tbuckley/cabot-search huggingface dataset:
Epistasis Constrains Mutational Pathways of Hemoglobin Adaptation in High-Altitude Pikas
Authors: Danielle M. Tufts, Chandrasekhar Natarajan, Inge G. Revsbech, Joana Projecto-Garcia, Federico G. Hoffmann, Roy E. Weber, Angela Fago, Hideaki Moriyama, Jay F. Storz
Journal: Molecular Biology and Evolution (2014)

A fundamental question in evolutionary genetics concerns the roles of mutational pleiotropy and epistasis in shaping trajectories of protein evolution. This question can be addressed most directly by using site-directed mutagenesis to explore the mutational landscape of protein function in experimentally defined regions of sequence space. Here, we evaluate how pleiotropic trade-offs and epistatic interactions influence the accessibility of alternative mutational pathways during the adaptive evolution of hemoglobin (Hb) function in high-altitude pikas (Mammalia: Lagomorpha). By combining ancestral protein resurrection with a combinatorial protein-engineering approach, we examined the functional effects of sequential mutational steps in all possible pathways that produced an increased Hb–O2 affinity. These experiments revealed that the effects of mutations on Hb–O2 affinity are highly dependent on the temporal order in which they occur: Each of three β-chain substitutions produced a significant increase in Hb–O2 affinity on the ancestral genetic background, but two of these substitutions produced opposite effects when they occurred as later steps in the pathway. The experiments revealed pervasive epistasis for Hb–O2 affinity, but affinity-altering mutations produced no significant pleiotropic trade-offs. These results provide insights into the properties of adaptive substitutions in naturally evolved proteins and suggest that the accessibility of alternative mutational pathways may be more strongly constrained by sign epistasis for positively selected biochemical phenotypes than by antagonistic pleiotropy.
Whole-Genome Sequencing and Cancer Therapy: Is Too Much Ever Enough?
Authors: Levi A. Garraway, José Baselga
Journal: Cancer Discovery (2012)

Abstract Summary: This issue of Cancer Discovery features an article that describes the use of whole-genome sequencing to discover an actionable genetic alteration that was not detected using a lower resolution diagnostic approach. This finding highlights the growing debate surrounding the optimal deployment of powerful new genomics technologies in the clinical oncology arena. Cancer Discov; 2(9); 766–8. ©2012 AACR. Commentary on Dahlman et al., p. 791.
Syndecan-2 Exerts Antifibrotic Effects by Promoting Caveolin-1–mediated Transforming Growth Factor-β Receptor I Internalization and Inhibiting Transforming Growth Factor-β1 Signaling
Authors: Yuanyuan Shi, Bernadette R. Gochuico, Guoying Yu, Xiaomeng Tang, Juan C. Osorio, Isis E. Fernandez, Cristobal F. Risquez, Avignat S. Patel, Ying Shi, Marc G. Wathelet, Andrew J. Goodwin, Jeffrey A. Haspel, Stefan W. Ryter, Eric M. Billings, Naftali Kaminski, Danielle Morse, Ivan O. Rosas
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Alveolar transforming growth factor (TGF)-β1 signaling and expression of TGF-β1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-β receptor TβRI inhibits TGF-β signaling and could attenuate development of experimental lung fibrosis.To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-β1 signaling in alveolar epithelial cells.Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with IPF versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell TGF-β1 signaling, TGF-β1, and TβRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury.We observed significant increases in alveolar macrophage syndecan-2 levels in patients with IPF. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting TGF-β1 signaling and downstream expression of TGF-β1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1-dependent internalization of TGF-β1 and TβRI in alveolar epithelial cells, which inhibited TGF-β1 signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice.Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting caveolin-1-dependent TGF-β1 and TβRI internalization and inhibiting TGF-β1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TβRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.
Kinin generation in acute pneumonia and chronic bronchitis
Authors: M Zhang, B Peng, J Niehus, CR Baumgarten, T Brunnee, S Thalhofer, P Dorow, G Kunkel
Journal: European Respiratory Journal (1997)

