tbuckley/cabot-search huggingface dataset:
Drug Interactions With Non–Vitamin K Oral Anticoagulants
Authors: Nan Wang, Erika Giblin, Jo Ellen Rodgers
Journal: JAMA (2018)

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Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice
Authors: Juan‐Li Duan, Bai Ruan, Xian‐Chun Yan, Liang Liang, Ping Song, Zi‐Yan Yang, Yuan Liu, Ke‐Feng Dou, Hua Han, Lin Wang
Journal: Hepatology (2018)

Liver sinusoidal endothelial cells (LSECs) critically regulate liver homeostasis and diseases through angiocrine factors. Notch is critical in endothelial cells (ECs). In the current study, Notch signaling was activated by inducible EC‐specific expression of the Notch intracellular domain (NIC). We found that endothelial Notch activation damaged liver homeostasis. Notch activation resulted in decreased fenestration and increased basement membrane, and a gene expression profile with decreased LSEC‐associated genes and increased continuous EC‐associated genes, suggesting LSEC dedifferentiation. Consistently, endothelial Notch activation enhanced hepatic fibrosis (HF) induced by CCl 4 . Notch activation attenuated endothelial nitric oxide synthase (eNOS)/soluble guanylate cyclase (sGC) signaling, and activation of sGC by 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole (YC‐1) reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte‐supporting angiocrine profile of LSECs by down‐regulating critical hepatocyte mitogens, including Wnt2a, Wnt9b, and hepatocyte growth factor (HGF). This led to compromised hepatocyte proliferation under both quiescent and regenerating conditions. Whereas expression of Wnt2a and Wnt9b was dependent on eNOS‐sGC signaling, HGF expression was not rescued by the sGC activator, suggesting heterogeneous mechanisms of LSECs to maintain hepatocyte homeostasis. Conclusion: Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through eNOS‐sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (LR). (H epatology 2018).
Diagnosis of LVAD Thrombus using a High-Avidity Fibrin-Specific <sup>99m</sup>Tc Probe
Authors: Grace Cui, Walter J. Akers, Michael J. Scott, Michael Nassif, John S. Allen, Anne H. Schmieder, Krishna S. Paranandi, Akinobu Itoh, Dmitry D. Beyder, Samuel Achilefu, Gregory A. Ewald, Gregory M. Lanza
Journal: Theranostics (2018)

Treatment of advanced heart failure with implantable LVADs is increasing, driven by profound unmet patient need despite potential serious complications: bleeding, infection, and thrombus.The experimental objective was to develop a sensitive imaging approach to assess early thrombus accumulation in LVADs under operational high flow and high shear rates.Methods: A monomeric bifunctional ligand with a fibrin-specific peptide, a short spacer, and 99m Tc chelating amino acid sequence (F1A) was developed and compared to its tetrameric PEG analogue (F4A).Results: 99m Tc attenuation by LVAD titanium (1 mm) was 23%.99m Tc-F1A affinity to fibrin was Kd ~10 µM, whereas, the bound 99m Tc-F4A probe was not displaced by F1A (120,000:1).Human plasma interfered with 99m Tc-F1A binding to fibrin clot (p<0.05) in vitro, whereas, 99m Tc-F4A targeting was unaffected.The pharmacokinetic half-life of 99m Tc-F4A was 28% faster (124±41 min) than 99m Tc-F1A (176±26 min) with both being bioeliminated through the urinary system with negligible liver or spleen biodistribution.In mice with carotid thrombus, 99m Tc-F4A binding to the injured carotid was much greater (16.3±3.3 %ID/g, p=0.01) than that measured with an irrelevant negative control, 99m Tc-I4A (3.4±1.6 %ID/g).In an LVAD mock flow-loop (1:1, PBS:human plasma:heparin) operating at maximal flow rate, 99m Tc-F4A bound well to phantom clots in 2 min (p<0.05),whereas 99m Tc-F1A had negligible targeting.Excised LVADs from patients undergoing pump exchange or heart transplant were rewired, studied in the mock flow loop, and found to have spatially variable fibrin accumulations in the inlet and outlet cannulas and bearings.Conclusions: 99m Tc-F4A is a high-avidity prototype probe for characterizing thrombus in LVADs that is anticipated to help optimize anticoagulation, reduce thromboembolic events, and minimize pump exchange.
<i>Demodex</i> mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea
Authors: N. Lacey, A. Russell-Hallinan, C.C. Zouboulis, F.C. Powell
Journal: British Journal of Dermatology (2018)

