tbuckley/cabot-search huggingface dataset:
Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer’s disease and down syndrome
Authors: Harutsugu Tatebe, Takashi Kasai, Takuma Ohmichi, Yusuke Kishi, Tomoshi Kakeya, Masaaki Waragai, Masaki Kondo, David Allsop, Takahiko Tokuda
Journal: Molecular Neurodegeneration (2017)

There is still a substantial unmet need for less invasive and lower-cost blood-based biomarkers to detect brain Alzheimer's disease (AD) pathology. This study is aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181) is informative in the diagnosis of AD. We have developed a novel ultrasensitive immunoassay to quantify plasma p-tau181, and measured the levels of plasma p-tau181 in three cohorts. In the first cohort composed of 20 AD patients and 15 age-matched controls, the plasma levels of p-tau181 were significantly higher in the AD patients than those in the controls (0.171 ± 0.166 pg/ml in AD versus 0.0405 ± 0.0756 pg/ml in controls, p = 0.0039). The percentage of the subjects whose levels of plasma p-tau181 exceeded the cut-off value (0.0921 pg/ml) was significantly higher in the AD group compared with the control group (60% in AD versus 16.7% in controls, p = 0.0090). In the second cohort composed of 20 patients with Down syndrome (DS) and 22 age-matched controls, the plasma concentrations of p-tau181 were significantly higher in the DS group (0.767 ± 1.26 pg/ml in DS versus 0.0415 ± 0.0710 pg/ml in controls, p = 0.0313). There was a significant correlation between the plasma levels of p-tau181 and age in the DS group (R2 = 0.4451, p = 0.0013). All of the DS individuals showing an extremely high concentration of plasma p-tau181 (> 1.0 pg/ml) were older than the age of 40. In the third cohort composed of 8 AD patients and 3 patients with other neurological diseases, the levels of plasma p-tau181 significantly correlated with those of CSF p-tau181 (R2 = 0.4525, p = 0.023). We report for the first time quantitative data on the plasma levels of p-tau181 in controls and patients with AD and DS, and these data suggest that the plasma p-tau181 is a promising blood biomarker for brain AD pathology. This exploratory pilot study warrants further large-scale and well-controlled studies to validate the usefulness of plasma p-tau181 as an urgently needed surrogate marker for the diagnosis and disease progression of AD.
Impaired Renal Function Predicts Increased Risk of Gastrointestinal Bleeding Events in Patients with Atrial Fibrillation
Authors: Nishida Kunihiro, Sakamoto Tamotsu, Nakatani Yosuke, Kataoka Naoya, Tsujino Yasushi, Mizumaki Koichi, Kinugawa Koichiro
Journal: Circulation (2016)
Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption
Authors: Kymberleigh A. Romano, Ana Martinez-del Campo, Kazuyuki Kasahara, Carina L. Chittim, Eugenio I. Vivas, Daniel Amador-Noguez, Emily P. Balskus, Federico E. Rey
Journal: Cell Host & Microbe (2017)
Optic and Peripheral Neuropathy in Cuba
Authors: Alfredo A. Sadun
Journal: JAMA (1994)

<i>The following letters were accepted after Hirano et al had responded to Hedges et al</i>.—Ed. <h3>To the Editor.</h3> —We read with great interest the Letter From Havana by Lincoff et al.<sup>1</sup>By invitation from the Cuban Ministry of Health, we visited Cuba in May 1993, the week after the visit by Lincoff et al, and again in September 1993. By the end of May 1993, the Cuban government was frantically trying to address a crisis that affected 42 653 people. In our systematic neuro-ophthalmological examinations, certain clinical features were regularly noted. Remarkably, about half of the conditions that we identified in May were misdiagnosed. We, as representatives of ORBIS International and the Pan American Health Organization, proposed that the Cuban Ministry of Health adopt a strict case definition (Table).<sup>2</sup> With this strict case definition and a smaller but more reliable database, many risk factors appeared more
Evidence for distinct intramolecular pathways transmitting stimulatory and inhibitory signals in human P-glycoprotein
Authors: Karobi Moitra, Saibal Dey
Journal: Cancer Research (2008)

