tbuckley/cabot-search huggingface dataset:
PTH-102 Stat2 is a key inflammatory molecule in human non-alcoholic fatty liver disease and murine liver injury
Authors: W Alazawi, H Heath, G Petts, H Kudu, R Feakins, A O’Brien, R Goldin, GR Foster
Journal: Gut (2015)

<h3>Introduction</h3> In patients with non-alcoholic fatty liver disease (NAFLD), liver inflammation is a key histological feature that distinguishes benign simple steatosis from progressive non-alcoholic steatohepatitis (NASH). The mechanisms that underlie this process are poorly understood. We recently showed that <i>Stat2</i>plays a pivotal role in acute inflammation, independent of its role as an interferon mediator. The aim of the current study is to test the hypothesis that STAT2 is associated with hepatic inflammation in patients with NASH and in a murine model of liver injury. <h3>Method</h3> Expression of (phosphorylated, p) STAT2 and STAT1 was assessed by immunohistochemistry in anonymised sections of archived liver tissue taken from consenting patients with NASH at The Royal London and St Mary’s Hospitals (London, UK). STAT2<sup>-/-</sup>and WT mice were injected with incremental doses of carbon tetrachloride (CCl4) for 4 or 6 weeks. Serum and liver tissue were harvested 24 or 72hrs after the last injection. Immunohistochemistry for activated stellate cells (anti-alpha smooth muscle actin, aSMA) and macrophage/Kupfer cells (anti-F4/80) was performed. <h3>Results</h3> Tissue from 62 patients was examined. Hepatocyte nuclear expression in NASH liver tissue was significantly greater for STAT1 (74% vs 10%, p &lt; 0.0001) and STAT2 (98% vs 35%, p &lt; 0.0001) compared to normal liver. There was a significant correlation between STAT1 expression (r = 0.6, p = 0.02), but not STAT2 and the NAFLD activity score (NAS). Animal models confirm that Stat 2 plays a role in liver inflammation – <i>Stat2<sup>-/-</sup></i>mice were protected from CCl<sub>4</sub>-mediated liver injury with reduced serum alanine aminotransferase (ALT, 2165 vs 1090 iU/ml, p = 0.03), inflammation and necrosis histologically and fibrosis (Picrosirius red staining). There were no significant differences in the number of aSMA or F4/80-positive cells between WT and <i>Stat2<sup>-/-</sup></i>mice. <h3>Conclusion</h3> These data identify a novel role for STAT2 in the development of liver disease, with expression of STAT1 and STAT2 relating to disease grade. The protection afforded by Stat2 loss in murine models is unrelated to macrophage and stellate cell activation, and we hypothesise that the mechanism of protection is therefore reduced production of Stat2-mediated cytokine production. <h3>Disclosure of interest</h3> None Declared.
Multiplicity of Cell Response to the BAI Strain A (Myeloblastosis) Avian Tumor Virus. IV. Ultrastructural Characters of the Thymus in Myeloblastosis and of the Adenosinetrisphosphatase Activity of Thymic Cells and Associated Virus&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: G DE THE, U HEINE, J R SOMMER, L ARVY, D BEARD, J W BEARD
Journal: JNCI Journal of the National Cancer Institute (1963)
Ten towns that promote health to be built in England
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The NHS will support 10 areas of England to become “healthy towns” in a bid to tackle the country’s obesity crisis.

NHS England has outlined plans to create new communities with a focus on healthy living and will test solutions to tackle obesity, help people with dementia, and improve community cohesion. 

The new towns, which will accommodate more than 76 000 new homes, will test strategies such as fast food free zones near schools, “dementia friendly” streets, and newly designed green spaces.

Announcing the plans at the King’s Fund on 1 March, NHS England’s chief executive, Simon Stevens, said that it was important for the NHS to play a central role in shaping the towns from the start to help embed a healthy living ethos.

