tbuckley/cabot-search huggingface dataset:
Molecular and Physiopathologic Aspects of Mammalian Cyclic GMP-Dependent Protein Kinase
Authors: J F Kuo, M Shoji, W Kuo
Journal: The Annual Review of Pharmacology and Toxicology (1978)

Following the initial discovery of adenosine 3',5'-monophosphate (cyclic AMP)­ dependent protein kinase (hereafter referred to as A-PK) in rabbit skeletal muscle (1), the cyclic AMP target enzyme was subsequently found to occur ubiquitously in mammalian (2) and nonmammalian (2-4) tissues. The molecular properties and biological roles of the enzyme have been extensively investigated; reviews dealing with them have appeared (5-7). Guanosine 3',5'-monophosphate (cyclic GMP)­ dependent protein kinase (hereafter referred to as G-PK), activated preferentially by cyclic GMP rather than by cyclic AMP, was later found to be present in every one of many arthropod tissues examined. Its concentrations are generally compara­ ble to those of A-PK also present in the same tissues (3, 4). One interesting tissue is the fat body of the silkmoth pupae and larvae, which was found to contain almost exclusively G-PK (4). The arthropod G-PK has many properties similar to those of A-PK of either mammalian or arthropod origins (3, 4, 8). Some differences, however, do exist between the two classes of protein kinases, such as specificity for substrate proteins (8-11) and differential effects of protein kinase modulators (12).
Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma
Authors: Michelle N. Edelmann, Vinay M. Daryani, Michael W. Bishop, Wei Liu, Tara M. Brinkman, Clinton F. Stewart, Daniel A. Mulrooney, Cara Kimberg, Kirsten K. Ness, Yin Ting Cheung, Deo Kumar Srivastava, Leslie L. Robison, Melissa M. Hudson, Kevin R. Krull
Journal: JAMA Oncology (2015)

<h3>Importance</h3> This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma. <h3>Objective</h3> To examine neurocognitive, neurobehavioral, emotional, and quality-of-life outcomes in long-term survivors of childhood osteosarcoma. <h3>Design, Setting, and Participants</h3> Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls. <h3>Main Outcomes and Measures</h3> Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03. <h3>Results</h3> Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (−0.21 [95% CI, −0.32 to −0.10] vs 0.05 [95% CI, −0.13 to 0.23];<i>P</i> = .01), attention (−0.78 [95% CI, −1.32 to −0.24] vs 0.24 [95% CI, −0.07 to 0.55];<i>P</i> = .002), memory (−0.24 [95% CI, −0.48 to 0] vs 0.27 [95% CI, −0.08 to 0.62];<i>P</i> = .01), and processing speed (−0.15 [95% CI, −0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03];<i>P</i> &lt; .001). Results of pharmacokinetic analysis showed that high-dose methotrexate maximum plasma concentration (estimate = 0;<i>P</i> = .48), median clearance (estimate = −0.11;<i>P</i> = .76), and median/cumulative exposure (estimate = 0;<i>P</i> = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory (<i>t</i> = 2.93;<i>P</i> = .006) and slower processing speed (<i>t</i> = 3.03;<i>P</i> = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24;<i>P</i> = .05) and processing speed (estimate = 0.34;<i>P</i> = .005). <h3>Conclusions and Relevance</h3> Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.
Civilian deaths from weapons used in the Syrian conflict
Authors: Debarati Guha-Sapir, Jose M Rodriguez-Llanes, Madelyn H Hicks, Anne-Françoise Donneau, Adam Coutts, Louis Lillywhite, Fouad M Fouad
Journal: BMJ (2015)

The ongoing Syrian conflict is one of the largest humanitarian crises of the 21st century so far. <b>Debarati Guha-Sapir and colleagues</b> analyse the impact of weapons on civilian deaths, with a focus on women and children
Hepatitis B Virus Immunopathogenesis
Authors: F V Chisari, C Ferrari
Journal: Annual Review of Immunology (1995)

Approximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.
Definitions of Metabolic Health and Risk of Future Type 2 Diabetes in BMI Categories: A Systematic Review and Network Meta-analysis
Authors: Luca A. Lotta, Ali Abbasi, Stephen J. Sharp, Anna-Stina Sahlqvist, Dawn Waterworth, Julia M. Brosnan, Robert A. Scott, Claudia Langenberg, Nicholas J. Wareham
Journal: Diabetes Care (2015)