Kinins are potent inflammatory mediators, liberated from kininogens by different kininogenases. The aim of this study was to investigate the kinin generation pathways in acute and chronic inflammation of the lower airways. We studied bronchoalveolar lavage fluid (BALF) of patients with acute pneumonia, patients with chronic bronchitis and healthy controls. Kinins were determined by radioimmunoassay (RIA). Plasma kallikrein (pl-Kal), alpha2-macroglobulin (alpha2-M) and toluenesulphonylarginine methyl ester (TAME) esterase activity (TAME-ea) were studied in BALF before and after gel filtration chromatography. Plasma kallikrein and alpha2-M were measured using two newly developed sandwich enzyme-linked immunosorbent assays (ELISAs). TAME-ea was measured by a radiochemical assay. After gel filtration, inhibition of TAME-ea with benzamidine, soy-bean-trypsin inhibitor (SBTI) and aprotinin was performed. Kinins and TAME-ea did not differ significantly between acute pneumonia and chronic bronchitis, whereas pl-Kal and alpha2-M values were significantly higher in acute pneumonia. Gel filtration revealed the highest TAME-ea peak in acute pneumonia corresponding with the first alpha2-M peak at approximately 800 kDa, whereas in chronic bronchitis the highest peak was found at approximately 40 kDa. The inhibition test showed that the TAME-ea peak at approximately 800 kDa was due to pl-Kal and the TAME-ea peak at approximately 40 kDa was mainly due to tissue kallikrein. High peaks of alpha2-M and pl-Kal were found in pneumonia and only small peaks were seen in chronic bronchitis. We conclude that in acute airway inflammation kinins seem to be mainly generated by plasma kallikrein whereas in chronic inflammation, kininogenases other than plasma kallikrein, such as tissue kallikrein, seem to be more important.
Results of E1496: A phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma (NHL)
Authors: H. S. Hochster, E. Weller, T. Ryan, T. M. Habermann, R. Gascoyne, S. R. Frankel, S. J. Horning
Journal: Journal of Clinical Oncology (2004)

6502 Background: Despite high overall response rates, indolent NHL is characterized by continuous relapse. E1496 evaluated the ability of two years (yr) of maintenance rituximab to prolong progression-free survival (PFS, progression or death) after chemotherapy. Methods: Eligible patients (pt) included stage III-IV follicular grade 1 and 2 (small cleaved, mixed) and small lymphocytic NHL. 516 pt were randomized to CVP (cyclophosphamide 1 g/m2 d 1, vincristine 1.4 mg/m2 d 1, prednisone 100 mg/m2 d 1–5) or CF (CYC 1 g/m2 d 1, fludara 20 mg/m2 d 1–5) stratified by age, histology, B symptoms, and tumor burden (low v high). CF (115 pt) was discontinued 9/01 for toxicity (ASCO 2002). 401 CVP pt were treated to maximum response (6–8 cycles); 9% progressed. Of stable/responding pt, 322 were randomized to rituximab (375 mg/m2 weekly x 4) q 6 months x 4 cycles or observation, stratified by residual disease (minimal v greater) and histology. Results: The study was terminated early as the O'Brien-Fleming boundary for PFS was crossed with 303 of 322 randomized pt assessable (one-sided p=0.00008). The rituximab (n=154) and observation (n=149) pt were respectively balanced for age (59, 56 yr), residual disease (58%, 55% minimal), histology (77%, 77% follicular) & tumor burden (62%, 67% high) as well as gender, stage, marrow involvement and International Prognostic Index. 31 rituximab and 56 observation pt have progressed or died. For randomized pt, PFS estimates at 2 & 4 yr from maintenance randomization (∼2.5 & 4.5 yr post study entry) were 74% v 42% and 58% v 34% for rituximab and observation pt, respectively. PFS was significantly longer after rituximab regardless of histology (p<0.02) or residual disease (p<0.008); pt with high tumor burden (p=0.00005) also had significantly longer PFS after rituximab. With 17 (6%) deaths and median follow-up of 1.2 year among survivors, estimated 2 yr survival from maintenance randomization was 95% for rituximab v 91% for observation pt. Conclusion: Maintenance rituximab significantly prolongs PFS after CVP chemo in pt with advanced indolent NHL. Extended follow-up will determine whether longer PFS translates into improved survival. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech; Genetech Biooncology Genentech
Quantitative intact proteomics investigations of alveolar macrophages in sarcoidosis
Authors: Ernesto Silva, Serhiy Souchelnytskyi, Kie Kasuga, Anders Eklund, Johan Grunewald, Åsa M. Wheelock
Journal: European Respiratory Journal (2012)

