tbuckley/cabot-search huggingface dataset:
Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells
Authors: Zhen Yang, Hiroshi Fujii, Shalini V. Mohan, Jorg J. Goronzy, Cornelia M. Weyand
Journal: The Journal of Experimental Medicine (2013)

In the HLA class II–associated autoimmune syndrome rheumatoid arthritis (RA), CD4 T cells are critical drivers of pathogenic immunity. We have explored the metabolic activity of RA T cells and its impact on cellular function and fate. Naive CD4 T cells from RA patients failed to metabolize equal amounts of glucose as age-matched control cells, generated less intracellular ATP, and were apoptosis-susceptible. The defect was attributed to insufficient induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting glycolytic enzyme known to cause the Warburg effect. Forced overexpression of PFKFB3 in RA T cells restored glycolytic flux and protected cells from excessive apoptosis. Hypoglycolytic RA T cells diverted glucose toward the pentose phosphate pathway, generated more NADPH, and consumed intracellular reactive oxygen species (ROS). PFKFB3 deficiency also constrained the ability of RA T cells to resort to autophagy as an alternative means to provide energy and biosynthetic precursor molecules. PFKFB3 silencing and overexpression identified a novel extraglycolytic role of the enzyme in autophagy regulation. In essence, T cells in RA patients, even those in a naive state, are metabolically reprogrammed with insufficient up-regulation of the glycolytic activator PFKFB3, rendering them energy-deprived, ROS- and autophagy-deficient, apoptosis-sensitive, and prone to undergo senescence.
Progress in the pursuit of therapeutic adenosine receptor antagonists
Authors: Stefano Moro, Zhan‐Guo Gao, Kenneth A. Jacobson, Giampiero Spalluto
Journal: Medicinal Research Reviews (2005)

Abstract Ever since the discovery of the hypotensive and bradycardiac effects of adenosine, adenosine receptors continue to represent promising drug targets. First, this is due to the fact that the receptors are expressed in a large variety of tissues. In particular, the actions of adenosine (or methylxanthine antagonists) in the central nervous system, in the circulation, on immune cells, and on other tissues can be beneficial in certain disorders. Second, there exists a large number of ligands, which have been generated by introducing several modifications in the structure of the lead compounds (adenosine and methylxanthine), some of them highly specific. Four adenosine receptor subtypes (A 1 , A 2A , A 2B , and A 3 ) have been cloned and pharmacologically characterized, all of which are G protein‐coupled receptors. Adenosine receptors can be distinguished according to their preferred mechanism of signal transduction: A 1 and A 3 receptors interact with pertussis toxin‐sensitive G proteins of the G i and G o family; the canonical signaling mechanism of the A 2A and of the A 2B receptors is stimulation of adenylyl cyclase via G s proteins. In addition to the coupling to adenylyl cyclase, all four subtypes may positively couple to phospholipase C via different G protein subunits. The development of new ligands, in particular, potent and selective antagonists, for all subtypes of adenosine receptors has so far been directed by traditional medicinal chemistry. The availability of genetic information promises to facilitate understanding of the drug–receptor interaction leading to the rational design of a potentially therapeutically important class of drugs. Moreover, molecular modeling may further rationalize observed interactions between the receptors and their ligands. In this review, we will summarize the most relevant progress in developing new therapeutic adenosine receptor antagonists. © 2005 Wiley Periodicals, Inc.
Imipramine in Depressive Illness
Authors: S. W. V. Davies
Journal: BMJ (1964)

MEBDCLOUUpast year.It is remarkable that this has been achieved without accurate proof of specific pathological damage by these drugs.It is more remarkable that the Witts and Dunlop Committees have issued guidance to the profession on these matters without in- cluding any psychiatrist among their num- bers.This unusual attitude is placing psychiatrists in an extremely difficult posi- tion.It does not seem to be realized adequately enough that there are now more psychiatrists than general physicians, and that psychiatric disorders account for the bulk of general practice.It is most remark-
Dendritic cells are the principal cells in mouse spleen bearing immunogenic fragments of foreign proteins.
Authors: M Crowley, K Inaba, R M Steinman
Journal: The Journal of Experimental Medicine (1990)

