tbuckley/cabot-search huggingface dataset:
Tumor Suppressor Activity and Epigenetic Inactivation of Hepatocyte Growth Factor Activator Inhibitor Type 2/SPINT2 in Papillary and Clear Cell Renal Cell Carcinoma
Authors: Mark R. Morris, Dean Gentle, Mahera Abdulrahman, Esther N. Maina, Kunal Gupta, Rosamonde E. Banks, Michael S. Wiesener, Takeshi Kishida, Masahiro Yao, Bin Teh, Farida Latif, Eamonn R. Maher
Journal: Cancer Research (2005)

Abstract Following treatment with a demethylating agent, 5 of 11 renal cell carcinoma (RCC) cell lines showed increased expression of hepatocyte growth factor (HGF) activator inhibitor type 2 (HAI-2/SPINT2/Bikunin), a Kunitz-type protease inhibitor that regulates HGF activity. As activating mutations in the MET proto-oncogene (the HGF receptor) cause familial RCC, we investigated whether HAI-2/SPINT2 might act as a RCC tumor suppressor gene. We found that transcriptional silencing of HAI-2 in RCC cell lines was associated with promoter region methylation and HAI-2/SPINT2 protein expression was down-regulated in 30% of sporadic RCC. Furthermore, methylation-specific PCR analysis revealed promoter region methylation in 30% (19 of 64) of clear cell RCC and 40% (15 of 38) of papillary RCC, whereas mutation analysis (in 39 RCC cell lines and primary tumors) revealed a missense substitution (P111S) in one RCC cell line. Restoration of HAI-2/SPINT2 expression in a RCC cell line reduced in vitro colony formation, but the P111S mutant had no significant effect. Increased cell motility associated with HAI-2/SPINT2 inactivation was abrogated by treatment with extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phospholipase C-γ inhibitors, but not by an inhibitor of atypical protein kinase C. These findings are consistent with frequent epigenetic inactivation of HAI-2/SPINT2, causing loss of RCC tumor suppressor activity and implicate abnormalities of the MET pathway in clear cell and papillary sporadic RCC. This information provides opportunities to develop novel targeted approaches to the treatment of RCC.
Methylenetetrahydrofolate reductase (<i>MTHFR</i>): could it be a small piece in vitiligo jigsaw puzzle?
Authors: R. Begum
Journal: British Journal of Dermatology (2014)

Journal Article Methylenetetrahydrofolate reductase (MTHFR): could it be a small piece in vitiligo jigsaw puzzle? Get access R. Begum R. Begum Department of Biochemistry Faculty of Science The Maharaja Sayajirao University of Baroda Vadodara Gujarat 390002 India Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 170, Issue 5, 1 May 2014, Pages 1009–1010, https://doi.org/10.1111/bjd.13017 Published: 01 May 2014
First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma
Authors: L. Blais, S. Suissa, J.-F. Boivin, P. Ernst
Journal: Thorax (1998)

Early treatment with inhaled corticosteroids appears to improve clinical symptoms in asthma. Whether a first treatment initiated in the year following the recognition of asthma can prevent major outcomes such as admission to hospital has yet to be studied.A case-control study nested within a cohort of 13,563 newly treated asthmatic subjects selected from the databases of Saskatchewan Health (1977-1993) was undertaken to investigate the effectiveness of a first treatment with inhaled corticosteroids in preventing admissions to hospital for asthma. Study subjects were aged between five and 44 years at cohort entry. First time users of inhaled corticosteroids were compared with first time users of theophylline for a maximum of 12 months of treatment. The two treatments under study were further classified into initial and subsequent therapy to minimize selection bias and confounding by indication. Odds ratios associated with hospital admissions for asthma were estimated using conditional logistic regression. Markers of asthma severity, as well as age and sex, were considered as potential confounders.Three hundred and three patients admitted to hospital with asthma were identified and 2636 matched controls were selected. subjects initially treated with regular inhaled corticosteroids were 40% less likely to be admitted to hospital for asthma than regular users of theophylline (odds ratio 0.6; 95% CI 0.4 to 1.0). The odds ratio decreased to 0.2 (95% CI 0.1 to 0.5) when inhaled corticosteroids and theophylline were given subsequently.The first regular treatment with inhaled corticosteroids initiated in the year following the recognition of asthma can reduce the risk of admission to hospital for asthma by up to 80% compared with regular treatment with theophylline. This is probably due, at least in part, to reducing the likelihood of a worsening in the severity of asthma.
CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice
Authors: Weiliang Xie, John T. Fisher, Thomas J. Lynch, Meihui Luo, Turan I.A. Evans, Traci L. Neff, Weihong Zhou, Yulong Zhang, Yi Ou, Nigel W. Bunnett, Andrew F. Russo, Michael J. Goodheart, Kalpaj R. Parekh, Xiaoming Liu, John F. Engelhardt
Journal: Journal of Clinical Investigation (2011)

