tbuckley/cabot-search huggingface dataset:
βIII-Tubulin Is a Multifunctional Protein Involved in Drug Sensitivity and Tumorigenesis in Non–Small Cell Lung Cancer
Authors: Joshua A. McCarroll, Pei Pei Gan, Marjorie Liu, Maria Kavallaris
Journal: Cancer Research (2010)

Advanced non-small cell lung cancer (NSCLC) has a dismal prognosis. betaIII-Tubulin, a protein highly expressed in neuronal cells, is strongly associated with drug-refractory and aggressive NSCLC. To date, the role of this protein in in vivo drug resistance and tumorigenesis has not been determined. NSCLC cells stably expressing betaIII-tubulin short hairpin RNA displayed reduced growth and increased chemotherapy sensitivity when compared with control clones. In concordance with these results, stable suppression of betaIII-tubulin reduced the incidence and significantly delayed the growth of tumors in mice relative to controls. Our findings indicate that betaIII-tubulin mediates not only drug sensitivity but also the incidence and progression of lung cancer. betaIII-Tubulin is a cellular survival factor that, when suppressed, sensitizes cells to chemotherapy via enhanced apoptosis induction and decreased tumorigenesis. Findings establish that upregulation of a neuronal tubulin isotype is a key contributor to tumor progression and drug sensitivity in lung adenocarcinoma.
Effect of Rosiglitazone on Endothelial Function and Inflammatory Markers in Patients With the Metabolic Syndrome
Authors: K. Esposito
Journal: Diabetes Care (2006)

The aim of this study was to assess the effect of rosiglitazone on endothelial function and inflammatory markers in patients with the metabolic syndrome.This was a randomized, double-blind, controlled clinical trial. One hundred subjects (54 men and 46 women) with the metabolic syndrome, as defined by the Adult Treatment Panel III, were followed for 12 months after random assignment to rosiglitazone (4 mg/day) or placebo. Primary end points were flow-mediated dilation and high-sensitivity C-reactive protein (hs-CRP) levels; secondary end points were lipid and glucose parameters, homeostasis model assessment (HOMA) of insulin sensitivity, endothelial function score, and circulating levels of interleukin (IL)-6, IL-18, and adiponectin.Compared with 60 control subjects matched for age and sex, patients with the metabolic syndrome had decreased endothelial function, raised concentrations of inflammatory markers, and reduced insulin sensitivity. After 12 months, subjects with the metabolic syndrome receiving rosiglitazone showed improved flow-mediated vasodilation (4.2%, P < 0.001) and reduced hs-CRP levels (-0.7 mg/dl, P = 0.04), compared with the placebo group. Moreover, HOMA (-0.8, P = 0.01) and serum concentrations of IL-6 (-0.5 pg/ml, P = 0.045) and IL-18 (-31 pg/ml, P = 0.036) were significantly reduced in subjects receiving rosiglitazone, whereas adiponectin levels showed a significant increment (2.3 microg/ml, P = 0.02). High-density lipoprotein-cholesterol levels increased more and triglyceride levels decreased more in the rosiglitazone group compared with the placebo group. At 1 year of follow-up, 30 subjects receiving rosiglitazone still had features of the metabolic syndrome, compared with 45 subjects receiving placebo (P < 0.001).Rosiglitazone might be effective in reducing the prevalence of the metabolic syndrome.
Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome
Authors: Brian L. McClune, Daniel J. Weisdorf, Tanya L. Pedersen, Gisela Tunes da Silva, Martin S. Tallman, Jorge Sierra, John DiPersio, Armand Keating, Robert P. Gale, Biju George, Vikas Gupta, Theresa Hahn, Luis Isola, Madan Jagasia, Hillard Lazarus, David Marks, Richard Maziarz, Edmund K. Waller, Chris Bredeson, Sergio Giralt
Journal: Journal of Clinical Oncology (2010)

