tbuckley/cabot-search huggingface dataset:
FineMAV: prioritizing candidate genetic variants driving local adaptations in human populations
Authors: Michał Szpak, Massimo Mezzavilla, Qasim Ayub, Yuan Chen, Yali Xue, Chris Tyler-Smith
Journal: Genome biology (2018)

We present a new method, Fine-Mapping of Adaptive Variation (FineMAV), which combines population differentiation, derived allele frequency, and molecular functionality to prioritize positively selected candidate variants for functional follow-up. We calibrate and test FineMAV using eight experimentally validated "gold standard" positively selected variants and simulations. FineMAV has good sensitivity and a low false discovery rate. Applying FineMAV to the 1000 Genomes Project Phase 3 SNP dataset, we report many novel selected variants, including ones in TGM3 and PRSS53 associated with hair phenotypes that we validate using available independent data. FineMAV is widely applicable to sequence data from both human and other species.
PD-L1 expression and response to neo-adjuvant chemotherapy in esophageal adenocarcinoma.
Authors: Eileen E. Parkes, Jaine K. Blayney, Eamon McCarron, Rosalie V. Douglas, Leanne Stevenson, Damian McManus, Stephen McQuaid, Ken Arthur, Jacqueline James, Manuel Salto-Tellez, Fergus Noble, Timothy J Underwood, Robert O'Neill, Rebecca C. Fitzgerald, Richard D. Kennedy, Richard C. Turkington
Journal: Journal of Clinical Oncology (2017)

4023 Background: Programmed Death-1 Receptor (PD-1) and its ligand (PD-L1) downregulate T cell activation and suppress tumor killing. This study investigated the role of PD-L1 and tumor infiltrating lymphocytes (TILs) in response to neo-adjuvant therapy and prognosis in esophageal adenocarcinoma (EAC). Methods: Transcriptional profiling of 273 formalin fixed paraffin embedded pre-treatment endoscopic EAC biopsies was carried out using the Almac Diagnostics Xcel array and the expression levels of PD-L1 probesets corresponding to protein encoding extracted. Response was assessed by tumor regression grade (TRG; score ≤ 2 = response). Immunohistochemistry (IHC) for PD-L1 and CD8 was performed in matched resection specimens from 135 patients. All EAC patients were treated with cisplatin-based neo-adjuvant chemotherapy followed by surgical resection between 2003 and 2014 at four UK centers as part of the OCCAMS consortium. Associations between expression, protein levels and TRG were assessed by Kruskal-Wallis, Mann-Whitney Unpaired, Spearman rank correlation or chi-squared tests. Survival analysis was performed using Cox Proportional Hazards regression. Results: High PD-L1 gene expression in the pre-chemotherapy biopsies was associated with pathological response (TRG ≤ 2; p = 0.02) following neo-adjuvant chemotherapy. PD-L1 ( &gt; 5%) was expressed in the tumor or stromal cells in 4% and 15% of resection specimens respectively. PD-L1 gene and IHC expression ( &gt; 5%) were closely associated between the biopsies and both the tumor (p = 0.032) and stroma (p = 0.019) of the matched resection specimens. Patients with PD-L1 IHC positivity in tumor cells demonstrated improved relapse-free survival (HR 0.314; 95% CI 0.099-0.997; p = 0.049) and positive stromal PD-L1 IHC staining correlated with pathological response (p = 0.05). Biopsy gene expression of PD-L1 and CD8 was closely associated (p = 0.024) and the presence of CD8+ TILs in the microenvironment strongly correlated with tumor (p &lt; 0.001) and stromal (p &lt; 0.001) PD-L1 positivity. Conclusions: High PD-L1 expression in the pre-treatment biopsies in EAC is predictive of response to neo-adjuvant chemotherapy and may aid selection of conventional and immune-targeted agents.
Physiological and Symptom Correlates of Exercise Tolerance in COPD Patients
Authors: N. Ambrosino, G. De Angelis, F. Pasqua, P. Paggiaro, A. Cogo, G. Balzano, K. Foglio, A. Spanevello, G. Barisione, M. Confalonieri, P. Lessi
Journal: American Journal of Respiratory and Critical Care Medicine (2006)
Abstract 17928: Parity, Job Stress, and Cardiovascular Risk in the Women’s Health Study
Authors: Eva M Durazo, Tomas Cabeza de Baca, Natalie Slopen, David R Williams, Alan M Zaslavsky, Julie E Buring, Michelle A Albert
Journal: Circulation (2016)