In cystic fibrosis (CF), a lack of functional CF transmembrane conductance regulator (CFTR) chloride channels causes defective secretion by submucosal glands (SMGs), leading to persistent bacterial infection that damages airways and necessitates tissue repair. SMGs are also important niches for slow-cycling progenitor cells (SCPCs) in the proximal airways, which may be involved in disease-related airway repair. Here, we report that calcitonin gene-related peptide (CGRP) activates CFTR-dependent SMG secretions and that this signaling pathway is hyperactivated in CF human, pig, ferret, and mouse SMGs. Since CGRP-expressing neuroendocrine cells reside in bronchiolar SCPC niches, we hypothesized that the glandular SCPC niche may be dysfunctional in CF. Consistent with this hypothesis, CFTR-deficient mice failed to maintain glandular SCPCs following airway injury. In wild-type mice, CGRP levels increased following airway injury and functioned as an injury-induced mitogen that stimulated SMG progenitor cell proliferation in vivo and altered the proliferative potential of airway progenitors in vitro. Components of the receptor for CGRP (RAMP1 and CLR) were expressed in a very small subset of SCPCs, suggesting that CGRP indirectly stimulates SCPC proliferation in a non-cell-autonomous manner. These findings demonstrate that CGRP-dependent pathways for CFTR activation are abnormally upregulated in CF SMGs and that this sustained mitogenic signal alters properties of the SMG progenitor cell niche in CF airways. This discovery may have important implications for injury/repair mechanisms in the CF airway.
Contemporary Definitions and Classification of the Cardiomyopathies
Authors: Barry J. Maron, Jeffrey A. Towbin, Gaetano Thiene, Charles Antzelevitch, Domenico Corrado, Donna Arnett, Arthur J. Moss, Christine E. Seidman, James B. Young
Journal: Circulation (2006)

Classifications of heart muscle diseases have proved to be exceedingly complex and in many respects contradictory. Indeed, the precise language used to describe these diseases is profoundly important. A new contemporary and rigorous classification of cardiomyopathies (with definitions) is proposed here. This reference document affords an important framework and measure of clarity to this heterogeneous group of diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular genetics in cardiology, as well as the introduction of several recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy.
HLA-DQB1 codon 57 is critical for peptide binding and recognition.
Authors: W W Kwok, M E Domeier, M L Johnson, G T Nepom, D M Koelle
Journal: The Journal of Experimental Medicine (1996)

