tbuckley/cabot-search huggingface dataset:
The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition
Authors: Ghazaleh Eskandari-Sedighi, Nathalie Daude, Hristina Gapeshina, David W. Sanders, Razieh Kamali-Jamil, Jing Yang, Beipei Shi, Holger Wille, Bernardino Ghetti, Marc I. Diamond, Christopher Janus, David Westaway
Journal: Molecular Neurodegeneration (2017)

MAPT mutations cause neurodegenerative diseases such as frontotemporal dementia but, strikingly, patients with the same mutation may have different clinical phenotypes.Given heterogeneities observed in a transgenic (Tg) mouse line expressing low levels of human (2 N, 4R) P301L Tau, we backcrossed founder stocks of mice to C57BL/6Tac, 129/SvEvTac and FVB/NJ inbred backgrounds to discern the role of genetic versus environmental effects on disease-related phenotypes.Three inbred derivatives of a TgTauP301L founder line had similar quality and steady-state quantity of Tau production, accumulation of abnormally phosphorylated 64-68 kDa Tau species from 90 days of age onwards and neuronal loss in aged Tg mice. Variegation was not seen in the pattern of transgene expression and seeding properties in a fluorescence-based cellular assay indicated a single "strain" of misfolded Tau. However, in other regards, the aged Tg mice were heterogeneous; there was incomplete penetrance for Tau deposition despite maintained transgene expression in aged animals and, for animals with Tau deposits, distinctions were noted even within each subline. Three classes of rostral deposition in the cortex, hippocampus and striatum accounted for 75% of pathology-positive mice yet the mean ages of mice scored as class I, II or III were not significantly different and, hence, did not fit with a predictable progression from one class to another defined by chronological age. Two other patterns of Tau deposition designated as classes IV and V, occurred in caudal structures. Other pathology-positive Tg mice of similar age not falling within classes I-V presented with focal accumulations in additional caudal neuroanatomical areas including the locus coeruleus. Electron microscopy revealed that brains of Classes I, II and IV animals all exhibit straight filaments, but with coiled filaments and occasional twisted filaments apparent in Class I. Most strikingly, Class I, II and IV animals presented with distinct western blot signatures after trypsin digestion of sarkosyl-insoluble Tau.Qualitative variations in the neuroanatomy of Tau deposition in genetically constrained slow models of primary Tauopathy establish that non-synchronous, focal events contribute to the pathogenic process. Phenotypic diversity in these models suggests a potential parallel to the phenotypic variation seen in P301L patients.
Regulatory T‐cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis
Authors: Rodrigo Liberal, Charlotte R. Grant, Muhammed Yuksel, Jonathon Graham, Alireza Kalbasi, Yun Ma, Michael A. Heneghan, Giorgina Mieli‐Vergani, Diego Vergani, Maria Serena Longhi
Journal: Hepatology (2017)

Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4 + CD127 + CD25 high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood–derived CD4 + CD127 + CD25 high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL‐17) production as well as by high levels of T‐bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4 + CD127 + CD25 high cells are unresponsive to low‐dose IL‐2 and in patients have marked proliferative ability, further enhanced by stimulation with IL‐7. CD4 + CD127 + CD25 high cells obtained from CD4 + cells exposed to Treg polarizing conditions display enhanced IL‐10 production; up‐regulate CD49b and LAG‐3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL‐17. The suppressive function of CD4 + CD127 + CD25 high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. Conclusion : Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (H epatology 2017;66:1570–1584).
Ovarian Follicular Theca Cell Recruitment, Differentiation, and Impact on Fertility: 2017 Update
Authors: JoAnne S Richards, Yi A Ren, Nicholes Candelaria, Jaye E Adams, Aleksandar Rajkovic
Journal: Endocrine Reviews (2017)

