tbuckley/cabot-search huggingface dataset:
International Union of Pharmacology. LV. Nomenclature and Molecular Relationships of Two-P Potassium Channels
Authors: Steve A. N. Goldstein, Douglas A. Bayliss, Donghee Kim, Florian Lesage, Leigh Daniel Plant, Sindhu Rajan
Journal: Pharmacological Reviews (2005)

In less than a decade since their discovery, the study of K2P channels has revealed that background leak of potassium ions via dedicated pathways is a highly regulated mechanism to control cellular excitability. Potassium leak pathways, active at rest, stabilize membrane potential below firing
Hypertension may be transplanted with the kidney in humans
Authors: E Guidi, D Menghetti, S Milani, G Montagnino, P Palazzi, G Bianchi
Journal: Journal of the American Society of Nephrology (1996)

In several genetic hypertensive rat strains, transplantation studies have established that the kidney carries at least a portion of the genetic message for hypertension. In man it has, of course, been more difficult to obtain clearcut results. This historical prospective observational study, double-blinded for knowledge of donors' and recipients' family history for hypertension, concerns 85 transplanted patients, not treated with cyclosporine and with stable renal function, followed up for an average of 8 yr. Both the donors' and the recipients' families were carefully characterized for presence or absence of hypertension. After transplantation, in recipients without hypertension in their own families, a kidney coming from a "hypertensive" family determines less withdrawal and more introduction of antihypertensive therapy (AHT) than a kidney from a "normotensive" family (odds ratio for AHT introduction 5.0, confidence interval, 1.4 to 17.8; P = 0.017). In recipients with familial hypertension, the origin of the kidney does not influence the prevalence of hypertension after transplantation. More detailed analyses show that, in recipients without familial hypertension, the transplantation of a "hypertensive" kidney determines a tenfold larger increase in the requirement of antihypertensive therapy than the transplantation of a "normotensive" kidney, to obtain a similar blood pressure control (P = 0.003). This results is confirmed by the analysis of time-profile trends for antihypertensive therapy, adjusted for missing data, in the most clinically stable period (2nd to 10th yr after transplantation). The transmission of familial hypertension with the kidney is thus seen only in recipients coming from "normotensive" families, because a familial tendency for hypertension blunts the effect of receiving a "hypertensive" kidney.
Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients.
Authors: J M Fernández-Real, J Vendrell, W Ricart, M Broch, C Gutiérrez, R Casamitjana, J Oriola, C Richart
Journal: Diabetes Care (2000)

