tbuckley/cabot-search huggingface dataset:
Influence of Extracellular pH on the Viability and Morphology of Tumor Cells Exposed to Hyperthermia
Authors: J. Overgaard
Journal: JNCI Journal of the National Cancer Institute (1976)

The influence of hyperthermia (42.5 degrees C) on the viability and morphology of L1A2 ascites cells incubated at various pH levels (6.4-7.2) was studied. In contrast to unheated cells, increased extracellular acidity in hyperthermically treated tumor cells was associated with markedly reduced viability of the tumor cells exposed to hyperthermia. The cells heated at neutral pH underwent ultrastructural nuclear changes; the most prominent were the appearance of filamentous bundles and increased perichromatin granules. The cells heated under more acid conditions had an increased lysosomal activity and intense cell lysis resulting in lethal damage to the entire cell population within 6 hours after treatment. The active mechanism was not clear, but cell membrane lesions combined with the increased lysosome activity seemed of major importance in the mechanism of heat-induced damage to tumor cells kept in an acid milieu.
An Analysis of Lipoproteins, Bile Acids, and Red Cell Membranes Associated with Target Cells and Spur Cells in Patients with Liver Disease
Authors: Richard A. Cooper, Milagros Diloy-Puray, Patricia Lando, Mortimer S. Greenberg
Journal: Journal of Clinical Investigation (1972)

Most patients with stable cirrhosis of the alcoholic have "target" red cells; however, a minority have "spur" cells and severe hemolytic anemia. These two syndromes were studied in 27 patients with target cells and 17 patients with spur cells, all of whom had advanced cirrhosis. The cholesterol and phospholipid content of red cell membranes effectively distinguished target cells from spur cells. Target cells alone were rich in lecithin, and both the cholesterol/phospholipid and cholesterol/lecithin mole ratios were greater in spur cells. The cholesterol/phospholipid mole ratio of both types of red cells correlated closely with the free cholesterol saturation of serum lipoproteins, as defined by the amount of free cholesterol relative to phospholipid and protein in these lipoproteins. Lecithin: cholesterol acyltransferase (LCAT) activity was decreased in most patients with target cells and spur cells; however, the relationship between this activity and the lipid abnormalities observed was weak. Serum bile acid levels also correlated poorly with serum and cell lipids. However, in patients with target cells the amount of cholic and deoxycholic acids in serum was approximately equal to the amount of chenodeoxycholic acid, whereas in patients with spur cells chenodeoxycholic acid (the precursor of lithocholic acid) predominated.
Leukocyte degranulation and vacuole formation in patients with chronic granulomatous disease of childhood
Authors: Emanuel Kauder, Louis L. Kahle, Hernan Moreno, John C. Partin
Journal: Journal of Clinical Investigation (1968)

A cellular defect associated with decreased bactericidal activity of the polymorphonuclear leukocyte has been found in a 2(1/2) yr old Negro boy with the typical clinical and pathological findings of chronic granulomatous disease. Unlike previously described patients his polymorphonuclear leukocytes were shown to undergo apparently normal degranulation and vacuole formation after phagocytosis. Metabolic studies of the leukocytes indicated a failure to increase oxygen consumption with phagocytosis or to reduce Nitroblue tetrazolium dye. These metabolic abnormalities are identical with those previously reported in patients with chronic granulomatous disease. Two additional patients with chronic granulomatous disease have also been found to have apparently adequate degranulation of polymorphonuclear leukocytes after phagocytosis. Our studies suggest that failure of degranulation may not be a necessary part of this functional leukocyte abnormality.
Silencing of TonEBP/NFAT5 Transcriptional Activator by RNA Interference
Authors: Ki Young Na, Seung Kyoon Woo, Sang Do Lee, H. Moo Kwon
Journal: Journal of the American Society of Nephrology (2003)

