tbuckley/cabot-search huggingface dataset:
The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition
Authors: Veronique Michaud, Tamara Bar-Magen, Jacques Turgeon, David Flockhart, Zeruesenay Desta, Mark A. Wainberg
Journal: Pharmacological Reviews (2012)

Significant intra- and interindividual variability has been observed in response to use of pharmacological agents in treatment of HIV infection. Treatment of HIV infection is limited by high rates of adverse drug reactions and development of resistance in a significant proportion of patients as a result of suboptimal drug concentrations. The efficacy of antiretroviral therapy is challenged by the emergence of resistant HIV-1 mutants with reduced susceptibility to antiretroviral drugs. Moreover, pharmacotherapy of patients infected with HIV is challenging because a great number of comorbidities increase polypharmacy and the risk for drug-drug interactions. Drug-metabolizing enzymes and drug transporters regulate drug access to the systemic circulation, target cells, and sanctuary sites. These factors, which determine drug exposure, along with the emergence of mutations conferring resistance to HIV medications, could explain variability in efficacy and adverse drug reactions associated with antiretroviral drugs. In this review, the major factors affecting the disposition of antiretroviral drugs, including key drug-metabolizing enzymes and membrane drug transporters, are outlined. Genetic polymorphisms affecting the activity and/or the expression of cytochromes P450 or UGT isozymes and membrane drug transport proteins are highlighted and include such examples as the association of neurotoxicity with efavirenz, nephrotoxicity with tenofovir, hepatotoxicity with nevirapine, and hyperbilirubinemia with indinavir and atazanavir. Mechanisms of drug resistance conferred by specific viral mutations are also reviewed, with particular attention to replicative viral fitness and transmitted HIV drug resistance with the objectives of providing a better understanding of mechanisms involved in HIV drug resistance and helping health care providers to better manage interpatient variability in drug efficacy and toxicity.
Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression
Authors: Victor R. Gordeuk, Galina Y. Miasnikova, Adelina I. Sergueeva, Xiaomei Niu, Mehdi Nouraie, Daniel J. Okhotin, Lydia A. Polyakova, Tatiana Ammosova, Sergei Nekhai, Tomas Ganz, Josef T. Prchal
Journal: Blood (2011)
Exposure to the Chinese Famine in Early Life and the Risk of Metabolic Syndrome in Adulthood
Authors: Yanping Li, Vincent W. Jaddoe, Lu Qi, Yuna He, Dong Wang, Jianqiang Lai, Jian Zhang, Ping Fu, Xiaoguang Yang, Frank B. Hu
Journal: Diabetes Care (2011)

To examine whether exposure to the Chinese famine during fetal life and early childhood is associated with the risks of metabolic syndrome and whether this association is modified by later life environment.We used data of 7,874 adults born between 1954 and 1964 from the 2002 China National Nutrition and Health Survey. Famine exposure groups were defined as nonexposed; fetal exposed; and early childhood, midchildhood, or late childhood exposed. Excess death rate was used to determine the severity of the famine. The ATP III criteria were used for the definition of metabolic syndrome (three or more of the following variables: elevated fasting triglyceride levels, lower HDL cholesterol levels, elevated fasting glucose levels, higher waist circumference, high blood pressure).In severely affected famine areas, adults who were exposed to the famine during fetal life had a higher risk of metabolic syndrome, as compared with nonexposed subjects (odds ratio 3.13 [95% CI 1.24-7.89, P = 0.016]). Similar associations were observed among adults who were exposed to the famine during early childhood, but not for adults exposed to the famine during mid- or late childhood. Participants who were born in severely affected famine areas and had Western dietary habits in adulthood or were overweight in adulthood had a particularly high risk of metabolic syndrome in later life.Exposure to the Chinese famine during fetal life or infancy is associated with an increased risk of metabolic syndrome in adulthood. These associations are stronger among subjects with a Western dietary pattern or who were overweight in adulthood.
(Cost)-effectiveness of self-treatment of exacerbations on the severity of exacerbations in patients with COPD: the COPE II study
Authors: T Effing, H Kerstjens, P van der Valk, G Zielhuis, J van der Palen
Journal: Thorax (2009)

