic melanoma. Clinical trial information: NCT01772004.
Paediatricians condemn treatment of Bawa-Garba
Authors: Ingrid Torjesen
Journal: BMJ (2018)

Paediatricians have denounced the criminal prosecution of Hadiza Bawa-Garba for gross negligence manslaughter, warning that the decision undermines safe care because it inhibits learning from errors.

Doctors attending the Royal College of Paediatrics and Child Health’s annual general meeting in Glasgow unanimously passed a motion on 15 March saying, “This College considers [that] the criminal prosecution of dedicated doctors for gross negligence manslaughter, following systemic errors, impairs the advancement of safe healthcare for patients.”

An explanatory note said that Bawa-Garba’s conviction, and the General Medical Council’s (GMC) successful appeal to the High Court to erase her from the medical register after the Medical Practitioners Tribunal Service had decided not to strike her off,1 “not only inhibits learning from errors, but fails to understand the …
How is a trust house officer job different from a regular preregistration house officer job?
Authors: Simon Eccles
Journal: BMJ (2005)

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 (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.
BENEFIT OF TACROLIMUS/MYCOPHENOLATE TO REDUCE CARDIAC ALLOGRAFT VASCULOPATHY AFTER HEART TRANSPLANTATION
Authors: Alistair Aaronson, Michelle Kittleson, Jignesh Patel, Matthew Rafiei, Ashley Osborne, David Chang, Lawrence Czer, Jon Kobashigawa
Journal: Journal of the American College of Cardiology (2013)
Abstract P1-10-16: <i>In vitro</i> delivery of model fluorescent dyes through the mammary papilla
Authors: SL Kurtz, LB Lawson
Journal: Cancer Research (2018)

Abstract In the United States, 100,000 women each year are diagnosed with atypical hyperplasia (AH), significantly increasing their risk of developing breast cancer. However, only 40% of patients accept breast cancer preventive treatment, in part, due to systemic side effects. The localization of pre-cancerous cells within the ducts or lobules of the breast permits a local treatment strategy employing the innate mammary ducts. This expansive tree-like structure extends throughout the entire breast and may serve as a conduit for local delivery of therapeutics, thereby minimizing side effects associated with current preventive treatment strategies. This study examines how lipophilicity influences diffusion through porcine tissue using a model hydrophilic dye, Sulforhodamine B (SRB), and a model lipophilic dye, Nile Red (NR). Porcine nipple or skin tissue was positioned in a Franz diffusion cell and the formulations were applied topically. With equivalent dye concentrations applied to the donor surface, we noted no significant difference in total dye permeation when comparing diffusion through skin versus nipple tissue or when comparing SRB versus NR after 48 hours. However, the diffusion coefficient for both NR and SRB through the nipple was almost 700-fold greater compared to through the skin indicating improved drug delivery via the nipple. Additionally, after 48 hours there was significantly higher retention of SRB in the nipple and skin compared to NR. When we further looked at the distribution of each dye within the nipple using fluorescence microscopy, we saw a distinction in the localization of each dye. Fluorescence micrographs show that lipophilic NR is retained within the ducts while the hydrophilic SRB diffuses throughout the entire tissue section, suggesting that hydrophobicity impacts the ability of molecules to diffuse from the duct into the surrounding tissue. This suggests that lipophilic carriers may be effective for delivery of cancer therapeutics or preventative agents targeting the mammary ducts, where AH is localized. Citation Format: Kurtz SL, Lawson LB. In vitro delivery of model fluorescent dyes through the mammary papilla [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 P1-10-16.
Abstract P3-04-06: Genomic analysis of cancers arising in breasts with different mammographic density
Authors: KL Gorringe, S Hughes, C Nickson, L Devereux, V Pridmore, SM Rowley, DJ Byrne, D Cheasley, AM Kavanagh, GB Mann, SB Fox, IG Campbell
Journal: Cancer Research (2018)

Abstract Background: High mammographic density (MD) is a known risk factor for breast cancer, but it is currently unknown whether this altered microenvironment leads to the development of genomically different tumours. Method: We used lifepool, an Australian prospective population-based cohort of over 53,000 women currently in a mammographic screening program, to identify &amp;gt;1000 cases of breast carcinoma (in situ and invasive breast cancer) for analysis. Pathology reports, detection modality (screen-detected/interval), MD data (AutoDensity, Nickson et al., 2013 DOI:10.1186/bcr3474), germline DNA and tumor tissue were available for a subset of cases. Tumours were classified into quintiles, depending on the relative MD ranking of the most recent normal mammogram. Tumour DNA was analysed using Affymetrix OncoScan MIP arrays or using a targeted Agilent SureSelect and Illumina sequencing panel of 105 genes relevant to breast cancer. Copy number and mutation data were compared between tumours from the highest (high-MD) and lowest (low-MD) quintiles of MD. Results: Preliminary analysis found no significant differences in clinico-pathological features between tumours from breasts with high-MD (n=38) and low-MD (n=35). Genomic analysis of 8 high-MD tumours and 8 low-MD tumours identified chromosome 15 loss as being significantly enriched in low-MD tumours. Only Low-MD tumours to date contained TP53 mutation (3/8). Data will be presented from at least an additional 9 low-MD and 15 high-MD tumours currently undergoing genomic assays. Conclusion: When complete, our data will be the first to evaluate the somatic genetic events in tumours arising in low-MD and high-MD breasts. Although our cohort to date is small, it may be possible that tumours from extremes of MD have different genomic characteristics. Citation Format: Gorringe KL, Hughes S, Nickson C, Devereux L, Pridmore V, Rowley SM, Byrne DJ, Cheasley D, Kavanagh AM, Mann GB, Fox SB, Campbell IG. Genomic analysis of cancers arising in breasts with different mammographic density [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 P3-04-06.
Molecular allergen profiling in horses by microarray reveals Fag e 2 from buckwheat as a frequent sensitizer
Authors: L. Einhorn, G. Hofstetter, S. Brandt, E. K. Hainisch, I. Fukuda, K. Kusano, A. Scheynius, I. Mittermann, Y. Resch‐Marat, S. Vrtala, R. Valenta, E. Marti, C. Rhyner, R. Crameri, R. Satoh, R. Teshima, A. Tanaka, H. Sato, H. Matsuda, I. Pali‐Schöll, E. Jensen‐Jarolim
Journal: Allergy (2018)