Alveolar macrophages are important for granuloma formation, which is the histological hallmark in sarcoidosis. Their function as antigen-presenting cells in sarcoidosis is also believed to be relevant to the outcome of disease, resulting either in remission or a prolonged chronic inflammation in the lungs. Our aim was to study alterations in the expression levels of the soluble proteome of alveolar macrophages in pulmonary sarcoidosis as compared with healthy controls, with the goal of identifying specific proteins and pathways important for the mechanisms of disease and/or disease phenotype. Quantitative proteomics approach using two-dimensional difference gel electrophoresis coupled to mass spectrometry was applied. Data was evaluated using multivariate modelling and pathway analyses. 69 protein spots were found to be significantly altered between sarcoidosis and healthy controls. Among these, 25 unique proteins were identified. Several of the identified proteins were related to key alveolar macrophage functionality, including the Fcγ-mediated phagocytosis and clathrin-mediated endocytosis pathways. Global proteomics analysis provided identification of alterations of a subset of proteins not previously reported in sarcoidosis. These alterations primarily affect biological pathways related to phagocytic macrophage functionality. These findings provide important insights into the role of macrophages in sarcoidosis pathogenesis.
Endothelial cell-borne platelet bridges selectively recruit monocytes in human and mouse models of vascular inflammation
Authors: Christopher J. Kuckleburg, Clara M. Yates, Neena Kalia, Yan Zhao, Gerard B. Nash, Steve P. Watson, George Ed. Rainger
Journal: Cardiovascular Research (2011)

Cells of the monocyte lineage are the most abundant inflammatory cells found in atherosclerotic lesions. Dominance of the inflammatory infiltrate by monocytes indicates that there is a disease-driven mechanism supporting their selective recruitment. Previous studies have demonstrated that interactions between endothelial cells (ECs) and platelets may promote monocyte recruitment. In this study, we sought to expand on this knowledge using a complex coculture model of the diseased vessel wall. Using primary human cells in an in vitro flow-based adhesion assay, we found that secretory arterial smooth muscle cells (SMCs), cocultured with ECs, promote preferential recruitment of monocytes from blood in a TGF-β1-dependent manner. Approximately 85% of leucocytes recruited to the endothelium were CD14+. Formation of adhesive platelet bridges on ECs was essential for monocyte recruitment as platelet removal or inhibition of adhesion to the ECs abolished monocyte recruitment. Monocytes were recruited from flow by platelet P-selectin and activated by EC-derived CC chemokine ligand 2 (CCL2), although the presentation of CCL2 to adherent monocytes was dependent upon platelet activation and release of CXC chemokine ligand 4 (CXCL4). In an intravital model of TGF-β1-driven vascular inflammation in mice, platelets were also necessary for efficient leucocyte recruitment to vessels of the microcirculation in the cremaster muscle. In this study, we have demonstrated that stromal cells found within the diseased artery wall may promote the preferential recruitment of monocytes and this is achieved by establishing a cascade of interactions between SMCs, ECs, platelets, and monocytes.
Climate Change
Authors: Jonathan A. Patz, Howard Frumkin, Tracey Holloway, Daniel J. Vimont, Andrew Haines
Journal: JAMA (2014)