3229   The human multidrug transporter P-glycoprotein (ABCB1 or Pgp) functions as an ATP-dependent efflux pump for a variety of structurally unrelated anticancer agents, conferring multidrug resistance in cancer cells and contributing to poor bioavailability of many chemotherapeutic agents. Several pharmacological agents have been identified that can modulate the transport function of Pgp. Although the structure-function relationship has been studied in great length the molecular determinants of modulation of its ATPase activity and substrate binding remain poorly understood. In this study we demonstrate that the amino acid residue F978 in TM12, previously known to alter drug resistance profile of Pgp, plays a crucial role in stimulation of both ATP hydrolysis as well as IAAP (a Pgp substrate) binding. Substituting F978 with an alanine (F978A) affects stimulation of ATP hydrolysis by Pgp substrate verapamil, as well as, allosteric modulator  cis (Z)-flupentixol. However, inhibition of ATP hydrolysis by  trans (E)-flupentixol remains unaffected. Similarly, stimulation of substrate (IAAP) binding by the  cis  isomer of flupentixol was significantly lowered without any considerable effect on the inhibitory potentials of the  trans  isomer of flupentixol or cyclosporin A. Changing F978 to a structurally similar tyrosine residue (F978Y) partially recovers the stimulatory effects of both verapamil and  cis (Z)-flupentixol. These results suggest that the stimulatory and the inhibitory signals from modulator binding gets transmitted through distinct intramolecular pathways, in which F978 might have an important role in the mediation of the stimulatory signals but not inhibitory ones. The effect of F978 substitution seems to be specific, since a similar replacement of residue F983 (also in TM 12) with alanine (F983A) results in alteration of both stimulatory as well as inhibitory signals generated by the two isomers of flupentixol, but leaves modulation by verapamil and cyclosporin A unaffected.
Integrated performance support: facilitating effective and collaborative performance teams
Authors: Ben C Sporer, Johann Windt
Journal: British Journal of Sports Medicine (2017)

Integration is the process of combining smaller components into a single system so they function as a cohesive, singular unit. Houses are constructed as skilled professionals integrate a host of materials, using specialised tools, to build a home. Similarly, athletes are surrounded by a variety of professionals from sports medicine and the sport sciences, who (hopefully) integrate with coaches to manage the athletes’ health and performance.1 Ideally, this creates a situation where ‘the whole is more than the sum of the parts’. In many cases, however, support team professionals and coaches may operate without coordinated direction and in ‘silos’, possibly with conflicting agendas, redundant procedures and in worst-case scenarios, ‘turf wars’, summing to even less than their individual parts.2

Integration of the support team and coaching staff is demanded by the interconnected nature of performance—it is dependent on a multitude of factors combining to produce an outcome.3 Performance is dynamic, changing daily as fatigue, recovery, training status, health and well-being fluctuate. This is further accentuated by individual differences in physiology, injury and training history, and the impacts of personal lives. With the unified goal of performance success, coaches design the technical and tactical strategies for the athlete or team, …
梗塞後左心室機能不全の治療におけるcardiopoietic幹細胞の安全性と有効性‐翻訳ブタ梗塞モデルにおける機能的修復への心臓保護【Powered by NICT】
Authors: Y Emmert Maximilian, Wolint Petra, Jakab Andras, P Sheehy Sean, S Pasqualini Francesco, Nguyen Thi Dan Linh, Hilbe Monika, Seifert Burkhardt, Weber Benedikt, E Brokopp Chad, Macejovska Dominika, Caliskan Etem, von Eckardstein Arnold, Schwartlander Ruth, Vogel Viola, Falk Volkmar, Parker Kevin Kit, Gyongyosi Mariann, P Hoerstrup Simon
Journal: Biomaterials (2017)
Impact of Central Sleep Apnea on Infarct Size and Left Ventricular Systolic Function in Patients with Acute Myocardial Infarction
Authors: Mashimo Yuka, Nakashima Hiroshi, Kurobe Masaya, Minami Kazutoshi, Mutoh Shigenori, Furudono Shinnosuke, Suenaga Hidetaka, Nunohiro Tatsuya, Takeshita Satoshi, Maemura Koji
Journal: Circulation (2016)
Evolution of Functional Mitral Regurgitation and Prognosis in Medically Managed Heart Failure Patients With Reduced Ejection Fraction
Authors: Riwa Nasser, Lauranne Van Assche, Anne Vorlat, Tom Vermeulen, Emeline Van Craenenbroeck, Viviane Conraads, Vicky Van der Meiren, Bharati Shivalkar, Paul Van Herck, Marc J. Claeys
Journal: JACC Heart Failure (2017)
Targeting a Single Alternative Polyadenylation Site Coordinately Blocks Expression of Androgen Receptor mRNA Splice Variants in Prostate Cancer
Authors: Jamie L. Van Etten, Michael Nyquist, Yingming Li, Rendong Yang, Yeung Ho, Rachel Johnson, Olivia Ondigi, Daniel F. Voytas, Christine Henzler, Scott M. Dehm
Journal: Cancer Research (2017)