Background: Reproductive milestones and employment are critical events in a woman’s life that can affect chronic disease risk. Hence, we examined the relationship between parity and cardiovascular ...
Abstract 19256: Prognostic Impact of Combination of Widened QRS Plus Gadlinium Enhancement on Mortality in DIlated Cardiomyopathy
Authors: Kyohei Marume, Emi Tateishi, Tsukasa Kamakura, Yoichi Goto, Yoshiaki Morita, Kengo F Kusano, Satoshi Yasuda, Teruo Noguchi
Journal: Circulation (2016)

Background: Late gadolinium enhancement (LGE) has been established as a prognostic indicator in non-ischemic cardiomyopathy. However, it is not necessarily ideal for detecting diffuse myocardial fi...
Targeting the GAS6/AXL Pathway with a Newly Developed AXL-Selective Inhibitor SLC-0211 for the Treatment of Acute Myeloid Leukemia
Authors: Xiaojia Niu, Katharina Roche, Min Chen, Hong Zhang, Jun Yan, Yubin Ge, Zaihui Zhang, Xiaoyan Jiang
Journal: Blood (2017)
Identification and characterization of a fully human antibody directed against epidermal growth factor receptor for cancer therapy
Authors: Meilin Liu, Haifan Zhang, Xenia Jimenez, Dale Ludwig, Larry Witte, Peter Bohlen, Dan J. Hicklin, Zhenping Zhu
Journal: Cancer Research (2004)

706  Epidermal growth factor receptor (EGFR) has been implicated in promoting oncogenesis and progression of many human tumors, and is expressed in a variety of human solid tumors including carcinomas of head and neck, lung, colorectum, pancreas, prostate, and kidney. We have previously demonstrated that a chimeric anti-EGFR antibody, ErbituxTM (cetuximab), was an efficacious agent in inhibiting the growth of a variety of human xenograft tumors in animal models. In this study, we produced a fully human antibody directed against EGFR, IMC-11F8 (IgG1), from a Fab fragment originally identified from a naive phage display library. IMC-11F8 binds to EGFR with an affinity of ∼ 0.28 nM, and effectively blocks EGF-stimulated receptor phosphorylation and activation of MAP kinases in a number of tumor cell lines. The antibody also inhibits the in vitro growth of several EGFR-overexpressing tumor cell lines including DiFi (colorectal), A431 (epidermal) and BxPC3 (pancreatic). Taken together, these results suggest that IMC-11F8 may have great clinical potential in the treatment of EGFR+ human cancers.
The differential role of JAK-2 / STAT-1 in the r egulation of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 productions by CKD712
Authors: Ki-Mun Kang, Hye Jung Kim, Hong Seok Jang, Gyu Young Chai, Ki Churl Chang, Jae-Soo Shin, Sung Sook Lee, Sun Kil Ahn
Journal: Cancer Research (2007)

2389   Inflammation is commonly associated with carcinogenesis. CKD712, an  S  enantiomer of YS 49, is under phase I clinical trial for the treatment of inflammatory diseases such as sepsis. It differentially regulates the induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2  (COX-2) by lipopolysaccharide (LPS) in RAW 264.7 macrophage cells. Here we investigated how CKD712 affected the production of these enzymes when activated by LPS in RAW264.7 cells. CKD712 strongly inhibited iNOS induction, but showed a weak inhibitory effect on COX-2 induction in LPS-stimulated cells. Treatment with SP600125, a specific JNK inhibitor and TPCK, an inhibitor of NF-κB, but not the ERK inhibitor PD98059 or the p38 inhibitor SB203580, significantly inhibited LPS-mediated iNOS and COX-2 induction. However, AG490, a specific inhibitor of JAK-2/STAT-1, efficiently prevented LPS-mediated iNOS induction, but not induction of COX-2. CKD712 inhibited NF-κB (p65) activity and translocation, but failed to prevent JNK activation and completely blocked STAT-1 phosphorylation by LPS, suggesting that the NF-κB and JAK-2/STAT-1 pathways_but not the JNK pathway_are important for its action. Further, CKD712 induced upregulated heme oxygenase 1 (HO-1) gene expression in LPS-treated cells. Differential inhibition of iNOS and COX-2 were shown in LPS-activated HO-1 transfected cells. Taken together, we conclude that CKD712 can efficiently inhibit induction of iNOS rather than COX-2 by LPS in RAW 264.7 cells, by regulating the HO-1 and STAT-1 pathways. These results highlight another potential use of CKD712 as a therapeutic candidate against inflammatory diseases including cancer.
Adoptively transferred tumor-specific T cells expanded ex vivo using HSV amplicons encoding 4-1BBL show increased anti-tumor activity in vivo
Authors: Maria N. Jure-Kunkel, Sandra Calarota, Emel Girit, Ralph Abraham, Praveen Balimane, Karen Price, David Weiner, Laura Hefta
Journal: Cancer Research (2006)

