tbuckley/cabot-search huggingface dataset:
Quantitative Promoter Hypermethylation Analysis of Cancer-Related Genes in Salivary Gland Carcinomas: Comparison with Methylation-Specific PCR Technique and Clinical Significance
Authors: Eung-Seok Lee, Jean-Pierre Issa, Dianna B. Roberts, Michelle D. Williams, Randal S. Weber, Merrill S. Kies, Adel K. El-Naggar
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To compare the methylation status of tumor-associated genes by quantitative pyrosequencing and qualitative methylation-specific PCR (MSP) techniques and to correlate the results with clinicopathologic features and patients outcome to determine which method might have greater clinical utility. Experimental Design: The hypermethylation status of the retinoid acid receptor β2 (RARβ2), RAS association domain family 1A (RASSF1A), O6-methylguanine-DNA methyltransferase (MGMT), and E-cadherin genes was analyzed in five salivary carcinoma cell lines and 69 human salivary gland carcinoma specimens by pyrosequencing and MSP techniques. The two datasets were compared by linear regression. Correlations between methods and with clinicopathologic characteristics were assessed by Pearson's χ2 test or the two-tailed Fisher exact test, as applicable, using cutoff points determined from the regression curves and empirical fitting. We also investigated the effect of demethylating agents on methylated genes in cell lines to assess their effect on the expression of these genes. Results: Overall, regression analysis indicated high degrees of correlation of the two methods for measurement of methylation for the RARb2, RASSF1A, and MGMT genes (adjusted R2 = 0.319, 0.835, and 0.178; P &amp;lt; 0.001, &amp;lt;0.001, and 0.0002, respectively) among the 69 tumors tested. However, the pyrosequencing technique yielded four more instances of methylation above background levels than MSP for RARβ2 and three more for RASSF1. Methylation of either RARβ2 and RASSF1A alone or both by pyrosequencing were correlated with tumor type (P = 0.027, 0.014, and 0.012, respectively). Methylation of RARβ2 alone and in combination with RASSF1A by pyrosequencing were also significantly correlated with tumor grade (P = 0.014 and 0.011, respectively) and 3-year survival (P = 0.002 and 0.004, respectively). The survival curves of patients who had hypermethylation at both RARβ2 and RASSF1A were significantly lower than those of patients who had hypermethylation at neither or just for the RASSF1A (P = 0.008 and 0.007, respectively). 5-Azadeoxycytidine treatment of methylated cell lines led to the reactivation of RARβ2 expression in only one of the five cell lines. Conclusions: (a) Although the methylation status of RARb2, RASSF1A, and MGMT genes by both techniques were significantly correlated, pyrosequencing is generally more sensitive and its results correlate better with the clinical variables than those of MSP. (b) The methylation level of the RARβ2 and/or RASSF1A by pyrosequencing is significantly associated with aggressive tumor phenotypes and patients survival.
Guanylyl Cyclase-A Inhibits Angiotensin II Type 1A Receptor-Mediated Cardiac Remodeling, an Endogenous Protective Mechanism in the Heart
Authors: Yuhao Li, Ichiro Kishimoto, Yoshihiko Saito, Masaki Harada, Koichiro Kuwahara, Takehiko Izumi, Nobuki Takahashi, Rika Kawakami, Keiji Tanimoto, Yasuaki Nakagawa, Michio Nakanishi, Yuichiro Adachi, David L. Garbers, Akiyoshi Fukamizu, Kazuwa Nakao
Journal: Circulation (2002)

Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice.We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta1 and beta3, were also strongly inhibited. Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals.These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling.
Endoscopic ultrasound-guided transluminal drainage of pancreatic duct obstruction: long-term outcome
Authors: M. Ergun, T. Aouattah, C. Gillain, J.-F. Gigot, C. Hubert, P. Deprez
Journal: Endoscopy (2011)