TonEBP is a transcriptional activator that is expressed throughout development in many tissues and cell types. In the kidney medulla, TonEBP appears to be an important local regulator of differentiation by virtue of stimulating several genes. To study the function of TonEBP, two small interfering RNA (siRNA) duplexes were developed that reduced TonEBP expression effectively via RNA interference. The silencing lasted only 3 d after introduction of the TonEBP-siRNA's. As expected, TonEBP-driven reporter gene expression and expression of the sodium/myo-inositol cotransproter (SMIT), aldose reductase (AR) and heat shock protein 70 (HSP70) mRNA were significantly decreased in cells where TonEBP expression was silenced. These data provide direct evidence that the SMIT, AR, and HSP70 genes are targets of TonEBP, although the potential role of other proteins, such as accessory proteins, cannot be excluded. The TonEBP-siRNA is an effective tool that should prove useful in the investigation of loss-of-function relationship in cells.
From gene expression to serum proteins: biomarker discovery in ankylosing spondylitis
Authors: N Haroon, F W L Tsui, F D O’Shea, B Chiu, H W Tsui, H Zhang, K W Marshall, R D Inman
Journal: Annals of the Rheumatic Diseases (2008)

Studying post-infliximab gene expression changes could provide insights into the pathogenesis of ankylosing spondylitis (AS).Gene expression changes were screened by microarray on peripheral blood RNA of 16 AS patients at baseline and 2 weeks post-infliximab, and selected results were confirmed by quantitative real-time (qRT)-PCR. Corresponding serum-soluble LIGHT (sLIGHT) was estimated by ELISA and the fold change in sLIGHT was correlated to the fold change in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and the Bath AS disease activity index.Post-infliximab, 69% of the patients (11/16) achieved an ASAS20 response. Six candidate genes were differentially expressed by microarray; four of which were validated by qRT-PCR. sLIGHT showed the most significant difference. There was good correlation of baseline sLIGHT with CRP (R = 0.60; p = 0.01) and ESR (R = 0.51; p = 0.04). The fold change in sLIGHT correlated with change in both CRP (R = 0.71, p = 0.002) and ESR (R = 0.77, p<0.001).LIGHT is significantly downregulated by infliximab. sLIGHT correlated well with changes in inflammatory markers.
Alexithymia: a relevant psychological variable in near-fatal asthma
Authors: J. Serrano, V. Plaza, B. Sureda, J. de Pablo, C. Picado, S. Bardagí, J. Lamela, J. Sanchis
Journal: European Respiratory Journal (2006)

Alexithymia is a psychological trait characterised by difficulty in perceiving and expressing emotions and body sensations. Failure to perceive dyspnoea could lead alexithymic asthmatics to underestimate the severity of an asthma exacerbation, and thereby increase the risk of developing a fatal or near-fatal asthma (NFA) attack. The objective of the present study was to determine the prevalence of alexithymia in NFA patients and to analyse their clinical characteristics. Alexithymia was assessed using the Toronto Alexithymia Scale in this multicentric prospective observational study. From 33 Spanish hospitals, 179 NFA patients and 40 non-NFA patients, as a control group, were enrolled. There was a higher proportion of alexithymia in the NFA group than in the non-NFA group (36 versus 13%). Patients with NFA and alexithymia were older than the rest of the NFA group, and had a lower level of education, a higher level of psychiatric morbidity, a higher proportion of severe persistent asthma and a greater number of prior very severe asthma exacerbations (49 versus 27%). Alexithymia, severe persistent asthma and a low level of education were identified as independent variables related to repeated very severe asthma exacerbations. The results show that alexithymia is more frequent in near-fatal asthma patients compared to the rest of asthmatics and is associated with recurrent very severe asthma exacerbations.
Spatiotemporal Heterogeneity in the Induction of Ventricular Fibrillation by Rapid Pacing
Authors: Ji-Min Cao, Zhilin Qu, Young-Hoon Kim, Tsu-Juey Wu, Alan Garfinkel, James N. Weiss, Hrayr S. Karagueuzian, Peng-Sheng Chen
Journal: Circulation Research (1999)

