tbuckley/cabot-search huggingface dataset:
Haploinsufficiency of the Transcription Factor Ets-1 Is Renoprotective in Dahl Salt-Sensitive Rats
Authors: Wenguang Feng, Bo Chen, Dongqi Xing, Xingsheng Li, Huma Fatima, Edgar A. Jaimes, Paul W. Sanders
Journal: Journal of the American Society of Nephrology (2017)

Studies using Dahl salt-sensitive (SS) rats identified specific quantitative trait loci that predispose animals to hypertension-associated albuminuria and kidney injury. We explored the hypothesis that kidney-specific expression of the transcription factor Ets-1 , located within one of these loci on chromosome 8, mediates glomerular injury in SS hypertension. During the first week on a high-salt diet, SS rats and SS rats with only one functioning Ets-1 gene (ES rats) demonstrated similar increases in BP. However, serum creatinine concentration, albuminuria, and glomerular expression of ETS-1 and two ETS-1 targets, MCP-1 and MMP2, did not increase as substantially in ES rats as in SS rats. Mean BP subsequently increased further in SS rats and remained higher than that of ES rats for the rest of the study. After 4 weeks of high-salt intake, ES rats still showed a lower mean serum creatinine concentration and less albuminuria, as well as less histologic evidence of glomerular injury and kidney fibrosis, than SS rats did. To investigate the specific contribution of renal Ets-1 , we transplanted kidneys from ES or SS rats into salt-resistant SS-Chr 13 BN/McwiCrl (SS-13BN) rats. Within 10 days on a high-salt diet, BP increased similarly in ES and SS allograft recipients, becoming significantly higher than the BP of control isograft recipients. However, mean serum creatinine concentration and albuminuria remained lower in ES allograft recipients than in SS allograft recipients at 2 weeks, and ES allografts showed less glomerular injury and interstitial fibrosis. In conclusion, reduced renal expression of ETS-1 prevented hypertension-associated kidney injury in SS rats.
Stretchable Dry Electrodes with Concentric Ring Geometry for Enhancing Spatial Resolution in Electrophysiology
Authors: Kaiping Wang, Udit Parekh, Tejaswy Pailla, Harinath Garudadri, Vikash Gilja, Tse Nga Ng
Journal: Advanced Healthcare Materials (2017)

Abstract The multichannel concentric‐ring electrodes are stencil printed on stretchable elastomers modified to improve adhesion to skin and minimize motion artifacts for electrophysiological recordings of electroencephalography, electromyography, and electrocardiography. These dry electrodes with a poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate interface layer are optimized to show lower noise level than that of commercial gel disc electrodes. The concentric ring geometry enables Laplacian filtering to pinpoint the bioelectric potential source with spatial resolution determined by the ring distance. This work shows a new fabrication approach to integrate and create designs that enhance spatial resolution for high‐quality electrophysiology monitoring devices.
PD-L1 up-regulation restrains Th17 cell differentiation in <i>STAT3</i> loss- and <i>STAT1</i> gain-of-function patients
Authors: Yuan Zhang, Chi A. Ma, Monica G. Lawrence, Timothy J. Break, Michael P. O’Connell, Jonathan J. Lyons, Diego B. López, John S. Barber, Yongge Zhao, Daniel L. Barber, Alexandra F. Freeman, Steven M. Holland, Michail S. Lionakis, Joshua D. Milner
Journal: The Journal of Experimental Medicine (2017)

Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4+ T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in both cohorts and that STAT1-dependent PD-L1 up-regulation—known to inhibit Th17 differentiation in mouse models—was markedly enhanced as well. Overexpression of SOCS3 strongly inhibited phosphorylation of STAT1 and PD-L1 up-regulation, suggesting that diminished SOCS3 expression may lead to the observed effects. Defects in Th17 differentiation could be partially overcome in vitro via PD-L1 inhibition and in a mouse model of STAT3 loss-of-function by crossing them with PD-1 knockout mice. PD-L1 may be a potential therapeutic target in several genetic diseases of immune deficiency affecting cytokine signaling.
Promoting Cell Migration in Tissue Engineering Scaffolds with Graded Channels
Authors: Degang Yang, Zhitong Zhao, Fan Bai, Shutao Wang, Antoni P. Tomsia, Hao Bai
Journal: Advanced Healthcare Materials (2017)