PURPOSE Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). PATIENTS AND METHODS We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS). RESULTS Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and > or = 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. CONCLUSION With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.
XPO1/CRM1-Selective Inhibitors of Nuclear Export (SINE) reduce tumor spreading and improve overall survival in preclinical models of prostate cancer (PCa)
Authors: Giovanni Luca Gravina, Monica Tortoreto, Andrea Mancini, Alessandro Addis, Ernesto Di Cesare, Andrea Lenzi, Yosef Landesman, Dilara McCauley, Michael Kauffman, Sharon Shacham, Nadia Zaffaroni, Claudio Festuccia
Journal: Journal of Hematology & Oncology (2014)

Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole exportin mediating transport of many multiple tumor suppressor proteins out of the nucleus. To verify the hypothesis that XPO1 inhibition affects prostate cancer (PCa) metastatic potential, orally available, potent and selective, SINE compounds, Selinexor (KPT- 330) and KPT-251, were tested in preclinical models known to generate bone lesions and systemic tumor spread. In vitro, Selinexor reduced both secretion of proteases and ability to migrate and invade of PCa cells. SINEs impaired secretion of pro-angiogenic and pro-osteolytic cytokines and reduced osteoclastogenesis in RAW264.7 cells. In the intra-prostatic growth model, Selinexor reduced DU145 tumor growth by 41% and 61% at the doses of 4 mg/Kg qd/5 days and 10 mg/Kg q2dx3 weeks, respectively, as well as the incidence of macroscopic visceral metastases. In a systemic metastasis model, following intracardiac injection of PCb2 cells, 80% (8/10) of controls, 10% (1/10) Selinexor- and 20% (2/10) KPT-251-treated animals developed radiographic evidence of lytic bone lesions. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in Selinexor and KPT-251 groups. Analogously, the serum levels of osteoclast markers (mTRAP and type I collagen fragment, CTX), were significantly higher in controls than in Selinexor- and KPT-251-treated animals. Importantly, overall survival and disease-free survival were significantly higher in Selinexor- and KPT-251-treated animals when compared to controls. Selective blockade of XPO1-dependent nuclear export represents a completely novel approach for the treatment of advanced and metastatic PCa.
Aortic Valve Bypass Surgery
Authors: James S. Gammie, Leandra S. Krowsoski, James M. Brown, Patrick N. Odonkor, Cindi A. Young, Mary J. Santos, John S. Gottdiener, Bartley P. Griffith
Journal: Circulation (2008)

Aortic valve bypass (AVB; apicoaortic conduit) surgery relieves aortic stenosis (AS) by shunting blood from the apex of the left ventricle to the descending thoracic aorta through a valved conduit. We have performed AVB surgery as an alternative to conventional aortic valve replacement for high-risk AS patients.Between 2003 and 2007, 31 high-risk AS patients were treated with AVB surgery. Twenty-two patients (71%) were undergoing reoperation with patent coronary bypass grafts, and 5 (16%) had a porcelain ascending aorta. The average age was 81 years. Cardiopulmonary bypass was used for 19 of 31 patients (61%); the median duration of cardiopulmonary bypass was 19 minutes. Cross-clamp time for all patients was 0 minutes. Perioperative mortality was 13% (4 of 31 patients); no perioperative deaths occurred in the last 16 consecutive patients. One patient experienced a stroke related to intraoperative hypotension. No strokes have occurred during follow-up. Renal function was unchanged after AVB (preoperative creatinine, 1.3+/-0.5 mg/dL; postoperative creatinine, 1.2+/-0.5 mg/dL). The mean gradient across the native aortic valve decreased from 43.5+/-15 to 10.4+/-5.4 mm Hg. Echocardiographically determined conduit flow expressed as a percentage of total cardiac output was 72+/-12%.AVB surgery is an important therapeutic option for high-risk patients with symptomatic AS. Ventricular outflow is distributed in a predictable fashion between the conduit and the left ventricular outflow tract, and AVB surgery reliably relieves AS. Stroke and renal dysfunction were uncommon.
The putative role of inflammation in the irritable bowel syndrome
Authors: S M COLLINS
Journal: Gut (2001)

The irritable bowel syndrome (IBS) may be defined as a painful chronic abdominal symptom complex which is usually associated with altered bowel habit, and for which there is no discernible underlying structural abnormality. It is generally accepted that symptoms are generated by abnormalities of gut function, including altered sensory perception, abnormal motility and, in some patients, abnormalities of epithelial function. Behavioural factors are important, particularly in the reporting of symptoms. What is lacking is an understanding of the pathogenetic mechanisms that alter gut function. IBS is a heterogeneous condition, not only in its clinical presentation and pathophysiology, but also in terms of its pathogenesis. While both central and peripheral factors have been implicated in the pathogenesis of IBS, this article will restrict itself to an evaluation of the evidence supporting inflammation as a basis for altered gut function in IBS.

