tbuckley/cabot-search huggingface dataset:
P2-purinergic receptor agonists inhibit the growth of androgen-independent prostate carcinoma cells.
Authors: W G Fang, F Pirnia, Y J Bang, C E Myers, J B Trepel
Journal: Journal of Clinical Investigation (1992)

To develop a new approach to the treatment of advanced, hormone-refractory prostate cancer, the signal transductions regulating the growth of human androgen-independent prostate carcinoma cell lines were studied. Agonist-stimulated Ca2+ mobilization, a critical regulatory event in other secretory cell types, was studied as a means of identifying previously undescribed plasma membrane receptors that may transduce a growth inhibitory signal. In all of the cell lines tested, P2-purinergic receptor agonists, including ATP and certain hydrolysis-resistant adenine nucleotides, induced a rapid, transient increase in cytoplasmic free Ca2+ that was detectable at 50 to 100 nM ATP, was maximal at 100 microM ATP, and was inhibited approximately 50% by chelation of extracellular Ca2+. Within 8 s after addition, ATP stimulated accumulation of the polyphosphatidylinositol products inositol (1, 4, 5) trisphosphate, inositol (1, 3, 4) trisphosphate, and inositol tetrakisphosphate. In addition to stimulating phosphatidylinositol turnover and Ca2+ mobilization, ATP and hydrolysis-resistant ATP analogues induced greater than 90% inhibition of the growth of all lines tested. These data demonstrate that human androgen-independent prostate carcinoma cells express functional P2-purinergic receptors linked to phospholipase C, and that agonists of this receptor are markedly growth inhibitory, suggesting a novel therapeutic approach to this common adult neoplasm.
Conditional Deletion of <b> <i>Rb</i> </b> Causes Early Stage Prostate Cancer
Authors: Lisette A. Maddison, Brent W. Sutherland, Roberto J. Barrios, Norman M. Greenberg
Journal: Cancer Research (2004)

Abstract Prostate cancer remains the second leading cause of cancer-related death for men in the United States. Mutations in tumor suppressor genes including retinoblastoma (Rb), p53, and PTEN have been linked to the development of prostate cancer in man and mouse models, and loss of heterozygosity of the Rb locus has been observed in up to 60% of clinical cases. In this study we demonstrate that conditional somatic deletion of even a single Rb allele in the epithelial cells of the mouse prostate causes focal hyperplasia, thereby establishing a causal relationship between Rb loss and development of early stage prostate cancer. As a consequence of Rb ablation we observed increased expression of E2F target genes and a concomitant increase in proliferation in the epithelial compartment. However, by 52 weeks of age these lesions had not become malignant and represent an early stage of the disease. Nevertheless, the multifocal nature of the phenotype in the mice closely resembled multifocality of clinical disease. Taken together, our data demonstrated that loss of pRB-mediated cell cycle control directly caused the initiation of proliferative prostate disease but was insufficient to cause malignancy. Establishment of this early initiation model will aid efforts to thoroughly characterize early prostate disease as well as the elucidation of molecular mechanisms that cooperate with Rb loss to facilitate progression and metastasis.
Benign Hemoglobinuria Following Transfusion of Accidentally Frozen Blood
Authors: S. Gerald Sandler
Journal: JAMA (1976)

A patient was transfused with a unit of red blood cells that had been frozen accidentally prior to transfusion. Although he had received approximately 60 gm of free hemoglobin intravenously, the patient's only clinical reaction was massive hemoglobinuria. The benign clinical response, in the presence of massive hemoglobinuria, is attributed to the absence of immunologic incompatibility and, thus, failure to activate vasoactive mediators and disseminated intravascular coagulation. The case illustrates revised concepts of the pathophysiology of acute renal failure associated with hemolytic blood transfusion reactions. (<i>JAMA</i>235:2850-2851, 1976)
Subcellular remodelling may induce cardiac dysfunction in congestive heart failure
Authors: N. S. Dhalla, H. K. Saini-Chohan, D. Rodriguez-Leyva, V. Elimban, M. R. Dent, P. S. Tappia
Journal: Cardiovascular Research (2008)

