tbuckley/cabot-search huggingface dataset:
Bcl-2 Sustains Increased Mucous and Epithelial Cell Numbers in Metaplastic Airway Epithelium
Authors: J. Foster Harris, Mark J. Fischer, Jon R. Hotchkiss, Brett P. Monia, Scott H. Randell, Jack R. Harkema, Yohannes Tesfaigzi
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Bcl-2, an inhibitor of apoptosis, is expressed in LPS-induced metaplastic goblet cells of rat airways. The present study investigated expression of Bcl-2 in airway mucous cells of persons with cystic fibrosis and tested in rats and mice whether its expression is responsible for sustaining metaplastic mucous cells. A significantly higher percentage of mucous cells expressed Bcl-2 in humans with cystic fibrosis compared with control subjects with no disease or subjects with other diseases. In LPS-instilled F344/N rats, the percentage of Bcl-2-positive mucous cells was decreased to background levels before the resolution of goblet cell metaplasia. Furthermore, intraperitoneal injection of rats with antisense oligonucleotides significantly reduced Bcl-2 expression and goblet cell metaplasia in nasal and pulmonary airway epithelia in rats. In contrast, sustained expression of Bcl-2 in transgenic mice by a metallothionein promoter caused increased LPS-induced goblet cell metaplasia over 8 days compared with wild-type mice. These studies demonstrate that Bcl-2 expression sustains goblet cell metaplasia in various species, that epithelial cell numbers are directly linked to the regulation of the numbers of goblet cells, and that downregulating Bcl-2 expression reduces goblet cell metaplasia.
An insight into the genetic pathway of adenocarcinoma of the small intestine
Authors: J M D Wheeler
Journal: Gut (2002)

Although the adenoma to carcinoma pathway in colorectal cancer is well described, the mechanisms of carcinogenesis in the small intestine remain unclear.The aim of this study was to investigate candidate genes in the genetic pathway of adenocarcinoma of the small intestine.A total of 21 non-familial, non-ampullary adenocarcinomas of the small intestine were analysed. DNA was extracted from formalin fixed paraffin wax embedded tissue using standard techniques. The replication error (RER) status was determined by amplification of BAT26. The mutation cluster region (MCR) of the adenomatous polyposis coli (APC) gene was screened using polymerase chain reaction single strand conformational polymorphism and direct sequencing. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for hMLH1, hMSH2, beta-catenin, E-cadherin, and p53.Fourteen male and seven female patients with a median age of 64 years (range 21-85) presented with adenocarcinoma of the duodenum (10), jejunum (7), and ileum (4). One cancer (5%) was found to be RER+, and all tumours stained positive for hMLH1 and hMSH2. No mutations were detected in the MCR of the APC gene. beta-Catenin showed increased nuclear expression with loss of membranous staining in 10 cancers (48%). Absent or decreased membrane expression of E-cadherin was found in eight cancers (38%). Strong staining of p53 was found in the nucleus of five cancers (24%).We did not detect mutations in the MCR of the APC gene, and this suggests that adenocarcinoma of the small intestine may follow a different genetic pathway to colorectal cancer. Abnormal expression of E-cadherin and beta-catenin was common and reflects an early alternative to APC in this pathway in which mutations may be found in adenocarcinoma of the small intestine.
Implantation of a pleurovenous shunt for massive chylothorax in a patient with yellow nail syndrome
Authors: E Tanaka
Journal: Thorax (2005)

