tbuckley/cabot-search huggingface dataset:
It’s time we paved a healthier path of least resistance
Authors: Jessica A Renzella, Alessandro R Demaio
Journal: British Journal of Sports Medicine (2018)

Inspiring and retaining interest, investment and action to prevent tomorrow’s health threats today is notoriously difficult. This is particularly true when the resulting future well-being may not be realised for years, or even decades. The outcome is a lack of political and societal prioritisation for disease prevention, accompanied by a pernicious rise in avoidable health burden.

Obesity is now the biological, environmental and social path of least resistance in most societies. Despite being entirely avoidable, an estimated 1.9 billion adults and 41 million children under 5 years are overweight, worldwide.1 2 Addressing the drivers of obesity through evidence-based structural and political responses is key, yet such action largely continues to evade us.

But what if we could shape obesity solutions as rapidly as we build our cities? What if our cities could make achieving and maintaining healthy weight easier?

For the first time in history, more than half of the global population lives in cities, and almost four in every ten adults are overweight or obese.1 3 With obesity and urbanisation on the rise, the built environments in which people work, live, eat and move are increasingly recognised to have a …
XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype
Authors: Myron K. Evans, Michael C. Brown, Joseph Geradts, Xuhui Bao, Timothy J. Robinson, Mohit Kumar Jolly, Peter B. Vermeulen, Gregory M. Palmer, Matthias Gromeier, Herbert Levine, Michael A. Morse, Steven J. Van Laere, Gayathri R. Devi
Journal: Cancer Research (2018)

Abstract Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), in vivo tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intravital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular cross-talk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited. Significance: Signaling by the MNK kinase is essential in inflammatory breast cancer, and it can be targeted to inhibit XIAP–NFκB signaling and the aggressive phenotype of this malignancy. Cancer Res; 78(7); 1726–38. ©2018 AACR.
Half of CCGs now fully authorised to commission in England
Authors: Helen Jaques
Journal: BMJ (2013)

A total of 63 of the 130 clinical commissioning groups (CCGs) given conditions in the first three waves of authorisation have now met all their conditions and do not require national support to carry out their functions, NHS England has announced. As a result, half (106) of the 211 CCGs taking over £65bn of the NHS commissioning budget in England this month are doing so …
Targeting DNA damage response to overcome taxane resistance.
Authors: Olivia Chao, Oscar B. Goodman
Journal: Journal of Clinical Oncology (2018)

312 Background: Overcoming taxane resistance in metastatic castrate-resistant prostate cancer (mCRPC) is an unmet need. We and others have observed that a significant proportion of patients with docetaxel (Dox)-refractory disease exhibit sensitivity to DNA-damaging agents. Conversely, loss of DNA repair proteins has been shown to confer resistance to anti-microtubule agents. We hypothesize that Dox exposure alters expression of DNA damage response (DDR) genes, promoting Dox-resistance; and targeting these changes would restore Dox sensitivity. Methods: Dox-resistant prostate cancer cells were developed by exposing DU145 cells to stepwise increasing Dox concentration. Resistance was confirmed by comparing viability (MTT assay) of DU-R (Dox-resistant) and DU-P (age-matched parent) cells after 72 h exposure to Dox (0.1 – 100 nM). Changes in gene expression between DU-DR and DU-P were measured using a DDR-specific 84 gene PCR array. Genes with &gt; 2-fold change in expression were confirmed by RT-PCR and immunoblotting. Sensitivity to Dox of DU-DR was measured in presence of candidate gene inhibitors. Effects of Dox + inhibitor on cell cycle and apoptosis were analyzed by flow cytometry. Results: DU-DR was significantly more resistant to Dox than DU-P (IC50 DU-DR vs DU-P: &gt; 100nM vs 0.86 nM), cabazitaxel (Cab) (9.48 nM vs 0.32 nM), and etoposide (Eto) (4.67 μM vs 1.32 μM) but not 4-hydroperoxy cyclophosphamide (4-HC) (4.50 μM vs 3.16 μM). DDR PCR array revealed three genes were significantly upregulated ( TP73, PRKDC, CDK7) and two downregulated ( BBC3, MSH3); and confirmed by RT-PCR and immunoblotting. DNA-PKc inhibitor, NU7441, treatment significantly increased sensitivity of DU-DR cells to Dox (IC50 = 30.7 nM). Similarly, NU7441 also re-sensitized DU-DR cells to Cab and Eto but not 4-HC. Dox did not induce apoptosis in DU-DR cells (sub-G1 = 2.54 ± 0.15 %; Annexin V + /PI - = 3.60 ± 0.58%) unlike in DU-P (sub-G1 = 39.4 ± 0.28 %; Annexin V + /PI - 28.6 ± 1.1%). NU7441 increased sub-G1 (15.8 ± 0.99 %) and Annexin V + /PI - (14.5 ± 1.4 %) population in Dox-treated DU-DR cells. Conclusions: Targeting prostatic DNA-PKc restores sensitivity to taxanes in vitro. Co-targeting these genes may lead to novel mCRPC therapies.
I have not worked in medicine for eight years and want to come back in a part time job—preferably term time. I don't have any postgraduate qualifications. Any advice?
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>
Enhanced Redox State and Efficiency of Glucose Oxidation With miR Based Suppression of Maladaptive NADPH-Dependent Malic Enzyme 1 Expression in Hypertrophied Hearts
Authors: Ryan Lahey, Andrew N. Carley, Xuerong Wang, Carley E. Glass, Kevin D. Accola, Scott Silvestry, J. Michael O’Donnell, E. Douglas Lewandowski
Journal: Circulation Research (2018)