4759  CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, is a critical receptor for the generation of effective immune responses to tumors and viruses. Signaling through CD137 results in costimulatory activity of antigen-specific activated T cells, and modulatory functions for natural killer and dendritic cells. In preclinical efficacy studies, agonistic anti-mouse CD137 (4-1BB) antibodies demonstrated potent antitumor activity against a variety of tumors as single agents or in combination with vaccines or other therapeutic modalities. We have generated fully human antibodies to the human CD137 receptor to be used as immuno-enhancers of antitumor immune responses. Antibody 10C7, an IgG4 kappa immunoglobulin, showed an overall affinity for human CD137 of 16.6 nM and presented costimulatory activities to anti-CD3-stimulated primary human and cynomolgus monkey lymphocytes. In addition, 10C7 led to increased survival and cell cycle progression of activated human T cells compared to cultures stimulated with an irrelevant immunoglobulin. Antibody 10C7 was weakly immunogenic in cynomolgus monkeys, and single or multiple intravenous administrations of the antibody demonstrated a typical antibody-like pharmacokinetic profile in macaques. The in vivo activity of mab 10C7 was evaluated in cynomolgus macaques in combination with a DNA vaccine encoding SIV Gag antigen (pSIVgag). Animals were immunized intramuscularly with pSIVgag on weeks 0, 4 and 8. Antibody 10C7 was administered intravenously on days 12, 15, and 19 after the first vaccine immunization. Treatment with 10C7 produced an enhancement of the pSIVgag-specific immune response compared to macaques immunized with pSIVgag alone as measured by ELISPOT assays for IFN-γ, granzyme B and perforin. Of note, 10C7-driven responses were long-lasting and were characterized by a shift towards a CD8+/CCR7-/CD45RA+ effector phenotype. The in vitro and in vivo characteristics of 10C7 are consistent with those demonstrated by anti-mouse CD137 antibodies that elicited antitumor responses in mouse tumor models. Therefore, evaluation of 10C7 is warranted in cancer clinical trials.
Beyond communication: Episodic memory is key to the self in time
Authors: Karl K. Szpunar, Jason C. K. Chan
Journal: Behavioral and Brain Sciences (2018)

Abstract Mahr &amp; Csibra (M&amp;C) propose that episodic memory evolved to support epistemic authority in social communication. We argue for a more parsimonious interpretation whereby episodic memory subserves a broader preparatory function for both social and non-social behavior. We conclude by highlighting that functional accounts of episodic memory may need to consider the complex interrelations between self and subjective time.
Subcutaneous (SC) vs Intravenous (IV) C1-esterase-inhibitor (C1-INH) Replacement Treatment For The Prevention Of Attacks Of Hereditary Angioedema (HAE): A Population-based Exposure-response Analysis
Authors: Bruce L. Zuraw, Marco Cicardi, Timothy J. Craig, Hilary J. Longhurst, William R. Lumry, Jonathan A. Bernstein, Ying Zhang, Dipti K. Pawaskar
Journal: Journal of Allergy and Clinical Immunology (2018)
Association of Combined Patterns of Tobacco and Cannabis Use in Adolescence With Psychotic Experiences
Authors: Hannah J. Jones, Suzanne H. Gage, Jon Heron, Matthew Hickman, Glyn Lewis, Marcus R. Munafò, Stanley Zammit
Journal: JAMA Psychiatry (2018)

