tbuckley/cabot-search huggingface dataset:
Molecular Basis for Estrogen Receptor Deficiency in BRCA1-Linked Breast Cancer
Authors: A. M. Hosey, J. J. Gorski, M. M. Murray, J. E. Quinn, W. Y. Chung, G. E. Stewart, C. R. James, S. M. Farragher, J. M. Mulligan, A. N. Scott, P. A. Dervan, P. G. Johnston, F. J. Couch, P. A. Daly, E. Kay, A. McCann, P. B. Mullan, D. P. Harkin
Journal: JNCI Journal of the National Cancer Institute (2007)

BRCA1-mutant breast tumors are typically estrogen receptor alpha (ERα) negative, whereas most sporadic tumors express wild-type BRCA1 and are ERα positive. We examined a possible mechanism for the observed ERα-negative phenotype of BRCA1-mutant tumors. We used a breast cancer disease–specific microarray to identify transcripts that were differentially expressed between paraffin-embedded samples of 17 BRCA1-mutant and 14 sporadic breast tumors. We measured the mRNA levels of estrogen receptor 1 (ESR1) (the gene encoding ERα), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ERα protein expression was assessed in human breast cancer HCC1937 cells that were stably reconstituted with wild-type BRCA1 expression construct and in human breast cancer T47D and MCF-7 cells transiently transfected with BRCA1-specific short-interfering RNA (siRNA). Chromatin immunoprecipitation assays were performed to determine if BRCA1 binds the ESR1 promoter and to identify other interacting proteins. Sensitivity to the antiestrogen drug fulvestrant was examined in T47D and MCF-7 cells transfected with BRCA1-specific siRNA. All statistical tests were two-sided. Mean ESR1 gene expression was 5.4-fold lower in BRCA1-mutant tumors than in sporadic tumors (95% confidence interval [CI] = 2.6-fold to 40.1-fold, P = .0019). The transcription factor Oct-1 recruited BRCA1 to the ESR1 promoter, and both BRCA1 and Oct-1 were required for ERα expression. BRCA1-depleted breast cancer cells expressing exogenous ERα were more sensitive to fulvestrant than BRCA1-depleted cells transfected with empty vector (T47D cells, the mean concentration of fulvestrant that inhibited the growth of 40% of the cells [IC 40 ] for empty vector versus ERα: >10 −5 versus 8.0 × 10 −9 M [95% CI = 3.1 × 10 −10 to 3.2 × 10 −6 M]; MCF-7 cells, mean IC 40 for empty vector versus ERα: >10 −5 versus 4.9 × 10 −8 M [95% CI = 2.0 × 10 −9 to 3.9 × 10 −6 M]). BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ERα expression.
Low Adiponectin Levels Are Associated With Atherogenic Dyslipidemia and Lipid-Rich Plaque in Nondiabetic Coronary Arteries
Authors: Steven P. Marso, Sameer K. Mehta, Andrew Frutkin, John A. House, Justin R. McCrary, Krishnaji R. Kulkarni
Journal: Diabetes Care (2008)

OBJECTIVE—The purpose of this study was to determine whether an association exists between adiponectin and plaque composition in human coronary arteries. RESEARCH DESIGN AND METHODS—Adiponectin is an adipocyte-derived protein with antiatherogenic and insulin-sensitizing properties. To date, the relationship between adiponectin and plaque composition is unknown. Fasting blood samples were collected from 185 patients undergoing coronary angiography and intravascular ultrasound (IVUS). Plaque composition was categorized as fibrous, fibrofatty, necrotic core, or dense calcium and further classified as IVUS-derived adaptive or pathological intimal thickening, fibroatheroma, fibrocalcific, or thin cap fibroatheroma. RESULTS—Adiponectin correlated with normalized plaque volume (r = −0.16, P = 0.025) and atheroma lipid content as measured by normalized fibrofatty volume (r = −0.19, P = 0.009). Low adiponectin levels were associated with IVUS-derived pathological intimal thickening (r = −0.18, P = 0.01). With increasing quartiles (Q) of adiponectin, the normalized volume of fibrofatty plaque decreased (P = 0.03), which was driven by reductions in the nondiabetic cohort (Q1 44.2 mm3; Q2 28.2 mm3; Q3 24.7 mm3; and Q4 23.4 mm3; P = 0.01). No similar association was present in diabetic patients. Low adiponectin levels were also associated with IVUS-derived pathological intimal thickening in nondiabetic (r = −0.20, P = 0.03) but not diabetic patients. CONCLUSIONS—Low adiponectin levels are associated with atherogenic lipoproteins (elevated triglycerides, small dense LDL cholesterol, and low HDL cholesterol), increased plaque volume, lipid-rich plaque, and IVUS-derived pathological intimal thickening in the total cohort that was driven by the nondiabetic population, suggesting an antiatherogenic role in the early stages of lesion development.
Cancer Incidence in Patients With Type 1 Diabetes Mellitus: A Population-Based Cohort Study in Sweden
Authors: K. Zendehdel
Journal: JNCI Journal of the National Cancer Institute (2003)