We monitored the APC function of cells taken from the spleen and peritoneal cavity of mice that had been given protein antigens via the intravenous or intraperitoneal routes. Using the mAb 33D1 and N418 to negatively and positively select dendritic cells, we obtained evidence that dendritic cells are the main cell type in spleen that carries the protein in a form that is immunogenic for antigen-specific T cells. In vivo pulsed macrophages were not immunogenic and did not appear capable of transferring peptide fragments to dendritic cells.
Thromboembolic Events During Chemotherapy for Germ Cell Cancer: A Cohort Study and Review of the Literature
Authors: Nir I. Weijl, Marc F. J. Rutten, Aeilko H. Zwinderman, H. Jan Keizer, Marianne A. Nooy, Frits R. Rosendaal, Frans J. Cleton, Susanne Osanto
Journal: Journal of Clinical Oncology (2000)

To evaluate the risk of major thromboembolic complications in male germ cell cancer patients receiving cisplatin-based chemotherapy and to review the literature on this subject.One hundred seventy-nine germ cell cancer patients treated between January 1979 and May 1997 in our hospital were analyzed with respect to risk factors for developing thromboembolic events, such as baseline tumor characteristics, prior tumor therapy, administration of cytostatic agents, and the use of antiemetic drugs. The patients were treated with a variety of combination chemotherapy regimens, primarily cisplatin-containing combination regimens.Of the 179 patients, 15 patients (8.4%) were identified who developed a total of 18 major thromboembolic complications in the time period between the start of chemotherapy and 6 weeks after administration of the last cytostatic drug in first-line treatment. Of these 18 events, three (16.7%) were arterial events, including two cerebral ischemic strokes, and 15 (83. 3%) were venous thromboembolic events, including 11 pulmonary embolisms. One (5.6%) of the 18 events was fatal. Liver metastases (odds ratio, 4.9; 95% confidence interval, 1.1 to 20.8) and the administration of high doses of corticosteroids (>/= 80 mg dexamethasone per cycle; odds ratio, 3.5; 95% confidence interval, 1. 2 to 10.3) as antiemetic therapy were identified as risk factors for the development of major thromboembolic complications.Germ cell cancer patients who receive chemotherapy, in particular those who have liver metastases or receive high doses of corticosteroids, are at considerable risk of developing thromboembolic complications.
Metabolic effects of human growth hormone in corticosteroid-treated children
Authors: Helen G. Morris, Jacqueline R. Jorgensen, Harold Elrick, Richard E. Goldsmith
Journal: Journal of Clinical Investigation (1968)

The effects of administered human growth hormone (HGH) were evaluated in dwarfed, prepubertal children who were receiving long-term corticosteroid therapy for a chronic disease. During 11 complete metabolic balance studies, the eight corticosteroid-treated children demonstrated impaired response to large doses of HGH with minimal nitrogen and no phosphorus retention. In contrast, two hypopituitary subjects and two asthmatic children not receiving corticosteroid responded to the same preparations of HGH with nitrogen, potassium, and phosphorus retention. Six corticosteroid-treated children were given large doses of HGH (40-120 mg/wk for 4 to 8 months and showed no improvement in their retarded rate of growth, whereas the hypopituitary subjects showed accelerated growth during administration of 10-15 mg of HGH/wk. It is concluded that dwarfism in steroid-treated children results from corticosteroid-induced antagonism of the effects of HGH at the peripheral tissue level.
Adenovirus-Mediated Gene Transfer of Human Platelet-Activating Factor–Acetylhydrolase Prevents Injury-Induced Neointima Formation and Reduces Spontaneous Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Rozenn Quarck, Bart De Geest, Dominique Stengel, Ann Mertens, Marleen Lox, Gregor Theilmeier, Carine Michiels, Martine Raes, Hidde Bult, Désiré Collen, Paul Van Veldhoven, Ewa Ninio, Paul Holvoet
Journal: Circulation (2001)