It is commonly held that cardiac remodelling, represented by changes in muscle mass, size, and shape of the heart, explains the progression of congestive heart failure (CHF). However, this concept does not provide any clear information regarding the development of cardiac dysfunction in CHF. Extensive research has revealed that various subcellular organelles such as the extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus undergo varying degrees of changes in their biochemical composition and molecular structure in CHF. This subcellular remodelling occurs due to alterations in cardiac gene expression as well as activation of different proteases and phospholipases in the failing hearts. Several mechanisms including increased ventricular wall stress, prolonged activation of the renin-angiotensin and sympathetic systems, and oxidative stress have been suggested to account for subcellular remodelling in CHF. Furthermore, subcellular remodelling is associated with changes in cardiomyocyte structure, cation homeostasis as well as functional activities of cation channels and transporters, receptor-mediated signal transduction, Ca(2+)-cycling proteins, contractile and regulatory proteins, and energy production during the development of heart failure. The existing evidence supports the view that subcellular remodelling may result in cardiac dysfunction and thus play a critical role in the transition of cardiac hypertrophy to heart failure.
Inhibitory Effect of Pulmonary Surfactant Proteins A and D on Allergen-induced Lymphocyte Proliferation and Histamine Release in Children with Asthma
Authors: JIU-YAO WANG, CHI-CHANG SHIEH, PEI-FEN YOU, HUAN-YAO LEI, KENNETH B. M. REID
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The role of pulmonary surfactant proteins in the pathogenesis of airway inflammation and the impact on asthma has not been elucidated. This study was designed to examine the effect of surfactant proteins A (SP-A) and D (SP-D) on phytohemagglutinin- (PHA) and mite allergen Dermatophagoides pteronyssinus (Der p)-induced histamine release and the proliferation of peripheral blood mononuclear cells (PBMC) in children with asthma in stable condition (n = 21), asthmatic children during acute attacks (n = 9), and age-matched control subjects (n = 7). The results show that SP-A and SP-D were able to reduce the incorporation of [3H]thymidine into PBMC in a dose-dependent manner. In addition to the intact, native SP-A and SP-D proteins, a recombinant peptide composed of the neck and carbohydrate recognition domain (CRD) of SP-D [SP-D(N/CRD)] was also found to have the same suppressive effect on lymphocyte proliferation. This effect was abolished by the presence of 100 mM mannose (for SP-A) or maltose (for SP-D) in the culture medium, which suggested that the CRD regions of SP-A and SP-D may interact with the carbohydrate structures on the surface molecules of lymphocytes. The inhibitory effects of surfactant proteins on PHA- and Der p-stimulated lymphocyte responses were observed in stable asthmatic children and age-matched control subjects, while only a mild suppression ( < 25%) was seen in activated lymphocytes derived from asthmatic children with acute attacks. SP-A and SP-D were also found to inhibit allergen-induced histamine release, in a dose-dependent manner, in the diluted whole blood of asthmatic children. We conclude that both SP-A and SP-D can inhibit histamine release in the early phase of allergen provocation and suppress lymphocyte proliferation in the late phase of bronchial inflammation, the two essential steps in the development of asthmatic symptoms. It appears that SP-A and SP-D may be protective against the pathogenesis of asthma.
Can intra-breath variations of reactance predict dyspnea
Authors: Bernt B. Aarli, Peter M.A. Calverley, Tomas M.L. Eagan, Per S. Bakke, Jon A. Hardie
Journal: European Respiratory Journal (2013)

