tbuckley/cabot-search huggingface dataset:
Abstract 4665: A combined IHC/Western method to measure phosphorylated histone H3 in skin biopsies as potential biomarker for anticancer drug action
Authors: Ralph Graeser, Marianne Birkle, Christine Rentzsch, Christoph Schaechtele
Journal: Cancer Research (2010)

Abstract In recent years there has been a rapid increase in targeted tumor therapy approaches. Hand in hand with these novel approaches, the need has arisen to monitor specific target inhibition by the drug. In contrast to classic chemotherapy, which non-specifically targets proliferating cells, these novel approaches attempt to specifically interfere with some process thought to be crucial for the tumor cell survival. Nevertheless, despite extensive validation, an immediate effect of target interference on tumor growth may not necessarily be expected. Thus, in order to demonstrate activity of anti-cancer drugs, a marker known to be modified upon inhibition of the target may serve as a surrogate to tumor inhibition. Ideally, tumor biopsies would be analysed for monitoring of drug-induced effects. However, taking in consideration the difficulties to perform sequential tumor biopsies, the use of surrogate tissues like blood or skin is being explored instead. Blood is relatively easily accessible, but unlike skin tissue, blood may not reflect the fact that drugs have to penetrate multiple layers of tissue in order to reach their target in the tumor. Also, to monitor the effects of anti-mitotic drugs, the investigated specimen must exhibit proliferating features, which is given only in a very poor manner blood samples, as peripheral blood cells have typically exited the cell cycle. However cells in the dermis still proliferate, albeit to a small percentage. Therefore, considering these issues, we set out to develop a method to analyse drug effects in skin biopsies. Traditionally, most analyses of skin biopsies have relied on immunohistochemistry (IHC) studies. However, the quantification of such results is time-consuming and error-prone. Western Blot analyses are easier to quantify, but require a considerable amount of protein lysate of sufficient concentration. We developed a protocol that reproducibly allows the detection and quantification of phosphorylated histone H3 in Western Blots from a single half of a skin biopsy. For normalization, the total amount of histone H3 present in the lysate is determined. The other half of the skin biopsy may be used for IHC analysis of phosphorylated histone H3, allowing the comparison to other studies relying solely on IHC. We will present data on the measurement of phosphorylated histone H3 via Western Blots and IHC from skin biopsies of healthy donors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4665.
A novel allergen-specific therapy for allergy using CD40-silenced dendritic cells
Authors: Motohiko Suzuki, Xiufen Zheng, Xusheng Zhang, Zhu-Xu Zhang, Thomas E. Ichim, Hongtao Sun, Yoshihisa Nakamura, Akira Inagaki, Marianne Beduhn, Aminah Shunnar, Bertha Garcia, Wei-Ping Min
Journal: Journal of Allergy and Clinical Immunology (2010)
Cryptochrome, Circadian Cycle, Cell Cycle Checkpoints, and Cancer
Authors: Michele A. Gauger, Aziz Sancar
Journal: Cancer Research (2005)

Abstract It has been reported that disruption of the circadian clock may lead to increased risk of breast cancer in humans and to a high rate or ionizing radiation–induced tumors and mortality in mice. Cryptochrome 1 and cryptochrome 2 proteins are core components of the mammalian circadian clock and mice mutated in both genes are arrhythmic. We tested Cry1−/−Cry2−/− mice and fibroblasts derived from these mice for radiation-induced cancer and killing and DNA damage checkpoints and killing, respectively. We find that the mutant mice are indistinguishable from the wild-type controls with respect to radiation-induced morbidity and mortality. Similarly, the Cry1−/−Cry2−/− mutant fibroblasts are indistinguishable from the wild-type controls with respect to their sensitivity to ionizing radiation and UV radiation and ionizing radiation–induced DNA damage checkpoint response. Our data suggest that disruption of the circadian clock in itself does not compromise mammalian DNA repair and DNA damage checkpoints and does not predispose mice to spontaneous and ionizing radiation–induced cancers. We conclude that the effect of circadian clock disruption on cellular response to DNA damage and cancer predisposition in mice may depend on the mechanism by which the clock is disrupted.
G+C content variation along and among Saccharomyces cerevisiae chromosomes
Authors: K. R. Bradnam, C. Seoighe, P. M. Sharp, K. H. Wolfe
Journal: Molecular Biology and Evolution (1999)