<h3>Background:</h3> Chronic obstructive pulmonary disease (COPD) is a chronic disease with a high prevalence and rapidly increasing incidence rates. The effect of self-treatment of COPD exacerbations on the severity of exacerbations during a 1-year period was examined and a cost-effectiveness analysis was performed. <h3>Methods:</h3> Patients were randomly allocated to four 2-hour self-management sessions, with or without training in self-treatment of exacerbations. Patients in the self-treatment group received an action plan with the possibility to initiate a course of prednisolone (with or without antibiotics). During follow-up, all participants kept a daily symptom diary. These provided the data to calculate the frequency of exacerbations, the number of exacerbation days and mean daily severity scores. <h3>Results:</h3> Data were analysed for 142 randomised patients (self-treatment: n = 70; control: n = 72). The frequency of exacerbations was identical in both study groups (mean (SD) 3.5 (2.7)). Patients in the self-treatment group reported fewer exacerbation days (median 31 (interquartile range (IQR) 8.9–67.5) in the self-treatment group vs 40 (IQR 13.3–88.2) in the control group; p = 0.064); the difference was significant in the group of patients with a high number of exacerbation days per year (&gt;137 (90th percentile of the whole study population); p = 0.028). The mean severity score of an exacerbation day was equal in both groups. No between-group differences were found in health-related quality of life. Cost-effectiveness analyses showed that applying self-treatment saved €154 per patient, with a trend towards a lower probability for hospital admissions (0.20/patient/year in the self-treatment group vs 0.33/patient/year in the control group; p = 0.388) and a significant reduction of health care contacts (5.37/patient/year in the self-treatment group vs 6.51/patient/year in the control group; p = 0.043). <h3>Conclusion:</h3> Self-treatment of exacerbations incorporated in a self-management programme leads to fewer exacerbation days and lower costs.
The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic Epithelial Cell Proliferation through Paracrine Mechanisms
Authors: Claes Bavik, Ilsa Coleman, James P. Dean, Beatrice Knudsen, Steven Plymate, Peter S. Nelson
Journal: Cancer Research (2006)

Abstract The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia. (Cancer Res 2006; 66(2): 794-802)
Do parents' and children's concerns about sports safety and injury risk relate to how much physical activity children do?
Authors: Amanda Telford, Caroline F Finch, Lisa Barnett, Gavin Abbott, Jo Salmon
Journal: British Journal of Sports Medicine (2012)

Objective To see whether concerns about injury risk relate to children's physical activity (PA). Methods Two cohorts were recruited from 19 Australian schools and assessed in 2001 (T1), 2004 (T2) and 2006 (T3). The younger (n=162) was assessed at 6, 9 and 11years old, and the older (n=259) at 11, 14 and 16 years old. At T1 and T2, parents of the younger cohort reported on fear of child being injured, and whether child would be at risk of injury if they played organised sport; the older cohort self-reported injury fear. Accelerometers assessed PA at each time point. Linear regression models examined cross-sectional associations, and also associations between T1 injury fear and risk and T2 PA, and T2 injury fear and risk and T3 PA. Results In the younger cohort at T2 (9 years), fear and risk were both negatively associated with moderate to vigorous PA (MVPA) (β=−0.17, 95% CI −0.30 to −0.03 and β=−0.26, 95% CI −0.41 to −0.10) and also vigorous PA (VPA). Fear was also associated with moderate PA (MPA). For the older cohort at T1, injury fear was negatively associated with MVPA (β=−0.21, 95% CI −0.35 to −0.07) and also MPA and VPA. Parental perception of risk at T1 (6 years) was negatively associated with children's MPA at T2 (9 years) (β=−0.17, 95% CI −0.32 to −0.02). Sex did not moderate any association. Conclusions Younger children and their parents need to know which sports have low injury risks. Some children may need increased confidence to participate. .
Ozone Exposure Increases Aldehydes in Epithelial Lining Fluid in Human Lung
Authors: MARK W. FRAMPTON, WILLIAM A. PRYOR, RAFAEL CUETO, CHRISTOPHER COX, PAUL E. MORROW, MARK J. UTELL
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We hypothesized that exposure of healthy humans to ozone causes both ozonation and peroxidation of lipids in lung epithelial lining fluid. Twelve smokers and 15 nonsmokers (eight lung function "responders" and seven "nonresponders") were exposed once to air and twice to 0.22 ppm ozone for 4 h with exercise in an environmental chamber, with each exposure separated by at least 3 wk. Bronchoalveolar lavage (BAL) was performed immediately after one ozone exposure and 18 h after the other ozone exposure. BAL fluid was analyzed for the aldehyde products of ozonation and lipid peroxidation, nonanal (C9) and hexanal (C6), as well as total protein, albumin, and immunoglobulin M as markers of changes in epithelial permeability. Ozone exposure resulted in a significant early increase in C9 (p = 0.0001), with no statistically significant relationship between increases in C9 and lung function changes, airway inflammation, or changes in epithelial permeability. Increases in C6 levels were not statistically significant (p = 0.16). Both C9 and C6 levels returned to baseline by 18 h after exposure. These studies confirm that exposure to ozone with exercise, at concentrations relevant to urban outdoor air, results in ozonation of lipids in the airway epithelial lining fluid of humans.
Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms
Authors: Yongfeng Gong, Jianghui Hou
Journal: Journal of the American Society of Nephrology (2013)