Rosacea is a common facial skin disorder mainly affecting middle-aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as an important factor. The Demodex mite population in the skin of rosacea patients is significantly higher than in patients with normal skin, suggesting that they may be of aetiological importance in this disorder.To determine the potential of Demodex mites to interact with the host immune system.Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalized SZ95 sebocyte line. Time- and mite-dose-dependent experiments were performed. Direct effects of Demodex and effects of the medium in which Demodex had been cultured were evaluated on the Toll-like receptor (TLR) signalling pathway on both a gene and protein expression level.Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards downmodulation of genes in this pathway was observed. A subsequent switch to positive gene upregulation was recorded after 48 h of coculture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced proinflammatory cytokine secretion, whereas lower numbers did not.Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalized human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced interleukin-8 secretion by these cells.
A localised skin reaction after chemotherapy
Authors: Jennifer Kahan, Russell Banner
Journal: BMJ (2018)

A 51 year old woman with metastatic endometrial cancer presented with well demarcated erythema and discomfort over her lower lumbar back (fig 1, fig 2). She had recently started paclitaxel chemotherapy. Five weeks before starting the paclitaxel, she had received a single fraction of radiotherapy to an L2 vertebral metastasis.



Fig 1 
Initial skin reaction of erythema, 10 days after starting paclitaxel





Fig 2 
Lumbar skin reaction (6×12 cm) four weeks after starting paclitaxel. Marked erythema and desquamation are evident



What is the skin reaction?

### Short answer

This is radiation recall dermatitis. It is a localised acute inflammatory skin reaction at the site of previous radiation, which follows administration of a promoting agent—usually a chemotherapeutic agent.

A true radiation recall reaction typically presents when chemotherapy is given between seven and 40 days after radiotherapy.1 However, onset is variable.

Painful erythema in radiation recall dermatitis is …
Membership of the London College of Osteopathic Medicine
Authors: David Soodeen
Journal: BMJ (2009)

The Membership of the London College of Osteopathic Medicine (MLCOM) course is diploma equivalent for people with a medical degree and an interest in musculoskeletal problems. It is appropriate for someone who needs more diagnostic skills and wants to do more than prescribe non-steroidal anti-inflammatory drugs and injections. The course is also for doctors who may be looking for a practical qualification that leads to registration with the General Osteopathic Council (the equivalent to the General Medical Council for all osteopaths).

I took the course in 2006-7 after ten years as a general practitioner, following a three year modular course in musculoskeletal …
A prospective multicenter trial of S-1 with lafutidine vs S-1 as adjuvant chemotherapy for gastric cancer in Japan: AEOLUS.
Authors: Nozomu Machida, Masanori Terashima, Keisei Taku, Takashi Daimon, Masashi Kimura, Akihisa Sugimoto, Hirofumi Yasui, Isao Nozaki, Norimasa Fukushima, Akinori Takagane, Yongil Kim, Nobuhiro Takiguchi, Masakazu Takagi, Kazunari Misawa, Taisei Kimura, Masato Maeda, Toshikazu Kanai, Mitsuhiko Ota, Hidetarou Yokoyama
Journal: Journal of Clinical Oncology (2018)