Past analyses of the genome of the yeast Saccharomyces cerevisiae have revealed substantial regional variation in G+C content. Important questions remain, though, as to the origin, nature, significance, and generality of this variation. We conducted an extensive analysis of the yeast genome to try to answer these questions. Our results indicate that open reading frames (ORFs) with similar G+C contents at silent codon positions are significantly clustered on chromosomes. This clustering can be explained by very short range correlations of silent-site G+C contents at neighboring ORFs. ORFs of high silent-site G+C content are disproportionately concentrated on shorter chromosomes, which causes a negative relationship between chromosome length and G+C content. Contrary to previous reports, there is no correlation between gene density and silent-site G+C content in yeast. Chromosome III is atypical in many regards, and possible reasons for this are discussed.
2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery
Authors: Lee A. Fleisher, Kirsten E. Fleischmann, Andrew D. Auerbach, Susan A. Barnason, Joshua A. Beckman, Biykem Bozkurt, Victor G. Davila-Roman, Marie D. Gerhard-Herman, Thomas A. Holly, Garvan C. Kane, Joseph E. Marine, M. Timothy Nelson, Crystal C. Spencer, Annemarie Thompson, Henry H. Ting, Barry F. Uretsky, Duminda N. Wijeysundera
Journal: Circulation (2014)
The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study
Authors: R. J. Hughes, X. Jais, D. Bonderman, J. Suntharalingam, M. Humbert, I. Lang, G. Simonneau, J. Pepke-Zaba
Journal: European Respiratory Journal (2006)

The treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). However, many patients develop a severe progressive small vessel pulmonary arteriopathy that is inaccessible to surgical intervention and is associated with poor survival. The purpose of the present study was to evaluate the medium-term efficacy and safety of the dual endothelin receptor antagonist, bosentan, in inoperable CTEPH. Forty-seven patients with inoperable CTEPH (distal disease or persistent pulmonary hypertension following PEA) underwent evaluation after 1 yr of bosentan therapy. Outcomes included assessment of 6-min walk test (6MWT), haemodynamics and World Health Organization functional classification. Monitoring of serious adverse effects and changes in therapy was undertaken. Patients showed sustained improvements in 6MWT (49±8 m), functional classification, cardiac index (+0.2±0.07 L·min -1 ·m -2 ) and total pulmonary resistance (-139±42 dyn·s·cm -5 ). Those patients with persisting pulmonary hypertension following PEA showed the greatest improvement. One-yr survival was 96%, and bosentan was well tolerated with only one patient developing deranged liver function. Although all patients with chronic thromboembolic pulmonary hypertension should be considered for pulmonary endarterectomy, bosentan provides an alternative medical therapy to improve function and delay the progression of this devastating disease in those in whom surgery is not suitable.
Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver
Authors: Adrien Guillot, Nabila Hamdaoui, Alexandra Bizy, Keve Zoltani, Rachid Souktani, Elie-Serge Zafrani, Ariane Mallat, Sophie Lotersztajn, Fouad Lafdil
Journal: Hepatology (2013)