Rationale: Metabolic remodeling in hypertrophic hearts includes inefficient glucose oxidation via increased anaplerosis fueled by pyruvate carboxylation. Pyruvate carboxylation to malate through elevated ME1 (malic enzyme 1) consumes NADPH necessary for reduction of glutathione and maintenance of intracellular redox state. Objective: To elucidate upregulated ME1 as a potential maladaptive mechanism for inefficient glucose oxidation and compromised redox state in hypertrophied hearts. Methods and Results: ME1 expression was selectively inhibited, in vivo, via non-native miR-ME1 (miRNA specific to ME1) in pressure-overloaded rat hearts. Rats subjected to transverse aortic constriction (TAC) or Sham surgery received either miR-ME1 or PBS. Effects of ME1 suppression on anaplerosis and reduced glutathione (GSH) content were studied in isolated hearts supplied 13 C-enriched substrate: palmitate, glucose, and lactate. Human myocardium collected from failing and nonfailing hearts during surgery enabled RT-qPCR confirmation of elevated ME1 gene expression in clinical heart failure versus nonfailing human hearts ( P &lt;0.04). TAC induced elevated ME1 content, but ME1 was lowered in hearts infused with miR-ME1 versus PBS. Although Sham miR-ME1 hearts showed no further reduction of inherently low anaplerosis in normal heart, miR-ME1 reduced anaplerosis in TAC to baseline: TAC miR-ME1=0.034±0.004; TAC PBS=0.081±0.005 ( P &lt;0.01). Countering elevated anaplerosis in TAC shifted pyruvate toward oxidation in the tricarboxylic acid cycle. Importantly, via the link to NADPH consumption by pyruvate carboxylation, ME1 suppression in TAC restored GSH content, reduced lactate production, and ultimately improved contractility. Conclusions: A maladaptive increase in anaplerosis via ME1 in TAC is associated with reduced GSH content. Suppressing increased ME1 expression in hypertrophied rat hearts, which is also elevated in failing human hearts, reduced pyruvate carboxylation thereby normalizing anaplerosis, restoring GSH content, and reducing lactate accumulation. Reducing ME1 induced favorable metabolic shifts for carbohydrate oxidation, improving intracellular redox state and enhanced cardiac performance in pathological hypertrophy.
A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite
Authors: Neville K Kisalu, Azza H Idris, Connor Weidle, Yevel Flores-Garcia, Barbara J Flynn, Brandon K Sack, Sean Murphy, Arne Schön, Ernesto Freire, Joseph R Francica, Alex B Miller, Jason Gregory, Sandra March, Hua-Xin Liao, Barton F Haynes, Kevin Wiehe, Ashley M Trama, Kevin O Saunders, Morgan A Gladden, Anthony Monroe, Mattia Bonsignori, Masaru Kanekiyo, Adam K Wheatley, Adrian B McDermott, S Katie Farney, Gwo-Yu Chuang, Baoshan Zhang, Natasha Kc, Sumana Chakravarty, Peter D Kwong, Photini Sinnis, Sangeeta N Bhatia, Stefan H I Kappe, B Kim Lee Sim, Stephen L Hoffman, Fidel Zavala, Marie Pancera, Robert A Seder
Journal: Nature Medicine (2018)
Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling
Authors: Pernilla Roswall, Matteo Bocci, Michael Bartoschek, Hong Li, Glen Kristiansen, Sara Jansson, Sophie Lehn, Jonas Sjölund, Steven Reid, Christer Larsson, Pontus Eriksson, Charlotte Anderberg, Eliane Cortez, Lao H Saal, Christina Orsmark-Pietras, Eugenia Cordero, Bengt Kristian Haller, Jari Häkkinen, Ingrid J G Burvenich, Elgene Lim, Akira Orimo, Mattias Höglund, Lisa Rydén, Holger Moch, Andrew M Scott, Ulf Eriksson, Kristian Pietras
Journal: Nature Medicine (2018)
Tumor-derived exosomes antagonize innate antiviral immunity
Authors: Liang Gao, Lin Wang, Tong Dai, Ke Jin, Zhengkui Zhang, Shuai Wang, Feng Xie, Pengfei Fang, Bing Yang, Huizhe Huang, Hans van Dam, Fangfang Zhou, Long Zhang
Journal: Nature Immunology (2018)
Doctors welcome push for parents to use pharmacies but urge caution in emergencies
Authors: Abi Rimmer
Journal: BMJ (2018)

