tbuckley/cabot-search huggingface dataset:
Effects of cytotoxic immunosuppressants on tuberculin-sensitive lymphocytes in guinea pigs.
Authors: A Winkelstein
Journal: Journal of Clinical Investigation (1975)

The immunosuppressive activities of two phase-specific drugs, 6-mercaptopurine (6-MP) and methotrexate, and a cycle-specific agent, cyclophosphamide, were evaluated on the lymphocytic component of established tuberculin hypersensitivity in guinea pigs. In these animals, purified protein derivative (PPD)-sensitive lymphocytes are in an intermitotic phase of their proliferative cycle. Neither phase-specific drug significantly altered either the number or functional activities of these lymphocytes. By two in vitro criteria, PPD-induced lymphoproliferation and elaboration of migration inhibition factor (MIF), the responses of lymph node cells were equivalent to sensitized controls. In addition, these agents did not deplete pools of T lymphocytes, impair responses to phytohemagglutinin (PHA), nor inhibit cutaneous reactivity if employed before sensitization. In contrast, cyclophosphamide showed broader immunosuppressive effects including significant toxicities for intermitotic lymphocytes. This drug depleted pools of T cells and markedly impaired the in vitro proliferative responses of residual lymphocytes. The latter occurred with both PHA and PPD. Suppression of PHA reactivity was a dose-dependent phenomenon but was evident even with small quantities of this alkylating agent. The suppression of antigen-induced responses was independent of the proliferative status of target lymphocytes in vivo, after a single large dose, it persisted for more than 3 wk. In total, these results indicate that the effective use of cytotoxic drugs as immunosuppressants must include consideration of both the cycle specificities of the agent and the proliferative activities of the target lymphoid population.
Angiotensin-(1-7) Reduces Fibrosis in Orthotopic Breast Tumors
Authors: Katherine L. Cook, Linda J. Metheny-Barlow, E. Ann Tallant, Patricia E. Gallagher
Journal: Cancer Research (2010)

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous 7-amino acid peptide hormone of the renin-angiotensin system that has antiproliferative properties. In this study, Ang-(1-7) inhibited the growth of cancer-associated fibroblasts (CAF) and reduced fibrosis in the tumor microenvironment. A marked decrease in tumor volume and weight was observed in orthotopic human breast tumors positive for the estrogen receptor (BT-474 or ZR-75-1) and HER2 (BT-474) following Ang-(1-7) administration to athymic mice. Ang-(1-7) concomitantly reduced interstitial fibrosis in association with a significant decrease in collagen I deposition, along with a similar reduction in perivascular fibrosis. In CAFs isolated from orthotopic breast tumors, the heptapeptide markedly attenuated in vitro growth as well as reduced fibronectin, transforming growth factor-β (TGF-β), and extracellular signal-regulated kinase 1/2 kinase activity. An associated increase in the mitogen-activated protein kinase (MAPK) phosphatase DUSP1 following treatment with Ang-(1-7) suggested a potential mechanism by which the heptapeptide reduced MAPK signaling. Consistent with these in vitro observations, immunohistochemical analysis of Ang-(1-7)-treated orthotopic breast tumors revealed reduced TGF-β and increased DUSP1. Together, our findings indicate that Ang-(1-7) targets the tumor microenvironment to inhibit CAF growth and tumor fibrosis.
Second malignancies following adjuvant chemotherapy:6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment ofnode-positive breast cancer patients
Authors: C. Bernard-Marty, M. Mano, M. Paesmans, C. Accettura, R. Munoz-Bermeo, T. Richard, K. Kleiber, F. Cardoso, J.P. Lobelle, D. Larsimont, M.J. Piccart, A. Di Leo
Journal: Annals of Oncology (2003)
Allelic mapping bias in RNA-sequencing is not a major confounder in eQTL studies
Authors: Nikolaos I Panousis, Maria Gutierrez-Arcelus, Emmanouil T Dermitzakis, Tuuli Lappalainen
Journal: Genome biology (2014)