NHS England said that it would consult clinicians, designers, and technology experts to “re-imagine” how health and care …
Distribution of Cytogenetic Abnormalities in African American Multiple Myeloma Patients May be Unique for Different Geographic Regions
Authors: Manisha Bhutani, Preeya Patel, Myra M Robinson, Rupali Bose, Kyle Madden, Jill Eddy, Candice G Roth, James Symanowski, Tammy Cogdill, Jordan Robinson, Belinda R Avalos, Edward A. Copelan, Saad Z Usmani
Journal: Blood (2015)
Abstract 11567: STXBP5 Regulates Endothelial Exocytosis, Platelet Secretion and Thrombosis
Authors: Qiuyu Zhu, Munekazu Yamakuchi, Sara Ture, Maria de la Luz Garcia-Hernandez, Kyung Ae Ko, Kristina L Modjeski, Michael B LoMonaco, Andrew D Johnson, Christopher J O’Donnell, Yoshimi Takai, Craig N Morrell, Charles J Lowenstein
Journal: Circulation (2014)

Introduction:  Von Willebrand factor (VWF) levels predict the risk of MI and thrombosis, but the factors influencing VWF levels are not completely understood. Recent genome wide association studies (GWAS) have identified syntaxin binding protein 5(STXBP5) as a candidate gene linked to changes in VWF plasma levels, but the functional significance of STXBP5 is unknown.   Hypothesis:  We hypothesized that STXBP5 regulates endothelial cell exocytosis and thrombosis.   Methods:  We knocked down STXBP5 in endothelial cells and measured VWF release changes. We searched for interactions between STXBP5 and proteins that regulates vesicle trafficking. We conducted phenotypic analyses including endothelial exocytosis, platelet function assay, and thrombosis in wild-type and STXBP5 null mice. We performed murine bone marrow transplantation to identify the relative importance of endothelial and platelet STXBP5 in regulating thrombotic phenotypes.   Results:  STXBP5 is expressed in human endothelial cells and co-localizes and interacts with syntaxin 4 and synaptotagmin 1. Knockdown of STXBP5 increased endothelial exocytosis of VWF. Mice lacking Stxbp5 have higher plasma VWF level, increased P-selectin translocation, and more platelet-endothelial interactions. These data suggest STXBP5 inhibits endothelial exocytosis. Surprisingly, mice lacking Stxbp5 also display hemostasis defects, with prolonged tail bleeding time, and severely impaired mesenteric arteriole and carotid artery thrombi formation. Moreover, platelets from Stxbp5 null mice have defects in secretion and activation. Therefore, STXBP5 inhibits endothelial exocytosis, but promotes platelet secretion and thrombosis. Finally, plasma VWF level was unchanged by alteration of the bone marrow phenotype, but thrombotic phenotype was transferable with the bone marrow, suggesting STXBP5 in endothelial cells determines plasma VWF level, but STXBP5 in bone marrow-derived cells, presumably platelets, dominates the thrombotic phenotype.   Conclusions:  Our study reveals a dual vascular role for STXBP5: STXBP5 inhibits endothelial exocytosis but promotes platelet exocytosis. Our data in combination with prior GWAS suggest that STXBP5 is a novel regulator of venous thromboembolic disease.
Useful Measures in Prevention of Deep Vein Thrombosis in the Legs
Authors: E M NANSON
Journal: JAMA (1963)

THE THREE PROBABLE FACTORS INVOLVED IN DEEP VENOUS THROMBOSIS ARE: (1) stasis, (2) alteration in the endothelium of the veins, and (3) alteration in the clotting mechanism of the blood.Control of stasis is assisted by elevation of the foot of the bed and by the use of washable elastic stockings and early ambulation, together with foot exercises. To prevent damage to the endothelium of the veins during operation, the heels should be elevated off the operating table by means of a small rolled towel in order to take weight off the calf muscles. The use of elastic stockings demonstrated in diagrams and some of the fallacies in connection with their use are outlined.
What outcome after the prescription of neoadjuvant chemotherapy in lung cancer
Authors: Hanene Smadhi, Mohamed Sadok Boudaya, Adel Marghli, Fatma Charmiti, Sonia Ouerghi, Jalel Mohamed, Emna Brahem, Belhassen Smati, Taher Mestiri, Tarek Kilani
Journal: European Respiratory Journal (2011)

Background: The treatment of patients with locally advanced non-small-cell lung cancer is controversial. Surgery remains the gold standard treatment even in this group. Neoadjuvant chemotherapy could allow surgical resection in patients initially judged inoperable.

Methods: From January 2009 to May 2010, neoadjuvant chemotherapy was indicated in 27 patients with NSCLC (25 men, 2 women). The mean age was 65 years. The different stages were: IIB, 5; IIIA, 17 (with 6 of whom in stage IIIAN2); IIIB, 2 and IV, 3.