Doctors have welcomed a campaign launched by NHS England which urges parents to take their children to pharmacies to treat minor illnesses. But they said that in emergencies or when parents were genuinely unsure they should always seek medical advice.

NHS England launched a campaign to promote the use of pharmacies for minor health problems on 12 February,1 saying that parents could get more timely advice by going to their pharmacist first, instead of their GP.

The Royal College of …
How do I migrate to work as a GP in Dubai?
Authors: Rodger Charlton
Journal: BMJ (2007)

Have a career related problem that needs answering? Can9t find the 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>
PRIOR CORONARY ARTERY BYPASS GRAFTING AND INCIDENT CARDIOVASCULAR EVENTS IN THE SETTING OF CONTEMPORARY MEDICAL THERAPY: INSIGHTS FROM ACCELERATE
Authors: Adam J. Nelson, Stephen Nicholls, A. Lincoff, Venu Menon, Jeffrey Riesmeyer, Giacomo Ruotolo, Kathy Wolski, Ellen McErlean, Steven Nissen
Journal: Journal of the American College of Cardiology (2018)
GP workforce will be grown at “fastest rate possible,” says HEE
Authors: Abi Rimmer
Journal: BMJ (2015)

Health Education England (HEE) is committed to growing the GP workforce at the “fastest rate possible” in 2015-16, the organisation has said.

The commitment was outlined in the organisation’s plan for medical education and training in 2015-16, which will form the basis of the postgraduate medical recruitment process.1 HEE said that it would fund 209 new GP training posts over this period, in addition to the 222 that it added in 2014-15.

Despite an unprecedented third round of recruitment, 12% of GP …
The contribution of chronic intermittent hypoxia to OSAHS: From the perspective of serum extracellular microvesicle proteins
Authors: Huina Zhang, Fan Yang, Yichen Guo, Li Wang, Fang Fang, Hao Wu, Shaoping Nie, Yifan Wang, Man-Lung Fung, Yu Huang, Haiteng Deng, Yanwen Qin, Xinliang Ma, Yongxiang Wei
Journal: Metabolism (2018)
Nasal epithelium as a proxy for bronchial epithelium for smoking-induced gene expression and expression Quantitative Trait Loci
Authors: Kai Imkamp, Marijn Berg, Cornelis J. Vermeulen, Irene H. Heijink, Victor Guryev, Huib A.M. Kerstjens, Gerard H. Koppelman, Maarten van den Berge, Alen Faiz
Journal: Journal of Allergy and Clinical Immunology (2018)
Patients prioritize local recurrence risk over other attributes for surgical treatment of facial melanomas—Results of a stated preference survey and choice-based conjoint analysis
Authors: Jeremy R. Etzkorn, Scott D. Tuttle, Ilya Lim, Elea M. Feit, Joseph F. Sobanko, Thuzar M. Shin, Donald E. Neal, Christopher J. Miller
Journal: Journal of the American Academy of Dermatology (2018)
Doctors are advised on how to deal with Valentine’s cards from patients
Authors: Ingrid Torjesen
Journal: BMJ (2012)