RNA sequencing (RNA-seq) is the current gold-standard method to quantify gene expression for expression quantitative trait locus (eQTL) studies. However, a potential caveat in these studies is that RNA-seq reads carrying the non-reference allele of variant loci can have lower probability to map correctly to the reference genome, which could bias gene quantifications and cause false positive eQTL associations. In this study, we analyze the effect of this allelic mapping bias in eQTL discovery. We simulate RNA-seq read mapping over 9.5 M common SNPs and indels, with 15.6% of variants showing biased mapping rate for reference versus non-reference reads. However, removing potentially biased RNA-seq reads from an eQTL dataset of 185 individuals has a very small effect on gene and exon quantifications and eQTL discovery. We detect only a handful of likely false positive eQTLs, and overall eQTL SNPs show no significant enrichment for high mapping bias. Our results suggest that RNA-seq quantifications are generally robust against allelic mapping bias, and that this does not have a severe effect on eQTL discovery. Nevertheless, we provide our catalog of putatively biased loci to allow better controlling for mapping bias to obtain more accurate results in future RNA-seq studies.
Identification by a Differential Proteomic Approach of Heat Shock Protein 27 as a Potential Marker of Atherosclerosis
Authors: Jose Luis Martin-Ventura, Mari Carmen Duran, Luis Miguel Blanco-Colio, Olivier Meilhac, Anne Leclercq, Jean-Baptiste Michel, Ole N. Jensen, Sergio Hernandez-Merida, José Tuñón, Fernando Vivanco, Jesús Egido
Journal: Circulation (2004)

We hypothesized that normal and pathological vessel walls display a differential pattern of secreted proteins. We have recently set up the conditions for comparing secretomes from carotid atherosclerotic plaques and control arteries using a proteomic approach to assess whether differentially secreted proteins could represent markers for atherosclerosis.Normal endartery segments and different regions of endarterectomy pieces (noncomplicated/complicated plaques) were incubated in protein-free medium, and the released proteins were analyzed by 2D electrophoresis (2-DE). Among the differently secreted proteins, we have identified heat shock protein-27 (HSP27). Surprisingly, compared with control arteries, HSP27 release was drastically decreased in atherosclerotic plaques and barely detectable in complicated plaque supernatants. HSP27 was expressed primarily by intact vascular cells of normal arteries and carotid plaques (immunohistochemistry). Plasma detection of soluble HSP27 showed that circulating HSP27 levels are significantly decreased in the blood of patients with carotid stenosis relative to healthy subjects (0.19 [0.1 to 1.95] versus 83 [71.8 to 87.8]) ng/mL, P<0.0001).HSP27 secretion is decreased in complicated atherosclerotic plaques, and sHSP27 plasma levels are decreased in atherosclerotic patients compared with healthy subjects. Plasma sHSP27 levels could be a potential index of atherosclerosis, although further validation is needed in large patient cohorts.
Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes
Authors: Sang Y Chun, Craig Johnson, Joseph G Washburn, Marcia R Cruz-Correa, Duyen T Dang, Long H Dang
Journal: Molecular Cancer (2010)

Abstract Background Activating KRAS mutations are important for cancer initiation and progression; and have recently been shown to cause primary resistance to therapies targeting the epidermal growth factor receptor. Therefore, strategies are currently in development to overcome treatment resistance due to oncogenic KRAS. The hypoxia-inducible factors-1α and -2α (HIF-1α and HIF-2α) are activated in cancer due to dysregulated ras signaling. Methods To understand the individual and combined roles of HIF-1α and HIF-2α in cancer metabolism and oncogenic KRAS signaling, we used targeted homologous recombination to disrupt the oncogenic KRAS , HIF-1α , and HIF-2α gene loci in HCT116 colon cancer cells to generate isogenic HCT116 WT KRAS , HCT116 HIF-1α-/- , HCT116 HIF-2α-/- , and HCT116 HIF-1α-/-HIF-2α-/- cell lines. Results Global gene expression analyses of these cell lines reveal that HIF-1α and HIF-2α work together to modulate cancer metabolism and regulate genes signature overlapping with oncogenic KRAS. Cancer cells with disruption of both HIF-1α and HIF-2α or oncogenic KRAS showed decreased aerobic respiration and ATP production, with increased ROS generation. Conclusion Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations.
A role for fungal β-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice
Authors: Hiroyuki Yoshitomi, Noriko Sakaguchi, Katsuya Kobayashi, Gordon D. Brown, Tomoyuki Tagami, Toshiko Sakihama, Keiji Hirota, Satoshi Tanaka, Takashi Nomura, Ichiro Miki, Siamon Gordon, Shizuo Akira, Takashi Nakamura, Shimon Sakaguchi
Journal: The Journal of Experimental Medicine (2005)