Pathologic dysregulation of extracellular calcium metabolism is difficult to correct. The extracellular Ca++-sensing receptor (CaSR), a G protein–coupled receptor that regulates renal Ca++ handling through changes in paracellular channel permeability in the thick ascending limb, has emerged as an effective pharmacological candidate for managing calcium metabolism. However, manipulation of CaSR at the systemic level causes promiscuous effects in the parathyroid glands, kidneys, and other tissues, and the mechanisms by which CaSR regulates paracellular transport in the kidney remain unknown. Here, we describe a CaSR-NFATc1-microRNA-claudin-14 signaling pathway in the kidney that underlies paracellular Ca++ reabsorption through the tight junction. With CaSR-specific pharmacological reagents, we show that the in vivo gene expression of claudin-14 is regulated through a transcriptional mechanism mediated by NFATc1-microRNA and associated chromatin remodeling. Transgenic knockout and overexpression approaches showed that claudin-14 is required for CaSR-regulated renal Ca++ metabolism. Together, our results define an important signaling cascade that, when dysregulated, may mediate Ca++ imbalance through changes in tight junction permeability.
Growth inhibition of clonogenic leukemic precursor cells by minor histocompatibility antigen-specific cytotoxic T lymphocytes.
Authors: J H Falkenburg, H M Goselink, D van der Harst, S A van Luxemburg-Heijs, Y M Kooy-Winkelaar, L M Faber, J de Kroon, A Brand, W E Fibbe, R Willemze
Journal: The Journal of Experimental Medicine (1991)

Minor histocompatibility (mH) antigens appear to play a major role in bone marrow transplantation (BMT) using HLA-identical donors. Previously, we reported the isolation of major histocompatibility complex (MHC)-restricted mH antigen-specific cytotoxic T lymphocytes (CTL) from patients with graft-vs.-host disease or rejection after HLA-identical BMT. We have demonstrated that mH antigens can be recognized on hematopoietic progenitor cells, and residual recipient CTL specific for mH antigens expressed on donor hematopoietic progenitor cells may be responsible for graft rejection in spite of intensive conditioning regimens in HLA-identical BMT. Here, we investigated whether mH antigen-specific CTL directed against the mH antigens HA-1 to HA-5 and the male-specific antigen H-Y were capable of antigen-specific inhibition of in vitro growth of clonogenic leukemic precursor cells. We demonstrate that mH antigen-specific CTL against all mH antigens tested can lyse freshly obtained myeloid leukemic cells, that these mH antigen-specific CTL can inhibit their clonogenic leukemic growth in vitro, and that this recognition is MHC restricted. We illustrate that leukemic (precursor) cells can escape elimination by mH antigen-specific CTL by impaired expression of the relevant MHC restriction molecule. We suggest that mH antigen-specific MHC-restricted CTL may be involved in vivo in the graft-vs.-leukemia reactivity after BMT.
Treatment of multiple actinic keratoses with topical diclofenac 3% gel in organ transplant recipients: a series of six cases
Authors: C. Ulrich, M. Hackethal, M. Ulrich, A. Howorka, T. Forschner, W. Sterry, E. Stockfleth
Journal: British Journal of Dermatology (2007)

Background Non‐melanoma skin cancer (NMSC) represents a significant cause of morbidity in organ transplant patients; the relative risk of squamous cell carcinoma and actinic keratosis (AK) is 100 and 250 times higher, respectively, compared with immunocompetent patients.
Flare in Neuropathy Following Rituximab Therapy for Waldenstrom’s Macroglobulinemia
Authors: Vanita Noronha, Thomas M. Fynan, Thomas Duffy
Journal: Journal of Clinical Oncology (2005)

TO THE EDITOR: Waldenstrom’s macroglobulinemia is a lowgrade lymphoma characterized by a serum monoclonal immunoglobin M (IgM) protein spike and monoclonal lymphoplasmacytic cells present in the bone marrow. Approximately 5% to 10% of patients develop peripheral neuropathy, which may be immune-mediated as a result of paraprotein directed against myelin-associated glycoprotein (anti-MAG) or glycolipids. Therapy is challenging, with some success reported with steroids, chemotherapy, intravenous immunoglobin (IVIg), or plasma exchange. Recently, the monoclonal anti-CD20 antibody, rituximab, has been used, sometimes in combination with chemotherapy, with improvement in more than 80% of treated pa
Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis
Authors: Bruce A. Buckingham, Dan Raghinaru, Fraser Cameron, B. Wayne Bequette, H. Peter Chase, David M. Maahs, Robert Slover, R. Paul Wadwa, Darrell M. Wilson, Trang Ly, Tandy Aye, Irene Hramiak, Cheril Clarson, Robert Stein, Patricia H. Gallego, John Lum, Judy Sibayan, Craig Kollman, Roy W. Beck
Journal: Diabetes Care (2015)