Various definitions of metabolic health have been proposed to explain differences in the risk of type 2 diabetes within BMI categories. The goal of this study was to assess their predictive relevance.We performed systematic searches of MEDLINE records for prospective cohort studies of type 2 diabetes risk in categories of BMI and metabolic health. In a two-stage meta-analysis, relative risks (RRs) specific to each BMI category were derived by network meta-analysis and the resulting RRs of each study were pooled using random-effects models. Hierarchical summary receiver operating characteristic curves were used to assess predictive performance.In a meta-analysis of 140,845 participants and 5,963 incident cases of type 2 diabetes from 14 cohort studies, classification as metabolically unhealthy was associated with higher RR of diabetes in all BMI categories (lean RR compared with healthy individuals 4.0 [95% CI 3.0-5.1], overweight 3.4 [2.8-4.3], and obese 2.5 [2.1-3.0]). Metabolically healthy obese individuals had a high absolute risk of type 2 diabetes (10-year cumulative incidence 3.1% [95% CI 2.6-3.5]). Current binary definitions of metabolic health had high specificity (pooled estimate 0.88 [95% CI 0.84-0.91]) but low sensitivity (0.40 [0.31-0.49]) in lean individuals and satisfactory sensitivity (0.81 [0.76-0.86]) but low specificity (0.42 [0.35-0.49]) in obese individuals. However, positive (<3.3 in all BMI categories) and negative (>0.4) likelihood ratios were consistent with insignificant to small improvements in prediction.Although individuals classified as metabolically unhealthy have a higher RR of type 2 diabetes compared with individuals classified as healthy in all BMI categories, current binary definitions of metabolic health have limited relevance to the prediction of future type 2 diabetes.
Gonadotropin hormone-releasing hormone analogues: a new therapeutic approach for prostatic carcinoma.
Authors: M A Eisenberger, P J O'Dwyer, M A Friedman
Journal: Journal of Clinical Oncology (1986)

The introduction of potent analogues of gonadotropin hormone-releasing hormone (GnRH) into clinical practice and their use in patients with metastatic prostatic carcinoma provides an effective alternative to the exogenous administration of pharmacologic doses of estrogens or surgical castration. Their advantages over estrogens are primarily related to a lower incidence of cardiovascular toxicity and gynecomastia. Their choice over orchiectomy is based on cosmetic and psychologic factors since their endocrine effects and clinical benefits are virtually the same. In this review, we describe the current experience with GnRH analogues in the treatment of prostatic carcinoma and discuss their use in the context of other endocrine manipulations. GnRH analogues act on the pituitary and indirectly affect gonadal function, and represent an opportunity for combination with other compounds capable of suppressing or interfering with the effects of circulating and androgens. The availability of several new compounds affecting different aspects of androgen metabolism provides promise for rational drug selection and testing.
Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa
Authors: Angelique Hölzemer, Christina F. Thobakgale, Camilo A. Jimenez Cruz, Wilfredo F. Garcia-Beltran, Jonathan M. Carlson, Nienke H. van Teijlingen, Jaclyn K. Mann, Manjeetha Jaggernath, Seung-gu Kang, Christian Körner, Amy W. Chung, Jamie L. Schafer, David T. Evans, Galit Alter, Bruce D. Walker, Philip J. Goulder, Mary Carrington, Pia Hartmann, Thomas Pertel, Ruhong Zhou, Thumbi Ndung’u, Marcus Altfeld
Journal: PLoS Medicine (2015)

Background Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure. Methods and Findings Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I—presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control. Conclusions These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells.
Abstract 5539: Antiproliferative and apoptotic effects of some African natural products in solid and hematopoietic malignant cell lines
Authors: Olufemi E. Akanni, Martin R. Berger
Journal: Cancer Research (2015)

Abstract Background: Natural products have played a very important role in health care from time immemorial in curation and prevention of diseases. Antiproliferative and apoptotic effects of extracts of some African natural products like Hymelocardia acida, Moringa oleifera leaves as well as Pleurotus pulmonarius mushroom metabolites were studied in a panel of solid and hematopoietic malignant derived cell lines such as SUIT2-007, MDA-MB 231, SW480, K562 and HL60 cells. Methods: MTT assay was used to determine the growth inhibition of respective cells in vitro. Apoptosis of the cells was demonstrated by fluorescence microscopy and Hoechst 33342 staining, DNA ladder formation assay and flow cytometry with propidium iodide staining. Results: MTT results showed that extracts of Hymelocardia acida stem, Moringa oleifera leaves as well as Pleurotus pulmonarius metabolites could inhibit the proliferation of SUIT2-007, MDA-MB 231, SW480, K562 and HL60 cells in a time and dose dependent manner. Our results show that the ethanol extract of Hymelocardia acida stem had a positive effect and induced apoptosis as shown by fluorescence microscopy and flow cytometry assay. Apoptotic effects were demonstrated by nuclear staining with Hoechst showing clear signs for nuclear fragmentation in cells treated with Hymelocardia acida stem and Moringa oleifera leaves extracts. FACS analysis with propidium iodide showed that the sub G1 fraction increased in treated cells. DNA ladder formation, however, showed no clear DNA fragmentation, which does not exclude a clearer picture with isolated compounds. Conclusion: The present study indicates that the extracts studied can effectively inhibit proliferation and induce apoptosis in cells of panel of tumor cell lines investigated. Citation Format: Olufemi E. Akanni, Martin R. Berger. Antiproliferative and apoptotic effects of some African natural products in solid and hematopoietic malignant cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5539. doi:10.1158/1538-7445.AM2015-5539
Placebo treatment was meaningless
Authors: L. Smeeth
Journal: BMJ (1995)