Any doctor who receives a Valentine’s card or gift from a patient has been warned by the Medical Defence Union to tell the patient that this is inappropriate behaviour and that their relationship is a professional one and must remain so.

Most doctors will never face unwanted amorous advances or attention from patients, but occasions such as Valentine’s Day may prompt patients who have feelings for their …
Eculizumab: A Review in Generalized Myasthenia Gravis
Authors: Sohita Dhillon
Journal: Drugs (2018)

The humanized monoclonal antibody eculizumab (Soliris®) is a complement inhibitor indicated for use in anti-acetylcholine receptor (AChR) antibody-positive adults with generalized myasthenia gravis (gMG) in the USA, refractory gMG in the EU, or gMG with symptoms that are difficult to control with high-dose IVIg therapy or PLEX in Japan. It is the first complement inhibitor to be approved for use in these patients. In the well-designed, 26-week REGAIN study in patients with anti-AChR-positive refractory gMG, although a statistically significant benefit of eculizumab over placebo in the prespecified primary endpoint analysis (change from baseline in MG-activities of daily living (ADL) score assessed by worst-rank ANCOVA) was not formally demonstrated, preplanned and post hoc sensitivity analyses of this outcome, as well as other secondary outcomes supported the efficacy of eculizumab. Overall, patients receiving eculizumab experienced significant improvements in the ADL, muscle strength and health-related quality of life (HR-QOL) parameters relative to patients receiving placebo. Moreover, an ongoing extension of REGAIN showed that treatment benefits with eculizumab were sustained during continued therapy for at least 52 weeks. Eculizumab was generally well tolerated in these studies, with a tolerability profile similar to that reported previously in other indications. Although several questions remain, such as duration of treatment, cost effectiveness and long-term efficacy and tolerability, current evidence indicates that eculizumab is a valuable emerging therapy for patients with refractory gMG.
Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study
Authors: Matteo Zignol, Andrea Maurizio Cabibbe, Anna S Dean, Philippe Glaziou, Natavan Alikhanova, Cecilia Ama, Sönke Andres, Anna Barbova, Angeli Borbe-Reyes, Daniel P Chin, Daniela Maria Cirillo, Charlotte Colvin, Andrei Dadu, Andries Dreyer, Michèle Driesen, Christopher Gilpin, Rumina Hasan, Zahra Hasan, Sven Hoffner, Alamdar Hussain, Nazir Ismail, S M Mostofa Kamal, Faisal Masood Khanzada, Michael Kimerling, Thomas Andreas Kohl, Mikael Mansjö, Paolo Miotto, Ya Diul Mukadi, Lindiwe Mvusi, Stefan Niemann, Shaheed V Omar, Leen Rigouts, Marco Schito, Ivita Sela, Mehriban Seyfaddinova, Girts Skenders, Alena Skrahina, Sabira Tahseen, William A Wells, Alexander Zhurilo, Karin Weyer, Katherine Floyd, Mario C Raviglione
Journal: The Lancet Infectious Diseases (2018)

In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis.Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing.Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87-94) for rpoB (rifampicin resistance), 86% (74-93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39-68) for pncA (pyrazinamide resistance), 85% (77-91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81-92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing.Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation.Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.
Royal college acts to temper workload of consultant psychiatrists
Authors: Helen Jaques
Journal: BMJ (2012)

Consultant psychiatrists are increasingly under pressure of time and resources as a result of the financial cutbacks in the NHS, the Royal College of Psychiatrists has said.