OBJECTIVE Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor–based overnight predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS In two age-groups of children with type 1 diabetes (11–14 and 4–10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time &amp;lt;70 mg/dL overnight. RESULTS Median time at &amp;lt;70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P &amp;lt; 0.001) in 11–14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P &amp;lt; 0.001) in 4–10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 ± 18 vs. 152 ± 19 mg/dL [P &amp;lt; 0.001] and 153 ± 14 vs. 160 ± 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 ± 29 vs. 176 ± 28 mg/dL (P &amp;lt; 0.001) in the 11–14-year-olds and 154 ± 25 vs. 158 ± 22 mg/dL (P = 0.11) in the 4–10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis. CONCLUSIONS In 4–14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.
Skin-Graft Rejection During Lymphomagenesis in Urethan-Treated Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Giorgio Parmiani
Journal: JNCI Journal of the National Cancer Institute (1971)

Journal Article Skin-Graft Rejection During Lymphomagenesis in Urethan-Treated Mice Get access Giorgio Parmiani Giorgio Parmiani The Institute For Cancer Research6, Philadelphia, Pennsylvania 19111 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 47, Issue 3, September 1971, Pages 569–573, https://doi.org/10.1093/jnci/47.3.569 Published: 01 September 1971 Article history Received: 19 January 1971 Revision received: 10 May 1971 Published: 01 September 1971
Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice
Authors: Liang Gao, David Brenner, Enric Llorens-Bobadilla, Gonzalo Saiz-Castro, Tobias Frank, Peter Wieghofer, Oliver Hill, Meinolf Thiemann, Saoussen Karray, Marco Prinz, Jochen H. Weishaupt, Ana Martin-Villalba
Journal: The Journal of Experimental Medicine (2015)

Neuroinflammation is increasingly recognized as a hallmark of neurodegeneration. Activated central nervous system–resident microglia and infiltrating immune cells contribute to the degeneration of dopaminergic neurons (DNs). However, how the inflammatory process leads to neuron loss and whether blocking this response would be beneficial to disease progression remains largely unknown. CD95 is a mediator of inflammation that has also been proposed as an apoptosis inducer in DNs, but previous studies using ubiquitous deletion of CD95 or CD95L in mouse models of neurodegeneration have generated conflicting results. Here we examine the role of CD95 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)–induced neurodegeneration using tissue-specific deletion of CD95 or CD95L. We show that DN death is not mediated by CD95-induced apoptosis because deletion of CD95 in DNs does not influence MPTP-induced neurodegeneration. In contrast, deletion of CD95L in peripheral myeloid cells significantly protects against MPTP neurotoxicity and preserves striatal dopamine levels. Systemic pharmacological inhibition of CD95L dampens the peripheral innate response, reduces the accumulation of infiltrating myeloid cells, and efficiently prevents MPTP-induced DN death. Altogether, this study emphasizes the role of the peripheral innate immune response in neurodegeneration and identifies CD95 as potential pharmacological target for neurodegenerative disease.
Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses
Authors: Donald W. Milligan, Savio Fernandes, Ranjit Dasgupta, Faith E. Davies, Estella Matutes, Christopher D. Fegan, Christopher McConkey, J. Anthony Child, David Cunningham, Gareth J. Morgan, Daniel Catovsky
Journal: Blood (2004)
<b><i>Lyn</i></b>Is a Target Gene for Prostate Cancer
Authors: Mirela Goldenberg-Furmanov, Ilan Stein, Eli Pikarsky, Hila Rubin, Shafika Kasem, Marc Wygoda, Irina Weinstein, Hadas Reuveni, Shmuel A. Ben-Sasson
Journal: Cancer Research (2004)

The Src-related protein kinase Lyn plays an important role in B-cell activation. However, several lines of evidence suggest that it is also involved in the control of cellular proliferation and the inhibition of apoptosis. We have discovered that Lyn is expressed in normal prostate epithelia, in 95% of primary human prostate cancer (PC) specimens examined, and in all of the PC cell lines that we assayed. Moreover, Lyn knockout mice display abnormal prostate gland morphogenesis, which suggests that Lyn plays an important role in prostate epithelium development and implies that Lyn is a candidate target for specific therapy for PC. Using a drug-design strategy to construct sequence-based peptide inhibitors, a Lyn-specific inhibitor, KRX-123, targeting a unique interaction site within Lyn, was synthesized. KRX-123 was found to inhibit cellular proliferation in three hormone-refractory PC cell lines, DU145, PC3, and TSU-Pr1 with IC(50) values of 2-4 micro M. In vivo, tumor volume of DU145 explants in nude mice was significantly reduced after once-a-week injections of KRX-123, at a dose of 10 mg/kg, for a period of 5 weeks. Histological analyses of the treated tumors indicated extensive apoptosis. Thus, we suggest that Lyn inhibition may serve as a prime target for the treatment of hormone-refractory PC.