In considering the role of inflammation in IBS, one is prompted to make a comparison with asthma. Like IBS, asthma was once considered a psychosomatic disorder, particularly in non-atopic children. For more than 50 years the treatment of asthma focused on the pharmacological correction of abnormal end organ physiology (that is, airways hyperresponsiveness), an approach that is similar to current therapeutic approaches to IBS, and which are aimed at modulating motor activity or sensory perception. The subsequent discovery of inflammatory cells in the normally sterile broncheoalveolar lavage led to the recognition of asthma as an inflammatory condition. There are two reasons why a similar shift in thinking in IBS will be difficult. Firstly, the gut is normally in a state of controlled inflammation and the challenge of identifying a subtle increase in inflammatory cell number or composition is not to be underestimated. Secondly, IBS is intuitively more heterogeneous than asthma, and inflammation is unlikely to be a factor in all …
IA-2 Antibody-Negative Status Predicts Remission and Recovery of C-Peptide Levels in Type 1 Diabetic Patients Treated With Cyclosporin
Authors: Michael R. Christie, Jens Mølvig, Charlotte J. Hawkes, Bendix Carstensen, Thomas Mandrup-Poulsen
Journal: Diabetes Care (2002)

OBJECTIVE—The use of cyclosporin in recent-onset type 1 diabetes has demonstrated the potential for immune intervention in the treatment and prevention of the disease. However, a proportion of patients failed to respond to cyclosporin treatment. Indicators of resistance to immune intervention would be valuable for the most effective use of such therapies in disease prevention. The aim of this study was to determine whether presence of IA-2 antibodies is such a marker. RESEARCH DESIGN AND METHODS—IA-2 antibodies were determined by radioligand binding assay in sera from patients recruited into the Canadian-European cyclosporin trial. Insulin dose requirements and glucagon-stimulated C-peptide secretion were analyzed in patients grouped according to IA-2 antibody status at entry. RESULTS—Cyclosporin treatment had no significant effect on frequency of IA-2 antibodies during the 1 year of treatment. Cyclosporin caused significant reduction in insulin requirements and significant increases in C-peptide secretion mainly in patients negative for IA-2 antibodies. Analysis of GAD antibodies in combination with antibodies to IA-2 indicated that the group most resistant to cyclosporin were IA-2 antibody positive, GAD antibody negative. CONCLUSIONS—The results demonstrate that IA-2 antibody analysis is valuable in identifying individuals for whom immunosuppressive treatment would be most effective.
Evolutionary Dynamics of Sex-Biased Genes in a Hermaphrodite Fungus
Authors: Carrie A. Whittle, Hanna Johannesson
Journal: Molecular Biology and Evolution (2013)

Differential gene expression is believed to largely explain sexually dichotomous phenotypes. This phenomenon is especially significant in hermaphrodites, in which male and female sexual tissues have identical genotypes. Sex differences in transcription have been linked to molecular evolution: genes with higher expression in male compared with female sexual tissues (i.e., male-biased genes) have been associated with rapid gene divergence in various animals and plants, implying that selective differences exist among the sexual structures. In the present investigation, we examined expressed sequence tags, microarrays, and gene sequence data from the hermaphroditic fungus Neurospora crassa and confirmed selective differences of genes with disparate expression among male versus female sexual structures in this organism. The results held across various genotypes and stages of sexual development. Furthermore, our data showed that N. crassa comprises a rare example of an organism where female-biased genes evolve rapidly; they exhibited faster evolution at the protein level and reduced optimal codon usage compared with male-biased genes, sexually unbiased genes, and vegetative genes. Female-biased genes also had a greater portion of sites that experienced positive selection and showed stronger signals of selective sweeps than male-biased genes, suggesting that the rapid evolution is at least partly driven by adaptive evolution. Distinctive aspects of the reproductive biology of N. crassa which might explain the rapid evolution of female-biased genes are discussed, particularly the propensity for female–female competition during mating, as well as the multifunctional nature of male structures. The present findings open new opportunities to test hypotheses about sex-biased gene expression and molecular evolution.
Pulmonary Arterial Pulse Wave Velocity and Impedance in Man
Authors: William R. Milnor, C. Richard Conti, Kenneth B. Lewis, Michael F. O'Rourke
Journal: Circulation Research (1969)