Although patients with type 2 diabetes have elevated risks of liver, pancreatic, kidney, and endometrial cancer, little is known about the risk of cancer for patients with type 1 diabetes. We conducted a cohort study to examine cancer incidence among 29 187 patients in Sweden who were hospitalized for type 1 diabetes from 1965 through 1999. Relative risks of cancer were estimated by age-, sex- and calendar year of follow-up--adjusted standardized incidence ratios (SIRs), using data for the entire Swedish population as a reference. After excluding cancers diagnosed during the first year after hospital discharge, we observed 355 incident cases of cancer, which corresponded to a 20% increase in overall cancer incidence among type 1 diabetes patients (SIR = 1.2, 95% confidence interval [CI] = 1.0 to 1.3). Patients with type 1 diabetes had elevated risks of cancers of the stomach (SIR = 2.3, 95% CI = 1.1 to 4.1), cervix (SIR = 1.6, 95% CI = 1.1 to 2.2), and endometrium (SIR = 2.7, 95% CI = 1.4 to 4.7). Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes.
Dense type I collagen matrices that support cellular remodeling and microfabrication for studies of tumor angiogenesis and vasculogenesis in vitro
Authors: Valerie L. Cross, Ying Zheng, Nak Won Choi, Scott S. Verbridge, Bryan A. Sutermaster, Lawrence J. Bonassar, Claudia Fischbach, Abraham D. Stroock
Journal: Biomaterials (2010)
Multipotent adult progenitor cells sustain function of ischemic limbs in mice
Authors: Xabier L. Aranguren, Jonathan D. McCue, Benoit Hendrickx, Xiao-Hong Zhu, Fei Du, Eleanor Chen, Beatriz Pelacho, Ivan Peñuelas, Gloria Abizanda, Maialen Uriz, Sarah A. Frommer, Jeffrey J. Ross, Betsy A. Schroeder, Meredith S. Seaborn, Joshua R. Adney, Julianna Hagenbrock, Nathan H. Harris, Yi Zhang, Xiaoliang Zhang, Molly H. Nelson-Holte, Yuehua Jiang, An D. Billiau, Wei Chen, Felipe Prósper, Catherine M. Verfaillie, Aernout Luttun
Journal: Journal of Clinical Investigation (2008)

Despite progress in cardiovascular research, a cure for peripheral vascular disease has not been found. We compared the vascularization and tissue regeneration potential of murine and human undifferentiated multipotent adult progenitor cells (mMAPC-U and hMAPC-U), murine MAPC-derived vascular progenitors (mMAPC-VP), and unselected murine BM cells (mBMCs) in mice with moderate limb ischemia, reminiscent of intermittent claudication in human patients. mMAPC-U durably restored blood flow and muscle function and stimulated muscle regeneration, by direct and trophic contribution to vascular and skeletal muscle growth. This was in contrast to mBMCs and mMAPC-VP, which did not affect muscle regeneration and provided only limited and transient improvement. Moreover, mBMCs participated in a sustained inflammatory response in the lower limb, associated with progressive deterioration in muscle function. Importantly, mMAPC-U and hMAPC-U also remedied vascular and muscular deficiency in severe limb ischemia, representative of critical limb ischemia in humans. Thus, unlike BMCs or vascular-committed progenitors, undifferentiated multipotent adult progenitor cells offer the potential to durably repair ischemic damage in peripheral vascular disease patients.
Associations between Organochlorine Contaminant Concentrations and Clinical Health Parameters in Loggerhead Sea Turtles from North Carolina, USA
Authors: Jennifer M. Keller, John R. Kucklick, M. Andrew Stamper, Craig A. Harms, Patricia D. McClellan-Green
Journal: Environmental Health Perspectives (2004)