Yellow nail syndrome is a type of lymphatic dysplasia syndrome characterised by the triad of yellow nails, lymphoedema, and pleural effusions. The case history is presented of a 70 year old patient with yellow nail syndrome who complained of dyspnoea caused by massive chylothorax. The patient underwent insertion of a pleuroperitoneal shunt which resulted in abdominal distension and deterioration of leg oedema. The pleuroperitoneal shunt was replaced by a pleurovenous shunt on the right side which led to an improvement in the bilateral pleural effusions, abdominal distension, and leg oedema. A pleurovenous shunt may be an alternative rescue therapy for yellow nail syndrome.
Reduced Growth, Increased Vascular Area, and Reduced Response to Cisplatin in CD13-Overexpressing Human Ovarian Cancer Xenografts
Authors: Yvette van Hensbergen, Henk J. Broxterman, Sareena Rana, Paul J. van Diest, Monique C. A. Duyndam, Klaas Hoekman, Herbert M. Pinedo, Epie Boven
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Expression of aminopeptidase N/CD13 can be detected in several solid tumor types. Thus far, the role of CD13 in ovarian cancer has not been studied. We have investigated the expression pattern and biological function of CD13 in ovarian cancer. Experimental Design: First, we studied the expression of CD13 in ovarian cancer tissue of 15 patients representing three different histological types (5 patients each) by immunohistochemistry. We then stably transfected the IGROV-1 human ovarian cancer cell line with a CD13 expression vector and examined the biological effect of CD13 in vitro and in vivo. Results: The expression of CD13 in ovarian cancer was associated with the histological subtype: CD13 expression in tumor cells was observed in 80–100% of the patients with a serous or mucinous carcinoma and in only 20% of the clear cell carcinoma patients. In all patients’ tumor samples, CD13-positive blood vessels were present. CD13 overexpression in IGROV-1 cells did not affect in vitro cell growth and sensitivity to doxorubicin, cisplatin, or gemcitabine. CD13 overexpression reduced invasion in Matrigel, which appeared to be independent of the aminopeptidase activity of CD13. Furthermore, the growth rate of IGROV-1/CD13 xenografts was reduced. The area of the vessel lumens was enlarged in a small percentage of vessels in the CD13-overexpressing xenografts. In addition, the CD13-overexpressing tumors were less sensitive to cisplatin. Conclusions: CD13 is expressed in tumor as well as endothelial cells in human ovarian cancer. Our results suggest that CD13 overexpression affects ovarian cancer growth, vascular architecture, and response to chemotherapy. Further elucidation of the mechanism of the observed effects of CD13 is warranted to better understand its role in the pathophysiology of ovarian cancer.
Pathogenetic Mechanisms and Cardiovascular Risk
Authors: Cristina Bianchi, Roberto Miccoli, Riccardo C. Bonadonna, Francesco Giorgino, Simona Frontoni, Emanuela Faloia, Giulio Marchesini, Maria A. Dolci, Franco Cavalot, Gisella M. Cavallo, Frida Leonetti, Stefano Del Prato
Journal: Diabetes Care (2012)

OBJECTIVE To ascertain to which extent the use of HbA1c and oral glucose tolerance test (OGTT) for diagnosis of glucose tolerance could identify individuals with different pathogenetic mechanisms and cardiovascular risk profile. RESEARCH DESIGN AND METHODS A total of 844 subjects (44% men; age 49.5 ± 11 years; BMI 29 ± 5 kg/m2) participated in this study. Parameters of β-cell function were derived from deconvolution of the plasma C-peptide concentration after a 75-g OGTT and insulin sensitivity assessed by homeostasis model assessment of insulin resistance (IR). Cardiovascular risk profile was based on determination of plasma lipids and measurements of body weight, waist circumference, and blood pressure. Glucose regulation categories by OGTT and HbA1c were compared with respect to insulin action, insulin secretion, and cardiovascular risk profile. RESULTS OGTT results showed 42% of the subjects had prediabetes and 15% had type 2 diabetes mellitus (T2DM), whereas the corresponding figures based on HbA1c were 38 and 11%, with a respective concordance rate of 54 and 44%. Subjects meeting both diagnostic criteria for prediabetes presented greater IR and impairment of insulin secretion and had a worse cardiovascular risk profile than those with normal glucose tolerance at both diagnostic methods. In a logistic regression analyses adjusted for age, sex, and BMI, prediabetic subjects, and even more T2DM subjects by OGTT, had greater chance to have IR and impaired insulin secretion. CONCLUSIONS HbA1c identifies a smaller proportion of prediabetic individuals and even a smaller proportion of T2DM individuals than OGTT, with no difference in IR, insulin secretion, and cardiovascular risk profile. Subjects fulfilling both diagnostic methods for prediabetes or T2DM are characterized by a worse metabolic profile.
Metastatic Heterogeneity of Breast Cancer Cells Is Associated with Expression of a Heterogeneous TGFβ-Activating miR424–503 Gene Cluster
Authors: Yun Li, Wei Li, Zhe Ying, Han Tian, Xun Zhu, Jun Li, Mengfeng Li
Journal: Cancer Research (2014)