IMPORTANCEHealth is inextricably linked to climate change.It is important for clinicians to understand this relationship in order to discuss associated health risks with their patients and to inform public policy.OBJECTIVES To provide new US-based temperature projections from downscaled climate modeling and to review recent studies on health risks related to climate change and the cobenefits of efforts to mitigate greenhouse gas emissions.DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS We searched PubMed and Google Scholar from 2009 to 2014 for articles related to climate change and health, focused on governmental reports, predictive models, and empirical epidemiological studies.Of the more than 250 abstracts reviewed, 56 articles were selected.In addition, we analyzed climate data averaged over 13 climate models and based future projections on downscaled probability distributions of the daily maximum temperature for 2046-2065.We also compared maximum daily 8-hour average ozone with air temperature data taken from the National Oceanic and Atmospheric Administration, National Climate Data Center.RESULTS By 2050, many US cities may experience more frequent extreme heat days.For example, New York and Milwaukee may have 3 times their current average number of days hotter than 32°C (90°F).High temperatures are also strongly associated with ozone exceedance days, for example, in Chicago, Illinois.The adverse health aspects related to climate change may include heat-related disorders, such as heat stress and economic consequences of reduced work capacity; respiratory disorders, including those exacerbated by air pollution and aeroallergens, such as asthma; infectious diseases, including vectorborne diseases and waterborne diseases, such as childhood gastrointestinal diseases; food insecurity, including reduced crop yields and an increase in plant diseases; and mental health disorders, such as posttraumatic stress disorder and depression, that are associated with natural disasters.Substantial health and economic cobenefits could be associated with reductions in fossil fuel combustion.For example, greenhouse gas emission policies may yield net economic benefit, with health benefits from air quality improvements potentially offsetting the cost of US and international carbon policies.CONCLUSIONS AND RELEVANCE Evidence over the past 20 years indicates that climate change can be associated with adverse health outcomes.Health care professionals have an important role in understanding and communicating the related potential health concerns and the cobenefits from policies to reduce greenhouse gas emissions.
Depression, Correlates of Depression, and Receipt of Depression Care Among Low-Income Women With Breast or Gynecologic Cancer
Authors: Kathleen Ell, Kathleen Sanchez, Betsy Vourlekis, Pey-Jiuan Lee, Megan Dwight-Johnson, Isabel Lagomasino, Laila Muderspach, Christy Russell
Journal: Journal of Clinical Oncology (2005)

Purpose To assess the prevalence of depression among low-income, ethnic minority women with breast or gynecologic cancer, receipt of antidepressant medications or counseling services, and correlates of depression. Patients and Methods Study patients were 472 women receiving cancer care in an urban public medical center. Women had a primary diagnosis of breast (stage 0 to III) or gynecologic cancer (International Federation of Gynecology and Obstetrics stage 0 to IIIB). A diagnostic depression screen and baseline questionnaire were administered before or during active treatment or during active follow-up. Self-report data were collected on receipt of depression treatment, use of supportive counseling, pain and receipt of pain medication, functional status and well-being, and perceived barriers to cancer care. Results Twenty-four percent of women reported moderate to severe levels of depressive disorder (30% of breast cancer patients and 17% of gynecologic cancer patients). Only 12% of women meeting criteria for major depression reported currently receiving medications for depression, and only 5% of women reported seeing a counselor or participating in a cancer support group. Neither cancer stage nor treatment status was correlated with depression. Primary diagnosis of breast cancer, younger age, greater functional impairment, poorer social and family well-being, anxiety, comorbid arthritis, and fears about treatment side effects were correlated with depression. Conclusion Findings indicate that depressive disorder among ethnic minority, low-income women with breast or gynecologic cancer is prevalent and is correlated with pain, anxiety, and health-related quality of life. Because these women are unlikely to receive depression treatment or supportive counseling, there is a need for routine screening, evaluation, and treatment in this population.
Serum aluminum levels as a reflection of renal osteodystrophy status and bone surface aluminum staining.
Authors: A B Hodsman, B M Steer
Journal: Journal of the American Society of Nephrology (1992)