Rationale:   Reduced lung tissue elasticity in COPD allows small airways to collapse during exhalation. An oscillatory pressure signal applied at the mouth no longer reaches the distal airways, and the corresponding reactance measured during expiration becomes more negative. We used forced impulse oscillation technique (IOS) to measure inspiratory-expiratory reactance difference at 5 Hz (DX5) to determine if DX5 relates to the severity of dyspnea.   Methods:   426 COPD patients and 232 controls performed spirometry and IOS measurements. The Modified Medical Research Dyspnea scale (mMRC) was used to define dyspnea. ROC analysis was performed to examine DX5’s ability to identify mMRC≥2.   Results   Mean mMRC and DX5 was close to zero in controls and increase with increasing severity of COPD, see table. ROC-analysis: At the DX5 cutoff .06 kPa/L/s a sensitivity of 75% and a specificity of 72% was found for mMRC≥2. Cutoff .26kPa/L/s rendered 95% specificity for mMRC≥2.   Conclusion   Non-invasively measured DX5 tracks mMRC and is a potential marker for the presence of significant dyspnea.
Cooperativity within and among Pten, p53, and Rb Pathways Induces High-Grade Astrocytoma in Adult Brain
Authors: Lionel M.L. Chow, Raelene Endersby, Xiaoyan Zhu, Sherri Rankin, Chunxu Qu, Junyuan Zhang, Alberto Broniscer, David W. Ellison, Suzanne J. Baker
Journal: Cancer Cell (2011)
Rare variants at 16p11.2 are associated with common variable immunodeficiency
Authors: S. Melkorka Maggadottir, Jin Li, Joseph T. Glessner, Yun Rose Li, Zhi Wei, Xiao Chang, Frank D. Mentch, Kelly A. Thomas, Cecilia E. Kim, Yan Zhao, Cuiping Hou, Fengxiang Wang, Silje F. Jørgensen, Elena E. Perez, Kathleen E. Sullivan, Jordan S. Orange, Tom H. Karlsen, Helen Chapel, Charlotte Cunningham-Rundles, Hakon Hakonarson
Journal: Journal of Allergy and Clinical Immunology (2015)
Facial expression of pain: “Just So Stories,” spandrels, and patient blaming
Authors: Patrick J. McGrath
Journal: Behavioral and Brain Sciences (2002)

Facial responses to pain might be the result of evolution but Williams' interesting “Just So” story provides no convincing evidence for her hypothesis. Contrary to her hope, casting facial action in an evolutionary perspective will probably not reduce the common practice of health care professionals blaming patients for their problems; instead, it may discourage appropriate treatment.
Physical Activity and Quality of Life in Adult Survivors of Non-Hodgkin's Lymphoma
Authors: Keith M. Bellizzi, Julia H. Rowland, Neeraj K. Arora, Ann S. Hamilton, Melissa Farmer Miller, Noreen M. Aziz
Journal: Journal of Clinical Oncology (2009)

To examine the prevalence and correlates of physical activity in adult survivors of aggressive non-Hodgkin's Lymphoma (NHL) and to explore the association between physical activity level and health-related quality of life (HRQOL).
Effect of nutritional iron deficiency on acute and chronic inflammation.
Authors: F J Andrews, C J Morris, E J Lewis, D R Blake
Journal: Annals of the Rheumatic Diseases (1987)

Mild nutritional iron deficiency significantly reduced the severity of adjuvant induced joint inflammation assessed by histology, microfocal radiography, and subjective scoring. Other indices of adjuvant induced inflammation, such as increased levels of serum acute phase reactants, characteristic pathological changes in the inguinal lymph nodes, and granuloma formation at the site of adjuvant injection, were not different from those of control animals. The level of iron deficiency used did not affect the acute inflammatory response to a range of irritants and was not sufficient to suppress immune function. Both the hypersensitivity reaction to oxazalone and lymphocyte tritiated thymidine incorporation were normal. These observations support the view that iron has a selective influence on joint mediated inflammation.
Determinants of Racial/Ethnic Disparities in Incidence of Diabetes in Postmenopausal Women in the U.S.
Authors: Yunsheng Ma, James R. Hébert, JoAnn E. Manson, Raji Balasubramanian, Simin Liu, Michael J. Lamonte, Chloe E. Bird, Judith K. Ockene, Yongxia Qiao, Barbara Olendzki, Kristin L. Schneider, Milagros C. Rosal, Deidre M. Sepavich, Jean Wactawski-Wende, Marcia L. Stefanick, Lawrence S. Phillips, Ira S. Ockene, Robert C. Kaplan, Gloria E. Sarto, Lorena Garcia, Barbara V. Howard
Journal: Diabetes Care (2012)