The mechanism by which rapid pacing induces ventricular fibrillation (VF) is unclear. We performed computerized epicardial mapping studies in 10 dogs, using 19-beat pacing trains. The pacing interval (PI) of the first train was 300 ms and then was progressively shortened until VF was induced. For each PI, we constructed restitution curves for the effective refractory period (ERP). When the PI was long, the activation cycle length (CL) was constant throughout the mapped region. However, as the PI shortened, there was an increase in the spatiotemporal complexity of the CL variations and an increase in the slope of the ERP restitution curve. In 5 dogs, we documented the initiation of VF by wavebreak at the site of long-short CL variations. Computer simulation studies using the Luo-Rudy I ventricular action potential model in simulated 2-dimensional tissue reproduced the experimental results when normal ERP and conduction velocity (CV) restitution properties were intact. By altering CV and ERP restitutions in this model, we found that CV restitution creates spatial CL variations, whereas ERP restitution underlies temporal, beat-to-beat variations in refractoriness during rapid pacing. Together, the interaction of CV and ERP restitutions produces spatiotemporal oscillations in cardiac activation that increase in amplitude as the PI decreases, ultimately causing wavebreak at the site of intrinsic heterogeneity. This initial wavebreak then leads to the formation of spiral waves and VF. These findings support a key role for both CV and ERP restitutions in the initiation of VF by rapid pacing.
Hearing Loss in an Aging American Population: Extent, Impact, and Management
Authors: Kathleen E. Bainbridge, Margaret I. Wallhagen
Journal: Annual Review of Public Health (2014)

Despite contributing substantially to disability in the United States, age-related hearing loss is an underappreciated public health concern. Loss of hearing sensitivity has been documented in two-thirds of adults aged 70 years and older and has been associated with communication difficulties, lower health-related quality of life, and decreased physical and cognitive function. Management strategies for age-related hearing loss are costly, yet the indirect costs due to lost productivity among people with communication difficulties are also substantial and likely to grow. Hearing aids can improve health-related quality of life, but the majority of people with documented hearing loss do not report using them. Uncovering effective means to improve the utilization of hearing health care services is essential for meeting the hearing health care demands of our aging population. The importance of hearing for general well-being warrants an effort to enhance awareness among the general population of the indications of hearing loss and options for assistance.
Maintenance of Androgen Receptor Inactivation by S-Nitrosylation
Authors: Yu Qin, Anindya Dey, Hamsa Thayele Purayil, Yehia Daaka
Journal: Cancer Research (2013)

Antiandrogens target ligand-binding domain of androgen receptor (AR) and are used as first-line therapeutics to treat patients diagnosed with locally advanced and metastatic prostate cancer. Although initially beneficial as judged with actual tumor mass shrinkage, this therapy invariably fails and the cancer reappears as castration-resistant disease. Here, we report that increased intracellular nitric oxide (NO) levels lead to growth inhibition of both androgen-dependent and castration-resistant prostate tumors through a mechanism that involves AR function inactivation by S-nitrosylation of a single C601 residue present in the DNA-binding domain. AR S-nitrosylation does not impact its subcellular distribution but attenuates its ability to bind AR-responsive elements in promoter region of target genes. Mechanistically, AR is transnitrosylated by its partner HSP90 protein. Ubiquitous small-molecule NO donors promote the AR S-nitrosylation and inhibit growth of castration-resistant prostate tumors. These findings reveal a new mechanism of regulating AR function and suggest that sequential targeting of distinct domains of AR may extend therapeutic efficacy for patients with advanced prostate cancer.
Comprehensive Field Synopsis and Systematic Meta-analyses of Genetic Association Studies in Cutaneous Melanoma
Authors: F. Chatzinasiou, C. M. Lill, K. Kypreou, I. Stefanaki, V. Nicolaou, G. Spyrou, E. Evangelou, J. T. Roehr, E. Kodela, A. Katsambas, H. Tsao, J. P. A. Ioannidis, L. Bertram, A. J. Stratigos
Journal: JNCI Journal of the National Cancer Institute (2011)