Widespread and persistent organochlorine (OC) contaminants, such as polychlorinated biphenyls (PCBs) and pesticides, are known to have broad-ranging toxicities in wildlife. In this study we investigated, for the first time, their possible health effects on loggerhead sea turtles (Caretta caretta). Nonlethal fat biopsies and blood samples were collected from live turtles for OC contaminant analysis, and concentrations were compared with clinical health assessment data, including hematology, plasma chemistry, and body condition. Concentrations of total PCBs (Sigma PCBs), Sigma DDTs, Sigma chlordanes, dieldrin, and mirex were determined in 44 fat biopsies and 48 blood samples. Blood concentrations of Sigma chlordanes were negatively correlated with red blood cell counts, hemoglobin, and hematocrit, indicative of anemia. Positive correlations were observed between most classes of OC contaminants and white blood cell counts and between mirex and Sigma TCDD-like PCB concentrations and the heterophil:lymphocyte ratio, suggesting modulation of the immune system. All classes of OCs in the blood except dieldrin were correlated positively with aspartate aminotransferase (AST) activity, indicating possible hepatocellular damage. Mirex and Sigma TCDD-like PCB blood concentrations were negatively correlated with alkaline phosphatase (ALP) activity. Significant correlations to levels of certain OC contaminant classes also suggested possible alteration of protein (increasing blood urea nitrogen, decreasing albumin:globulin ratio), carbohydrate (decreasing glucose), and ion (increasing sodium, decreasing magnesium) regulation. These correlations suggest that OC contaminants may be affecting the health of loggerhead sea turtles even though sea turtles accumulate lower concentrations of OCs compared with other wildlife.
The Role of Endoplasmic Reticulum Stress in Human Pathology
Authors: Scott A. Oakes, Feroz R. Papa
Journal: Annual Review of Pathology Mechanisms of Disease (2014)

Numerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the endoplasmic reticulum (ER), leading to a buildup of misfolded proteins in this organelle--a condition called ER stress. ER-stressed cells must rapidly restore protein-folding capacity to match protein-folding demand if they are to survive. In the presence of high levels of misfolded proteins in the ER, an intracellular signaling pathway called the unfolded protein response (UPR) induces a set of transcriptional and translational events that restore ER homeostasis. However, if ER stress persists chronically at high levels, a terminal UPR program ensures that cells commit to self-destruction. Chronic ER stress and defects in UPR signaling are emerging as key contributors to a growing list of human diseases, including diabetes, neurodegeneration, and cancer. Hence, there is much interest in targeting components of the UPR as a therapeutic strategy to combat these ER stress-associated pathologies.
Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases
Authors: Brice Korkmaz, Marshall S. Horwitz, Dieter E. Jenne, Francis Gauthier
Journal: Pharmacological Reviews (2010)