The major goal of this review is to summarize recent exciting findings that have been published within the past 10 years that, to our knowledge, have not been presented in detail in previous reviews and that may impact altered follicular development in polycystic ovarian syndrome (PCOS) and premature ovarian failure in women. Specifically, we will cover the following: (1) mouse models that have led to discovery of the derivation of two precursor populations of theca cells in the embryonic gonad; (2) the key roles of the oocyte-derived factor growth differentiation factor 9 on the hedgehog (HH) signaling pathway and theca cell functions; and (3) the impact of the HH pathway on both the specification of theca endocrine cells and theca fibroblast and smooth muscle cells in developing follicles. We will also discuss the following: (1) other signaling pathways that impact the differentiation of theca cells, not only luteinizing hormone but also insulinlike 3, bone morphogenic proteins, the circadian clock genes, androgens, and estrogens; and (2) theca-associated vascular, immune, and fibroblast cells, as well as the cytokines and matrix factors that play key roles in follicle growth. Lastly, we will integrate what is known about theca cells from mouse models, human-derived theca cell lines from patients who have PCOS and patients who do not have PCOS, and microarray analyses of human and bovine theca to understand what pathways and factors contribute to follicle growth as well as to the abnormal function of theca.
Abstract 13428: A Scoring System for Early Prognostication of Neurologic Outcomes in Out-of-hospital Sudden Cardiac Arrest Treated With Mild Therapeutic Hypothermia
Authors: Erich L Kiehl, Alex M Parker, Michelle C Johansen, Kate L Bidwell, Mark P Adams, Kyle B Enfield, Lawrence W Gimple
Journal: Circulation (2013)

Background:  Out of hospital sudden cardiac arrest (SCA) is highly fatal, with estimated survival to hospital discharge 10-37%. The leading cause of death is neurologic injury, but with mild therapeutic hypothermia (MTH), favorable neurologic outcomes (NO) improve by 20%. Current guidelines recommend delayed prognostication for 72 hours post-SCA; our study aims to determine if early quantitative stratification of NO can be made using data available at hospital presentation.   Methods:  A retrospective chart review identified adult patients who received intravascular MTH for out of hospital SCA at a single institution from 2008-12 (n = 122). Patient demographics, pre-arrest diagnoses, resuscitation timing, and initial laboratory/imaging studies were compared between favorable and poor NO. As in landmark studies, favorable NO was defined as cerebral performance category (CPC) 1-2, poor 3-5. CPC assignment was made retrospectively by neurology using consultation and discharge physical exams. Univariate analysis was performed on all collected variables; those with ρ    Results:  42 patients survived to hospital discharge (34%), 33 with favorable NO (27%). The final model included the following variables: age >45, CAD, non-VT/VF arrest, initial blood glucose >200, and initial pH    Conclusions:  This scoring system may allow for stratification of neurologic outcomes at hospital presentation and may identify a subset of patients who do not derive benefit from MTH and continued intensive care. Future multi-site, prospective investigation is needed.
Cost-Effectiveness Analysis of Monthly Zoledronic Acid, Zoledronic Acid Every 3 Months, and Monthly Denosumab in Women With Breast Cancer and Skeletal Metastases: CALGB 70604 (Alliance)
Authors: Charles L. Shapiro, James P. Moriarty, Stacie Dusetzina, Andrew L. Himelstein, Jared C. Foster, Stephen S. Grubbs, Paul J. Novotny, Bijan J. Borah
Journal: Journal of Clinical Oncology (2017)