Mice lacking the tumor necrosis factor-alpha receptor 2 (TNFR2) gene fed a high-fat diet gain less weight and display reduced leptin and insulin levels. In humans, plasma levels of the soluble fraction of TNFR2 (sTNFR2) circulate in proportion to the degree of insulin resistance. The purpose of this study was to evaluate a polymorphism in the 3' untranslated region of the TNFR2 gene on chromosome 1 in relation to BMI, leptin levels, and insulin resistance.Using single-strand conformation polymorphism, the polymorphism was analyzed in 107 nondiabetic subjects (60 women, 47 men) and in 110 consecutive patients with type 2 diabetes (79 women, 31 men). In a subset of 33 healthy subjects, insulin sensitivity (minimal model analysis) was also evaluated.Four alleles of the TNFR2 gene were identified (A1, A2, A3, and A4). BMI and serum leptin levels were significantly increased in young carriers of the A2 allele. Plasma sTNFR2 levels were similar among the different TNFR2 gene variants. However, in subjects who did not carry the A2 allele, in young subjects, and in women, plasma sTNFR2 levels were proportional to BMI and leptin levels. In the study sample, carriers of the A2 allele (n = 18) showed significantly increased BMI, fat mass, waist-to-hip ratio, serum total and VLDL triglyceride levels, and leptin levels and had a lower insulin sensitivity index than noncarriers of the A2 variant (n = 15). The frequency of the different alleles among diabetic subjects was similar to that in the control population. However, diet-treated diabetic subjects (n = 49) who were carriers of the A2 allele exhibited significantly higher BMI and leptin levels than diet-treated noncarriers of the A2 allele.The presence of the A2 allele in the TNFR2 gene may predispose subjects to obesity and higher leptin levels, which may in turn predispose them to insulin resistance or vice versa. The TNFR2 gene may be involved in weight-control mechanisms.
Adjuvant Trastuzumab in HER2-Positive Breast Cancer: Observational Monocentric Study of 84 Cases
Authors: M. Aitelhaj, S. Lkhoyaali, G. Rais, A. Mohtaram, S. Boutayeb, Y. Bensouda, H. Errihani
Journal: Annals of Oncology (2013)
Prenatal Exposure, Maternal Sensitization, and Sensitization<i>In Utero</i>To Indoor Allergens in an Inner-City Cohort
Authors: RACHEL L. MILLER, GINGER L. CHEW, COURTNEY A. BELL, STEPHANIE A. BIEDERMANN, MANEESHA AGGARWAL, PATRICK L. KINNEY, WEI YANN TSAI, ROBIN M. WHYATT, FREDERICA P. PERERA, JEAN G. FORD
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Primary sensitization to antigens may occur prenatally. We hypothesized that high prenatal exposure to indoor antigens increases the risk for sensitization in newborns in New York City populations with increased risk for asthma. We also investigated whether maternal sensitization is required for in utero sensitization to occur. One hundred sixty-seven pregnant African American or Dominican women residing in northern Manhattan were recruited and antigen was measured from home dust. After delivery, newborn cord and maternal blood were assayed for IgE and mononuclear cell proliferation and cytokine production in response to antigen. Cockroach, mouse, but not dust mite antigens, were commonly elevated in the kitchens and pregnant mothers' beds. Increased mononuclear cell proliferation occurred in 54% of newborns in response to cockroach, 25% in response to dust mite Dermatophagoides pteronyssinus, 40% in response to dust mite D. farinae, and 34% in response to mouse protein extracts. Antigen-induced mononuclear cell proliferation occurred in cord blood even in the absence of antigen-induced mononuclear cell proliferation in the mother. Proliferation in response to antigens did not correlate with IgE levels, but proliferation in response to dust mite extracts correlated with interluekin-5 (IL-5) production in cord blood. These results suggest that (1) high prenatal exposures to cockroach and mouse antigens are prevalent; (2) in utero sensitization to multiple indoor antigens is common, occurs to a different degree than maternal sensitization, and may involve IL-5 upregulation.
The pentraxins, C-reactive protein and serum amyloid P component, are cleared and catabolized by hepatocytes in vivo.
Authors: W L Hutchinson, G E Noble, P N Hawkins, M B Pepys
Journal: Journal of Clinical Investigation (1994)

The cellular sites of clearance and degradation of the pentraxin plasma proteins, C-reactive protein, the classical acute phase reactant, and serum amyloid P component (SAP), a universal constituent of amyloid deposits, were sought using the ligand 125I-tyramine cellobiose (TC) which is substantially retained within the cells in which catabolism takes place. Pentraxins labeled with 125I-TC showed the same in vitro and in vivo ligand binding and the same in vivo plasma t1/2 as the directly iodinated proteins and the native unlabeled pentraxins, indicating that their mode of clearance was likely to be physiological. After intravenous injection into mice and rabbits of human C-reactive protein, human SAP, and mouse SAP, each labeled with 125I-TC, most of the radioactivity remaining in the body at 24 h was located in hepatocytes. None was detected in other liver cells, and only traces were present in other viscera; the rest was in the carcass, representing intact pentraxins in the blood and extravascular compartment, and escaped label which had not yet been excreted. Hepatocytes are thus the single major site of pentraxin clearance and catabolism in vivo. This is consistent with the observation that SAP that has localized to amyloid deposits persists there and is not degraded.
Targeting the Stroma by T Cells to Limit Tumor Growth
Authors: Bin Zhang
Journal: Cancer Research (2008)