91 Background: From the result of ACTS-GC study, adjuvant chemotherapy with S-1 for one year is standard therapy of gastric cancer in Japan. In this study, completion rate of pre-planned S-1 treatment was 65.8% and there is still room for improvement on this rate. Lafutidine is a H2 blocker and enhances submucosal blood flow via capsaicin-sensitive afferent neurons. Alleviating effect of lafutidine on toxicity of 5FU leading to discontinuation of adjuvant treatment could be expected. Methods: Patients with histologically confirmed stage II (excluding T1 cases), IIIA, or IIIB (Japanese Classification of Gastric Carcinoma 13th) who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive S-1 with lafutidine(L) or S-1 (S). All patients were given S-1 (40mg/m 2 ) for 4 weeks with 2 weeks rest, repeated for 1 year after surgery. Patients of L group received lafutidine (20mg/day) every day for 1 year with S-1. The primary end point was treatment completion rate (TCR) of S-1. Definition of treatment completion was S-1 continuation for 1 year with over 70% planned dose. The secondary end points were toxicity (CTCAE v3.0) and relative total administration dose (RD) of S-1. Results: We randomly assigned 101 patients to the L group and 101 patients to the S group between February 2010 and December 2012 from 17 centers in Japan. After randomization, two patients were found to be ineligible in L group (the absence of cytologic examination of the peritoneal fluid, stageIB) and 1 in S group (allocation violation). TCR was 68.3% in the L group and 60.4% in the S group (p = 0.072, Cochran-Mantel-Haenzel test at a pre-specified one-sided significance level of 0.1). Adverse events of grade 3/4 excluding ineligible example was 30.0% in the L group, and 36.0% in the S group. Patients who require a dose reduction and/or delay of S-1 was 41.6% in the L group, and 51.5% in the S group. RD was 83.9% (range: 1.6-103.7) in the L group, and 84.0% (range: 1.7-103.8) in the S group. No any toxicity of lafutidine was observed. Conclusions: Lafutidine may increase a completion rate of adjuvant chemotherapy using S-1 within a 30% dose reduction for gastric cancer. This result need to be confirmed in double-blind placebo control study. Clinical trial information: UMIN000002703.
Recollections of a researcher
Authors: Arun Natarajan
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.
Yleaf: Software for Human Y-Chromosomal Haplogroup Inference from Next-Generation Sequencing Data
Authors: Arwin Ralf, Diego Montiel González, Kaiyin Zhong, Manfred Kayser
Journal: Molecular Biology and Evolution (2018)

Next-generation sequencing (NGS) technologies offer immense possibilities given the large genomic data they simultaneously deliver. The human Y-chromosome serves as good example how NGS benefits various applications in evolution, anthropology, genealogy, and forensics. Prior to NGS, the Y-chromosome phylogenetic tree consisted of a few hundred branches, based on NGS data, it now contains many thousands. The complexity of both, Y tree and NGS data provide challenges for haplogroup assignment. For effective analysis and interpretation of Y-chromosome NGS data, we present Yleaf, a publically available, automated, user-friendly software for high-resolution Y-chromosome haplogroup inference independently of library and sequencing methods.
Real-world experience with cabozantinib in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Emily Lemke, Amishi Yogesh Shah, Anuradha Chandramohan, Matthew T. Campbell, Michael VanAlstine, Eric Jonasch, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2018)

684 Background: Cabozantinib (C) inhibits tyrosine kinase activity at MET, AXL, and VEGF receptors and is approved in mccRCC after progression on prior VEGFR-TKI. Little off-protocol data exists on tolerability and response. Methods: We retrospectively gathered baseline and treatment details on mccRCC patients treated with C at MD Anderson from 2015-present. Blinded radiologist determined best response by RECIST 1.1. Descriptive statistics were utilized. Results: We report on 38 patients with mccRCC treated with C in a “real-world” setting. Median age at mccRCC diagnosis was 58 years (range 37-71). 25 patients (66%) were male. 22 (58%) had de-novo metastatic disease. 4 patients had sarcomatoid dedifferentiation. 32 (84%) underwent nephrectomy. Cohort had a median of 3 sites of metastatic disease, including: bone 22 (57%), liver 9 (23%), and brain 6 (16%). 6 patients (16%) received C as 2 nd line therapy, 10 (26%) as 3 rd line, and 22 (58%) as 4 th line or later. By IMDC risk score, 7 (18%) were favorable, 22 (58%) were intermediate, and 9 (24%) were poor risk. All patients had received at least 1 prior VEGFR-TKI and 24 (63%) had received prior immune checkpoint inhibitor. At C initiation, 20 (53%) patients had unfavorable neutrophil to lymphocyte ratio (NLR) of ≥ 3. 12 (32%) patients had favorable shift of NLR to &lt; 3 on C. 22 patients (58%) required dose reduction and 24 (63%) required treatment break due to C-related toxicity. At time of analysis, 26 patients had discontinued treatment, with median time on treatment of 32.2 weeks (range 15.7-130.7 weeks). For the 12 patients remaining on C, median duration of therapy has been 54.3 weeks (range 26.6-68.9 weeks). 1 (3%) patient had CR, 11 patients (29%) had PR, 23 (60%) had SD, and 3 (8%) had PD as best response to C. Conclusions: C has a high disease control rate (92%) even as a late line of therapy in mccRCC. However, careful monitoring is warranted as many patients require treatment breaks and dose reductions for therapy-related toxicity. [Table: see text]
Targeting CD14 on blood derived cells improves intracortical microelectrode performance
Authors: Hillary W. Bedell, John K. Hermann, Madhumitha Ravikumar, Shushen Lin, Ashley Rein, Xujia Li, Emily Molinich, Patrick D. Smith, Stephen M. Selkirk, Robert H. Miller, Steven Sidik, Dawn M. Taylor, Jeffrey R. Capadona
Journal: Biomaterials (2018)
Abstract 13189: Traumatic Bleeding Severity Score (TBSS) based Initiation of Massive Transfusion Results in Earlier Transfusion and Improved Outcomes in Severely Injured Trauma Patients With Hemorrhagic Shock: A Prospective Interventional Study
Authors: Takayuki Ogura, Alan K Lefor, Kenji Fujizuka, Mitsunobu Nakamura, Minoru Nakano
Journal: Circulation (2016)