Abstract Prostate cancer is the second leading cause of male cancer deaths due to disease progression to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) splice variants including AR-V7 function as constitutively active transcription factors in CRPC cells, thereby promoting resistance to AR-targeted therapies. To date, there are no AR variant–specific treatments for CRPC. Here we report that the splicing of AR variants AR-V7 as well as AR-V1 and AR-V9 is regulated coordinately by a single polyadenylation signal in AR intron 3. Blocking this signal with morpholino technology or silencing of the polyadenylation factor CPSF1 caused a splice switch that inhibited expression of AR variants and blocked androgen-independent growth of CRPC cells. Our findings support the development of new therapies targeting the polyadenylation signal in AR intron 3 as a strategy to prevent expression of a broad array of AR variants in CRPC. Cancer Res; 77(19); 5228–35. ©2017 AACR.
Detection of human herpesvirus 6 (HHV6) in CNS tumors: A predominance of active viral replication in glial tumors.
Authors: John Crawford, Maria Rita Santi, Robert Cornelison, Hannu Haapasalo, Steven Jacobson, Tobey MacDonald
Journal: Cancer Research (2008)

LB-136   Human herpesvirus 6 (HHV6) infection has been associated with CNS diseases of encephalitis, multiple sclerosis, and chronic epilepsy. HHV6 gene sequences have been detected by PCR in a variety of adult CNS tumors at frequencies non suggestive of a causative role for HHV6 in tumorigenesis. Since prior studies examined only the prevalence of viral DNA, indicative of latent infection, the presence of active viral replication as determined by protein expression has never been reported in adult CNS tumors. To address this issue, we screened a series of CNS tumor tissue microarrays containing a variety of CNS tumor subtypes with known clinical information for the presence of HHV6 nucleic acid and protein. One hundred six of 224 (47%) CNS tumors were positive for HHV6 by in situ hybridization using probes specific for Major Capsid Protein without differences in frequency between glial and non glial tumor subtypes. (P=0.069). Nested PCR using HHV6 Major Capsid Protein primers was performed on a subset of ISH positive and negative paraffin embedded tumors as validation. Fourteen of 29 (48%) of tumors were HHV6 positive by nested PCR. HHV6 sequence subtype analysis revealed HHV6 Variant A in 6 of 14 samples. Using two HHV6A/B-specific monoclonal antibodies gp116/54/64 and gp41, active viral replication was observed by immunohistochemistry (IHC) in 84 of 282 (35%) and 66 of 277 (24%) of tumors respectively. Interestingly, glial tumors showed a three-fold higher IHC positivity compared to non glial tumors for both HHV6 gp116/54/64 (P=0.0001) and HHV6gp41 (P=0.007) antibodies. No correlation was observed between patient age or sex and HHV6 positivity by either ISH (P=0.0003) or IHC (P=0.002). Kaplan Meier analysis revealed no significant difference in survival between IHC positivity using either HHV6gp116/54/64 (P=0.4492) or HHV6gp41 (P= 0.4906) antibody. We conclude that active HHV6 is present in adult CNS tumors at a higher frequency in tumors of glial origin. While the presence of HHV6 was not associated with a significant difference in overall survival in our series, we hypothesize that the glial-tropic features of HHV6 may play an important modifying role in tumor biology that warrants further investigation.
CD4+CD8+段階を迂回して,CD4-CD8-胸腺細胞から直接Vα14+NKT細胞を発生する別経路
Authors: Dashtsoodol Nyambayar, Shigeura Tomokuni, Aihara Minako, Ozawa Ritsuko, Kojo Satoshi, Harada Michishige, Endo Takaho A, Watanabe Takashi, Ohara Osamu, Taniguchi Masaru
Journal: Nature Immunology (2017)
A Phase I/II Trial of Ixazomib (Ix), Pomalidomide (POM), and Dexamethasone (DEX), in Relapsed/Refractory (R/R) Multiple Myeloma (MM) Patients: Responses in Double/Triple Refractory Myeloma and Poor Risk Cytogenetics
Authors: Amrita Krishnan, Prashant Kapoor, Joycelynne Palmer, Ni-Chun Tsai, Shaji Kumar, Sagar Lonial, Myo Htut, Chatchada Karanes, Nitya Nathwani, Michael Rosenzweig, Firoozeh Sahebi, George Somlo, Lupe Duarte, Stephen J. Forman, James F Sanchez, Jesus G. Berdeja
Journal: Blood (2016)
Abstract 12050: Cardiomyocyte Specific Deletion of Sirt1 Gene Alters Substrate Metabolism and Sensitizes Myocardium to Ischemia and Reperfusion Injury
Authors: Lin Wang, Nanhu Quan, Dongyang Chu, Xu Chen, Xuezhong Zhao, Ji Li
Journal: Circulation (2016)