Background —Atherosclerosis is characterized by an early inflammatory response involving proinflammatory mediators such as platelet-activating factor (PAF)-like phospholipids, which are inactivated by PAF-acetylhydrolase (PAF-AH). The effect of adenovirus-mediated expression of PAF-AH on injury-induced neointima formation and spontaneous atherosclerosis was studied in apolipoprotein E–deficient mice. Methods and Results —Intravenous administration of an adenovirus (5×10 8 plaque-forming units) directing liver-specific expression of human PAF-AH resulted in a 3.5-fold increase of plasma PAF-AH activity at day 7 ( P &lt;0.001); this was associated with a 2.4- and 2.3-fold decrease in malondialdehyde-modified LDL autoantibodies and the lysophosphatidylcholine/phosphatidylcholine ratio, respectively ( P &lt;0.001 for both). Non-HDL and HDL cholesterol levels in PAF-AH –treated mice were similar to those of control virus-treated mice. Seven days after virus injection, endothelial denudation of the common left carotid artery was induced with a guidewire. Neointima formation was assessed 18 days later. PAF-AH gene transfer reduced oxidized lipoproteins by 82% ( P &lt;0.001), macrophages by 69% ( P =0.006), and smooth muscle cells by 84% ( P =0.002) in the arterial wall. This resulted in a 77% reduction ( P &lt;0.001) of neointimal area. Six weeks after adenovirus-mediated gene transfer, spontaneous atherosclerotic lesions in the aortic root were analyzed. PAF-AH gene transfer reduced atherosclerotic lesions by 42% ( P =0.02) in male mice, whereas a nonsignificant 14% reduction was observed in female mice. Basal and PAF-AH activity after gene transfer were higher in male mice than in female mice ( P =0.01 and P =0.04, respectively). Conclusions —Gene transfer of PAF-AH inhibited injury-induced neointima formation and spontaneous atherosclerosis in apolipoprotein E–deficient mice. Our data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation, is a potent protective enzyme against atherosclerosis.
Abstract A04: Changes in matrix metalloproteinase expression in SN-38 resistant colorectal cancer cells
Authors: Spencer I T Berg, Murray J. Cutler, Jonathan Blay
Journal: Clinical Cancer Research (2015)

Abstract The matrix metalloproteinases (MMPs) are a complex family of zinc-dependent proteolytic enzymes, which collectively are capable of degrading all components of the extracellular matrix (ECM). The ECM provides structure and support for normal tissues, and acts both as a barrier to and support for cancer cell invasion and metastasis. MMPs are therefore believed to play an important role in regulating the rate of cancer progression. However, the repeated failure of MMP inhibitors in clinical trials, as well as recent discoveries of novel MMP activities and localizations, has led to a re-evaluation of the roles of MMPs to the cancer process. In colorectal cancer (CRC) the outlook following disease relapse after surgery and initial chemotherapy is poor, due both to drug resistance and further dissemination of disease. We investigated the involvement of MMPs and related molecules in this context. We have generated a series of derivatives of the human CRC cell line HT29 that are resistant to SN-38, the active metabolite of the chemotherapeutic agent irinotecan. The principal representative cell line, HT29-S, has a slower proliferation rate than parental HT29 cells, and yet forms denser outgrowths in monolayer culture. The abundance and localization of several MMPs and tissue inhibitors of metalloproteinases (TIMPs) have been assessed in both HT29 and HT29-S cells by western blotting of cytosolic and nuclear protein fractions,and by immunofluorescence. HT29-S cells showed a lower expression of MMP1, MMP7, and MMP9, but also TIMP1 and TIMP2, compared to their parental counterparts, with some differences in cellular distribution. In particular, MMP1 gave a strong nuclear signal by both methods in HT29 cells, which was strongly reduced in HT29-S. A reduction in MMP expression will allow for an increased accumulation of ECM components. This may act through integrin receptors to activate survival pathways and contribute to the chemoresistance observed in HT29-S cells, and may also facilitate the spread of cancer cells by refining the ECM framework in advanced CRC. Citation Format: Spencer I T Berg, Murray J. Cutler, Jr., Jonathan Blay. Changes in matrix metalloproteinase expression in SN-38 resistant colorectal cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A04.
Recovery of airway structure and function after hyperoxic exposure in immature rats.
Authors: M B Hershenson, M K Abe, M D Kelleher, E T Naureckas, A Garland, A Zimmermann, V J Rubinstein, J Solway
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