Abstract Solid tumors may modulate their environment and keep stromal cells in an immunosuppressive and tumor-promoting state. Recent findings indicate that targeting not only cancer cells but also nonmalignant stromal cells by T cells is required for the eradication of established tumor. Interestingly, a single adoptive transfer of effector T cells that recognize tumor antigen-loaded stromal cells, but not the cancer cells themselves, causes long-term inhibition of tumor growth associated with T cell–mediated killing of stromal CD11b+/Gr1+ myeloid cells. Therefore, targeting tumor stroma by T cells points to an important alternative approach to the effective control of tumor growth, particularly in the absence of direct targeting of cancer cells. [Cancer Res 2008;68(23):9570–3]
Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study
Authors: Federica Grosso, Robin L Jones, George D Demetri, Ian R Judson, Jean-Yves Blay, Axel Le Cesne, Roberta Sanfilippo, Paola Casieri, Paola Collini, Palma Dileo, Carlo Spreafico, Silvia Stacchiotti, Elena Tamborini, Juan Carlos Tercero, Josè Jimeno, Maurizio D'Incalci, Alessandro Gronchi, Jonathan A Fletcher, Silvana Pilotti, Paolo G Casali
Journal: The Lancet Oncology (2007)
Effect of Angiotensin-Converting Enzyme Inhibition on Glomerular Basement Membrane Permeability and Distribution of Zonula Occludens-1 in MWF Rats
Authors: DANIELA MACCONI, MARINA GHILARDI, MARIA ENRICA BONASSI, EHAB I. MOHAMED, MAURO ABBATE, FRANCESCA COLOMBI, GIUSEPPE REMUZZI, ANDREA REMUZZI
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The mechanism(s) by which angiotensin-converting enzyme (ACE) inhibitors prevent glomerular membrane loss of permselective function is still not understood. In male MWF rats, which develop spontaneous proteinuria with age, ACE inhibitors prevent proteinuria and increase glomerular ultrafiltration coefficient. These renoprotective effects are not associated with ultrastructural changes of capillary wall components. This study was undertaken to investigate whether ACE inhibitors modulate functional properties of glomerular basement membrane (GBM) and/or of epithelial cells, both of which have been suggested to play a role in the maintenance of the glomerular filtration barrier. The hydraulic and macromolecular permeability of the GBM were determined, by an in vitro filtration system, in untreated or lisinopril-treated rats and in Wistar rats taken as controls. By indirect immunofluorescence and immunoelectron microscopy, glomerular distribution of the tight junction protein zonula occludens-1 (ZO-1), a component of the slit diaphragm, was also studied. Results document that spontaneous proteinuria in MWF rats develops without significant changes in the permeability of the GBM to water and albumin, or in the ultrastructure of the podocyte foot processes, but is associated with an important alteration in the distribution of ZO-1 at the glomerular level. Lisinopril, which prevented proteinuria, also prevented glomerular redistribution of the protein. Thus, renoprotective effects of ACE inhibitors are not associated with changes in intrinsic functional properties of GBM, or ultrastructural changes of the epithelial cells, but rather with preservation of glomerular ZO-1 distribution and slit diaphragm function, which are essential for maintaining the filtration barrier.
Genome Scan of Schizophrenia
Authors: Douglas F. Levinson, Melanie M. Mahtani, Derek J. Nancarrow, Donna M. Brown, Leonid Kruglyak, Andrew Kirby, Nicholas K. Hayward, Raymond R. Crowe, Nancy C. Andreasen, Donald W. Black, Jeremy M. Silverman, Jean Endicott, Lawrence Sharpe, Richard C. Mohs, Larry J. Siever, Marilyn K. Walters, David P. Lennon, Helen L. Jones, Deborah A. Nertney, Mark J. Daly, Madeline Gladis, Bryan J. Mowry
Journal: American Journal of Psychiatry (1998)