Introduction: A longevity gene, sirtuin 1 (SIRT1) is a conserved NAD + -dependent protein deacetylase. AMP-activated protein kinase (AMPK) is an energy sensor. AMPK and SIRT1 signaling pathways have common activators such as caloric restriction, oxidative stress and exercise. Hypothesis: Aging-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults are due to a decreased SIRT1 levels in aging. Methods: Mice were subjected to ligation of left anterior descending coronary artery for in vivo ischemic models. The glucose and fatty acid oxidation were measured in a working heart perfusion system. Results: The cardiac functions by echocardiography show no difference in young (SIRT1 flox/flox ), aged (SIRT1 flox/flox ) and young inducible cardiomyocyte specific SIRT1 knockout (icSIRT1 KO) mice under physiological conditions, but after 45 mins ischemia and 24 hours reperfusion, the ejection fraction of aged and icSIRT1 KO mice were impaired. The aged and icSIRT1 KO hearts versus young hearts also show an impaired post-ischemic contractile function in Langendorff perfusion system. The infarct size of aged and icSIRT1 KO hearts was larger than that of young hearts (p&lt;0.05). The immunoblotting data demonstrated that aged and icSIRT1 KO hearts versus young hearts had impaired phosphorylation of AMPK and downstream acetyl-CoA carboxylase during ischemia. Intriguingly, AMPK upstream LKB1 is hyper-acetylated in both aged and icSIRT1 KO hearts that could blunt activation of LKB1, leading to an impaired AMPK activation. The working heart perfusion results demonstrated that SIRT1 deficiency significantly impair substrate metabolism in the hearts, fatty acid oxidation is augmented and glucose oxidation is blunted during ischemia and reperfusion. Aged and icSIRT1 KO hearts versus young hearts demonstrated significant cardiac fibrosis and macrophage infiltration during ischemia and reperfusion. Furthermore, AMPK agonist A769662 treatment can rescue the tolerance of aged heart but not icSIRT1 KO hearts to ischemic insults. Conclusions: Cardiac SIRT1 mediates AMPK activation via LKB1 deacetylation during ischemia. SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease.
Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football
Authors: Jesse Mez, Daniel H. Daneshvar, Patrick T. Kiernan, Bobak Abdolmohammadi, Victor E. Alvarez, Bertrand R. Huber, Michael L. Alosco, Todd M. Solomon, Christopher J. Nowinski, Lisa McHale, Kerry A. Cormier, Caroline A. Kubilus, Brett M. Martin, Lauren Murphy, Christine M. Baugh, Phillip H. Montenigro, Christine E. Chaisson, Yorghos Tripodis, Neil W. Kowall, Jennifer Weuve, Michael D. McClean, Robert C. Cantu, Lee E. Goldstein, Douglas I. Katz, Robert A. Stern, Thor D. Stein, Ann C. McKee
Journal: JAMA (2017)

<h3>Importance</h3> Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). <h3>Objective</h3> To determine the neuropathological and clinical features of deceased football players with CTE. <h3>Design, Setting, and Participants</h3> Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. <h3>Exposures</h3> Participation in American football at any level of play. <h3>Main Outcomes and Measures</h3> Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. <h3>Results</h3> Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre–high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. <h3>Conclusions and Relevance</h3> In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.
Abstract 189: Natriuretic Peptide Receptor-A Regulates Angiotensin-II Mediated NF-κB Via Mkp-1 Dependent Pathway
Authors: Gopi Venkatachalam, Umadevi Subramanian, Parthasarathy Arumugam, Elangovan Vellaichamy
Journal: Circulation Research (2013)