Although genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies published in the field and systematic meta-analysis for all eligible polymorphisms have not been reported. We systematically annotated data from all genetic association studies published in the CM field (n = 145), including data from genome-wide association studies (GWAS), and performed random-effects meta-analyses across all eligible polymorphisms on the basis of four or more independent case–control datasets in the main analyses. Supplementary analyses of three available datasets derived from GWAS and GWAS-replication studies were also done. Nominally statistically significant associations between polymorphisms and CM were graded for the strength of epidemiological evidence on the basis of the Human Genome Epidemiology Network Venice criteria. All statistical tests were two-sided. Forty-two polymorphisms across 18 independent loci evaluated in four or more datasets including candidate gene studies and available GWAS data were subjected to meta-analysis. Eight loci were identified in the main meta-analyses as being associated with a risk of CM (P < .05) of which four loci showed a genome-wide statistically significant association (P < 1 × 10−7), including 16q24.3 (MC1R), 20q11.22 (MYH7B/PIGU/ASIP), 11q14.3 (TYR), and 5p13.2 (SLC45A2). Grading of the cumulative evidence by the Venice criteria suggested strong epidemiological credibility for all four loci with genome-wide statistical significance and one additional gene at 9p23 (TYRP1). In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility. To the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis to identify genes associated with an increased susceptibility to CM.
Structural Basis of Integrin Regulation and Signaling
Authors: Bing-Hao Luo, Christopher V. Carman, Timothy A. Springer
Journal: Annual Review of Immunology (2007)

Integrins are cell adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cell-pathogen interactions. They play critical roles for the immune system in leukocyte trafficking and migration, immunological synapse formation, costimulation, and phagocytosis. Integrin adhesiveness can be dynamically regulated through a process termed inside-out signaling. In addition, ligand binding transduces signals from the extracellular domain to the cytoplasm in the classical outside-in direction. Recent structural, biochemical, and biophysical studies have greatly advanced our understanding of the mechanisms of integrin bidirectional signaling across the plasma membrane. Large-scale reorientations of the ectodomain of up to 200 A couple to conformational change in ligand-binding sites and are linked to changes in alpha and beta subunit transmembrane domain association. In this review, we focus on integrin structure as it relates to affinity modulation, ligand binding, outside-in signaling, and cell surface distribution dynamics.
Corticosteroids in acute traumatic brain injury: systematic review of randomised controlled trials
Authors: P. Alderson, I. Roberts
Journal: BMJ (1997)

To quantify the effectiveness and safety of corticosteroids in the treatment of acute traumatic brain injury.Systematic review of randomised controlled trials of corticosteroids in acute traumatic brain injury. Summary odds ratios were estimated as an inverse variance weighted average of the odds ratios for each study.Randomised trials available by March 1996.The included trials with outcome data comprised 2073 randomised participants.The effect of corticosteroids on the risk of death was reported in 13 included trials. The pooled odds ratio for the 13 trials was 0.91 (95% confidence interval 0.74 to 1.12). Pooled absolute risk reduction was 1.8% (-2.5% to 5.7%). For the 10 trials that reported death or disability the pooled odds ratio was 0.90 (0.72 to 1.11). For infections of any type the pooled odds ratio was 0.92 (0.69 to 1.23) and for the seven trials reporting gastrointestinal bleeding it was 1.05 (0.44 to 2.52). With only those trials with the best quality of concealment of allocation, the pooled odds ratio estimates for death and death or disability became closer to unity.This systematic review of randomised controlled trials of corticosteroids in acute traumatic brain injury shows that there remains considerable uncertainty over their effects. Neither moderate benefits nor moderate harmful effects can be excluded. The widely practicable nature of the drugs and the importance of the health problem suggest that large simple trials are feasible and worth while to establish whether there are any benefits from use of corticosteroids in this setting.
Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease
Authors: Winston Dunn, Ronghui Xu, Jeffrey B. Schwimmer
Journal: Hepatology (2008)