Twenty eight (14%) out of 196 patients in a regional dialysis population were found to have serum aluminum levels greater than or equal to 5 mumol/L or 135 micrograms/L; 21 consented to undergo a bone biopsy to identify the spectrum of renal osteodystrophy associated with this degree of hyperaluminemia. Both the Aluminon reagent and the acid solochrome azurine (ASA) stain were used to identify aluminum deposits. A control group of 13 patients with biochemical and histological evidence of severe secondary hyperparathyroidism was used to contrast the measured parameters of bone histology in the hyperaluminemic group. Al(OH)3 was used as the principal phosphate binder in all patients. In the hyperaluminemic group, 67% had either dialysis osteomalacia or aplastic bone lesions, and all except one aplastic lesion were positive for bone surface aluminum deposits by the Aluminon stain. The Aluminon stain was also positive in one of three cases of osteitis fibrosa and three of four mild lesions, whereas it was negative in all biopsies from the control group. However, the ASA stain was positive in all biopsies from the hyperaluminemic group and in 11 of 13 control biopsies from the patients with "pure" osteitis fibrosa. For all biopsy data from both groups, there were significant (P less than 0.01) negative correlations between the ASA-stained surface aluminum deposits and resorption indices (total eroded surface, r = -0.68; surface osteoclast counts, r = -0.53) and indices of bone formation (surface osteoblast counts, r = -0.61; mineral apposition rate, r = -0.63; bone formation rate, r = -0.69). These correlations were not significant for Aluminon-stained surface deposits with the exception of the bone formation indices, which had lower correlation coefficients (r = -0.44). These data suggest that hyperaluminemia greater than or equal to 5 mumol/L has a predictive value to identify impaired mineralization in dialysis patients that is high enough to affect clinical decision making. However, the more sensitive ASA stain identifies surface aluminum across the whole spectrum of renal osteodystrophy and is consistent with a toxic role for aluminum at any level of exposure.
High-Dose Carboplatin With Diethyldithiocarbamate Chemoprotection in Treatment of Women With Relapsed Ovarian Cancer
Authors: M. L Rothenberg, Y. Ostchega, S. M. Steinberg, R. C. Young, S. Hummel, R. F. Ozols
Journal: JNCI Journal of the National Cancer Institute (1988)

Diethyldithiocarbamate (DDTC) has been found to protect the bone marrow, kidneys, and gastrointestinal tract from the toxic effects of cisplatin and carboplatin (CBDCA) in animal models. In an attempt to minimize the toxic effects of high-dose CBDCA (800 mg/m2), a pilot study was undertaken in which women with relapsed or refractory epithelial ovarian cancer were treated with high-dose CBDCA, which was followed 3 hours later with DDTC (4 g/m2). There were four partial responses and no complete response in 21 patients who could be evaluated (overall response rate, 19%). Significant toxic effects, including three treatment-related deaths, were associated with the regimen. This study suggests that while high-dose CBDCA plus DDTC may be active in relapsed or refractory ovarian cancer, it is associated with clinically significant hematologic and autonomic toxic effects.
Co-localisation of non-cartilaginous articular pathology increases risk of cartilage loss in the tibiofemoral joint—the MOST study
Authors: Frank W Roemer, David T Felson, Ke Wang, Michel D Crema, Tuhina Neogi, Yuqing Zhang, Michael C Nevitt, Monica D Marra, Cora E Lewis, James Torner, Ali Guermazi
Journal: Annals of the Rheumatic Diseases (2012)

To assess risk of cartilage loss in the tibiofemoral joint in relation to baseline damage severity, and to analyse the association of nearby pathologic findings on the risk of subsequent cartilage loss.