Introduction: The Traumatic Bleeding Severity Score (TBSS) classifies the need for massive transfusion (MT) in severely in cured trauma patients. We showed that 95% of trauma patients with TBSS &gt;/= 17 need MT (Fig. 1, 2A). We hypothesized that the TBSS-guided activation of MT protocol can achieve early initiation of transfusion and improve the outcome of trauma patients with hemorrhagic shock. Methods: A single center prospective, interventional, and observational study was performed, which enrolled trauma patients admitted from 2013 to 2015 (TBSS-guided). In this group, the MT protocol was activated with a TBSS &gt;/= 17 (Fig. 2B). Outcomes were compared with historical controls (2010-2012) who underwent MT, initiated without specific guidance (No-guidance). Patients resending in cardiac arrest or diagnosed with severe brain injury (GCS&lt;6) were excluded. Results: A total of 119 patients were enrolled. The TBSS-guided group included 47, with 72 in the No-guidance group. There was no significant difference between the groups regarding injury severity score, vital signs, amount of transfusion, transfusion ratio ( red blood cells / fresh frozen plasma), and TBSS. In the TBSS-guided group, the time from admission to activation of MT protocol was shorter (100.1 minutes vs 32.7 minutes, p&lt;0.001), the calculated probability of survival was lower (85.6% vs 75.0%, p=0.026), but observed 30-day survival was higher (91.5% vs 69.4%, p=0.004), compared to the No-guidance group. Conclusion: TBSS based initiation of MT results in earlier transfusion and improved outcomes of severely injured trauma patients with hemorrhagic shock.
Advances in studies of tyrosine kinase inhibitors and their acquired resistance
Authors: Qinlian Jiao, Lei Bi, Yidan Ren, Shuliang Song, Qin Wang, Yun-shan Wang
Journal: Molecular Cancer (2018)

Protein tyrosine kinase (PTK) is one of the major signaling enzymes in the process of cell signal transduction, which catalyzes the transfer of ATP-γ-phosphate to the tyrosine residues of the substrate protein, making it phosphorylation, regulating cell growth, differentiation, death and a series of physiological and biochemical processes. Abnormal expression of PTK usually leads to cell proliferation disorders, and is closely related to tumor invasion, metastasis and tumor angiogenesis. At present, a variety of PTKs have been used as targets in the screening of anti-tumor drugs. Tyrosine kinase inhibitors (TKIs) compete with ATP for the ATP binding site of PTK and reduce tyrosine kinase phosphorylation, thereby inhibiting cancer cell proliferation. TKI has made great progress in the treatment of cancer, but the attendant acquired acquired resistance is still inevitable, restricting the treatment of cancer. In this paper, we summarize the role of PTK in cancer, TKI treatment of tumor pathways and TKI acquired resistance mechanisms, which provide some reference for further research on TKI treatment of tumors.
TRENDS, MANAGEMENT PATTERNS AND PREDICTORS OF LEAVING AGAINST MEDICAL ADVICE AMONG PATIENTS WITH DOCUMENTED NON-COMPLIANCE ADMITTED FOR ACUTE MYOCARDIAL INFARCTION
Authors: Gbolahan Ogunbayo, Naoki Misumida, Karam Ayoub, Le Dung Ha, Meera Marji, Samy Elayi, Ahmed Abdel-Latif, Adrian Messerli, Khaled Ziada
Journal: Journal of the American College of Cardiology (2018)
I am an international medical graduate and have completed my internship (PRHO) in India as per GMC advice before PLAB. Am I eligible for foundation year 2 posts?
Authors: Anne Hastie
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 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>
How can I safely return to work after maternity leave?
Authors: Abi Rimmer
Journal: BMJ (2018)