The association of specific HLA-DQ alleles with autoimmunity is correlated with discrete polymorphisms in the HLA-DQ sequence that are localized within sites suitable for peptide recognition. The polymorphism at residue 57 of the DQB1 polypeptide is of particular interest since it may play a major structural role in the formation of a salt bridge structure at one end of the peptide-binding cleft of the DQ molecules. This polymorphism at residue 57 is a recurrent feature of HLA-DQ evolution, occurring in multiple distinct allelic families, which implies a functional selection for maintaining variation at this position in the class II molecule. We directly tested the amino acid polymorphism at this site as a determinant for peptide binding and for antigen-specific T cell stimulation. We found that a single Ala--&amp;gt;Asp amino acid 57 substitution in an HLA-DQ3.2 molecule regulated binding of an HSV-2 VP-16-derived peptide. A complementary single-residue substitution in the peptide abolished its binding to DQ3.2 and converted it to a peptide that can bind to DQ3.1 and DQ3.3 Asp-57-positive MHC molecules. These binding studies were paralleled by specific T cell recognition of the class II-peptide complex, in which the substituted peptide abolished T cell reactivity, which was directed to the DQ3.2-peptide complex, whereas the same T cell clone recognized the substituted peptide presented by DQ3.3, a class II restriction element differing from DQ3.2 only at residue 57. This structural and functional complementarity for residue 57 and a specific peptide residue identifies this interaction as a key controlling determinant of restricted recognition in HLA-DQ-specific immune response.
Does AKI Truly Lead to CKD?
Authors: Dena E. Rifkin, Steven G. Coca, Kamyar Kalantar-Zadeh
Journal: Journal of the American Society of Nephrology (2012)

Acute kidney injury (AKI) has been implicated as an independent risk factor for the development of CKD in recent observational studies. The presumption in the nephrology community is that this association represents a causal relationship. However, because of potential problems related to residual confounding (shared risk factors), ascertainment bias (sicker patients have more follow-up assessments), misclassification of exposure (problems with defining baseline kidney function and AKI representing a discrete event versus progression of renal disease), and misclassification of outcome (de novo CKD versus CKD progression), it is difficult to conclude with certainty that AKI is truly causal for CKD. In this review we highlight several of the Hill causality criteria to examine the existing evidence and point out the missing elements that preclude defining AKI as a cause of CKD in the general population. Only well-designed studies with rigorous assessment of kidney function in all participants (AKI and non-AKI) before and after the episode or hospitalization or randomized, controlled trials demonstrating that prevention or treatment of AKI reduces the incidence of subsequent CKD can clarify the causal nature of the AKI-CKD relationship.
Plasma levels of TIMP-1 are higher in 34-year-old individuals with severe 1-antitrypsin deficiency
Authors: S. Janciauskiene, D. Subramaniyam, E. Piitulainen, T. Kohnlein, T. Sveger
Journal: Thorax (2010)