TGFβ signaling is known to drive metastasis in human cancer. Under physiologic conditions, the level of TGFβ activity is tightly controlled by a regulatory network involving multiple negative regulators. At metastasis, however, these inhibitory mechanisms are usually overridden so that oncogenic TGFβ signaling can be overactivated and sustained. To better understand how the TGFβ inhibitors are suppressed in metastatic breast cancer cells, we compared miRNA expression profiles between breast cancers with or without metastasis and found that the miR424-503 cluster was markedly overexpressed in metastatic breast cancer. Mechanistic studies revealed that miR424 and miR503 simultaneously suppressed Smad7 and Smurf2, two key inhibitory factors of TGFβ signaling, leading to enhanced TGFβ signaling and metastatic capability of breast cancer cells. Moreover, antagonizing miR424-503 in breast cancer cells suppressed metastasis in vivo and increased overall host survival. Interestingly, our study also found that heterogeneous expression of the miR424-503 cluster contributed to the heterogeneity of TGFβ activity levels in, and metastatic potential of, breast cancer cell subsets. Overall, our findings demonstrate a novel mechanism, mediated by elevated expression of the miR424-503 cluster, underlying TGFβ activation and metastasis of human breast cancer.
Cyclooxygenase-2 Activation Mediates the Proangiogenic Effect of Nitric Oxide in Colorectal Cancer
Authors: Fabio Cianchi, Camillo Cortesini, Ornella Fantappiè, Luca Messerini, Iacopo Sardi, Nadia Lasagna, Federico Perna, Valentina Fabbroni, Annamaria Di Felice, Giuliano Perigli, Roberto Mazzanti, Emanuela Masini
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Up-regulation of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) enzymes has been reported in colorectal cancer. We aimed at evaluating the possible interaction between the nitric oxide and COX-2 pathways, and its effect on promoting tumor angiogenesis. Experimental Design: Expression of iNOS, COX-2, vascular endothelial growth factor (VEGF), and CD31 was analyzed in tumor samples and corresponding normal mucosa obtained from 46 surgical specimens. We also evaluated iNOS activity, prostaglandin E2 (PGE2), cyclic GMP and cyclic AMP production in the same specimens. Nitrite/nitrate levels, and PGE2 and VEGF production were assessed in HCT116 and HT29 colon cancer cell lines after induction and selective inhibition of the two enzyme pathways. Results: A significant correlation was found between iNOS and COX-2 immunohistochemical expression. PGE2 production significantly correlated with iNOS activity and cGMP levels. A significant correlation was also found among PGE2 production, microvessel density, and VEGF expression. Coinduction of both iNOS and COX-2 activities occurred after lipopolysaccharide (LPS) and epidermal growth factor (EGF) treatment in HCT116 and HT29 cells. Inhibition of iNOS by 1400W significantly reduced both LPS- and EGF-induced PGE2 production. Treatment with LPS, EGF, and arachidonic acid significantly increased VEGF production in the iNOS-negative/COX-2-positive HT29 cells. This effect was completely reversed by treatment with the selective COX-2 inhibitor celecoxib. Conclusions: Our data showed a prominent role of nitric oxide in stimulating COX-2 activity in colorectal cancer. This interaction is likely to produce a cooperative effect in promoting angiogenesis through PGE2-mediated increase in VEGF production.
Changing trends in malignant transformation of hepatocellular adenoma
Authors: O. Farges, N. Ferreira, S. Dokmak, J. Belghiti, P. Bedossa, V. Paradis
Journal: Gut (2010)

Hepatocellular adenomas (HCAs) classically develop in women who are taking oral contraceptives and have a risk of malignant transformation into hepatocellular carcinoma (HCC). HCA with malignant transformation is, however, an ill-defined entity thought to be an anecdotic pathway to HCC. The objective of this study was to characterise malignancy occurring within HCA.A series of histology proven HCAs managed between 1993 and 2008 in a tertiary hepato-biliary centre (218 patients, 184 women and 34 men) were screened to identify HCA with malignant transformation.The incidence of HCA with malignant transformation was analysed through the study period and associated conditions were retrieved. They were sub-typed according to their molecular features and the malignant compartment was mapped.Areas of HCC within HCA were observed in 23 patients and the risk of malignant transformation was 4% in women and 47% in men. The number of women whose HCA had malignant changes has remained stable during the study period and oral contraception was the only associated condition. The number of men with such transformation has markedly increased since 2000 and the metabolic syndrome has become the most frequent associated condition. Two-thirds of HCAs with malignant transformation were β-catenin activated and one-third displayed cell atypias. Both features were more prevalent in men. The median diameter of HCA with malignancy was 10 cm and only three were 5 cm or less.Prevalence of malignancy within HCA is 10 times more frequent in men than in women and management of HCA should primarily be based on gender. Whereas oral contraception is a classical cause of HCA in women but a marginal cause of HCC, the metabolic syndrome appears as an emerging condition associated with malignant transformation of HCA in men, and is the likely predisposing condition for HCC in this setting.
Revisiting the Relationship Between Autism and Schizophrenia: Toward an Integrated Neurobiology
Authors: Nina de Lacy, Bryan H. King
Journal: Annual Review of Clinical Psychology (2013)