To examine determinants of racial/ethnic differences in diabetes incidence among postmenopausal women participating in the Women's Health Initiative.Data on race/ethnicity, baseline diabetes prevalence, and incident diabetes were obtained from 158,833 women recruited from 1993-1998 and followed through August 2009. The relationship between race/ethnicity, other potential risk factors, and the risk of incident diabetes was estimated using Cox proportional hazards models from which hazard ratios (HRs) and 95% CIs were computed.Participants were aged 63 years on average at baseline. The racial/ethnic distribution was 84.1% non-Hispanic white, 9.2% non-Hispanic black, 4.1% Hispanic, and 2.6% Asian. After an average of 10.4 years of follow-up, compared with whites and adjusting for potential confounders, the HRs for incident diabetes were 1.55 for blacks (95% CI 1.47-1.63), 1.67 for Hispanics (1.54-1.81), and 1.86 for Asians (1.68-2.06). Whites, blacks, and Hispanics with all factors (i.e., weight, physical activity, dietary quality, and smoking) in the low-risk category had 60, 69, and 63% lower risk for incident diabetes. Although contributions of different risk factors varied slightly by race/ethnicity, most findings were similar across groups, and women who had both a healthy weight and were in the highest tertile of physical activity had less than one-third the risk of diabetes compared with obese and inactive women.Despite large racial/ethnic differences in diabetes incidence, most variability could be attributed to lifestyle factors. Our findings show that the majority of diabetes cases are preventable, and risk reduction strategies can be effectively applied to all racial/ethnic groups.
Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration
Authors: Janet S. Sunness, Joel Gonzalez-Baron, Carol A. Applegate, Neil M. Bressler, Yan Tian, Barbara Hawkins, Yolanda Barron, Akiva Bergman
Journal: Ophthalmology (1999)

ObjectiveTo describe the progression of geographic atrophy (GA) from age-related macular degeneration (AMD) with respect to visual acuity (VA) loss and enlargement of atrophy.DesignA prospectively observed case series.SettingTertiary retinal referral center.ParticipantsOne hundred twenty-three patients with GA due to AMD who completed at least 1 year of follow-up (median follow-up, 3 years) were examined annually.MethodsAt each examination, a protocol best-corrected VA of each eye was measured, a clinical examination was performed, and color fundus photographs were taken. The areas of atrophy were drawn and measured.Main outcome measuresVisual acuity loss and enlargement of total and central atrophy.ResultsAt baseline, median VA was poorer with larger areas of atrophy, but there was wide variation related to sparing of the fovea. Thirty-one percent of all study eyes suffered a three-line VA loss from baseline by 2 years, and 53% had a three-line loss by 4 years. Those eyes with VA better than 20/50 had the highest rate of acuity loss; 27% of these eyes had acuities of 20/200 or worse at 4 years. Visual acuity loss in the GA study eye was similar in patients with bilateral GA and in those with choroidal neovascularization in the fellow eye. Total atrophy enlarged a median of 1.8 Macular Photocoagulation Study disc areas (DA) at 2 years; atrophy within a 4-DA circle centered on the fovea enlarged a median of 0.9 DA. Two (22%) of nine patients with GA in one eye and only drusen without advanced AMD in the fellow eye developed GA in the fellow eye at 2 years.ConclusionsGeographic atrophy is associated with a significant decline in VA over time in many eyes. Areas of atrophy continue to enlarge over time, even when already large at baseline. The combination of reduced VA with enlargement of atrophy, occurring bilaterally in most patients, can lead to significant impairment of visual function.
Putative association of a <i>TLR9</i> promoter polymorphism with atopic eczema
Authors: N. Novak, C.‐F. Yu, C. Bussmann, L. Maintz, W.‐M. Peng, J. Hart, T. Hagemann, A. Diaz‐Lacava, H.‐J. Baurecht, N. Klopp, S. Wagenpfeil, H. Behrendt, T. Bieber, J. Ring, T. Illig, S. Weidinger
Journal: Allergy (2007)