A combination of genetic and environmental factors can cause autoimmune disease in animals. SKG mice, which are genetically prone to develop autoimmune arthritis, fail to develop the disease under a microbially clean condition, despite active thymic production of arthritogenic autoimmune T cells and their persistence in the periphery. However, in the clean environment, a single intraperitoneal injection of zymosan, a crude fungal beta-glucan, or purified beta-glucans such as curdlan and laminarin can trigger severe chronic arthritis in SKG mice, but only transient arthritis in normal mice. Blockade of Dectin-1, a major beta-glucan receptor, can prevent SKG arthritis triggered by beta-glucans, which strongly activate dendritic cells in vitro in a Dectin-1-dependent but Toll-like receptor-independent manner. Furthermore, antibiotic treatment against fungi can prevent SKG arthritis in an arthritis-prone microbial environment. Multiple injections of polyinosinic-polycytidylic acid double-stranded RNA also elicit mild arthritis in SKG mice. Thus, specific microbes, including fungi and viruses, may evoke autoimmune arthritis such as rheumatoid arthritis by stimulating innate immunity in individuals who harbor potentially arthritogenic autoimmune T cells as a result of genetic anomalies or variations.
The localization of the target antigens and antibodies in linear IgA disease is heterogeneous, and dependent on the methods used
Authors: F. WOJNAROWSKA, P.M. COLLIER, J. ALLEN, P.R. MILLARD
Journal: British Journal of Dermatology (2006)

Fifty‐nine patients with linear IgA disease, 24 with onset in childhood and 35 with adult onset, were studied. Sera from all patients were tested by indirect immunofluorescence, using as substrates intact normal skin and normal skin which had been split through the lamina lucida region of the basement membrane zone by suction and by prolonged incubation with molar NaCl. This enabled the site of the target antigen for the circulating IgA antibodies to be determined. The sites of deposition of the IgA antibodies in vivo were detected by raising a suction blister in eight patients, and splitting seven patients' biopsies by prolonged incubation with molar NaCl. Eighteen sera were positive with intact skin, and 34 with split skin. Twenty‐nine sera were positive with suction blisters as substrate; 14 bound to the epidermal aspect of the split skin, seven in a combined pattern (binding to the epidermis and dermis) and six to the dermal aspect. Thirty‐one sera bound to salt‐split skin, 24 to the epidermal side and seven on the dermal side. There was discordance between the two methods of skin splitting in 15 sera. Seven sera gave a combined pattern with suction but with salt‐split skin, five of these bound epidermally, one was dermal, and one negative. Five sera showed epidermal binding on saltsplit skin and were negative on suction blisters, and the reverse was seen with one serum. Two sera gave variable results on suction blisters. Direct immunofluorescence studies showed dermal binding on all eight patients with suction blisters, and epidermal binding in four and dermal binding in three patients with salt splitting. These results demonstrate that the location of the target antigens and the sites of deposition of the antibodies are dependent on the methods used. They also suggest that there are at least two different antigens, an epidermal‐ and a dermal‐associated antigen. The sera reacting in the combined pattern may represent antibodies reacting with a different epitope of the epidermal antigen, with a further epidermal antigen, or with two target antigens.
Plant proteinase inhibitor from Enterolobium contortisiliquum (EcTI) attenuates elastase-induced pulmonary inflammatory, remodeling and mechanical alterations in mice
Authors: Osmar A. Theodoro-Junior, Ricardo Henrique Marques, Rafael Almeida-Reis, Bruno T. Martins-Oliveira, Leandro V. Oliva, Tales Lopes, Carla M. Prado, Maria L.V. Oliva, Milton Martins, Iolanda F.L.C. Tibério
Journal: European Respiratory Journal (2012)