Results: Twenty-three patients received neoadjuvant chemotherapy, 2 refused the induction treatment and 2 had impaired their status. The neoadjuvant chemotherapy regimen was gemcitabine-cisplatin in 17 patients and vinorelbine-cisplatin in 6. Only 5 patients underwent complete surgical treatment after induction: stage IIB, 1; IIIAN0, 1; IIIB, 1 and IV, 2 (operated brain metastasis in one patient and operated adrenal metastasis in one other). Surgical treatment was not achieved after neoadjuvant chemotherapy in 18 patients because of progressive disease.

Conclusion: Neoadjuvant chemotherapy offers several potential benefits. But, it may delay surgery or eliminate eligibility as a surgical candidate. A patient's rigorous selection for this type of multimodal treatment is essential.
Abstract 5523: A novel aptamer targeting agent for prostate cancer
Authors: Bethany Powell Gray, Linsley Kelly, Matthew Levy, Bruce A. Sullenger
Journal: Cancer Research (2015)

Abstract Background: Prostate cancer is both the most common cancer diagnosis and the second most common cause of cancer-related death for men in the United States. An ideal new therapy would selectively deliver the drug to the tumor while also preventing toxicity in normal tissue. Methods and Results: Recent exciting clinical advances with antibody drug conjugates have resulted in FDA approval of such tumor-targeting therapies. However, antibodies are difficult to chemically modify, require humanization, and their large size hinders tumor penetration. Aptamers - small nucleic acid ligands - have many advantages over traditional antibody targeting agents, including ease of synthesis, amenability to chemical modification, and reversibility. Moreover, they exhibit antibody-like target affinities and specificities at a fraction of the size, allowing more efficient tumor penetration. We have identified an aptamer, termed E3, which selectively internalizes into prostate cancer cells, but does not target normal cells. Additionally, E3 targets and internalizes into a variety of other cancer types, including breast, ovarian, lung, colon, melanoma, glioblastoma, liver, and leukemia cancers. Linking the E3 aptamer to a deimmunized version of the Pseudomonas exotoxin (PE38) kills prostate cancer cells in vitro with an IC50 of 0.4-1.1 nM while displaying no measured toxicity towards normal cells, and linking E3 to the highly toxic auristatin drugs, MMAE or MMAF, kills prostate cancer cells in vitro with an IC50 of 5-12 nM. Significantly, E3 maintains its tumor-targeting abilities in vivo, targeting both prostate tumors and patient-derived colon cancer tumors in mice as evidenced by near-infrared in vivo imaging. Conclusions: Together, these studies show the potential therapeutic benefit of E3 drug targeting for the treatment of prostate cancer. Citation Format: Bethany Powell Gray, Linsley Kelly, Matthew Levy, Bruce A. Sullenger. A novel aptamer targeting agent for prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5523. doi:10.1158/1538-7445.AM2015-5523
P0788 : Estimating the cost-effectiveness of daclatasvir plus sofosbuvir in treatment-naïve, treatment-experienced and interferon-ineligible/intolerant patients with advanced chronic hepatitis C genotype 1 infection
Authors: P. McEwan, S. Webster, T. Ward, A. Kalsekar, Y. Yuan, M. Brenner
Journal: Journal of Hepatology (2015)
Dasatinib Treatment Induces Fast and Deep Responses In Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients In Chronic Phase: Clinical Results From a Randomized Phase 2 Study (NordCML006)
Authors: Henrik Hjorth-Hansen, Johan Richter, Leif Stenke, Hans Ehrencrona, Bjørn Tore Gjertsen, Tobias Gedde-Dahl, Perttu Koskenvesa, Claes Malm, Waleed Majeed, Lotta Ohm, Martin Hoglund, Ulla Olsson-Strömberg, Stina Söderlund, Merja Suominen, Kari Remes, Berit Markevärn, Bengt Simonsson, Kimmo Porkka, Satu Mustjoki
Journal: Blood (2013)
The epidemiology of childhood psoriasis: a scoping review
Authors: E. Burden‐Teh, K.S. Thomas, S. Ratib, D. Grindlay, E. Adaji, R. Murphy
Journal: British Journal of Dermatology (2016)