Schizophrenia and autism have been linked since their earliest descriptions. Both are disorders of cerebral specialization originating in the embryonic period. Genetic, molecular, and cytologic research highlights a variety of shared contributory mechanisms that may lead to patterns of abnormal connectivity arising from altered development and topology. Overt behavioral pathology likely emerges during or after neurosensitive periods in which resource demands overwhelm system resources and the individual's ability to compensate using interregional activation fails. We are at the threshold of being able to chart autism and schizophrenia from the inside out. In so doing, the door is opened to the consideration of new therapeutics that are developed based upon molecular, synaptic, and systems targets common to both disorders.
Prognostic Value of Ki67 Expression After Short-Term Presurgical Endocrine Therapy for Primary Breast Cancer
Authors: Mitch Dowsett, Ian E. Smith, Stephen R. Ebbs, J. Michael Dixon, Anthony Skene, Roger A'Hern, Janine Salter, Simone Detre, Margaret Hills, Geraldine Walsh
Journal: JNCI Journal of the National Cancer Institute (2007)

Tumor expression of the proliferation antigen Ki67 is widely used to assess the prognosis of cancer patients. A change in the expression of Ki67 after short-term exposure of patients to therapeutic agents is frequently used as a pharmacodynamic marker of efficacy, particularly among breast cancer patients before undergoing surgery. To determine the clinical significance of the level of tumor cell proliferation during endocrine therapy for breast cancer, we measured the expression of Ki67 in tumor biopsy samples taken before and after 2 weeks of presurgical treatment with anastrozole or tamoxifen or the combination of anastrozole plus tamoxifen in 158 patients with hormone receptor–positive primary disease. In a multivariable analysis, we found that higher Ki67 expression after 2 weeks of endocrine therapy was statistically significantly associated with lower recurrence-free survival ( P = .004) whereas higher Ki67 expression at baseline was not. Larger baseline tumor size and lower estrogen receptor level after 2 weeks of treatment were also statistically significantly associated with poorer recurrence-free survival ( P <.001 and P = .04, respectively). Our data indicate that measurements of tumor Ki67 level after short-term endocrine treatment may improve the prediction of recurrence-free survival by integrating the prognostic value of Ki67 level at baseline with changes in Ki67 level that are associated with treatment benefit.
Endothelial Cells of Hematopoietic Origin Make a Significant Contribution to Adult Blood Vessel Formation
Authors: Jeffrey R. Crosby, Wolfgang E. Kaminski, Gina Schatteman, Paul J. Martin, Elaine W. Raines, Ron A. Seifert, Daniel F. Bowen-Pope
Journal: Circulation Research (2000)

Granulation tissue formation is an example of new tissue development in an adult. Its rich vascular network has been thought to derive via angiogenic sprouting and extension of preexisting vessels from the surrounding tissue. The possibility that circulating cells of hematopoietic origin can differentiate into vascular endothelial cells (ECs) in areas of vascular remodeling has recently gained credibility. However, no quantitative data have placed the magnitude of this contribution into a physiological perspective. We have used hematopoietic chimeras to determine that 0.2% to 1.4% of ECs in vessels in control tissues derived from hematopoietic progenitors during the 4 months after irradiation and hematopoietic recovery. By contrast, 8.3% to 11.2% of ECs in vessels that developed in sponge-induced granulation tissue during 1 month derived from circulating hematopoietic progenitors. This recruitment of circulating progenitors to newly forming vessels would be difficult to observe in standard histological studies, but it is large enough to be encouraging for attempts to manipulate this contribution for therapeutic gain.
Forced vital capacity paired with Framingham Risk Score for prediction of all-cause mortality
Authors: H.M. Lee, H. Le, B.T. Lee, V.A. Lopez, N.D. Wong
Journal: European Respiratory Journal (2010)