<b>387</b> <b>Objectives: </b>Relatively slow kinetics of available PET radioligands(e.g. 2FA) for α4β2 subtype cerebral nicotinic acetylcholine receptor(nAChRs),is a practical confounding factor (i.e. an infusion period of 6 hours with the bolus-plus-infusion scheme). We examined eight newly synthesized nAChR radioligands with improved brain kinetics on non-human primates. <b>Methods: </b>Eight radioligands which survived screening were studied on non-human primates (n=4) with a GE Advance® PET scanner (n=3) or High Resolution Research Tomograph® (n=5) under Saffan® anesthesia. Arterial blood samples were taken to generate time activity curves (TACs) in plasma with metabolite correction. A standard template of volumes of interest (VOIs, a total of 17 regions) including Thalamus (Th) and cerebellum (Cb), was spatially normalized to PET to obtain regional TACs. Regional Binding Potential (BP) were obtained by the multilinear reference tissue method with 2 parameters (MRTM2; Ichise et al., 2002) using Cb as the reference region. <b>Results: </b>Four radioligands (JHU85208, JHU85157, JHU15103, and JHU85270) reached a steady-state within one hour of a bolus injection (i.e., stable Th-Cb ratios over time), but showed relatively low BP values in Th (range: 0.66 – 1.52). Two radioligands (JHU86328 and JHU86358) reached a near steady state around 90 min and showed relatively high BP values (Table). The remaining JHU86390 and (-)-[11C]methyl-IPHNMI-IPBB (Ding et al., 2006) showed slower kinetics. Active isomer of (-)-[11C]NMI-IPB methyl-IPHB was used in this study, while racemic mixture (±)-[11C]NMI-IPB was used in the original publication. (Ding et al., 2005) [table] <b>Conclusions: </b>Two radioligands (JHU86328 and JHU86358) showed relatively faster kinetics while maintaining reasonable BP values in cortical and subcortical regions. The findings warrant further investigations of the radioligands on the human brain to assess whether it is possible to resolve the above-mentioned practical confounding factor. <b>Research Support (if any): </b>Grant support: K24 DA00412
Gender and Age Influences on Human Brain Mu-Opioid Receptor Binding Measured by PET
Authors: Jon-Kar Zubieta, Robert F. Dannals, J. James Frost
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: Both age and gender are being increasingly recognized as important factors influencing CNS structure and function. However, there are relatively few data on actual neurochemical differences between the sexes in human subjects or on their interaction with age. One of the central neurotransmitter systems for which sex differences have been suggested by animal models and clinical human data is the opioid. In this study the authors examined age- and gender-associated variations in mu-opioid receptor binding with positron emission tomography (PET). METHOD: Healthy human subjects were studied with PET and the radiotracer [11C]carfentanil, a selective mu-opioid agonist. Two separate subject groups were examined: one group of 24 men and 12 women was studied in a retrospective analysis of data, and a second group of 12 men and 18 women was recruited prospectively and studied with a higher-resolution scanner. RESULTS: Mu-opioid receptor binding potential (Bmax/Kd) was found to increase with age in neocortical areas and the putamen. Sex differences, with higher mu-opioid binding in women, were observed in a number of cortical and subcortical areas. Gender-by-age interactions were observed in the thalamus and the amygdala; in vivo mu-opioid binding declined in postmenopausal women to levels below those of men. CONCLUSIONS: These data imply that both age and gender are important variables to consider in the interpretation of investigations of human function in which the opioid system plays a role. Also, women’s reproductive status (reproductive age versus postmenopausal) may influence the function of CNS opioid systems.
Availability of organs for transplantation.
Authors: D J Hill
Journal: BMJ (1986)

Oncologic <sup>18</sup>F-FDG PET/CT is rapidly gaining acceptance in clinical practice. However, the referring physician’s attitude toward the usefulness of this diagnostic modality is unknown. This survey was undertaken to collect information regarding the current perspective of referring physicians on oncologic PET/CT. <b>Methods:</b> We conducted a prospective worldwide, Web-based survey of physicians who manage cancer patients. A total of 963 referring physicians completed a 20-question survey focused on their experience with oncologic <sup>18</sup>F-FDG PET/CT. Attention was directed toward their confidence about indications, their satisfaction with related educational resources, the quality of interaction with interpreting physicians, and practical problems encountered. The respondents included oncologists (38.5%, <i>n</i> = 371), hematologists (16.4%, <i>n</i> = 158), radiation oncologists (9.0%, <i>n</i> = 87), surgeons (30.3%, <i>n</i> = 292), and other physicians (5.7%, <i>n</i> = 55). <b>Results:</b> Only 25.2% of respondents considered the oncologic <sup>18</sup>F-FDG PET/CT indications to be well established and defined. Frequent uncertainty about the need for a PET scan was indicated by 62.3% of the respondents. High cost and overinterpretation of findings were the most commonly reported concerns (47.0% and 40.9%, respectively). The experience and skill level of the interpreting physician was considered very important by 96.8% of the surveyed physicians. <b>Conclusion:</b> Referring physicians expressed considerable uncertainty about the appropriate use of oncologic PET/CT. Additional major concerns are procedure costs and quality of interpretation. The responses suggest a strong need for efforts to educate referring and interpreting physicians about the appropriate use of <sup>18</sup>F-FDG PET/CT in oncology.
Tumor Cell Plasticity in Ewing Sarcoma, an Alternative Circulatory System Stimulated by Hypoxia
Authors: Daisy W.J. van der Schaft, Femke Hillen, Patrick Pauwels, Dawn A. Kirschmann, Karolien Castermans, Mirjam G.A. oude Egbrink, Maxine G.B. Tran, Rafael Sciot, Esther Hauben, Pancras C.W. Hogendoorn, Olivier Delattre, Patrick H. Maxwell, Mary J.C. Hendrix, Arjan W. Griffioen
Journal: Cancer Research (2005)