Interleukin (IL)-17 is a proinflammatory and fibrogenic cytokine mainly produced by T-helper (Th)17 lymphocytes, together with the hepatoprotective and antifibrogenic cytokine, IL-22. Cannabinoid receptor 2 (CB2) is predominantly expressed in immune cells and displays anti-inflammatory and antifibrogenic effects. In the present study, we further investigated the mechanism underlying antifibrogenic properties of CB2 receptor and explored its effect on the profibrogenic properties of IL-17. After bile duct ligation (BDL), the hepatic expression of Th17 markers and IL-17 production were enhanced in CB2(-/-) mice, as compared to wild-type (WT) counterparts, and correlated with increased fibrosis in these animals. In contrast, IL-22-induced expression was similar in both animal groups. Inhibition of Th17 differentiation by digoxin lowered Th17 marker gene expression and IL-17 production and strongly reduced liver fibrosis in CB2(-/-) BDL mice. In vitro, differentiation of CD4(+) naïve T cells into Th17 lymphocytes was decreased by the CB2 agonist, JWH-133, and was associated with reduced Th17 marker messenger RNA expression and IL-17 production, without modification of IL-22 release. The inhibitory effect of JWH-133 on IL-17 production relied on signal transducer and activator of transcription (STAT)5 phosphorylation. Indeed, STAT5 phosphorylation and translocation into the nucleus was enhanced in JWH133-treated Th17 lymphocytes, and the addition of a STAT5 inhibitor reversed the inhibitory effect of the CB2 agonist on IL-17 production, without affecting IL-22 levels. Finally, in vitro studies also demonstrated that CB2 receptor activation in macrophages and hepatic myofibroblasts blunts IL-17-induced proinflammatory gene expression.These data demonstrate that CB2 receptor activation decreases liver fibrosis by selectively reducing IL-17 production by Th17 lymphocytes via a STAT5-dependent pathway, and by blunting the proinflammatory effects of IL-17 on its target cells, while preserving IL-22 production.
Vitamin E, Vitamin C, Beta Carotene, and Cognitive Function Among Women With or at Risk of Cardiovascular Disease
Authors: Jae Hee Kang, Nancy R. Cook, JoAnn E. Manson, Julie E. Buring, Christine M. Albert, Francine Grodstein
Journal: Circulation (2009)

Cardiovascular factors are associated with cognitive decline. Antioxidants may be beneficial.
Evaluation of Toxicity following Electrically Mediated Interleukin-12 Gene Delivery in a B16 Mouse Melanoma Model
Authors: Loree Heller, Kathleen Merkler, Jeffrey Westover, Yolmari Cruz, Domenico Coppola, Kaaron Benson, Adil Daud, Richard Heller
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Interleukin-12 (IL-12) has potential as an immunotherapeutic agent for the treatment of cancer but is unfortunately associated with toxicity. Delivery of a plasmid encoding IL-12 with electroporation induces an antitumor effect in the B16 mouse melanoma model without serious side effects. To translate this observation to the clinic, an evaluation of toxicity was done in the mouse model. Experimental Design: Weight change, tumor response, blood chemistry and hematology values, and serum IL-12 levels were evaluated. Multiple tissues were analyzed histopathologically. Results: A pronounced reduction in tumor volume, including a large percentage of complete regressions, was observed after electrically mediated gene therapy. No significant increases in serum IL-12 levels were detected. Tumor-bearing mice showed an increased number of atypical hematology values when compared with normal naive controls. Statistically significant differences in chemistry and hematology values were observed sporadically in most of the standard chemistry and hematology categories in all groups. The only histopathologic abnormality specific to the animals receiving both plasmid and electroporation was inflammation associated with the kidney at the last time point. Conclusions: In general, mice that received both plasmid and electroporation showed the least abnormal histopathologic findings and were found to be in the best health, reflecting the reduced burden of disease. No significant toxic effects due to the IL-12 gene therapy were observed.
Accurate Prediction of the Response of Freshwater Fish to a Mixture of Estrogenic Chemicals
Authors: Jayne V. Brian, Catherine A. Harris, Martin Scholze, Thomas Backhaus, Petra Booy, Marja Lamoree, Giulio Pojana, Niels Jonkers, Tamsin Runnalls, Angela Bonfà, Antonio Marcomini, John P. Sumpter
Journal: Environmental Health Perspectives (2005)