We have previously demonstrated that hyperoxic exposure (> 95% O2 for 8 d) induces airway cholinergic hyperresponsiveness and remodeling in 21-d-old rats. To examine the potential relationship between airway hyperresponsiveness and remodeling in these animals, we exposed rats to air or hyperoxia for 8 d, returned them to air-breathing, and measured airway responsiveness to inhaled acetylcholine (ACh) and layer thicknesses immediately after or 16 or 48 d after cessation of air or O2 exposure. The ACh concentration required to increase resistance by 100% (EC200ACh) was calculated by linear interpolation. Small airway (circumference < 1,000 microns) and medium-sized, conducting airway (1,000 to 3,000 microns) epithelial and smooth muscle layer mean thicknesses and fractional areas (layer area/luminal cross-sectional area) were determined from lung sections by contour tracing using a digitizing pad and computer. As we reported previously, after 8 d of O2 exposure, group mean log EC200ACh was significantly reduced relative to that in control animals (p < 0.001). Similarly, hyperoxic exposure was associated with significant increases in all parameters of airway layer thickness assessed (p < 0.05). However, by 16 d after cessation of O2 exposure, there were no longer statistically significant differences in log EC200ACh, airway layer thickness, or fractional area between control and O2-exposed animals. Further studies, in a second cohort of animals killed 0, 3, 6, 8, or 13 d after cessation of O2 exposure, demonstrated progressive reductions in small airway epithelial and smooth muscle layer thicknesses, confirming that hyperoxia-induced airway remodeling resolves by approximately 2 wk after termination of O2 exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological Relevance of Adduct Detection to the Chemoprevention of Cancer
Authors: Ricky A. Sharma, Peter B. Farmer
Journal: Clinical Cancer Research (2004)

Abstract Adducts arise from the chemical modification of bases in DNA or amino acids in proteins by toxic chemicals. Many chemicals known to be carcinogenic in humans have been shown to form adducts or to cause oxidative damage to genomic DNA in model systems. Biomarkers of carcinogenesis reflect biological events that take place between exposure to external or endogenous carcinogens and the subsequent development of cancer. Therapeutic intervention for the purpose of cancer chemoprevention may modify these biomarkers. In this article, the potential efficacy of DNA adducts as biomarkers of carcinogenesis and chemoprevention is discussed using criteria defined for phases of biomarker development. The sensitivity of adduct detection in histologically normal tissue offers opportunities for the early detection of carcinogenesis. Extensive evidence for aflatoxin B1 adducts as biomarkers of risk and progression of hepatic carcinogenesis and for oxidative DNA adducts as biomarkers of the development of prostate carcinogenesis is reviewed together with the clinical trials measuring these adducts as biomarkers of the efficacy of chemoprevention. Favorable modification of oxidative DNA adducts by dietary intervention and chemoprevention has been demonstrated in preclinical and clinical studies. Protein adducts and DNA adducts in blood constituents or urine may act as useful surrogates for the target organ. Additional information regarding reliability, reproducibility, specificity, and confounding variables are required at the clinical level to validate adducts as suitable biomarkers of chemoprevention. “We do not administer antihypertensive drugs to patients in clinical trials without checking their blood pressure, so why should we give antioxidants without checking that they have decreased oxidant status (B. Halliwell, Lancet 2000:355:1179–80)?”
Enhancing the Effectiveness of Smoking Cessation Interventions: A Cancer Prevention Imperative
Authors: A. J. Alberg, M. J. Carpenter
Journal: JNCI Journal of the National Cancer Institute (2012)