Endoscopic ultrasound-guided pancreatic drainage (EUS-PD) has been reported as an alternative to surgery, when transpapillary access to the main pancreatic duct (MPD) is impossible. The aim of the study was to investigate the feasibility of the procedure and long-term clinical outcome in patients treated with EUS-PD.We retrospectively analyzed our single-center experience over a 10-year period.EUS-PD was attempted in 20 patients (24 interventions), with a median age of 64 years (range 36 - 78). Indications for the procedure were post-Whipple symptomatic anastomotic stricture (n = 10) and chronic pancreatitis (n = 10). EUS-PD was performed by a transgastric (n = 16) or transbulbar (n = 3) route or with a rendezvous technique (n = 5). Wirsungography was performed in all interventions and successful drainage was achieved in 18 / 20 (90 %) patients. There were two minor procedure-related complications: bleeding that was treated endoscopically, and a perigastric collection that resolved spontaneously. Median follow up was 37 months (range 3 - 120 months), stent dysfunction occurred in 9 / 18 (50 %) patients. Out of 18 patients with successful EUS-PD, long-term pain resolution was observed in 13 (72 %). At the last follow-up visit, there were significant decreases in pain scores, from 7.5 to 1.6, and in MPD size from 8.1 mm to 3.9 mm. Failure was associated with cancer presence or recurrence.Technical success rate of EUS-PD and clinical long-term pain resolution were 90 % and 72 %, respectively. EUS-PD is a reliable procedure with a low complication rate. It might therefore replace surgery at expert centers.
High glucose sensitizes adult cardiomyocytes to ischaemia/reperfusion injury through nitrative thioredoxin inactivation
Authors: R. Luan, S. Liu, T. Yin, W. B. Lau, Q. Wang, W. Guo, H. Wang, L. Tao
Journal: Cardiovascular Research (2009)

AimsIschaemic cardiac injury is significantly increased in diabetic patients, but its underlying mechanisms remain incompletely understood. The current study attempted to identify new molecular mechanisms potentially contributive to hyperglycaemic-exaggeration of myocardial ischaemic injury.
Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01)
Authors: F. Barlesi, R. Gervais, H. Lena, J. Hureaux, H. Berard, D. Paillotin, S. Bota, I. Monnet, A. Chajara, G. Robinet
Journal: Annals of Oncology (2011)
Level of <i>HER2</i> Gene Amplification Predicts Response and Overall Survival in HER2-Positive Advanced Gastric Cancer Treated With Trastuzumab
Authors: Carlos Gomez-Martin, Jose Carlos Plaza, Roberto Pazo-Cid, Antonieta Salud, Francesc Pons, Paula Fonseca, Ana Leon, Maria Alsina, Laura Visa, Fernando Rivera, M. Carmen Galan, Elena del Valle, Felipe Vilardell, Mar Iglesias, Soledad Fernandez, Stefania Landolfi, Miriam Cuatrecasas, Marta Mayorga, M. Jose Paulés, Pilar Sanz-Moncasi, Clara Montagut, Elena Garralda, Federico Rojo, Manuel Hidalgo, Fernando Lopez-Rios
Journal: Journal of Clinical Oncology (2013)