There is concern about potentially causal effects of tobacco use on psychosis, but epidemiological studies have been less robust in attempts to minimize effects of confounding than studies of cannabis use have been.To examine the association of patterns of cigarette and cannabis use with preceding and subsequent psychotic experiences, and to compare effects of confounding across these patterns.This cohort study used data from the Avon Longitudinal Study of Parents and Children, which initially consisted of 14 062 children. Data were collected periodically from September 6, 1990, with collection ongoing, and analyzed from August 8, 2016, through June 14, 2017. Cigarette and cannabis use data were summarized using longitudinal latent class analysis to identify longitudinal classes of substance use. Associations between classes and psychotic experiences at age 18 years were assessed.Depending on the analysis model, exposures were longitudinal classes of substance use or psychotic experiences at age 12 years.Logistic regression was used to examine the associations between substance use longitudinal classes and subsequent onset of psychotic experiences.Longitudinal classes were derived using 5300 participants (56.1% female) who had at least 3 measures of cigarette and cannabis use from ages 14 to 19 years. Prior to adjusting for a range of potential confounders, there was strong evdience that early-onset cigarette-only use (4.3%), early-onset cannabis use (3.2%), and late-onset cannabis use (11.9%) (but not later-onset cigarette-only use [14.8%]) latent classes were associated with increased psychotic experiences compared with nonusers (65.9%) (omnibus P < .001). After adjusting for confounders, the association for early-onset cigarette-only use attenuated substantially (unadjusted odds ratio [OR], 3.03; 95% CI, 1.13-8.14; adjusted OR, 1.78; 95% CI, 0.54-5.88), whereas those for early-onset cannabis use (adjusted OR, 3.70; 95% CI, 1.66-8.25) and late-onset cannabis use (adjusted OR, 2.97; 95% CI, 1.63-5.40) remained consistent.In this study, our findings indicate that while individuals who use cannabis or cigarettes during adolescence have an increased risk of subsequent psychotic experiences, epidemiological evidence is substantively more robust for cannabis use than it is for tobacco use.
Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer
Authors: Xavier Pivot, Igor Bondarenko, Zbigniew Nowecki, Mikhail Dvorkin, Ekaterina Trishkina, Jin-Hee Ahn, Yuriy Vinnyk, Seock-Ah Im, Tomasz Sarosiek, Sanjoy Chatterjee, Marek Z. Wojtukiewicz, Vladimir Moiseyenko, Yaroslav Shparyk, Maximino Bello, Vladimir Semiglazov, Sujeong Song, Jaeyun Lim
Journal: Journal of Clinical Oncology (2018)

Purpose This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2-positive early breast cancer in the neoadjuvant setting ( ClinicalTrials.gov identifier: NCT02149524). Patients and Methods Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference was within ± 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Results Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCR rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259 (95% CI, 1.085 to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8% and the overall response rates were 96.3% and 91.2% with SB3 and TRZ, respectively. Overall, 96.6% and 95.2% of patients experienced one or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively. Conclusion Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCR rates. Safety and immunogenicity were comparable.
A Tyrosine Phosphorylation Cycle Regulates Fungal Activation of a Plant Receptor Ser/Thr Kinase
Authors: Jun Liu, Bing Liu, Sufen Chen, Ben-Qiang Gong, Lijuan Chen, Qi Zhou, Feng Xiong, Menglong Wang, Dongru Feng, Jian-Feng Li, Hong-Bin Wang, Jinfa Wang
Journal: Cell Host & Microbe (2018)
Estimated Effect of Temperature on Years of Life Lost: A Retrospective Time-Series Study of Low-, Middle-, and High-Income Regions
Authors: Maquins Odhiambo Sewe, Aditi Bunker, Vijendra Ingole, Thaddaeus Egondi, Daniel Oudin Åström, David M. Hondula, Joacim Rocklöv, Barbara Schumann
Journal: Environmental Health Perspectives (2018)

Numerous studies have reported a strong association between temperature and mortality. Additional insights can be gained from investigating the effects of temperature on years of life lost (YLL), considering the life expectancy at the time of death.The goal of this work was to assess the association between temperature and YLL at seven low-, middle-, and high-income sites.We obtained meteorological and population data for at least nine years from four Health and Demographic Surveillance Sites in Kenya (western Kenya, Nairobi), Burkina Faso (Nouna), and India (Vadu), as well as data from cities in the United States (Philadelphia, Phoenix) and Sweden (Stockholm). A distributed lag nonlinear model was used to estimate the association of daily maximum temperature and daily YLL, lagged 0-14 d. The reference value was set for each site at the temperature with the lowest YLL.Generally, YLL increased with higher temperature, starting day 0. In Nouna, the hottest location, with a minimum YLL temperature at the first percentile, YLL increased consistently with higher temperatures. In Vadu, YLL increased in association with heat, whereas in Nairobi, YLL increased in association with both low and high temperatures. Associations with cold and heat were evident for Phoenix (stronger for heat), Stockholm, and Philadelphia (both stronger for cold). Patterns of associations with mortality were generally similar to those with YLL.Both high and low temperatures are associated with YLL in high-, middle-, and low-income countries. Policy guidance and health adaptation measures might be improved with more comprehensive indicators of the health burden of high and low temperatures such as YLL. https://doi.org/10.1289/EHP1745.
Abstract 18869: Characteristics and Outcomes of Out of Hospital Cardiac Arrest in Women
Authors: Nicole Karam, Pechmajou Louis, Wulfran Bougouin, Frankie Beganton, Lionel Lamhaut, Jean-Philipe Empana, Florence Dumas, Alain Cariou, Christian Spaulding, Eloi Marijon, Xavier Jouven
Journal: Circulation (2016)