The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes.A genomewide map of 310 microsatellite DNA markers with average spacing of 11 centimorgans was genotyped in 269 individuals--126 of them with schizophrenia-related psychoses--from 43 pedigrees. Nonparametric linkage analysis was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease.Nonparametric linkage scores did not reach a genomewide level of statistical significance for any marker. There were five chromosomal regions in which empirically derived p values reached nominal levels of significance at eight marker locations. There were p values less than 0.01 at chromosomes 2q (with the peak value in this region at D2S410) and 10q (D10S1239), and there were p values less than 0.05 at chromosomes 4q (D4S2623), 9q (D9S257), and 11q (D11S2002).The results do not support the hypothesis that a single gene causes a large increase in the risk of schizophrenia. The sample (like most others being studied for psychiatric disorders) has limited power to detect genes of small effect or those that are determinants of risk in a small proportion of families. All of the most positive results could be due to chance, or some could reflect weak linkage (genes of small effect). Multicenter studies may be useful in the effort to identify chromosomal regions most likely to contain schizophrenia susceptibility genes.
Progressive Loss of Renal Function Is an Age-Dependent Heritable Trait in Type 1 Autosomal Dominant Polycystic Kidney Disease
Authors: Andrew D. Paterson, Riccardo Magistroni, Ning He, Kairong Wang, Ann Johnson, Pamela R. Fain, Elizabeth Dicks, Patrick Parfrey, Peter St. George-Hyslop, York Pei
Journal: Journal of the American Society of Nephrology (2005)

Significant intrafamilial phenotypic variability is well documented in autosomal dominant polycystic kidney disease (ADPKD) and suggests a modifier effect. In this study, variance components analysis was performed to estimate the contribution of genetic factors for within-family renal disease variability in 406 patients from 66 type 1 ADPKD families. Overall, 39% of the study patients had ESRD at their last follow-up, and their renal survival did not differ by gender (P = 0.35, log-rank test). Because their frequency plot of creatinine clearance (Ccr) assumed a bimodal distribution with a marked kurtosis that was not improved by transformations, the study cohort was decomposed into two separate groups (non-ESRD [n = 247] and ESRD [n = 159]) in which the Ccr plots were normally distributed. The heritability (h(2)) of Ccr and age at ESRD (age(ESRD)) and the genetic correlations between these measures and their covariates were estimated. In patients without ESRD, a significant heritability was found for Ccr (h(2) = 0.42; P = 0.0015) after adjusting for age (P = 0.0001), systolic BP (P = 0.0006), and treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (P = 0.00001). Birth year, gender, BMI, diastolic and mean BP, and pack-years of cigarette smoking did not significantly influence the heritability of this trait. In patients with ESRD, age(ESRD) provides a better measure than Ccr, which was very narrowly distributed. A significant heritability was found for age(ESRD) (h(2) = 0.78; P = 0.00009) in these latter patients. None of the above covariates influenced the heritability of this trait. It is concluded that a significant modifier gene effect influences the progression of renal disease in type 1 ADPKD.
Abstract PR02: “Guardians of repeats”: Novel and significant relationship of p53 and interferon
Authors: Katerina Leonova, Andrei Gudkov
Journal: Cancer Research (2013)

Abstract Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53, along with DNA methylation, plays an essential role in maintaining silencing of a large portion of the mouse genome. In the absence of functional p53, hypomethylation of DNA results in massive transcription of major classes of short interspersed repeats (SINEs B1 and B2), both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of non-coding RNAs. In p53-deficient mouse fibroblasts treated with the DNA demethylating agent 5-aza-2'-deoxycytidine, the abundance of these new transcripts exceeds the level of β-actin mRNA by more than 150-fold. Accumulation of these largely double-stranded transcripts, in the absence of p53, is accompanied with a strong endogenous type I interferon response that induces apoptotic cell death. Transcriptional activation of repeats and non-coding RNAs is observed in a significant proportion of spontaneous mouse tumors, presumably reflecting naturally occurring DNA hypomethylation and p53 inactivation. These observations suggest that p53 and IFN cooperate to prevent accumulation of cells with activated repeats. This model, which we have named TRAIN (Transcription of Repeats Activates INterferon), assigns a novel role to p53 as a guardian of repeats. TRAIN model provides plausible explanation for frequent deregulation of interferon pathway observed in a variety of tumors. Overall, this work highlights the cooperation between p53 and interferon as key players needed to maintain genetic stability, and even further outlines their significance in tumor progression and the evolution of the species. Citation Format: Katerina Leonova, Andrei Gudkov. “Guardians of repeats”: Novel and significant relationship of p53 and interferon. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR02.
Blunted excitability of aortic baroreceptor neurons in diabetic rats: involvement of hyperpolarization-activated channel
Authors: Y.-L. Li, T. P. Tran, R. Muelleman, H. D. Schultz
Journal: Cardiovascular Research (2008)