Ideal bone scaffolds having good biocompatibility, good biodegradability, and beneficial mechanical properties are the basis for bone tissue engineering. Specifically, cell migration within 3D scaffolds is crucial for bone regeneration of critical size defects. In this research, hydroxyapatite scaffolds with three different types of architectures (tortuous, parallel, and graded channels) are fabricated using the freeze-casting (ice-templating) method. While most studies promote cell migration by chemical factors, it can be greatly enhanced by introducing only graded channels as compared with tortuous or parallel channels. The results provide insights and guidance in designing novel scaffolds to enhance cell migration behavior for bone tissue regeneration.
R-CHOP VS R-FC FOLLOWED BY MAINTENANCE WITH RITUXIMAB OR IFN: FIRST RESULTS OF MRD ASSESSMENT WITHIN THE RANDOMIZED TRIAL FOR ELDERLY PATIENTS WITH MCL
Authors: C. Pott, M. Delfau-Larue, K. Beldjord, E. Macintyre, S. Boettcher, V. Asnafi, R. Siebert, A. Plonquet, E. Callet-Bauchut, W. Klapper, F. Berger, M. Unterhalt, M. Dreyling, J. C. Kluin-Nelemans, E. Hoster
Journal: Annals of Oncology (2011)
Drug strategy will fail without new money, say critics
Authors: Matthew Limb
Journal: BMJ (2017)

The government’s plans to reduce illicit drug use and improve rates of recovery from dependence are unlikely to succeed without new investment, as local councils struggle to provide services with reduced budgets, experts have warned.

The new drug strategy, published on 14 July by the home secretary, Amber Rudd, is the first since 2010, but it seems to carry no new funding.1

Rudd will chair a new cross government drug strategy board to oversee a supposedly more balanced approach, designed to ensure that fewer people use drugs in the first place, prevent escalation to more harmful use, and provide more effective, individually tailored treatment options.

She said that coordinated action by the police, health professionals, and local authorities would protect people most at risk of harm, including homeless people, victims of domestic abuse, and people with mental health problems.

“I am determined to confront the scale of this issue and prevent drug misuse devastating our families and communities,” she said.

Drug service specialists have welcomed key elements of the strategy but …
Outcomes of invasive ductal (ID) or invasive lobular (IL) early stage breast cancer in women treated with anastrozole or exemestane in the Canadian cancer trials Group MA.27.
Authors: Kathrin Strasser-Weippl, Gautam Sudan, Ravi Ramjeesingh, Lois E. Shepherd, Joyce O'Shaughnessy, Bingshu E. Chen, Wendy R. Parulekar, Pedro Emanuel Rubini Liedke, Paul E. Goss
Journal: Journal of Clinical Oncology (2016)

521 Background: Previous data suggest histologic subtype, invasive ductal (ID) versus (vs) invasive lobular (IL), might be a marker for response to hormone therapy in receptor positive (HR+) breast cancer [Metzger O, et al: Cancer Res 2012, 72:S1-1]. Methods: MA.27 compared five years of adjuvant anastrozole (A) or exemestane (E) in patients with HR+ early breast cancer. We evaluated ID versus IL histology (based on original pathology reports) as a prognostic marker for outcomes. Results: We were able to include 5,709 patients (5,021 with ID and 688 with IL histology, out of 7,576 patients in MA.27) who had a median follow-up of 4.1 years. Histologic subtype did not influence overall survival (OS) or event-free survival (EFS) in the overall study cohort (HR 1.04, P = 0.81 and HR 1.14, P = 0.49, respectively). In univariable analysis of OS, there was no significant difference between treatment with E vs A in the ID group (HR = 0.92, P = 0.46). In the IL group, a marginally significant difference in favor of treatment with anastrozole was seen (HR = 1.79, P = 0.055). In multivariable analysis a prognostic effect of the interaction between treatment and histological subtype on OS (but not on EFS) was noted, suggesting a better outcome for patients with IL cancer when treated with anastrozole (HR 2.1, P = 0.05). After a stepwise selection process in the multivariable model, a marginally significant prognostic effect for the interaction variable (treatment with histological subtype) on OS (but not on EFS) was noted (Ratio of HR 2.1, P = 0.05). Conclusions: Histologic subtype did not have an effect on OS or EFS in patients in MA.27. Neither A or E had a differential effect on ID versus IL cancers with respect to EFS. However, similar to data from the BIG 1-98 trial, our data suggest an interaction effect between treatment and histology (P = 0.05) on OS. Here, patients with IL cancers had a better OS when treated with A vs E (HR 1.79, P = 0.055), whereas no difference was noted for patients with ID cancers (HR 0.92, P = 0.47).
Tocilizumab Is Highly Active for Severe Steroid-Refractory Acute Graft-Versus-Host Disease of the Gastrointestinal Tract
Authors: Alex Ganetsky, Noelle V Frey, Alison W Loren, Elizabeth O. Hexner, James K Mangan, Saar I Gill, Selina Luger, Adam D. Cohen, Daria V Babushok, Edward A Stadtmauer, Jacqueline Smith, William R. Drobyski, Sarah K Kraus, Colleen Timlin, David L. Porter
Journal: Blood (2016)
CRISPR/Cas9 Mediated Gene Repair in Inherited Bleeding Disorders
Authors: Satoshi Morishige, Hidetoshi Ozawa, Shinichi Mizuno, Satoko Koteda, Kuniki Kawaguchi, Takayuki Nakamura, Kei Nomura, Harumi Takeda, Yuka Takata, Ritsuko Seki, Fumihiko Mouri, Koichi Osaki, Michitoshi Hashiguchi, Koji Yoshimoto, Takashi Okamura, Koji Nagafuji
Journal: Blood (2015)
INJURY TYPES, INJURY RISKED BODY PARTS AND SPORT TYPE SPECIFICITY OF ELITE ATHLETES
Authors: Victor Wang, Frank Mayer, Yi-Hsiong Hang
Journal: British Journal of Sports Medicine (2017)