Polymorphonuclear neutrophils are the first cells recruited to inflammatory sites and form the earliest line of defense against invading microorganisms. Neutrophil elastase, proteinase 3, and cathepsin G are three hematopoietic serine proteases stored in large quantities in neutrophil cytoplasmic azurophilic granules. They act in combination with reactive oxygen species to help degrade engulfed microorganisms inside phagolysosomes. These proteases are also externalized in an active form during neutrophil activation at inflammatory sites, thus contributing to the regulation of inflammatory and immune responses. As multifunctional proteases, they also play a regulatory role in noninfectious inflammatory diseases. Mutations in the <i>ELA2/ELANE</i> gene, encoding neutrophil elastase, are the cause of human congenital neutropenia. Neutrophil membrane-bound proteinase 3 serves as an autoantigen in Wegener granulomatosis, a systemic autoimmune vasculitis. All three proteases are affected by mutations of the gene (<i>CTSC</i>) encoding dipeptidyl peptidase I, a protease required for activation of their proform before storage in cytoplasmic granules. Mutations of <i>CTSC</i> cause Papillon-Lefèvre syndrome. Because of their roles in host defense and disease, elastase, proteinase 3, and cathepsin G are of interest as potential therapeutic targets. In this review, we describe the physicochemical functions of these proteases, toward a goal of better delineating their role in human diseases and identifying new therapeutic strategies based on the modulation of their bioavailability and activity. We also describe how nonhuman primate experimental models could assist with testing the efficacy of proposed therapeutic strategies.
Detection of anti-dsDNA as a diagnostic tool: a prospective study in 441 non-systemic lupus erythematosus patients with anti-dsDNA antibody (anti-dsDNA).
Authors: T Swaak, R Smeenk
Journal: Annals of the Rheumatic Diseases (1985)

The diagnostic significance of anti-double-stranded deoxyribonucleic acid (anti-dsDNA) determination was evaluated in a prospective manner from 1974 to 1982 in a group of 441 patients without systemic lupus erythematosus whose sera were found to contain antibodies to dsDNA on routine screening (Farr assay). Within one year 69% (304) of these patients fulfilled the preliminary American Rheumatism Association (ARA) criteria for systemic lupus erythematosus (SLE). Eighty-two of the remaining 137 patients were followed up for several years. At the end of the study 52% of these patients had also developed systemic lupus erythematosus. Patients who developed systemic lupus erythematosus were characterised by the occurrence of relatively high avidity anti-dsDNA in the circulation compared with patients who did not develop systemic lupus erythematosus. It can be concluded that about 85% of patients without systemic lupus erythematosus with anti-dsDNA in the circulation will develop SLE within a few years. Taking into account the relative avidity of anti-dsDNA, as determined by calculation of Farr/polyethylene glycol (PEG) ratios, we conclude that patients with relatively high avidity anti-dsDNA are more prone to develop systemic lupus erythematosus than patients with relatively low avidity anti-dsDNA.
Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus–Exposed Uninfected Infants
Authors: Paige L. Williams, Marilyn J. Crain, Cenk Yildirim, Rohan Hazra, Russell B. Van Dyke, Kenneth Rich, Jennifer S. Read, Emma Stuard, Mobeen Rathore, Hermann A. Mendez, D. Heather Watts
Journal: JAMA Pediatrics (2014)

Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)-infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents.To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children.Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012.First-trimester exposure to any ARV and to specific ARV medications.The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics.Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs.Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted.
Imported Malaria in the United Kingdom
Authors: P. G. Shute, M. Maryon
Journal: BMJ (1969)

Over 2,000 cases of imported malaria have been confirmed by blood examination. Ninety percent. of cases from tropical Africa were infected with P. falciparum. Most of the patients were Caucasians and had primary infections. All developed fever within a month after arrival and most of them within two weeks of arrival. In some patients malaria parasites were seen in routine blood films.Developing forms of P. falciparum were always present in the peripheral blood of patients suffering from a primary attack which was not diagnosed or treated until a week or more after the onset of fever.All deaths investigated were caused by P. falciparum and were primary infections.In not one of the P. falciparum infections did the victim continue taking prophylactic drugs for more than a few days after leaving the endemic area. Had drugs been continued for one month probably not a single overt case of P. falciparum would have occurred.A primary attack of P. falciparum malaria is seldom, if ever, classical in that the fever is never tertian and may resemble clinically many other diseases.Children in boarding-schools returning from the tropics should be supplied with prophylactic tablets and instructions to the matron. If there is an epidemic of a fever any students who have recently returned from the tropics should have a blood film examined for malaria.The risk of contracting malaria among drug addicts is considerable, especially with P. falciparum.
Adeno-associated virus type 2 infection activates caspase dependent and independent apoptosis in multiple breast cancer lines but not in normal mammary epithelial cells
Authors: Samina Alam, Brian S Bowser, Michael J Conway, Mohd Israr, Apurva Tandon, Craig Meyers
Journal: Molecular Cancer (2011)