Aims:  to evaluate if a plant  Kunitz  proteinase inhibitor  EcTI  contributes to inactivation of elastase-induced mechanical, inflammatory and remodelling alterations.  Methods:  C57Bl6 mice received elastase (E group). Control group received saline (Ve group). Mice were treated with  EcTI  (2mg/kg) on days 1, 14 and 21 after elastase instillation (I-E group). On day 30, mice were anesthetized, mechanically ventilated and we analyzed respiratory system resistance (Rrs) and elastance (Ers), tissue elastance (Htis), tissue damping (Gtis), airway resistance (Raw) and exhaled nitric oxide (E NO ). Bronchoalveolar lavage fluid (BALF) was performed, lungs were removed and by morphometry, we quantified the mean linear intercept (Lm), collagen and elastic fibers in lung parenchyma.  Results : In E-group there was a significant increase in the Ers, Rrs, Raw, Htis, Lm, E NO , total cells and macrophages,neutrophils and lymphocytes in BALF, elastic and collagen fibres compared to controls (p 2 O/ml/s), Ers (34.71±3.16cmH 2 O/L), Htis (36.30±4.42cmH 2 O/mL/s), macrophages (94.86±2.36%), neutrophils (3.29±2.31%), and lymphocytes (0.91±0.28%) in the BALF, E NO  (31.67±2.23ppb) and collagen fibers (0.69%±0.04%) compared to E-group (p Conclusions:  This proteinase inhibitor ( EcTI ) reduced elastase-induced pulmonary inflammatory, remodeling and mechanical alterations induced by elastase. Although more studies need to be performed, this inhibitor may contribute as potential therapeutic tool for COPD management.  Financial Support : FAPESP, CNPq, LIM-20 HCFMUSP.
Obstructive Sleep Apnea and Endothelial Function in School-Aged Nonobese Children
Authors: David Gozal, Leila Kheirandish-Gozal, Laura D. Serpero, Oscar Sans Capdevila, Ehab Dayyat
Journal: Circulation (2007)

Obstructive sleep apnea (OSA) in children is associated with cardiovascular morbidity such as systemic and pulmonary hypertension. However, it remains unclear whether endothelial dysfunction occurs in pediatric OSA and whether it is reversible on effective treatment of OSA.Consecutive nonobese children (aged 6 to 11 years) who were diagnosed with OSA after overnight polysomnography and control children matched on the basis of age, gender, ethnicity, and body mass index underwent blood draw the next morning for soluble CD40 ligand, asymmetric dimethylarginine (ADMA), and nitrotyrosine levels, as well as 2 iterations of 60-second cuff-occlusion tests for assessment of endothelial function. These tests were repeated 4 to 6 months after adenotonsillectomy. OSA children showed blunted reperfusion kinetics after release of occlusion, which completely normalized in 20 of 26 patients after adenotonsillectomy. All 6 children in whom no improvements occurred had a strong family history of cardiovascular disease (versus 2 of the remaining 20 patients; P<0.04). Plasma nitrotyrosine and ADMA levels were similar in OSA and control children; however, soluble CD40 ligand levels were higher in OSA children and were reduced after treatment, particularly in those with normalized hyperemic responses.Postocclusive hyperemia is consistently blunted in children with OSA, and such altered endothelial function is reversible 4 to 6 months after treatment, particularly if a family history of cardiovascular disease is not present. Although no evidence for either nitric oxide-dependent oxidative/nitrosative stress or for the increased presence of the circulating nitric oxide synthase inhibitor ADMA was found in children with OSA, soluble CD40 ligand levels were increased in OSA and reflected the changes in endothelial function after treatment.
Efficacy of oral methotrexate in paediatric Crohn’s disease: a multicentre propensity score study
Authors: Dan Turner, Etti Doveh, Ayala Cohen, Michelle L Wilson, Andrew B Grossman, Joel R Rosh, Ying Lu, Athos Bousvaros, Colette Deslandres, Angela Noble, Robert N Baldassano, Arie Levine, Aaron Lerner, David C Wilson, Anne M Griffiths
Journal: Gut (2014)

Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn's disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD.226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and 'doubly robust' weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups.76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test).In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth.
Psychosocial Factors and Survival of Young Women With Breast Cancer: A Population-Based Prospective Cohort Study
Authors: Kelly-Anne Phillips, Richard H. Osborne, Graham G. Giles, Gillian S. Dite, Carmel Apicella, John L. Hopper, Roger L. Milne
Journal: Journal of Clinical Oncology (2008)

Purpose Most women with early-stage breast cancer believe that psychosocial factors are an important influence over whether their cancer will recur. Studies of the issue have produced conflicting results. Patients and Methods A population-based sample of 708 Australian women diagnosed before age 60 years with nonmetastatic breast cancer was observed for a median of 8.2 years. Depression and anxiety, coping style, and social support were assessed at a median of 11 months after diagnosis. Hazard ratios for distant disease-free survival (DDFS) and overall survival (OS) associated with psychosocial factors were estimated separately using Cox proportional hazards survival models, with and without adjustment for known prognostic factors. Results Distant recurrence occurred in 209 (33%) of 638 assessable patients, and 170 (24%) of 708 patients died during the follow-up period. There were no statistically significant associations between any of the measured psychosocial factors and DDFS or OS from the adjusted analyses. From unadjusted analyses, associations between greater anxious preoccupation and poorer DDFS and OS were observed (P = .02). These associations were no longer evident after adjustment for established prognostic factors; greater anxious preoccupation was associated with younger age at diagnosis (P = .03), higher tumor grade (P = .02), and greater number of involved axillary nodes (P = .008). Conclusion The findings do not support the measured psychosocial factors being an important influence on breast cancer outcomes. Interventions for adverse psychosocial factors are warranted to improve quality of life but should not be expected to improve survival.
Duration of Smoking Abstinence and Success in Quitting
Authors: E. A. Gilpin, J. P. Pierce, A. J. Farkas, A. J. Farkas
Journal: JNCI Journal of the National Cancer Institute (1997)

The 1990 California Tobacco Survey used a random-digit-dialed computer-assisted telephone survey to interview 24 296 California adults from June 1990 through February 1991.A stratified random sample of 4642 adults was reinterviewed from March through July 1992, with the probability of selection much higher for those who reported smoking within 5 years of the baseline interview (18).Both surveys assessed smoking status using standard questions on lifetime use of 100 cigarettes and self-classification of current smoking: 1) ''Have you
Physiology of Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder
Authors: Laura F. Martin, Mei-Hua Hall, Randal G. Ross, Gary Zerbe, Robert Freedman, Ann Olincy
Journal: American Journal of Psychiatry (2007)

Objective: Endophenotypes have been proposed to identify the genetic and biological substrates of complex disorders. Three physiological inhibitory endophenotypes of large effect size in schizophrenia include suppression of P50 auditory evoked responses, inhibition of leading (small anticipatory) saccades during smooth pursuit eye movements, and cancellation of reflexive saccades in the antisaccade eye movement task. The aim of this study was to determine if the pattern of endophenotype abnormalities within individuals with schizophrenia differed from that within individuals with bipolar disorder. A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder. Method: Endophenotypes were recorded for subjects diagnosed with schizophrenia (N=29), bipolar disorder (DSM-IV-TR) (N=40), and schizoaffective disorder, bipolar type (N=18). Data from normal comparison subjects were used to establish normal performance. Results: Logistic regression determined that P50 ratio and frequency of leading saccades identified subjects with schizophrenia and bipolar disorder with a sensitivity of 95% and a specificity of 83%. The schizoaffective disorder group was split, with six subjects physiologically classified as schizophrenia-like and 12 subjects as bipolar-like. Those classified as schizophrenia-like were significantly younger at illness onset and had higher symptom ratings. Conclusion: A composite endophenotype of P50 ratio and frequency of leading saccades is consistent with the current clinical nosology of schizophrenia and bipolar disorder and parses patients with schizoaffective disorder, bipolar type, into two subgroups.