Abstract A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis. (Cancer Res 2005; 65(24): 11520-8)
Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells
Authors: Wallace H. Mondesire, Weiguo Jian, Haixia Zhang, Joe Ensor, Mien-Chie Hung, Gordon B. Mills, Funda Meric-Bernstam
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The serine-threonine kinase mammalian target of rapamycin has emerged as a potential target for cancer therapy. Rapamycin and rapamycin analogs are undergoing clinical trials and have induced clinical responses in a subgroup of patients. Rapamycin has also been reported to enhance the efficacy of several cytotoxic agents. The aim of this study was to determine the nature of the interactions between rapamycin and chemotherapeutic agents used as first- and second-line agents against breast cancer. Experimental Design: We performed a multiple drug effect/combination index isobologram analysis in cells sensitive and resistant to rapamycin alone in vitro, and we evaluated the in vivo efficacy of combination therapy in a rapamycin-sensitive model. Results: In vitro, synergistic interactions were observed in combinations with paclitaxel, carboplatin, and vinorelbine. Additive effects were observed in combinations with doxorubicin and gemcitabine. Rapamycin dramatically enhanced paclitaxel- and carboplatin-induced apoptosis. This effect was sequence dependent and mediated at least partly through caspase activation. Furthermore, rapamycin enhanced chemosensitivity to paclitaxel and carboplatin in HER2/neu-overexpressing cells, suggesting a potential approach to these poorly behaving tumors. Cell lines that are resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. In vivo, rapamycin combined with paclitaxel resulted in a significant reduction in tumor volume compared with either agent alone in rapamycin-sensitive tumors. Conclusions: Rapamycin potentiates the cytotoxicity of selected chemotherapeutic agents in cell lines sensitive to the effects of rapamycin due to aberrations in the phosphatidylinositol 3′-kinase/Akt pathway, suggesting that combination therapy may be effective in patients selected for aberrations in this pathway.
Combined Increased Chemosensitivity to Hypoxia and Hypercapnia as a Prognosticator in Heart Failure
Authors: Alberto Giannoni, Michele Emdin, Francesca Bramanti, Giovanni Iudice, Darrel P. Francis, Antonio Barsotti, Massimo Piepoli, Claudio Passino
Journal: Journal of the American College of Cardiology (2009)
Sleep disordered breathing and pregnancy
Authors: N Edwards
Journal: Thorax (2002)

Many changes in the respiratory system occur during pregnancy, particularly during the third trimester, which can alter respiratory function during sleep, increasing the incidence and severity of sleep disordered breathing. These changes include increased ventilatory drive and metabolic rate, reduced functional residual capacity and residual volume, increased alveolar-arterial oxygen gradients, and changes in upper airway patency. The clinical importance of these changes is indicated by the increased incidence of snoring during pregnancy, which is likely also to reflect an increased incidence of obstructive sleep apnoea/hypopnoea syndrome. For the respiratory physician asked to review a pregnant patient, the possibility of sleep disordered breathing should always be considered. This review first examines the normal physiological changes of pregnancy and their relationship to sleep disordered breathing, and then summarises the current knowledge of sleep disordered breathing in pregnancy.
Compact organization of the hepatitis B virus genome
Authors: Roger H. Miller, Shuichi Kaneko, Cathie T. Chung, Rosina Girones, Robert H. Purcell
Journal: Hepatology (1989)

The genome of hepatitis B virus (HBV) is a circular DNA molecule approximately 3,200 base pairs (bp) in length. Relative to other double-stranded DNA viruses capable of independent replication, HBV possesses the smallest genome of any virus known to infect man. Therefore, it is not surprising that HBV utilizes its genetic material economically. This is accomplished by two rare genetic arrangements: proteins are encoded from overlapping translation frames, and all regulatory signal sequences reside within protein-encoding sequences. Thus, HBV obtains multiple use from many regions of its genome, which underscores the sophistication of this virus from an evolutionary standpoint.