Laura Hamilton, consultant orthopaedic hand surgeon at Brighton and Sussex University Hospital, says, “Returning to work after months of maternity leave is daunting. Some people attend paid ‘keep in touch’ days to keep their skills up, however everything comes back to you very quickly once you start.

“When returning to work, a mother may ask for less than full time working arrangements, but an employer is under no obligation to agree. Following the Deech Report on women doctors,1 the General Medical Council began working with the royal colleges to improve access to flexible training and part time working. If a worker is breast feeding, their employer must support them with facilities to rest and pump, as well as a fridge to store collected breast milk.

“Good childcare is crucial for a smooth return to work. Unfortunately, long hours and shift work can be difficult to plan for. …
Becoming an instructor in advanced life support
Authors: Rob Morrison
Journal: BMJ (2004)

Being an approved instructor for the Resuscitation Council UK can be rewarding, fun, and a good way to learn teaching skills and keep your knowledge of resuscitation up to date. Whether you're interested in advanced life support (ALS) or advanced paediatric life support (APLS), here are some tips

The first step is to be put forward by the relevant course faculty …
Two-Year Trends of Taxane-Induced Neuropathy in Women Enrolled in a Randomized Trial of Acetyl-L-Carnitine (SWOG S0715)
Authors: Dawn L Hershman, Joseph M Unger, Katherine D Crew, Cathee Till, Heather Greenlee, Lori M Minasian, Carol M Moinpour, Danika L Lew, Louis Fehrenbacher, James L Wade, Siu-Fun Wong, Michael J Fisch, N Lynn Henry, Kathy S Albain
Journal: JNCI Journal of the National Cancer Institute (2017)

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect of taxanes. Acetyl-L-carnitine (ALC) was unexpectedly found to increase CIPN in a randomized trial. We investigated the long-term patterns of CIPN among patients in this trial. S0715 was a randomized, double-blind, multicenter trial comparing ALC (1000 mg three times a day) with placebo for 24 weeks in women undergoing adjuvant taxane-based chemotherapy for breast cancer. CIPN was measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale at weeks 12, 24, 36, 52, and 104. We examined NTX scores over two years using linear mixed models for longitudinal data. Individual time points were examined using linear regression. Regression analyses included stratification factors and the baseline score as covariates. All statistical tests were two-sided. Four-hundred nine subjects were eligible for evaluation. Patients receiving ALC had a statistically significantly (P = .01) greater reduction in NTX scores (worse CIPN) of –1.39 points (95% confidence interval [CI] = –2.48 to –0.30) than the placebo group. These differences were particularly evident at weeks 24 (–1.68, 95% CI = –3.02 to –0.33), 36 (–1.37, 95% CI = –2.69 to –0.04), and 52 (–1.83, 95% CI = –3.35 to –0.32). At 104 weeks, 39.5% on the ALC arm and 34.4% on the placebo arm reported a five-point (10%) decrease from baseline. For both treatment groups, 104-week NTX scores were statistically significantly different compared with baseline (P < .001). For both groups, NTX scores were reduced from baseline and remained persistently low. Twenty-four weeks of ALC therapy resulted in statistically significantly worse CIPN over two years. Understanding the mechanism of this persistent effect may inform prevention and treatment strategies. Until then, the potential efficacy and harms of commonly used supplements should be rigorously studied.