The emergence of the epidemic of tobacco addiction, primarily to cigarette smoking, in the United States and other developed nations in the first half of the 1900s was a global public health tragedy of untoward proportions. After the deleterious health effects of cigarette smoking began to be recognized, a major public health accomplishment was the success of tobacco control efforts in initiating a turnaround in the epidemic. In the United States, the prevalence of current smokers was reduced by 55% (from 42% to 19%) between 1965 and 2010 (1).
Single Nucleotide Polymorphisms in the <i>TP53</i> Region and Susceptibility to Invasive Epithelial Ovarian Cancer
Authors: Joellen M. Schildkraut, Ellen L. Goode, Merlise A. Clyde, Edwin S. Iversen, Patricia G. Moorman, Andrew Berchuck, Jeffrey R. Marks, Jolanta Lissowska, Louise Brinton, Beata Peplonska, Julie M. Cunningham, Robert A. Vierkant, David N. Rider, Georgia Chenevix-Trench, Penelope M. Webb, Jonathan Beesley, Xiaoqing Chen, Catherine Phelan, Rebecca Sutphen, Thomas A. Sellers, Leigh Pearce, Anna H. Wu, David Van Den Berg, David Conti, Christopher K. Elund, Rebecca Anderson, Marc T. Goodman, Galina Lurie, Michael E. Carney, Pamela J. Thompson, Simon A. Gayther, Susan J. Ramus, Ian Jacobs, Susanne Krüger Kjaer, Estrid Hogdall, Jan Blaakaer, Claus Hogdall, Douglas F. Easton, Honglin Song, Paul D.P. Pharoah, Alice S. Whittemore, Valerie McGuire, Lydia Quaye, Hoda Anton-Culver, Argyrios Ziogas, Kathryn L. Terry, Daniel W. Cramer, Susan E. Hankinson, Shelley S. Tworoger, Brian Calingaert, Stephen Chanock, Mark Sherman, Montserrat Garcia-Closas
Journal: Cancer Research (2009)

Abstract The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07–1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01–1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. [Cancer Res 2009;69(6):2349–57]
Effectiveness of Antihistamines in the Symptomatic Management of the Common Cold
Authors: J. Campbell Howard
Journal: JAMA (1979)

A multicentric trial compared the effect of chlorpheniramine maleate with a placebo on the signs and symptoms of the common cold. Two hundred seventy-one patients were domiciled for 48 hours and evaluated during this period and for four days afterwards. Evaluations by both patients and physicians showed that chlorpheniramine maleate was superior to placebo in lessening the degree of symptoms of the common cold. Statistically significant differences were found both on the first day and as late as the seventh day. Significant differences and trends were shown in such measures as total objective score, physicians' evaluation of symptoms. The overall incidence of side effects other than drowsiness did not differ between the treatment groups.
Effect of overweight and obesity on assisted reproductive technology—a systematic review
Authors: A. Maheshwari, Lawrize Stofberg, S. Bhattacharya
Journal: Human Reproduction Update (2007)

Obesity is known to be associated with sub-optimal reproductive performance but its direct effect on the outcome of assisted reproduction techniques (ART) is less clear. This present study aimed to perform a systematic review of the available evidence to assess the effects of obesity on the outcome of ART. A number of observational studies were identified. Interpretation of the results was compromised by variations in the methods used to define overweight and obese populations and inconsistencies in the choice and definition of outcome measures. Compared with women with a BMI of 25 kg/m2 or less, women with a BMI ≥ 25 kg/m2 have a lower chance of pregnancy following IVF [odds ratio (OR) 0.71, 95% CI: 0.62, 0.81], require higher dose of gonadotrophins (weighed mean differences 210.08, 95% CI: 149.12, 271.05) and have an increased miscarriage rate (OR 1.33, 95% CI: 1.06, 1.68). There is insufficient evidence on the effect of BMI on live birth, cycle cancellation, oocyte recovery and ovarian hyperstimulation syndrome. Further studies with clear entry criteria and uniform reporting of outcomes are needed to investigate the true impact of weight on the outcome of ART.