Purpose Skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, or the necessity for radiation or surgery to bone metastasis cause considerable morbidity, decrements in quality of life, and costs to the health care system. The results of a recent large randomized trial (Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology [CALGB/Alliance 70604]) showed that zoledronic acid (ZA) every 3 months was noninferior to monthly ZA in reducing the risks of SREs. We sought to determine the cost-effectiveness (CE) of monthly ZA, ZA every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases. Methods Using a Markov model, costs per SRE avoided were calculated for the three treatments. Sensitivity analyses were performed where denosumab SRE probabilities were assumed to be 50%, 75%, and 90% lower than the ZA SRE probabilities. Quality-adjusted life-years were also calculated. The analysis was from the US payer perspective. Results The mean costs of the denosumab treatment strategy are nine-fold higher than generic ZA every 3 months. Quality-adjusted life-years were virtually identical in all the three treatment arms; hence, the optimal treatment would be ZA every 3 months because it was the least costly treatment. The sensitivity analyses showed that relative to ZA every 3 months, the incremental costs per mean SRE avoided for denosumab ranged from $162,918 to $347,655. Conclusion ZA every 3 months was more CE in reducing the risks of SRE than monthly denosumab. This analysis was one of the first to incorporate the costs of generic ZA and one of the first independent CE analyses not sponsored by either Novartis or Amgen, the makers of ZA and denosumab, respectively. ZA every 3 months is the more CE option and more reasonable alternative to monthly denosumab.
Development and validation of multiplex biomarker assay to stratify colorectal cancer (CRC) patient samples into subtypes
Authors: A. Sadanandam, K. Eason, E. Fontana, G. Nyamundanda, M. Del Rio, K. Si-Lin, T.W. Siew, P. Martineau, I.B. Tan, C. Ragulan
Journal: Annals of Oncology (2017)
Abstract 10123: Evidence Against the J-shaped Curve in Treated Hypertensive Patients With Increased Cardiovascular Risk: The VALUE Trial
Authors: Sverre E Kjeldsen, Sripal Bangalore, Franz Messerli, Giuseppe Mancia, Björn Holzhauer, Tsushung A Hua, Dion Zappe, Michael A Weber, Stevo Julius
Journal: Circulation (2015)

Introduction: It has been postulated that low blood pressure (BP) during treatment is associated with increased risk for cardiovascular (CV) disease. Hypothesis: We tested whether low BP had unfavorable effect on CV outcomes in a high risk population of 15,244 hypertensive patients of whom 45% had a coronary heart disease (CHD) history. Methods: Patients were followed for 4.2 years (mean) in the VALUE Trial with no difference of the primary endpoint between valsartan and amlodipine arms. Cox proportional hazard models were used to evaluate relationships between average on-treatment BP and clinical outcomes, unadjusted and adjusted for baseline covariates such as age, BMI, history of CHD, history of stroke, left ventricular hypertrophy, diabetes mellitus, smoking, cholesterol and proteinuria. Results: Diastolic BP ≥90 mmHg but not diastolic BP &lt;70 mmHg was associated with increased CV outcomes after covariate adjustment. We had similar results for death, myocardial infarction (MI), heart failure and stroke. Nadir for MI was at diastolic BP of 76 mmHg and for stroke 60 mmHg. The ratio of MI to stroke increased with lower diastolic BP (fig), but there was no significant J-curve regardless of CHD history. Also, systolic BP ≥140 but not &lt;130 mmHg was associated with increased risk for CV outcomes, and systolic BP &lt;130 mmHg significantly prevented stroke. Conclusions: Patients in BP strata ≥140/90 mmHg, but not patients in BP strata &lt;130/70 mmHg, were at increased risk for adverse outcomes in this hypertensive, high risk population. Our data provide evidence against a J-curve in the treatment of hypertensive patients with high risk and support the concept “of the lower the better” in stroke prevention. However, the increase in the ratio of MI to stroke with lower diastolic BP indicates target organ heterogeneity in that the optimal on-treatment diastolic BP for cerebroprotection is below the one for cardioprotection.
A dose-response study of ramucirumab treatment in patients with gastric cancer/gastroesophageal junction adenocarcinoma: Primary results of 4 dosing regimens in the phase 2 trial I4T-MC-JVDB
Authors: J.A. Ajani, A. Udrea, T. Sarosiek, M. Shenker, C. Morgan, J. Pikiel, E. Wojcik, D. Swinson, M. Joseph, A. Luft, T. Salek, C. Tournigand, D. Ferry, Y. Zhang, A. Long, W-L. Kuo, L. Gao, J. Kauh, W. Mansoor
Journal: Annals of Oncology (2017)
In vivo study of the vaccine adjuvants prothymosin alpha and prothymosin alpha(100-109) in melanoma
Authors: P. Samara, K. Ioannou, N. Kavrohorianou, S. Haralambous, P. Selemenakis, A. Kotsinas, H. Kalbacher, W. Voelter, O. Tsitsilonis
Journal: Annals of Oncology (2017)
Whole body PD-1 and PD-L1 PET in pts with NSCLC
Authors: A.-L. Niemeijer, E. Smit, I. Bahce, O. Hoekstra, M. Huisman, G.A. van Dongen, B. Windhorst, N. Hendrikse, A.J. Poot, D. Vugts, D.K. Leung, W. Hayes, R.A. Smith, L.M. Wilson, E. Thunnissen, J. de Langen
Journal: Annals of Oncology (2017)
구연 : 마우스 간암모델에서 TLR-7 agonist 보조요법으로 강화된 수지상세포 백신의 항암효과
Authors: 성영림, 장진아, 윤선옥, 민미경, 박수영, 장자준, 이정훈, 황상연, 김휘영, 배용수, 김윤준
Journal: Clinical and Molecular Hepatology (2009)
Outcomes of patients with metastatic urothelial carcinoma (mUC) with exclusive bone metastases: Focus on a special patient population
Authors: A. Necchi, G.R. Pond, S.K. Pal, N. Agarwal, D. Bowles, E. Plimack, E.Y. Yu, S. Ladoire, J. Baniel, S. Crabb, G. Niegisch, A.R. Golshayan, S. Sridhar, D. Berthold, J.E. Rosenberg, T. Powles, A. Bamias, L.C. Harshman, J. Bellmunt, M.D. Galsky
Journal: Annals of Oncology (2017)
Abstract 17725: Improved Discriminatory Power to Predict Early LVAD Mortality: The Mechanical Circulatory Support Network Risk Score
Authors: Vakhtang Tchantchaleishvili, Simon Maltais, Nicholas A Haglund, Mary E Davis, Jennifer A Cowger, Palak Shah, Keith D Aaronson, Francis D Pagani, Shannon M Dunlay, John M Stulak
Journal: Circulation (2015)