Atrial natriuretic peptide (ANP) exerts local anti-hypertrophic activity in heart tissue by binding to natriuretic peptide receptor (NPR)-A. However, patients with cardiac hypertrophy and congestive heart failure have elevated plasma and tissue levels of ANP and brain natriuretic peptide (BNP) along with Angiotensin II (Ang II). However, the rationale behind the impaired action of ANP in diseased state is not well understood. In this study, we sought to examine the signaling mechanism by which Ang II modulates local anti-hypertrophic effect through inhibition of Npr1 gene, which codes for NPR-A, in the heart. Hence, in vivo , Wistar male rats (n=8/group) were administered suppressor dose of Ang II (50ng/kg/min) for 14 days through implanted mini-osmotic pumps. Also, in vitro , H9C2 (2-1) cardio myofibroblast cells were exposed to Ang II (10 -7 M) for 20 hours. Upon treatment with Ang II, the mRNA and protein expression of Npr1 (p&lt;0.01) was decreased with significant increase in expression of AT1R (p&lt;0.01) in the heart tissues. In addition, a concomitant decrease in cGMP activity and production in isolated heart tissue membrane preparation was found in Ang II infused rats. Moreover, Ang II infusion causes a suppression of MKP-1 phosphatase; while enhancing the phosphorylation of ERK1/2 (p&lt;0.01) and NF-κB (p&lt;0.01) proteins. Similarly, H9C2 cells exhibited the hypertrophic growth with increased expression of AT1R and activation of ERK1/2 proteins on stimulation with Ang II. Furthermore, gene silencing using siRNA-NPR-A prior to Ang II treatment augmented the translocation of NF-κB and activation of ERK1/2 (3-fold). Whereas, pre-treatment with losartan or cGMP analog 8-Br-cGMP, an activator of cGMP-dependent protein kinases, abolished the stimulatory effects of Ang II on AT1R, NF-κB nuclear translocation and phosphorylation of MAPK, but activated the MKP-1 phosphatase. These results suggest that NPRA-cGMP signaling exerts inhibitory effects on Ang II by antagonizing the upstream signaling pathways and by activation of MKP-1 to counter-regulate NF-κB and MAPKs through cGMP dependent mechanism; thereby mediate local anti-hypertrophic activity in cardiac hypertrophy.
Results of stereotactic body radiation therapy (SBRT) for T2 lung cancer: Outcomes of longer term follow-up.
Authors: Stephen Shamp, Tangel C. Chang, Tithi Biswas, Philip Aaron Linden, Yaron Perry, Jordan Kazakov, Afshin Dowlati, Mitchell Machtay
Journal: Journal of Clinical Oncology (2017)

8542 Background: SBRT is a well-established, highly efficacious treatment for T1N0 non-small cell lung carcinoma (NSCLC). Its efficacy in T2N0 cancers is less clear. This is a review of our institutional experience with long-term follow-up. Methods: 45 patients with medically inoperable T2 N0/Nx M0 NSCLC who were treated with definitive SBRT between 2009 and 2013 were analyzed retrospectively. All patients underwent PET/CT staging and fiducial marker placement for image guided therapy with the Cyberknife platform. Radiation dose was 50 Gray in 5 fractions (N = 24), 50 Gray in 4 fractions (N = 11) or 54-60 Gray in 3 fractions (N = 10) delivered over 7 to 14 days. We analyzed overall survival from the date of start of SBRT, and we performed analyses actuarially using Cox regression analysis and Kaplan-Meier survival analysis for comparisons of hazard ratio (HR) among subgroups. Results: 45 patients were studied (median age 74). The 5-year actuarial overall survival was 18.7% (39.3% at 2 years), with most patients dying from lung cancer recurrence/progression outside of the treatment field. Subgroup analyses showed no statistically significant differences with respect to age, gender, histology, nominal radiation prescription dose, tumor diameter or PTV target volume (median PTV 87cc). There was statistically significantly better survival associated with increased maximum biologically effective dose (BED10) of radiation at the center of the tumor (p = 0.03). Conclusions: Unlike the outcomes for T1 NSCLC, our results in T2 NSCLC were disappointing, with a high rate of out-of-field failure and death from lung cancer. We stress the importance of diagnosis and treatment of NSCLC at the T1N0 stage. We suggest that patients with T2N0/Nx NSCLC be considered for SBRT dose intensification and/or combined modality therapy protocols.
Vasa Vasorum Neovascularization Predicts Peri-procedural Myocardial Injury during Coronary Stenting
Authors: Kume Teruyoshi, Yamada Ryotaro, Koyama Terumasa, Fukuhara Kenzo, Goryo Yutaka, Kawamura Ai, Okamoto Hiroshi, Kobayashi Yusuke, Tamada Tomoko, Obase Kikuko, Imai Koichiro, Neishi Yoji, Uemura Shiro
Journal: Circulation (2016)