The differential pressure method of Womersley and McDonald was used to measure instantaneous blood flow in the main pulmonary artery in ten human subjects. Three subjects had normal pulmonary arterial pressures and flows, seven had mitral stenosis and pulmonary hypertension. The spectrum of input impedance versus frequency was similar to that previously reported for the dog and rabbit, with the modulus decreasing from relatively high values at zero frequency to a minimum between 2 and 5 cycles/sec. Characteristic impedance and phase velocity were lower in the normal subjects than in those with pulmonary hypertension (averages, 23 dyne sec cm -5 and 1.68 m/sec in the normals; 46 dyne sec cm -5 and 4.77 m/sec in the hypertensives). Hydraulic energy dissipated per unit time by pulsations in the pulmonary bed was usually higher in the hypertensive than in the normal cases, because of the greater stiffness of the pulmonary arteries in the subjects with pulmonary hypertension. The elasticity of the pulmonary arterial tree appears to be as important as the state of the arterioles and capillaries in determining the energy required for pulsatile pulmonary blood flow.
Spontaneous Coronary Arteriosclerosis in Repeatedly Bred Male and Female Rats
Authors: BERNARD C. WEXLER
Journal: Circulation Research (1964)

Repeatedly bred male and female rats of several strains develop arteriosclerosis spontaneously, irrespective of diet. The severity of the lesions differs between male and female breeders. The morphology and pathogenesis of these lesions have been found to be the same in all of the strains examined. Once the process of arteriosclerosis has been initiated within the abdominal aorta, the subendocardial and medium-sized myocardial coronary arteries also show degenerative changes. The large epicardial coronary arteries become arteriosclerotic only when the process of arteriosclerosis has become severe and generally distributed throughout the aorta. The smaller subendocardial lesions are characterized by occlusive swelling of medial muscle cells and by the presence of vacuoles. These vacuoles react negatively to lipid stains but stain positively for mucopolysaccharide. The myocardial arteries show endothelial hyperplasia, elastosis and accumulations of mucopolysaccharides, especially in the region of fragmented elastic elements. The mucopolysaccharide-rich endothelial cushions eventually become fibrosed. The epicardial arteries show intense accumulations of calcium-mucopolysaccharide complexes. These arteries become greatly distended and can be detected grossly because of their size and tortuosity. Acute and chronic myocardial infarct-like lesions are found but these cannot be associated with specific coronary thrombi or arteriosclerotic lesions. Valvular scarring, calcification of the papillary muscles and disappearance of myocardial mast cells has been correlated with advancing arteriosclerosis. The relation between the intensity of coronary arteriosclerosis and the frequency of breeding, the sex of the animal, and the strain indicates that the pathogenesis of this disease in breeder rats is probably governed by hormonal factors, e.g., sex and adrenal steroids, as well as by genetic factors.
Transforming Growth Factor β1, in the Presence of Granulocyte/Macrophage Colony-stimulating Factor and Interleukin 4, Induces Differentiation of Human Peripheral Blood Monocytes into Dendritic Langerhans Cells
Authors: Frederic Geissmann, Catherine Prost, Jean-Paul Monnet, Michel Dy, Nicole Brousse, Olivier Hermine
Journal: The Journal of Experimental Medicine (1998)