In normal cells proliferation and apoptosis are tightly regulated, whereas in tumor cells the balance is shifted in favor of increased proliferation and reduced apoptosis. Anticancer agents mediate tumor cell death via targeting multiple pathways of programmed cell death. We have reported that the non-pathogenic, tumor suppressive Adeno-Associated Virus Type 2 (AAV2) induces apoptosis in Human Papillomavirus (HPV) positive cervical cancer cells, but not in normal keratinocytes. In the current study, we examined the potential of AAV2 to inhibit proliferation of MCF-7 and MDA-MB-468 (both weakly invasive), as well as MDA-MB-231 (highly invasive) human breast cancer derived cell lines. As controls, we used normal human mammary epithelial cells (nHMECs) isolated from tissue biopsies of patients undergoing breast reduction surgery.AAV2 infected MCF-7 line underwent caspase-independent, and MDA-MB-468 and MDA-MB-231 cell lines underwent caspase-dependent apoptosis. Death of MDA-MB-468 cells was marked by caspase-9 activation, whereas death of MDA-MB-231 cells was marked by activation of both caspase-8 and caspase-9, and resembled a mixture of apoptotic and necrotic cell death. Cellular demise was correlated with the ability of AAV2 to productively infect and differentially express AAV2 non-structural proteins: Rep78, Rep68 and Rep40, dependent on the cell line. Cell death in the MCF-7 and MDA-MB-231 lines coincided with increased S phase entry, whereas the MDA-MB-468 cells increasingly entered into G2. AAV2 infection led to decreased cell viability which correlated with increased expression of proliferation markers c-Myc and Ki-67. In contrast, nHMECs that were infected with AAV2 failed to establish productive infection or undergo apoptosis.AAV2 regulated enrichment of cell cycle check-point functions in G1/S, S and G2 phases could create a favorable environment for Rep protein expression. Inherent Rep associated endonuclease activity and AAV2 genomic hair-pin ends have the potential to induce a cellular DNA damage response, which could act in tandem with c-Myc regulated/sensitized apoptosis induction. In contrast, failure of AAV2 to productively infect nHMECs could be clinically advantageous. Identifying the molecular mechanisms of AAV2 targeted cell cycle regulation of death inducing signals could be harnessed for developing novel therapeutics for weakly invasive as well as aggressive breast cancer types.
Long-Term Exposure to Low-Level Arsenic in Drinking Water and Diabetes Incidence: A Prospective Study of the Diet, Cancer and Health Cohort
Authors: Elvira Vaclavik Bräuner, Rikke Baastrup Nordsborg, Zorana Jovanovic Andersen, Anne Tjønneland, Steffen Loft, Ole Raaschou-Nielsen
Journal: Environmental Health Perspectives (2014)

Established causes of diabetes do not fully explain the present epidemic. High-level arsenic exposure has been implicated in diabetes risk, but the effect of low-level arsenic exposure in drinking water remains unclear.We sought to determine whether long-term exposure to low-level arsenic in drinking water in Denmark is associated with an increased risk of diabetes using a large prospective cohort.During 1993-1997, we recruited 57,053 persons. We followed each cohort member for diabetes occurrence from enrollment until 31 December 2006. We traced and geocoded residential addresses of the cohort members and used a geographic information system to link addresses with water-supply areas. We estimated individual exposure to arsenic using all addresses from 1 January 1971 until the censoring date. Cox proportional hazards models were used to model the association between arsenic exposure and diabetes incidence, separately for two definitions of diabetes: all cases and a more strict definition in which cases of diabetes based solely on blood glucose results were excluded.Over a mean follow-up period of 9.7 years for 52,931 eligible participants, there were a total of 4,304 (8.1%) diabetes cases, and 3,035 (5.8%) cases of diabetes based on the more strict definition. The adjusted incidence rate ratios (IRRs) per 1-μg/L increment in arsenic levels in drinking water were as follows: IRR = 1.03 (95% CI: 1.01, 1.06) and IRR = 1.02 (95% CI: 0.99, 1.05) for all and strict diabetes cases, respectively.Long-term exposure to low-level arsenic in drinking water may contribute to the development of diabetes.