Background Elite athletes' injuries are multi-factorial and sport specific. However, the inter-relationships between sport type characteristics and injury types and related variables are not clear. Objective To test the inter-relationships between 2 injury related variables and 2 adapted sport types of elite athletes. Design and Setting A bi-national, cross-sectional and retrospective injury incident survey was conducted. Currently active or retired national delegation athletes trained for international competitions of Olympic sports were targeted. Participants 269 Taiwanese (f/m: 119/150, age 23±6.7) and 66 German (f/m: 32/34, age=25.8±6.9) elite athletes were recruited from national sport training centres, sport federations and universities. Assessment of Risk Factors The assessment of injury incidence and injury risk of body parts was conducted by adapting 8 injury types (muscle, bone_acute, bone_chronic, tissue_chronic, exceeded range of motion, connective tissue, soft tissue and others) and 4 body sections (head &amp; neck, chest &amp; back, upper_extremity and lower_extremity) categorized from total of 87 injury options on entry form. Five sport_formats (individual_no contact, team_no contact, team_contact, individual_combat, team_combat) and 5 sport_locations (on land_no locomotion, on land_with locomotion, on water, in snow, on ice) categories were used to classify 38 original Olympic sport types. Main Outcome Measurements Sport training related injury incidences were taken as outcome measurement. 2 adapted sport related category-variables (sport_format and sport_location) were formulated for test of hypothesis. Results Sport_format variable influenced the results of 4 injury types (muscle, bone_chronic, exceeded range-of-motion and connecting-tissues) and 1 injured body section (head&amp;neck) significantly. Sport_location variable influenced the results of 4 injury types (muscle, bone_acute, tissue_chronic and exceeded range-of-motion) and 3 injured body sections (head &amp; neck, upper extremity and lower extremity). Age influenced the results of 3 injury types (bone_chronic, tissues_chronic and other injuries) and all 4 body sections. Gender influenced the results of connecting tissue type of injury and the injury result of head &amp; neck section. Conclusions With these sport type, injury type/injury section specificity information, elite athletes, coach and sport trainer/therapist can further utilize and build detailed injury prevention or rehabilitation program.
Bone turnover markers in postmenopausal breast cancer patients treated with fulvestrant
Authors: A. Agrawal, R. A. Hannon, K. L. Cheung, R. Eastell, J. F. Robertson
Journal: Journal of Clinical Oncology (2006)