Langerhans cells (LCs) are dendritic cells (DCs) that are present in the epidermis, bronchi, and mucosae. Although LCs originate in bone marrow, little is known about their lineage of origin. In this study, we demonstrate that in vitro LCs may originate from monocytes. Adult peripheral blood CD14+ monocytes differentiate into LCs (CD1a+, E-cadherin+, cutaneous lymphocyte-associated antigen+, Birbeck granules+, Lag+) in the presence of granulocyte/macrophage colony-stimulating factor, interleukin 4, and transforming growth factor beta1 (TGF-beta1). This process occurs with virtually no cell proliferation and is not impaired by 30 Gy irradiation. Selection of monocyte subpopulations is ruled out since monocyte-derived DCs can further differentiate into LCs. Our data suggest that in vivo LC differentiation may be induced peripherally, from a nonproliferating myeloid precursor, i.e., the monocyte, in response to a TGF-beta1-rich microenvironment, as found in the skin and epithelia. Therefore, the monocyte may represent a circulating precursor critical to the immune response in vivo.
Early Weaning and Hospitalization With Alcohol-Related Diagnoses in Adult Life
Authors: Holger Sørensen
Journal: American Journal of Psychiatry (2006)

Objective: This study attempted to determine whether lack of breast-feeding or a short duration of breast-feeding during infancy is associated with an elevated risk of hospitalization with alcohol-related diagnoses in adult life. Method: The study was a prospective longitudinal birth cohort design conducted in a sample of 6,562 men and women, all of whom were born in Copenhagen, Denmark, between October 1959 and December 1961. The sample was divided into two categories based on duration of breast-feeding, as assessed by a physician interview with mothers at a 1-year examination. Psychiatric hospitalizations with alcohol-related diagnoses according to ICD-8 or ICD-10 were identified in the Danish Psychiatric Central Register in 1999. Nine potential confounders were included as covariates: gender of the cohort member, maternal age, parental social status, maternal prenatal smoking, unwanted pregnancy, maternal and paternal psychiatric hospitalization with alcohol-related diagnosis, and maternal and paternal psychiatric hospitalization with other diagnosis. Results: Alcohol-related diagnoses were more frequent in men, but the results were comparable for men and women. The adjusted predictive effect of early weaning was 1.47. Elevated relative risks were also associated with maternal smoking during pregnancy (1.52) and unwanted pregnancy status (1.59). Other independent predictors were male gender, maternal psychiatric hospitalization with alcohol-related diagnosis, and low parental social status. Conclusions: Independent of a number of other risk factors for alcoholism, a significant association between early weaning and elevated risk of hospitalization with alcohol-related diagnoses was observed.
A Novel Wnt Regulatory Axis in Endometrioid Endometrial Cancer
Authors: Yu Zhao, Yihua Yang, Jone Trovik, Kun Sun, Liang Zhou, Peiyong Jiang, Tat-San Lau, Erling A. Hoivik, Helga B. Salvesen, Hao Sun, Huating Wang
Journal: Cancer Research (2014)

Abstract The Protocadherin 10 (PCDH10) is inactivated often by promoter hypermethylation in various human tumors, but its possible functional role as a tumor suppressor gene is not established. In this study, we identify PCDH10 as a novel Wnt pathway regulatory element in endometrioid endometrial carcinoma (EEC). PCDH10 was downregulated in EEC tumor cells by aberrant methylation of its promoter. Restoring PCDH10 levels suppressed cell growth and triggered apoptosis in EEC cells and tumor xenografts. Gene expression profiling revealed as part of the transcriptomic changes induced by PCDH10 a reduction in levels of MALAT1, a long noncoding RNA, that mediated tumor suppression functions of PCDH10 in EEC cells. We found that MALAT1 transcription was regulated by Wnt/β-catenin signaling via TCF promoter binding and PCDH10 decreased MALAT1 by modulating this pathway. Clinically, MALAT1 expression was associated with multiple parameters in patients with EEC. Taken together, our findings establish a novel PCDH10–Wnt/β-catenin–MALAT1 regulatory axis that contributes to EEC development. Cancer Res; 74(18); 5103–17. ©2014 AACR.