Introduction:  A lower survival rate is observed among women in Out of Hospital Cardiac Arrest (OHCA).   Hypothesis:  The lower survival rate observed among women is rather due to a worse management than to intrinsic factors.   Methods:  Data was taken between May 2011 and May 2015 from the Paris Sudden Cardiac Death Expertise Center prospective registry that includes all patients who present OHCA in Paris and its suburbs (6.6 million inhabitants). OHCA related to non-cardiac causes such as trauma, respiratory failure, drowning, and drug overdose were excluded.   Results:  During the study period, 12,426 OHCA were recorded, of which 38.5% occurred among women. Mean age was higher among women (mean (SD), 75.6 (16.4) vs 67.5 (16.6) years, P   Conclusion:  In this real life population of OHCA, survival rate was lower among women than among men. However, after adjusting for traditional prognostic factors, including initial management, female gender per se is associated with a higher survival rate, highlighting the need for improving OHCA management among women.
Cost-Effectiveness of the Regimen Proposed By the International Consortium on Acute Promyelocytic Leukemia in the Treatment of Newly Diagnosed Patients with Acute Promyelocytic Leukemia
Authors: Sergio Rodriguez-Rodriguez, Roberta Demichelis-Gómez, Maria Jose Diaz-Huizar, Lorena Guerrero-Torres, Alan Pomerantz, Maria del Pilar Ortiz-Vilchis, Alvaro Aguayo
Journal: Blood (2017)
Experimental Allergen Immunotherapy with Monomeric Allergoid From House Dust Mite Dermatophagoides pteronyssinus in a Mouse Model of Allergic Rhinitis
Authors: Alexander A. Babakhin, Anton A. Laskin, Oleg Y. Kamishnikov, Denis G. Chuvirov, Svetlana V. Khlgatyan, Valentina M. Berzhets, Lawrence Dubuske, Musa R. Khaitov
Journal: Journal of Allergy and Clinical Immunology (2018)
A cellular antidote to specifically deplete anti-CD19 chimeric antigen receptor–positive cells
Authors: Marco Ruella, David M. Barrett, Olga Shestova, Jessica Perazzelli, Avery D. Posey, Seok Jae Hong, Miroslaw Kozlowski, Simon F. Lacey, J. Joseph Melenhorst, Carl H. June, Saar I. Gill
Journal: Blood (2019)
Relationship between tissue factor expression by human pancreatic cancer cells and activation of coagulation and thrombosis in a mouse model.
Authors: Julia E. Geddings, Jian-guo Wang, Jessica C Cardenas, Pichika Chantrathammachart, Julie C Williams, Ronald R Back, Frank C Church, Rafal Pawlinski, Nigel Key, Jen Jen Yeh, Nigel Mackman
Journal: Journal of Clinical Oncology (2012)

e14505 Background: The increased risk of thrombosis in patients with cancer has been well established. However, the triggers in these patients have yet to be fully defined. Under pathological conditions, the potent procoagulant protein Tissue Factor (TF) is found in the circulation and may trigger thrombosis. Methods: We evaluated the level of TF expression in 4 different human pancreatic cancer cell lines. We also measured TF microparticle (MP) release from these tumors in vivo by flow cytometry and TF activity assay. We then used these lines in a mouse model of pancreatic cancer to evaluate the sources of TF that activate coagulation and contribute to thrombosis using a saphenous vein model. Results: We found that mice bearing orthotopic pancreatic tumors which express higher levels of TF (HPAC and HPAF) show increased activation of coagulation (measured by thrombin-antithrombin complex) as compared to mice bearing TF negative tumors (MIA-PaCa-2 and PANC-1). This activation of coagulation could be reduced by treatment with a human TF antibody. Further, mice bearing tumors derived from TF high cell line HPAC demonstrated an activation of coagulation despite a lack of circulating TF-positive MPs. Mice bearing TF expressing pancreatic tumors also demonstrated increased thrombosis by a saphenous vein model. Treatment of tumor-free mice with TF MPs did not result in an activation of coagulation or increased thrombosis unless mice were given 40-100 fold higher levels of TF bearing MPs than are found in the circulation of tumor bearing mice. Conclusions: The data suggest that TF on the tumor itself is involved in the activation of coagulation whereas circulating TF-positive MPs is likely to contribute to thrombosis. Elevated levels of TF-positive MPs may be used as a biomarker to identify cancer patients at risk for thrombosis.