Introduction: Various risk models have been used to predict mortality after implantation of continuous-flow ventricular assist devices (CF-VADs). Discriminatory power and predictive accuracy vary, and there is a need to develop and validate a contemporary risk score in a large multicenter patient cohort. Hypothesis: We sought to develop an early mortality risk score utilizing a large voluntary research registry of patients implanted with CF-VADs, with the focus on increased discriminatory power. Methods: From May 2004 to May 2015, 1150 patients in the Mechanical Circulatory Support Research Network (MCSRN) registry were randomly divided into equal-sized derivation and validation samples (n=575, each group). Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified for predicting 90-day mortality. A risk score was developed based on the variables and their respective regression coefficients in the final model. Discriminatory power of the risk score was evaluated using receiver operating characteristic analysis, and calibration was assessed using Hosmer-Lemeshow goodness of fit test. Results: Overall 90-day mortality was 9.4% (n=99). The final logistic regression model consisted of 9 predictors: Age at implant, preoperative mechanical ventilation, serum total bilirubin, hemoglobin, tricuspid valve regurgitation severity, left ventricular end-diastolic diameter, cardiac index, pulmonary capillary wedge pressure, and destination therapy (DT) as an indication for pump placement. The area under the curve was 0.86 in the derivation sample (95% CI, 0.75-0.97) and 0.75 in the validation sample (95% CI, 0.63-0.86). Hosmer-Lemeshow goodness of fit test yielded insignificant values in both samples (p=0.75, p=0.58) consistent with good calibration. Conclusions: The proposed 90-day mortality MCSRN risk score provides highest-to-date discriminatory power when compared to already published models. The risk score is applicable to a contemporary large cohort of patients implanted with CF-VADs for either indication (bridge or DT).
Quality-adjusted survival of combined nivolumab plus ipilimumab (NIVO+IPI) or NIVO alone vs IPI among treatment-naïve patients (pts) with advanced melanoma (MEL): a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis
Authors: M. Botteman, R. Shah, K. Gupte-Singh, L. Luo, J. Sabater, S. Rao, D.F. McDermott, M.B. Atkins, M. Regan
Journal: Annals of Oncology (2017)
Targeting the Noncoding Genome: Superenhancers Meet Their Kryptonite
Authors: Eric Wang, Ioannis Aifantis
Journal: Cancer Discovery (2017)