Psoriasis is an inflammatory noncommunicable skin disease that affects both adults and children. At present, the epidemiology and natural history of psoriasis are not widely understood. This scoping review aimed to map the existing literature on the epidemiology of childhood psoriasis, identify research gaps for future studies and provide a comprehensive, clinically useful review. Search strategies were developed for Ovid Medline, Ovid Embase, Google Scholar and hand searching. In total, 131 articles met the inclusion criteria and were mapped; 107 articles were included for data extraction. Over the last 25 years there has been a dramatic increase in the volume of published observational epidemiological studies on childhood psoriasis. The majority were case series or cross‐sectional studies, concentrated in Europe, Asia and North America. The prevalence of childhood psoriasis was found to be higher in European countries, older children and girls. Up to 48·8% of children had a family history of psoriasis in a first‐degree relative. The most frequent subtype was plaque psoriasis and the most common initial sites of presentation were the scalp, limbs and trunk. Specific genetic differences have been found between child‐onset and adult‐onset populations. Case–control and cohort studies investigating risk factors for psoriasis onset, comorbidities and long‐term health outcomes were extremely limited. The choice of study design and heterogeneity in methodology limit the validity and generalizability of the information, consistency of the results, and comparability of the studies. Well‐designed epidemiological studies are needed to provide precise and consistent information about the frequency and clinical presentation, risk factors, associated diseases and long‐term outcomes in childhood psoriasis.
Changes in Energy Metabolism after Continuous Positive Airway Pressure for Obstructive Sleep Apnea
Authors: Ryo Tachikawa, Kaori Ikeda, Takuma Minami, Takeshi Matsumoto, Satoshi Hamada, Kimihiko Murase, Kiminobu Tanizawa, Morito Inouchi, Toru Oga, Takashi Akamizu, Michiaki Mishima, Kazuo Chin
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Disrupted energy homeostasis in obstructive sleep apnea (OSA) may lead to weight gain. Paradoxically, treating OSA with continuous positive airway pressure (CPAP) may also promote weight gain, although the underlying mechanism remains unclear.Objectives: To explore the underlying mechanism by which patients with OSA gain weight after CPAP.Methods: A comprehensive assessment of energy metabolism was performed in 63 newly diagnosed OSA study participants (51 men; 60.8 ± 10.1 yr; apnea–hypopnea index >20 h−1) at baseline, CPAP initiation, and at a 3-month follow-up. Measurements included polysomnography, body weight, body composition, basal metabolic rate (BMR), hormones (norepinephrine, cortisol, leptin, ghrelin, insulin-like growth factor-1), dietary intake, eating behavior, and physical activity.Measurements and Main Results: BMR significantly decreased after CPAP (1,584 kcal/d at baseline, 1,561 kcal/d at CPAP initiation, and 1,508 kcal/d at follow-up; P < 0.001), whereas physical activity and total caloric intake did not significantly change. In multivariate regression, baseline apnea–hypopnea index, Δurine norepinephrine, and CPAP adherence were significant predictors of ΔBMR. The weight gainers had higher leptin levels, lower ghrelin levels, and higher eating behavior scores than the non–weight gainers, indicating a positive energy balance and disordered eating behavior among the weight gainers. Among the parameters related to energy metabolism, increased caloric intake was a particularly significant predictor of weight gain.Conclusions: Although a reduction in BMR after CPAP predisposes to a positive energy balance, dietary intake and eating behavior had greater impacts on weight change. These findings highlight the importance of lifestyle modifications combined with CPAP.Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000012639).
Effects of calcium-modulating hormones on thiazide receptor density.
Authors: P Blakely, D A Vaughn, D D Fanestil
Journal: Journal of the American Society of Nephrology (1996)