Companion animals are also affected by IgE-mediated allergies, but the eliciting molecules are largely unknown. We aimed at refining an allergen microarray to explore sensitization in horses and compare it to the human IgE reactivity profiles.Custom-designed allergen microarray was produced on the basis of the ImmunoCAP ISAC technology containing 131 allergens. Sera from 51 horses derived from Europe or Japan were tested for specific IgE reactivity. The included horse patients were diagnosed for eczema due to insect bite hypersensitivity, chronic coughing, recurrent airway obstruction and urticaria or were clinically asymptomatic.Horses showed individual IgE-binding patterns irrespective of their health status, indicating sensitization. In contrast to European and Japanese human sensitization patterns, frequently recognized allergens were Aln g 1 from alder and Cyn d 1 from Bermuda grass, likely due to specific respiratory exposure around paddocks and near the ground. The most prevalent allergen for 72.5% of the tested horses (37/51) was the 2S-albumin Fag e 2 from buckwheat, which recently gained importance not only in human but also in horse diet.In line with the One Health concept, covering human health, animal health and environmental health, allergen microarrays provide novel information on the allergen sensitization patterns of the companion animals around us, which may form a basis for allergen-specific preventive and therapeutic concepts.
Quebec doctors reject pay rise in favour of investment in health system
Authors: Barbara Kermode-Scott
Journal: BMJ (2018)

Hundreds of doctors in Quebec are turning down pay rises, saying that they are too embarrassed to accept the higher payments while colleagues and patients are struggling in a health system beset by years of drastic cuts and restructuring. The doctors have asked the provincial government to instead invest the money in improving Quebec’s health system.

“The only thing that seems to be immune to cuts is our remuneration,” states the advocacy group Quebec Doctors for Public Health Care (known by the acronym MQRP) in a letter posted online on 25 February to …
LETTER OF THE MONTH Clothes maketh the junior doctor
Authors: Elizabeth A Martin
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.
Organ Dysfunction After Surgery in Patients Treated With Individualized or Standard Blood Pressure Management
Authors: Kelsey Mitchell, Douglas Adams, Stephen M. McHugh
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Association between circulating tumor DNA (ctDNA) detection and radiographic tumor burden (rTB) in advanced bladder and upper tract (UT) cancer patients.
Authors: Manuel C. Maia, Lorena Almeida, Nazli Dizman, Paulo Gustavo Bergerot, Richard B. Lanman, Kimberly Banks, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2018)

485 Background: In a series of 217 patients (pts) with advanced bladder cancer, ctDNA was detected in 89% (Grivas P et al ASCO GU 2017). We hav e previously reported an association between ctDNA detection and rTB in metastatic renal cell carcinoma (Maia et al ASCO 2017); it is unknown whether the same correlation exists in advanced bladder/UT cancers. Methods: Data was obtained from pts with advanced bladder or UT cancer from a single institution. Pts received ctDNA profiling as part of routine clinical care using a CLIA-certified platform assessing a panel of up to 73 genes. Clinicopathologic and radiographic data was obtained, including histology, Bajorin risk criteria and sum of longest diameter (SLD - a surrogate for rTB) from most proximal scan to ctDNA test. Results: A total of 36 pts (27:9 M:F) with a median age of 68 (range, 43-99) were assessed, with a total of 59 ctDNA tests. 3 tests were excluded due to lack of associated radiographic data. Primary site was bladder and UT for 26 and 10 pts, respectively. In total, 31 pts had metastatic disease and 5 pts locally advanced disease. Metastatic pts were characterized as having good and intermediate Bajorin risk in 15 and 16 cases, respectively (no poor risk pts were identified). Most proximal therapy to ctDNA test was cytotoxic chemotherapy in 19 cases, immunotherapy in 10 cases and a combination in 2 cases, while 5 pts did not receive any systemic treatment. Median number of genomic alterations (GAs) was 3 (range, 0-18). A significant association between ctDNA detection and SLD was found (p = 0.029). Furthermore, a correlation between cumulative mutant allele fraction and SLD was detected (R 2 = 0.39; p = 0.003). The most frequent GAs in the cohort were in TP53, MET and KRAS, occurring in 10%, 5.6% and 5.6% of the cases, respectively. Serially collected ctDNA assessments and corresponding rTB data will be presented at the meeting. Conclusions: Detection of ctDNA was significantly associated with rTB, and a positive correlation between rTB and cumulative mutant allele fraction was also observed. Given the modest sample size, we are confirming these findings in larger validation series.