Abstract Summary: In this study, McKeown and colleagues carried out a genome-wide characterization and stratification of the enhancer landscape in acute myeloid leukemia (AML). The authors' analysis led to the discovery of a novel RARA superenhancer found in a subset of patients with AML, rendering these leukemia cells highly sensitive to SY-1425, a highly potent RARA agonist able to induce myeloid differentiation in these high-expressing RARA AML subtypes. Cancer Discov; 7(10); 1065–6. ©2017 AACR. See related article by McKeown et al., p. 1136.
Abstract 16114: How Does the Symptom Experience Differ From Patient’s Expectations of What Having a Heart Attack is Like?
Authors: Janet E Bray, Dion Stub, Phil Ngu, Susie Cartledge, James Shaw, Judith Finn
Journal: Circulation (2014)

Introduction:  Early recognition of heart attack symptoms is key to reducing delays in seeking medical attention. Over a decade ago it was identified that the symptom experience in the majority of AMI patients (74%) did not match the patient’s expectations. Given the extent of public education since that time, this study aims to provide a current perspective and to examine how the experience was different.   Methods:  Interviews were conducted with consecutive acute myocardial infarction (AMI) patients admitted to a metropolitan hospital in Melbourne (Australia) between July 2013 and April 2014. Patients were included if they were: aged 35-75 years, competent to provide consent, English speaking, not in residential care, and medically stable. Content analysis was performed to identify themes around how the experience was different.   Results:  Interviews were conducted with 128 patients admitted for STEMI (32%), and NSTEMI (67%). The mean age was 59 years (SD=10), 71% (n=91) were male and 29% (n=37) had a history of ischaemic heart disease. Although the majority (81%) experienced chest pain, only 37% thought their symptoms were heart-related at symptom onset -other common attributions were stomach-related problems (22%) and muscular pain (10%). A small group (11%) had no previous expectation of what a heart attack might be like, the remainder thought their experience was nothing like their expectation (20%), somewhat like (32%) or exactly like (37%). Patients in the later group were more likely to have a history of IHD (42% vs. 21%, p=0.009). Four themes were identified in those in whom the experience was different to previous expectations: different pain severity (47%), different onset (33%), different symptoms experienced (21%) and different location of pain (21%).   Conclusion:  In most AMI patients the symptom experience was different to what they expected a heart attack to be like -this has not changed over the last decade. Interventions to address the public’s perception of the heart attack experience are still needed.
Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer
Authors: Nobuyuki Katakami, Toshiyuki Harada, Toru Murata, Katsunori Shinozaki, Masakazu Tsutsumi, Takaaki Yokota, Masatsugu Arai, Yukio Tada, Masaru Narabayashi, Narikazu Boku
Journal: Journal of Clinical Oncology (2017)

Purpose Opioid-induced constipation (OIC) is a frequent and debilitating adverse effect (AE) of opioids-common analgesics for cancer pain. We investigated the efficacy and safety of a peripherally acting μ-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer. Patients and Methods This phase III trial consisted of a 2-week, randomized, double-blind, placebo-controlled study (COMPOSE-4) and an open-label, 12-week extension study (COMPOSE-5). In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned on a 1:1 basis to receive once-daily oral naldemedine 0.2 mg or placebo. The primary end point was the proportion of spontaneous bowel movement (SBM) responders (≥ 3 SBMs/week and an increase of ≥ 1 SBM/week from baseline). The primary end point of COMPOSE-5 was safety. Results In COMPOSE-4, 193 eligible patients were randomly assigned to naldemedine (n = 97) or placebo (n = 96). The proportion of SBM responders in COMPOSE-4 was significantly greater with naldemedine than with placebo (71.1% [69 of 97 patients] v 34.4% [33 of 96 patients]; P < .0001). A greater change from baseline was observed with naldemedine than with placebo in the frequency of SBMs/week (5.16 v 1.54; P < .0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; P < .0001), and SBMs without straining/week (3.85 v 1.17; P = .0005). In COMPOSE-4, more patients treated with naldemedine than with placebo reported treatment-emergent AEs (TEAEs) (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; P = .01); in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients] v 7.3% [seven of 96 patients] with naldemedine v placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). Naldemedine was not associated with signs or symptoms of opioid withdrawal and had no notable impact on opioid-mediated analgesia. Conclusion Once-daily oral naldemedine 0.2 mg effectively treated OIC and was generally well tolerated in patients with OIC and cancer.