Thiazide diuretic drugs act in the distal convoluted tubule (DCT) to inhibit a Na+Cl- cotransporter and enhance reabsorption of luminal calcium. The density of receptors for thiazides in the rat DCT is known to be increased by adrenocortical steroids, furosemide, and bendroflumethiazide, but decreased by ischemia. Because the DCT is a physiologic site of action by calcitonin and parathyroid hormone, this study examined the effects of these calcitropic hormones in thyroparathyroidectomized Sprague-Dawley rats on (1) the density of the rat thiazide receptor (TZR), as quantitated by binding of (3H)metolazone to renal membranes, and (2) urinary electrolyte excretion rate. Salmon calcitonin (sCT) (20 to 100 ng/h) (1) increased the density of the renal TZR twofold, an effect that is maximal by 6 h after sCT administration, and (2) decreased urinary calcium excretion rate. Adequate dietary calcium must be provided for the effects of sCT to be observed. Regression analysis demonstrated that renal TZR density correlated negatively with total urinary calcium excretion rate but not with plasma calcium ion concentration. In addition, neither rat calcitonin (rCT), at doses that cause hypocalcemia, nor parathyroid hormone, at doses that cause hypercalcemia, produce direct effects on TZR density in the DCT of the thyroparathyroidectomized rat. Our findings indicate that upregulation of TZR by sCT, which occurs independently of plasma calcium-ion concentration, is likely via a calcitonin-like receptor other than that for rat calcitonin itself.
Investigation of the usefulness of zaleplon at two doses to induce afternoon-sleep under noise interference and its effects on psychomotor performance and vestibular function
Authors: Liang-En Chen, An-Dong Zhao, Qing-Jun Zhang, Feng Wu, Zhao-Li Ge, Hua Ge, Hao Zhan
Journal: Military Medical Research (2016)

Military operation personnel often suffer from sleep difficulty because of their work requirements. In this study, we investigated the efficacy of zaleplon at two doses to induce afternoon-sleep under noise interference and its effects on psychomotor performance and vestibular function; we subsequently established the optimal dosage regimen for military operation personnel.Twenty-two healthy young male volunteers were recruited for the study. Eight subjects took 10 mg or 15 mg of zaleplon and placebo alternately and then were exposed to noise. Changes in polysomnography (PSG) indices, including sleep latency (SL), sleep efficiency (SE) and sleep structure, were recorded after drug administration. After awakening, the volunteers' subjective judgments of sleep quality and sleepiness were measured. Eight volunteers underwent 3 psychomotor performance tests at a one-week interval, and the psychomotor performance tests were conducted before and after taking zaleplon and placebo. Six volunteers participated in the vestibular function test session, and parameters, including optokinetic nystagmus (OKN), vestibular ocular reflex (VOR), visual-vestibular ocular reflex (VVOR) and vestibular ocular reflex fixation suppression (VOR-Fix), were detected by the same experimental design as described above. The data of sleep observations were subjected to one-way variance analysis.Compared with the placebo group, SL was shortened significantly, and the scores of subjective sleep quality and sleep depth were clearly increased in the zaleplon 10 mg group (P < 0.05). Moreover, the SE and the percent of REM (rapid eye movement) sleep were increased remarkably in the zaleplon 15 mg group (P < 0.01). Furthermore, the SE, percent of REM sleep and scores of subjective sleep depth in the zaleplon 15 mg group were significantly higher than in the zaleplon 10 mg group (P < 0.05). The psychomotor performance did not change significantly after ingestion of 10 mg or 15 mg of zaleplon, whereas the OKN and VOR gains were lower in the two dose groups of zaleplon (P < 0.05) and restored to normal 3 h after drug ingestion.Zaleplon is an ideal hypnotic for military personnel, and its hypnotic efficiency is dose-related under noise interference; a 15 mg dose of zaleplon could provide significantly better sleep than a 10 mg dose of zaleplon.
Integration of innate into adaptive immune responses in ZAP-70–positive chronic lymphocytic leukemia
Authors: Michaela Wagner, Madlen Oelsner, Andrew Moore, Frederik Götte, Peer-Hendrik Kuhn, Torsten Haferlach, Michael Fiegl, Christian Bogner, E. Joanna Baxter, Christian Peschel, George A. Follows, Ingo Ringshausen
Journal: Blood (2015)
One in four COPD patients gets no treatment at first diagnosis, study shows
Authors: Susan Mayor
Journal: BMJ (2016)

More than a quarter of patients have no drug treatment prescribed for chronic obstructive pulmonary disease (COPD) in the first year of diagnosis despite having symptoms and poor lung function, an analysis of UK general practice data has shown.1

Guidelines for COPD management are generally based on evidence from clinical trials carried out in secondary care, but most patients are managed in primary care. Researchers wanted to know how GPs’ prescribing for patients with COPD compares with guideline recommendations and how this has changed over time.

The research group analysed data on 20 154 patients with …
I Went to See the Elephant.
Journal: JAMA (1963)

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