Background: Toll‐like receptors (TLR) play a pivotal role in the induction of first‐line defense mechanisms of the innate immune system and trigger adaptive immune responses to microbial pathogens. Genetic variations in innate immunity genes have been reported to be associated with a range of inflammatory disorders. Deficiencies on the level of immunity receptors such as pathogen‐recognition receptors are suspected to affect the maturation of our immune system and to avail thereby the high prevalence of atopic diseases and susceptibility of atopic patients to microbial infections. Aims of the study: We evaluated TLR9 as susceptibility gene for atopic eczema (AE). Methods: Analyses of four tag single‐nucleotide polymorphisms in two panels of families containing a total of 483 parent‐affected offspring trios as well as a cohort of 274 unrelated adult AE cases and 252 hypernormal population‐based controls have been performed. Results: In both family cohorts, polymorphism C‐1237T, which is located within the promoter region of the TLR9 gene, was significantly associated with AE, in particular the intrinsic subtype of AE. No associations were seen in the case–control cohort. Luciferase reporter gene assays revealed significantly higher promoter activity of the TT allelic variant at this single nucleotide polymorphism site. Conclusion: These observations suggest that the TLR9 promoter polymorphism C‐1237T might affect AE susceptibility in particular in patients with the intrinsic variant of AE.
Insulin-like Growth Factor Binding Proteins IGFBP3, IGFBP4, and IGFBP5 Predict Endocrine Responsiveness in Patients with Ovarian Cancer
Authors: Graeme Walker, Kenneth MacLeod, Alistair R.W. Williams, David A. Cameron, John F. Smyth, Simon P. Langdon
Journal: Clinical Cancer Research (2007)

Abstract Purpose: This study sought to explore the predictive value of the insulin-like growth factor (IGF) binding proteins (IGFBP) as markers of response in ovarian cancer patients treated with the aromatase inhibitor letrozole. Experimental Design: IGFBP mRNA expression in cell lines was measured by quantitative reverse transcription-PCR and IGFBP protein expression measured in sections from primary tumors of patients treated with letrozole by semiquantitative immunohistochemistry. Results: Quantitative reverse transcription-PCR analysis showed that IGFBP3 and IGFBP5 were down-regulated and IGFBP4 was up-regulated by 17β-estradiol (E2) in an estrogen receptor (ER)–positive ovarian cancer cell line. Expressions of IGFBP1, IGFBP2, and IGFBP6 were unaffected by E2. The E2 modulation of these genes was reversed by tamoxifen. Using ERα-specific (propyl pyrazole triol) and ERβ-specific (diarylpropionitrile) agonists, the gene expression modulations produced by E2 could be replicated by propyl pyrazole triol but not by diarylpropionitrile. For ovarian cancer patients being treated with letrozole, we tested the predictive value of the IGFBPs in paraffin-fixed sections from their primary tumors by semiquantitative immunohistochemistry. Using serum CA125 as an indicator of progression/response, significant differences in expression levels of IGFBPs were observed between tumors from CA125 responding/stable patients compared with tumors from progressing patients. Mean immunoscores for IGFBP3 and IGFBP5 were significantly lower, and mean expression of IGFBP4 was significantly higher in tumors from patients demonstrating CA125 response or stabilization compared with CA125 progression. Conclusion: These results indicate that expression levels of certain IGFBP family members in ovarian cancers are estrogen regulated and can, thus, help identify patients who could benefit from endocrine therapy.
TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality
Authors: Nadia Corazza, Sabine Jakob, Corinne Schaer, Steffen Frese, Adrian Keogh, Deborah Stroka, Daniela Kassahn, Ralph Torgler, Christoph Mueller, Pascal Schneider, Thomas Brunner
Journal: Journal of Clinical Investigation (2006)

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with potent apoptosis-inducing properties in tumor cells. In particular, TRAIL strongly synergizes with conventional chemotherapeutic drugs to induce tumor cell death. Thus, TRAIL has been proposed as a promising future cancer therapy. Little, however, is known regarding what the role of TRAIL is in normal untransformed cells and whether therapeutic administration of TRAIL, alone or in combination with other apoptotic triggers, may cause tissue damage. In this study, we investigated the role of TRAIL in Fas-induced (CD95/Apo-1-induced) hepatocyte apoptosis and liver damage. While TRAIL alone failed to induce apoptosis in isolated murine hepatocytes, it strongly amplified Fas-induced cell death. Importantly, endogenous TRAIL was found to critically regulate anti-Fas antibody-induced hepatocyte apoptosis, liver damage, and associated lethality in vivo. TRAIL enhanced anti-Fas-induced hepatocyte apoptosis through the activation of JNK and its downstream substrate, the proapoptotic Bcl-2 homolog Bim. Consistently, TRAIL- and Bim-deficient mice and wild-type mice treated with a JNK inhibitor were protected against anti-Fas-induced liver damage. We conclude that TRAIL and Bim are important response modifiers of hepatocyte apoptosis and identify liver damage and lethality as a possible risk of TRAIL-based tumor therapy.