Forced vital capacity (FVC) measures lung function and predicts coronary heart disease (CHD); whether it provides additive prediction over CHD risk factors has not been established. We examined whether FVC adds to the prediction of all-cause mortality provided by Framingham Risk Score (FRS) alone. We examined 5,485 (61.1 million projected) nonsmoking adults from the USA who were aged 20-79 yrs. Subjects were from the Third National Health and Nutrition Examination Survey, were without obstructive lung disease, had FVC measurements and had ≤ 12 yrs (mean 8.8 yrs) mortality follow-up. We performed Cox regression analysis to examine whether FVC and forced expiratory volume in 1 s (FEV(1)) (categorised as low ≤ 85% predicted, borderline 86-94% predicted and normal ≥ 95% predicted) within FRS groups (10-yr risk of cardiovascular disease low <10%, intermediate 10-20%, high 20%) predict mortality. Receiver operator characteristic analysis examined whether FVC and FEV(1) added to the prediction provided by FRS. Low-, intermediate- and high-risk FRS groups had 79.5% (n = 4,361), 10.1% (n = 555) and 10.4% (n = 569) persons, respectively. Only the intermediate FRS group showed a graded increase in mortality (10.7, 18.2 and 42.8% per 1,000 person-yrs from highest to lowest FVC categories, respectively); those with low FVC had an almost three-fold greater risk of mortality (hazard ratio 2.64; p<0.01) than those with normal FVC. FVC provided incremental additive value for predicting mortality in addition to FRS for only this group (area under curve 0.65 versus 0.58; p<0.05). Similar results were obtained for FEV(1). Evaluation of lung function may be useful to improve risk stratification in persons with intermediate CHD risk where it adds to prediction of mortality over global risk assessment.
The Microenvironment Matters: Estrogen Deficiency Fuels Cancer Bone Metastases
Authors: Laura E. Wright, Theresa A. Guise
Journal: Clinical Cancer Research (2014)

Factors released during osteoclastic bone resorption enhance disseminated breast cancer cell progression by stimulating invasiveness, growth, and a bone-resorptive phenotype in cancer cells. Postmenopausal bone loss may accelerate progression of breast cancer growth in bone, explaining the anticancer benefit of the bone-specific antiresorptive agent zoledronic acid in the postmenopausal setting. Clin Cancer Res; 20(11); 2817-9. ©2014 AACR.
Inhalation toxicology of isoprene in F344 rats and B6C3F1 mice following two-week exposures.
Authors: R L Melnick, J H Roycroft, B J Chou, H A Ragan, R A Miller
Journal: Environmental Health Perspectives (1990)

Isoprene (2-methyl-1,3-butadiene) was selected for toxicologic evaluations because of its structural similarity to 1,3-butadiene, a potent rodent carcinogen. Two-week inhalation toxicology studies of isoprene were conducted in F344 rats and B6C3F1 mice at exposure concentrations of 0, 438, 875, 1750, 3500, or 7000 ppm. For rats, there were no chemically related changes in survival, body weight gain, clinical signs, hematologic or clinical chemistry parameters, or gross or microscopic lesions. Exposure of mice to isoprene did not produce mortalities and only caused a decrease in body weight gain for male mice in the 7000 ppm exposure group; however, hematologic changes and microscopic lesions including testicular atrophy, olfactory epithelial degeneration, and forestomach epithelial hyperplasia were observed in isoprene-exposed mice. Similar toxicologic effects have been previously observed in B6C3F1 mice exposed to 1,3-butadiene. A species difference in susceptibility between rats and mice exposed to isoprene was evident in these short-term exposure studies.
Mutations in the pre-replication complex cause Meier-Gorlin syndrome
Authors: Louise S Bicknell, Ernie M H F Bongers, Andrea Leitch, Stephen Brown, Jeroen Schoots, Margaret E Harley, Salim Aftimos, Jumana Y Al-Aama, Michael Bober, Paul A J Brown, Hans van Bokhoven, John Dean, Alaa Y Edrees, Murray Feingold, Alan Fryer, Lies H Hoefsloot, Nikolaus Kau, Nine V A M Knoers, James MacKenzie, John M Opitz, Pierre Sarda, Alison Ross, I Karen Temple, Annick Toutain, Carol A Wise, Michael Wright, Andrew P Jackson
Journal: Nature Genetics (2011)