Definition ofdepression is questionable EDITOR,-Mynors-Wallis and colleagues claim that problem solving treatment and amitriptyline are equally effective in major depressive disorder.'Even though they required their patients to meet the research diagnostic criteria for depression, just how severely depressed they were comes into question.To be eligible to take part in the study patients had to score just 13 on the Hamilton depression rating scale.Drug licensing authorities, such as the Committee on Safety of Medicines and the Food and Drug Administration, and most
The Mechanisms of Antiinflammatory Steriod Action in Allergic Diseases
Authors: R P Schleimer
Journal: The Annual Review of Pharmacology and Toxicology (1985)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
HISTOCOMPATIBILITY STUDIES IN A CLOSELY BRED COLONY OF DOGS
Authors: F. T. Rapaport, K. Watanabe, F. D. Cannon, N. Mollen, D. Blumenstock, J. W. Ferrebee
Journal: The Journal of Experimental Medicine (1972)

17 Cooperstown beagles of known DL-A genotypes were exposed to supralethal total body irradiation and received a bone marrow allograft from a DL-A-identical donor; 11 littermate and 6 nonlittermate donor-recipient pairs were studied. The recipients are surviving uneventfully for 315, 364, 424, 440, 531, 531, 584, 605, 625, 635, and 649 days in the littermate group and for 211, 279, 280, 368, 479, and 480 days in the nonlittermate group. The radiation chimeras underwent bilateral nephrectomy and received a kidney allograft obtained from their respective marrow donor within 43-120 days after bone marrow transplantation. The renal allografts are surviving for 191, 200, 221, 234, 313, 349, 361, 377, 378, 405, 441, 444, 482, 557, 580, 581, and 586 days, respectively. 12 of 13 skin allografts obtained from the marrow donor are at present surviving in the recipients for 107, 110, 110, 110, 116, 122, 128, 143, 143, 162, 178, and 199 days, respectively; one graft was rejected at 84 days. In contrast, the radiation chimeras rejected 25 skin allografts obtained from DL-A-incompatible donors within 10.5-21 days (MST = 15.2 days). Skin transplants obtained from DL-A-identical siblings of the bone marrow donors were rejected within 20-36 days (MST = 25.8 days) in recipients of bone marrow cells obtained from littermate donors. Recipients of nonlittermate bone marrow transplants accorded such allografts a prolonged survival time of 27-76 days (MST = 56.2 days). Prospective selection of genotypically DL-A-identical donor-recipient pairs results in the regularly reproducible long-term survival of bone marrow allografts. The radiation chimeras produced in this manner have developed a donor-specific state of unresponsiveness to kidney and skin allografts. The results are consistent with the existence in the canine species of at least three closely linked genetic systems relevant to transplantation, including DL-A, MLC, and a possible bone marrow transplantation locus.
Inactivation and Metabolism of Neuropeptides
Authors: J F McKelvy, S Blumberg
Journal: Annual Review of Neuroscience (1986)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Calcium intake and risk of fracture: systematic review
Authors: Mark J Bolland, William Leung, Vicky Tai, Sonja Bastin, Greg D Gamble, Andrew Grey, Ian R Reid
Journal: BMJ (2015)

<b>Objective</b> To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures. <b>Design </b>Systematic review of randomised controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses. <b>Data sources </b>Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014. <b>Eligibility criteria for selecting studies </b>Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged &gt;50. <b>Results </b>There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58 573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48 967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56 648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51 775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger's regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44 505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture. <b>Conclusions </b>Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.
Cardiovascular Control by Cholinergic Mechanisms in the Central Nervous System
Authors: H E Brezenoff, R Giuliano
Journal: The Annual Review of Pharmacology and Toxicology (1982)

Despite an extensive research effort over the last few decades, under­ standing of how the central nervous system (CNS)! controls the circulation is at best still incomplete. Many symposia and reviews have detailed the function of catecholaminergic (CCA) pathways in the central connections of the autonomic nervous system (1-6). It is widely recognized that several methodological advances [e.g. chemical ablation by 6-hydroxydopamine (6-0HDA), sensitive and selective methods for detection and quantitation of CCA, use of specific substances which can alter formation, metabolism or release of catecholamines], paralleled by the development of drugs which lower blood pressure (BP) through stimulation of central adrenergic recep­ tor sites (e.g. alpha-methyldopa, clonidine), have fostered precocious ad­ vances involving the biogenic amines. Until recently, however, far less