680 Background: Aromatase inhibitor (AI) therapy in patients with breast cancer accelerates bone turnover with increased secretion and excretion of bone turnover markers. Here, we report the effect of fulvestrant, an estrogen receptor (ER) antagonist with no agonist activity, on bone metabolism. Methods: 23 patients with either locally advanced primary [LAPC] or metastatic [MBC] disease who had clinical benefit (objective response/stable disease ≥6 months) during fulvestrant therapy were included in the study. Sequential tumor biopsies and blood samples were taken at baseline and after 3, 6, 9, 12 and 18 months of fulvestrant treatment (disease being stable throughout the study period). Serum was analyzed for bone formation markers (N-terminal propeptide of procollagen Type 1 [PINP] and bone-specific alkaline phosphatase [bone ALP]) and for the resorption marker C-terminal telopeptide (CTX). Data are presented as median percentage change (from baseline) in marker level with 95% confidence intervals (CI). Data were analyzed separately for patients with LAPC and MBC. Results: Changes in bone ALP (reference range: 3.9–46.8 ng/mL), PINP (20.6–82.1 ng/mL) and CTX (0.14–1.35 ng/mL) in patients with LAPC, are shown in the table . In a further 5 patients with LAPC who were already established on fulvestrant, there were no significant changes in markers over a 15-month period. No changes in markers were noted in the 4 patients with MBC. Conclusions: In this study, there was long-term stability of bone turnover markers in postmenopausal women with LAPC treated with fulvestrant over a period of 18 months. This property may be exploited in future with the use of fulvestrant earlier in the sequence of endocrine therapies particularly in the adjuvant setting and/or in patients with pre-existing decreased bone mass. [Table: see text] [Table: see text]
Abstract 256: Renal Denervation Preconditions the Myocardium by Promoting Nitric Oxide Signaling and Attenuating Oxidative Stress in Spontaneously Hypertensive Rats
Authors: David J Polhemus, Juan Gao, Daniel R Kapusta, David J Lefer
Journal: Circulation Research (2015)