Existing environmental risk assessment procedures are limited in their ability to evaluate the combined effects of chemical mixtures. We investigated the implications of this by analyzing the combined effects of a multicomponent mixture of five estrogenic chemicals using vitellogenin induction in male fathead minnows as an end point. The mixture consisted of estradiol, ethynylestradiol, nonylphenol, octylphenol, and bisphenol A. We determined concentration-response curves for each of the chemicals individually. The chemicals were then combined at equipotent concentrations and the mixture tested using fixed-ratio design. The effects of the mixture were compared with those predicted by the model of concentration addition using biomathematical methods, which revealed that there was no deviation between the observed and predicted effects of the mixture. These findings demonstrate that estrogenic chemicals have the capacity to act together in an additive manner and that their combined effects can be accurately predicted by concentration addition. We also explored the potential for mixture effects at low concentrations by exposing the fish to each chemical at one-fifth of its median effective concentration (EC50). Individually, the chemicals did not induce a significant response, although their combined effects were consistent with the predictions of concentration addition. This demonstrates the potential for estrogenic chemicals to act additively at environmentally relevant concentrations. These findings highlight the potential for existing environmental risk assessment procedures to underestimate the hazard posed by mixtures of chemicals that act via a similar mode of action, thereby leading to erroneous conclusions of absence of risk.
Optimal Uses of Antiretrovirals for Prevention in HIV-1 Serodiscordant Heterosexual Couples in South Africa: A Modelling Study
Authors: Timothy B. Hallett, Jared M. Baeten, Renee Heffron, Ruanne Barnabas, Guy de Bruyn, Íde Cremin, Sinead Delany, Geoffrey P. Garnett, Glenda Gray, Leigh Johnson, James McIntyre, Helen Rees, Connie Celum
Journal: PLoS Medicine (2011)

Background Antiretrovirals have substantial promise for HIV-1 prevention, either as antiretroviral treatment (ART) for HIV-1–infected persons to reduce infectiousness, or as pre-exposure prophylaxis (PrEP) for HIV-1–uninfected persons to reduce the possibility of infection with HIV-1. HIV-1 serodiscordant couples in long-term partnerships (one member is infected and the other is uninfected) are a priority for prevention interventions. Earlier ART and PrEP might both reduce HIV-1 transmission in this group, but the merits and synergies of these different approaches have not been analyzed. Methods and Findings We constructed a mathematical model to examine the impact and cost-effectiveness of different strategies, including earlier initiation of ART and/or PrEP, for HIV-1 prevention for serodiscordant couples. Although the cost of PrEP is high, the cost per infection averted is significantly offset by future savings in lifelong treatment, especially among couples with multiple partners, low condom use, and a high risk of transmission. In some situations, highly effective PrEP could be cost-saving overall. To keep couples alive and without a new infection, providing PrEP to the uninfected partner could be at least as cost-effective as initiating ART earlier in the infected partner, if the annual cost of PrEP is <40% of the annual cost of ART and PrEP is >70% effective. Conclusions Strategic use of PrEP and ART could substantially and cost-effectively reduce HIV-1 transmission in HIV-1 serodiscordant couples. New and forthcoming data on the efficacy of PrEP, the cost of delivery of ART and PrEP, and couples behaviours and preferences will be critical for optimizing the use of antiretrovirals for HIV-1 prevention. Please see later in the article for the Editors' Summary
Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression
Authors: Yoshihiro Ikura, Masahiko Ohsawa, Takehisa Suekane, Hiroko Fukushima, Hiroyuki Itabe, Hisato Jomura, Shuhei Nishiguchi, Takeshi Inoue, Takahiko Naruko, Shoichi Ehara, Norifumi Kawada, Tetsuo Arakawa, Makiko Ueda
Journal: Hepatology (2006)