Job plans and job descriptions need to be drawn up in such a way as to ensure that consultants have the time to deliver the high quality care that is needed and also the time and resources to fulfil their non-clinical roles in service development, innovation, teaching, and management, said Laurence Mynors-Wallis, the college’s registrar.

“Consultant time is under pressure and will become even more under pressure as the financial difficulties …
Letter by Khan and Boyle Regarding Article, “Early Use of N-Acetylcysteine (NAC) With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Reduces Myocardial Infarct Size (The NACIAM Trial [ <i>N</i> -Acetylcysteine in Acute Myocardial Infarction])”
Authors: Arshad A. Khan, Andrew J. Boyle
Journal: Circulation (2018)
Why all the fuss about paediatric ACL rupture: isn’t the meniscus much more important?
Authors: Nicholas Mohtadi, Clare L Ardern, Lars Engebretsen
Journal: British Journal of Sports Medicine (2018)

When Ava, a 13-year-old basketball player, tried to change direction quickly to drive past her opponent, her knee buckled and she developed an acute haemarthrosis. Ava saw a general practitioner and a physiotherapist who advised her to ice her knee and regain her motion. She initially improved, obtained an over-the-counter brace and returned to playing basketball. The full extent of her injury was not recognised. Ava had weekly episodes of knee giving way when playing basketball and stopped playing her favourite sport. She continued to have a feeling of instability, swelling and pain with her daily activities.

Four months after her injury, MRI of Ava’s knee confirmed the ACL rupture and a lateral meniscal tear. By the time she had a surgical appointment and an arthroscopy her lateral meniscus was almost absent; nothing separated the lateral femoral condyle and the adjacent tibial plateau (figure 1). We will never know the extent of the original injury to Ava’s lateral meniscus. However, we might suspect that the lack of early and specific recognition of the problem and the subsequent recurrent giving way episodes aggravated meniscal damage.



Figure 1 
Lateral compartment of the knee with only a small …
THE RISING PREVALENCE OF DILATED MID ASCENDING AORTA: MEASURING THE BURDEN OF DISEASE
Authors: Ji Ae Yoon, Mirza Mujadil Ahmad, Muhammad Nabeel Syed, Mirza Nubair Ahmad, Sharmeen Fatima Hussaini, Mustafa Noor Muhammad, Muhammad Harris Pir, Bijoy K. Khandheria, A. Jamil Tajik, Khawaja Afzal Ammar
Journal: Journal of the American College of Cardiology (2018)
Biofunctionalized aligned microgels provide 3D cell guidance to mimic complex tissue matrices
Authors: Jonas C. Rose, David B. Gehlen, Tamás Haraszti, Jens Köhler, Christopher J. Licht, Laura De Laporte
Journal: Biomaterials (2018)

Natural healing is based on highly orchestrated processes, in which the extracellular matrix plays a key role. To resemble the native cell environment, we introduce an artificial extracellular matrix (aECM) with the capability to template hierarchical and anisotropic structures in situ, allowing a minimally-invasive application via injection. Synthetic, magnetically responsive, rod-shaped microgels are locally aligned and fixed by a biocompatible surrounding hydrogel, creating a hybrid anisotropic hydrogel (Anisogel), of which the physical, mechanical, and chemical properties can be tailored. The microgels are rendered cell-adhesive with GRGDS and incorporated either inside a cell-adhesive fibrin or bioinert poly(ethylene glycol) hydrogel to strongly interact with fibroblasts. GRGDS-modified microgels inside a fibrin-based Anisogel enhance fibroblast alignment and lead to a reduction in fibronectin production, indicating successful replacement of structural proteins. In addition, YAP-translocation to the nucleus increases with the concentration of microgels, indicating cellular sensing of the overall anisotropic mechanical properties of the Anisogel. For bioinert surrounding PEG hydrogels, GRGDS-microgels are required to support cell proliferation and fibronectin production. In contrast to fibroblasts, primary nerve growth is not significantly affected by the biomodification of the microgels. In conclusion, this approach opens new opportunities towards advanced and complex aECMs for tissue regeneration.