People at risk for coronary heart disease are often at risk for nonalcoholic fatty liver disease (NAFLD). The association of modest wine consumption with NAFLD has not been studied and the recommendation of wine for patients at risk for both diseases is controversial. The aim is to test the hypothesis that modest wine consumption is associated with decreased prevalence of NAFLD. We included Third National Health and Nutrition Examination Survey participants who either reported no alcohol consumption or preferentially drinking wine with total alcohol consumption up to 10 g per day. Suspected NAFLD was based on unexplained serum alanine aminotransferase (ALT) elevation over the cut point of the reference laboratory (ALT > 43) and the cut point based on the 95th percentile of healthy subjects (ALT > 30 for men; ALT > 19 for women). Multivariate analysis was adjusted for age, gender, race, neighborhood, income, education, caffeine intake, and physical activity. A total of 7,211 nondrinkers and 945 modest wine drinkers comprised the study sample. Based on the reference laboratory cut point, suspected NAFLD was observed in 3.2% of nondrinkers and 0.4% of modest wine drinkers. The adjusted odds ratio was 0.15 (95% confidence interval, 0.05-0.49). Using the healthy subject cut point, suspected NAFLD was observed in 14.3% of nondrinkers and 8.6% of wine drinkers. The adjusted odds ratio was 0.51 (95% confidence interval, 0.33-0.79).
Early Structural and Functional Changes of the Vasculature in HIV-Infected Children
Authors: Marietta Charakida, Ann E. Donald, Hannah Green, Clare Storry, Margaret Clapson, Muriel Caslake, David T. Dunn, Julian P. Halcox, Diana M. Gibb, Nigel J. Klein, John E. Deanfield
Journal: Circulation (2005)

Premature cardiovascular disease is increasingly recognized in HIV-infected patients, but the mechanisms involved are unclear. The purpose of this study was to determine the impact of HIV infection and antiretroviral therapy (ART) on markers of early vascular disease in children.We studied 83 HIV-infected children (56 had taken ART, of whom 31 received a regimen containing protease inhibitors [PIs]; 27 were never treated) and a control group of 59 healthy children. Carotid intima-media thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were measured. IMT was significantly greater in HIV-infected children compared with the control subjects (P<0.001). Among the HIV-infected children, age and treatment were significantly associated with increased IMT. Children exposed to PIs had greater IMT compared with both non-PI-treated children and untreated children (P=0.02). FMD was also significantly reduced in the HIV-infected children compared with control subjects (P=0.02). Pairwise comparisons of different treatment exposure groups revealed that FMD was impaired by a mean of 3.6% (95% CI, 1.8 to 5.3; P<0.001) for children exposed to PIs compared with untreated children and by a mean of 1.8% (95% CI, 0.01 to 3.5; P=0.05) compared with non-PI-treated children. HIV-infected children had lipid abnormalities, but they did not account for the observed differences in either FMD or IMT.HIV infection in childhood is associated with adverse structural and functional vascular changes that are most pronounced in children exposed to PI therapy. Longitudinal studies are required to differentiate the relative impact of HIV disease and ART and to assess the potential for prevention.
Exogenously-induced, natural killer cell-mediated neuronal killing: a novel pathogenetic mechanism.
Authors: W F Hickey, K Ueno, J C Hiserodt, R E Schmidt
Journal: The Journal of Experimental Medicine (1992)

Many human neurodegenerative diseases are characterized by the idiopathic death of cells narrowly restricted to a subset of neurons in a specific functional neuroanatomic system. Few in vivo models exist for the analysis of these types of degeneration. This report documents the death of sympathetic neurons resident in the superior cervical ganglia of rats after exposure to an exogenous chemical agent, the drug guanethidine, as being mediated by natural killer (NK) cells. This is the first in vivo model of a disorder of the nervous system in which NK cells appear to be the principal effector cell, and thus could serve a central role in dissecting the normal and pathological function of NK cells. In addition, this pathogenetic mechanism appears to represent a novel type of autoimmune reaction that could have a direct bearing on a number of human illnesses.