Nonalcoholic steatohepatitis/nonalcoholic fatty liver disease is considered to be a hepatic manifestation of various metabolic disorders. However, its precise pathogenic mechanism is obscure. Oxidative stress and consequent lipid peroxidation seem to play a pivotal role in disease progression. In this study, we analyzed the localization of oxidized phosphatidylcholine (oxPC), a lipid peroxide that serves as a ligand for scavenger receptors, in livers of patients with this steatotic disorder. Specimens of non-alcoholic fatty liver disease (15 autopsy livers with simple steatosis and 32 biopsy livers with steatohepatitis) were examined via immunohistochemistry and immunoelectron microscopy using a specific antibody against oxPC. In addition, scavenger receptor expression, hepatocyte apoptosis, iron deposition, and inflammatory cell infiltration in the diseased livers were also assessed. Oxidized phosphatidylcholine was mainly localized to steatotic hepatocytes and some macrophages/Kupffer cells. A few degenerative or apoptotic hepatocytes were also positive for oxPC. Immunoelectron microscopy showed oxPC localized to cytoplasmic/intracytoplasmic membranes including lipid droplets. Steatotic livers showed enhanced expression of scavenger receptors. The number of oxPC cells was correlated with disease severity and the number of myeloperoxidase-positive neutrophils, but not with the degree of iron deposition. In conclusion , distinct localization of oxPC in liver tissues suggest that neutrophil myeloperoxidase-derived oxidative stress may be crucial in the formation of oxPC and the progression of steatotic liver disease. (Hepatology 2006;43:506–514.)
Correlation of serum B lymphocyte stimulator and 2 microglobulin with autoantibody secretion and systemic involvement in primary Sjogren's syndrome
Authors: J-E Gottenberg
Journal: Annals of the Rheumatic Diseases (2005)

In primary Sjögren's syndrome (pSS), extraglandular involvement might result from more intense stimulation of autoreactive B cells. Thus markers of B cell activation could be useful in the clinical assessment of this disease.To investigate the association of serum B lymphocyte stimulator (BLyS) and beta2 microglobulin with autoantibody production and extraglandular involvement in pSS.Serum concentrations of BLyS and beta2 microglobulin were analysed in 177 patients with pSS according to the American-European consensus group criteria. Serum beta2 microglobulin was determined serially in 25 patients.Autoantibody secretion (presence of anti-SSA antibody alone or of both anti-SSA and anti-SSB) was associated with increased serum BLyS and beta2 microglobulin. No correlation was found between BLyS and beta2 microglobulin levels (p = 0.36). Serum concentrations of beta2 microglobulin and C reactive protein and positive anti-SSB antibody results were associated with extraglandular involvement on univariate analysis (p<10(-4), p = 0.003, and p = 0.004, respectively). Serum beta2 microglobulin was also significantly increased in patients with extraglandular involvement without autoantibodies (mean (SD): 1.75 (0.7) v 1.39 (0.5) mg/l, p = 0.039). Multivariate analysis showed that extraglandular involvement was associated only with increased serum beta2 microglobulin (p = 0.035, odds ratio = 2.78 (95% confidence interval, 1.07 to 7.22)). Among the 25 patients who had serial determinations of serum beta2 microglobulin, the concentrations were increased in all those with disease flare and decreased in three following treatment. Serum BLyS, gamma globulin, IgG, and rheumatoid factor levels were not associated with features of systemic involvement.Serum beta2 microglobulin and BLyS reflect B cell activation in different ways in pSS. Serum beta2 microglobulin assessment could be helpful as an activity marker in pSS.
AUTOGENOUS IMMUNITY TO ENDOGENOUS RNA TUMOR VIRUS
Authors: J. N. Ihle, M. G. Hanna, L. E. Roberson, F. T. Kenney
Journal: The Journal of Experimental Medicine (1974)

The viral antigenic determinants recognized in an autogenous immune response in mice against their endogenous C-type virus have been identified by SDS-polyacrylamide gel electrophoresis of immune precipitates between various sera and H(3)-labeled intact or disrupted AKR leukemia virus. Normal B6C3F(1) [(C57BL/6 x C3H/Anf)F(1)] serum reacts with viral envelope antigens having mol wt of approximately 68,000, 43,000, and 17,000. In addition, minor reactions with viral antigens having mol wts of approximately 19,000 and 15,000 are demonstrable. The 68,000 and 43,000 mol wt antigens can be labeled with [(3)H]glucosamine and may correspond to the major viral envelope antigens M(2) and M(1), respectively. The antigens recognized by autogenous immune sera do not differ with respect to age of the animal, nor are they significantly different in sera from various strains of mice (BALB/c, C57BL/6, and C3H/Anf). These results suggest that the age-asociated and strain variations in the autogenous immune response, as determined by radioimmune precipitation assays against intact virus, are due to quantitative and qualitative alterations of antibody levels against common antigens.