Background: Recent clinical studies suggest that renal denervation (RDN) not only decreases blood pressure (BP) and sympathetic nerve activity, but may also exert additional systemic cardioprotective actions. We investigated whether RDN preconditions the heart against subsequent myocardial ischemia/reperfusion (MI/R) injury in spontaneously hypertensive rats (SHR). Materials and Methods: SHR (20w old) received either bilateral radiofrequency (RF) RDN or sham RDN (Biosense Webster Stockert 70 RF generator). After 4w of BP recording, Plasma and left ventricle (LV) tissue were collected for measurement of nitric oxide (NO) metabolites, nitrite (NO2-, ion chromatography) and S-Nitrosothiol (RSNO). RT PCR was used to examine transcriptional changes. Colorimetric assays were used to quantify malondialdehyde (MDA) and carbonyl content. In additional studies, 4w after RDN (n = 8) or Sham (n = 9) treatment, SHR were subjected to 30m of left coronary artery ischemia followed by 24h reperfusion and myocardial infarct/area-at-risk (AAR) was determined. Results: 4w after treatment, mean BP was significantly decreased in RDN compared to Sham SHR (157±2 vs 142±2 mmHg, p &lt; 0.05). Plasma NO2- levels were elevated 4w following RDN (p &lt; 0.01). Cardiac NO2- levels increased from 2.6 to 3.2 nmol/mg (p &lt; 0.05) and RSNO levels increased from 0.5 to 1.1 nmol/mg (p &lt; 0.05) following RDN. Moreover, myocardial oxidative stress was markedly attenuated as measured by carbonyl content (p &lt; 0.05) and MDA levels (p &lt; 0.01). Greater transcription of antioxidants, SOD1 (p &lt; 0.05) and GPX-1 (p &lt; 0.05) were also observed in the RDN treated group. SHR receiving RDN therapy exhibited a trend in infarct size reduction (42% per AAR reduction, p = 0.09) compared to sham following MI/R. We observed 2-fold greater survival in the RDN treated group (88%, 7 of 8) compared to sham (44%, 4 of 9) following MI/R. Conclusions: RDN produced a sustained elevation in NO bioavailability and signaling in the heart and blood. Additionally, RDN attenuated myocardial oxidative stress and augmented the antioxidant defense system in SHR. Although further studies are warranted, preliminary results indicate that these mechanisms may promote myocardial preconditioning and improve survival in the setting of MI/R injury.
Safety and efficacy of progressive resistance exercise for Charcot-Marie-Tooth disease in children: a randomised, double-blind, sham-controlled trial
Authors: Joshua Burns, Amy D Sman, Kayla M D Cornett, Elizabeth Wojciechowski, Terri Walker, Manoj P Menezes, Melissa R Mandarakas, Kristy J Rose, Paula Bray, Hugo Sampaio, Michelle Farrar, Kathryn M Refshauge, Jacqueline Raymond, Joshua Burns, Amy D Sman, Kayla M D Cornett, Elizabeth Wojciechowski, Manoj P Menezes, Melissa R Mandarakas, Kristy J Rose, Paula Bray, Jennifer Baldwin, Marnee J McKay, Kathryn M Refshauge, Jacqueline Raymond, Terri Walker, Hugo Sampaio, Anita Mudge, Leanne Purcell, Clare Miller, Kelly Gray, Meghan Harman, Natalie Gabrael, Robert A Ouvrier, Michelle Farrar
Journal: The Lancet Child & Adolescent Health (2017)
An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
Authors: Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Trang Thi Mai, Neelam Chaudhary, Greg J Riely, Bob T Li, Kerry Scott, Fabiola Cechhi, Ulrika Stierner, Kalyani Chadalavada, Elisa de Stanchina, Sarit Schwartz, Todd Hembrough, Gouri Nanjangud, Michael F Berger, Jonas Nilsson, Scott W Lowe, Jorge S Reis-Filho, Neal Rosen, Piro Lito
Journal: Nature Medicine (2017)
Genetic Polymorphism On Methyl-Tetrahydrofolate-Reductase Affects Vascular Superoxide Generation and Nitric Oxide Bioavailability By Regulating eNOS Coupling in Human Arteries and Veins
Authors: C A Antoniades, C Shirodaria, P Leeson, T Van-Assche, C Ratnatunga, R Pillai, C Cunnington, D Tousoulis, A S Antonopoulos, C Stefanadis, H Refsum, K M Channon
Journal: Journal of the American College of Cardiology (2009)
FRI0128 The age distribution of the focal hyperintensities in brain mr in patients with neuropsychiatric lupus
Authors: V Peterová, C Dostál, Z Seidl, T Viták, J Obenberger, J Dane, M Olejarová
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The authors determined the extent of central nervous system affection in patients with systemic lupus erythematosus (SLE) by the means of brain magnetic resonance (MR). The results were correlated with the controls and the results were compared statistically. <h3>Methods</h3> Brain MR investigation was made by the routine protocol (T1 and T2 weighted images, FLAIR mode, transversal and sagittal scans) in 1,5T MR machine. 60 patients of all 3 groups (SLE, MS and controls) were investigated. The patients were divided into 3 groups due to the age distribution: 18–39, 40–49, 50 and more years. <h3>Results</h3> In the patients with neuropsychiatric lupus the focal white matter hyperintensities in FLAIR mode were the most common findings. Their distribution was most often present in frontal and parietal lobes, where the average numbers of foci were 9,8, resp. 8,4. While in occipital and temporal lobes lobes the average numbers of foci were significantly lower, it appeared 2,2, resp. 2,3. Among SLE patients aged from 50 to 59 years the focal hyperintensities were the most common (the average number of foci was 8,4), which was statistically significant in comparison with both other age groups of patients. The distribution of focal hyperintensities in control group appeared different. <h3>Conclusion</h3> MR method is the most sensitive method for establishing the central nervous system involvement in SLE patients. The number of focal hyperintensities was determined to be statistically different between SLE controls in all three age groups. <h3>References</h3> Dostál C, Peterová V, Pale ková A. et al. Cerebral disease in SLE: selected autoantibodies and major central nervous system disorders. Lupus 1996;544 Hachulla E, Michon Pasdturel U, Leys D, <i>et al</i>. Cerebral magnetic resonance imaging in patients with or without antiphospholipid antibodies. Lupus 1998;7:124–31 Kent L, Hayner DR, Longstreth WT, <i>et al</i>. The clinical efficacy of magnetic resonance imaging in neuroimaging. Ann Intern Med. 1994;120:856–61 Peterová V, Dostál C, Obenberger J, <i>et al</i>. MRI findings in patients with lupus erythematosus. Eur J Neurol. 1997;4:123 Peterová V, Dostál C, Seidl Z, <i>et al</i>. Postizení mozku u nemocných se SLE (Popis 2 prípado). Ceská Revmatologie 1998;275:178–81 Rovaris M, Viti B, Ciboddo G, <i>et al</i>. Brain involvement in systemic immune mediated diseases: magnetic resonance and magnetisation transfer imaging study. J Neurol Neurosurg Psychiatry 2000;68:170–7
Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed-repair-independent mechanism
Authors: Dwi U Kemaladewi, Eleonora Maino, Elzbieta Hyatt, Huayun Hou, Maylynn Ding, Kara M Place, Xinyi Zhu, Prabhpreet Bassi, Zahra Baghestani, Amit G Deshwar, Daniele Merico, Hui Y Xiong, Brendan J Frey, Michael D Wilson, Evgueni A Ivakine, Ronald D Cohn
Journal: Nature Medicine (2017)