Although dysfunction of arterial baroreflex occurs in human and animal models of type-1 diabetes (T1D), the mechanisms involved in the impairment of the baroreflex still remain unclear. The nodose ganglion (NG) contains the cell bodies of the aortic baroreceptor (AB) neurons. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed in AB neurons and play an important role in regulating the cell excitability. We investigated whether the excitability of AB neurons is depressed in streptozotocin (STZ)-induced T1D rats and whether HCN channels are involved in this depression.Using the whole-cell patch clamp technique, we found that AB neuron excitability (action potential frequency at 50 pA current stimulation) in the T1D rats was lower than that in the sham rats (0.4 +/- 0.5 vs. 4.8 +/- 0.6 spikes/s, P < 0.05; AB neurons were identified by DiI staining). In addition, HCN current density in AB neurons from the T1D rats was bigger than that from the sham rats (60.2 +/- 6.1 vs. 30.7 +/- 4.9 pA/pF at test pulse -140 from holding potential -40 mV, P < 0.05). Furthermore, HCN channel blockers (5 mM cesium chloride and 100 microM ZD7288) significantly reduced HCN currents and increased action potential frequency of the AB neurons in sham and T1D rats. Immunofluorescent and western blot analyses demonstrated that the expression of HCN1 and HCN2 channel protein in the NG from the T1D rats was higher than that from the sham rats.These results indicate that the HCN channels influence the excitability of AB neurons, and more importantly, contribute to the decreased excitability of AB neurons in T1D rats.
Metastatic Colonization Requires the Repression of the Epithelial-Mesenchymal Transition Inducer Prrx1
Authors: Oscar H. Ocaña, Rebeca Córcoles, Ángels Fabra, Gema Moreno-Bueno, Hervé Acloque, Sonia Vega, Alejandro Barrallo-Gimeno, Amparo Cano, M. Angela Nieto
Journal: Cancer Cell (2012)
Pulmonary tumours in the Netherlands: focus on temporal trends in histology and stage and on rare tumours
Authors: W K de Jong, M Schaapveld, J L G Blaauwgeers, H J M Groen
Journal: Thorax (2008)

<h3>Background:</h3> Recent temporal trends in histology and stage of pulmonary tumours in the Netherlands were studied. The incidence of rare pulmonary tumours was determined. <h3>Methods:</h3> All tumours originating from the trachea, bronchus and lung recorded in the Netherlands Cancer Registry were included. Based on ICD-O morphology codes, five major subgroups were constructed: squamous carcinoma (SC), adenocarcinoma (AC), large cell (undifferentiated) carcinoma (LC), small cell lung cancer (SCLC) and other (including uncommon tumours). <h3>Results:</h3> Between 1989 and 2003, 134 894 tumours were diagnosed. In men the age-adjusted incidence of SC and SCLC decreased, AC remained stable and LC increased. In women the incidence of all subgroups increased. Since 1996, a stage shift was observed with fewer patients in stage I and more patients in stage IV at diagnosis. This stage shift occurred equally in SC, AC and LC. In SC, fewer patients presented with stage IV disease than in AC and LC (25% vs 44% and 49% in 2003, respectively). The incidence of adenosquamous carcinoma decreased from 0.6 to 0.29/100 000 (p&lt;0.001). The incidence of carcinoid tumours, sarcomatoid carcinomas and primary pulmonary sarcomas remained stable (0.44, 0.17 and 0.08/100 000, respectively). <h3>Conclusion:</h3> The incidence of smoking-related tumours decreased in men (especially SC and SCLC) and increased in women (all subgroups). More patients presented with stage IV disease. The incidence of non-smoking-related uncommon tumours remained constant.
Estrogen Receptor Pathway: Resistance to Endocrine Therapy and New Therapeutic Approaches
Authors: Beverly Moy, Paul E. Goss
Journal: Clinical Cancer Research (2006)

Abstract Endocrine therapy is widely accepted as the most important treatment for all patients with hormone receptor–positive breast cancer. However, despite the positive effect of endocrine therapy on clinical outcome, resistance to these drugs inevitably develops. This article reviews the problem of resistance to hormonal therapy and addresses potential approaches to overcome intrinsic or acquired mechanisms of resistance.