Previous studies have highlighted the importance of an appropriate human epidermal growth factor receptor 2 (HER2) evaluation for the proper identification of patients eligible for treatment with anti-HER2 targeted therapies. Today, the relationship remains unclear between the level of HER2 amplification and the outcome of HER2-positive gastric cancer treated with first-line chemotherapy with trastuzumab. The aim of this study was to determine whether the level of HER2 gene amplification determined by the HER2/CEP17 ratio and HER2 gene copy number could significantly predict some benefit in overall survival and response to therapy in advanced gastric cancer treated with trastuzumab-based chemotherapy.Ninety patients with metastatic gastric cancer treated with first-line trastuzumab-based chemotherapy were studied. The optimal cutoff values for HER2/CEP17 ratio and HER2 gene copy number (GCN) for discriminating positive results in terms of response and prolonged survival were determined using receiver operating characteristic curves analyses.In this study, a median HER2/CEP17 ratio of 6.11 (95% CI, 2.27 to 21.90) and a median HER2 gene copy number of 11.90 (95% CI, 3.30 to 43.80) were found. A mean HER2/CEP17 ratio of 4.7 was identified as the optimal cutoff value discriminating sensitive and refractory patients (P = .005). Similarly, the optimal cutoff for predicting survival longer than 12 months was 4.45 (P = .005), and for survival longer than 16 months was 5.15 (P = .004). For HER2 GCN, the optimal cutoff values were 9.4, 10.0, and 9.5, respectively (P = .02).The level of HER2 gene amplification significantly predicts sensitivity to therapy and overall survival in advanced gastric cancer treated with trastuzumab-based chemotherapy.
Microcircuitry and function of the inferior olive
Authors: Chris I. De Zeeuw, Casper C. Hoogenraad, S.K.E. Koekkoek, Tom J.H. Ruigrok, Niels Galjart, John I. Simpson
Journal: Trends in Neurosciences (1998)

The inferior olive, which provides the climbing fibers to Purkinje cells in the cerebellar cortex, has been implicated in various functions, such as learning and timing of movements, and comparing intended with achieved movements. For example, climbing-fiber activity could transmit error signals during eye-blink conditioning or adaptation of the vestibulo-ocular reflex, or it could carry motor command signals beating on the rhythm of the oscillating and synchronous firing of ensembles of olivary neurons, or both. In this review, we approach the controversial issue of olivocerebellar function from the perspective of the unique organization of the microcircuitry of the olivary neuropil. The characteristic glomeruli are formed by a core of long dendritic or axonal spines, each of which is innervated by both an inhibitory terminal derived from the hindbrain and an excitatory terminal derived from either an ascending or descending input. The dendritic spines, which originate from dendrites with varicosities carrying dendritic lamellar bodies, are coupled by gap junctions. By drawing a comparison with a computational model by Segev and Rall,which might be applicable to the typical olivary spine with its unique morphological features and combined excitatory and inhibitory input, we propose that the microcircuitry of the inferior olive is capable of functioning both in motor learning and motor timing, but does not directly compare intended with achieved movements.
New Therapeutics for Chronic Heart Failure
Authors: Douglas L. Mann, Anita Deswal, Biykem Bozkurt, Guillermo Torre-Amione
Journal: Annual Review of Medicine (2002)

▪ Abstract Traditionally, clinicians have viewed heart failure either as a problem of excessive salt and water retention caused by abnormalities of renal blood flow, or as a hemodynamic problem associated with a reduced cardiac output and excessive peripheral vasoconstriction. Recently, clinicians have begun to adopt a neurohormonal model in which heart failure progresses because of the toxic effects of endogenous biological systems that become activated in heart failure. We review the rationale for existing heart failure therapies and discuss the reasoning behind the development of some emerging therapies.
Pharmacogenetics at 50: Genomic Personalization Comes of Age
Authors: Thomas J. Urban, David B. Goldstein
Journal: Science Translational Medicine (2012)

The study of the genetics of drug responses has a long history but has provided only a few examples of gene variants that are relevant clinically. Here, we discuss the current state of the pharmacogenomics field with emphasis on the potential of data generated through drug development in order to shed new light on genetic variants predictive of therapeutic outcomes-and likewise the potential of pharmacogenomics to improve clinical trial design. We note some examples in which data from clinical trials have already provided clear pharmacogenomic insights and suggest ways in which genomic technology might be used successfully in drug development.
Relaxing effect of interleukin-1 on rat cultured Ito cells
Authors: M Sakamoto, T Ueno, H Sugawara, T Torimura, R Tsuji, K Sujaku, M Sata, K Tanikawa
Journal: Hepatology (1997)

Interleukin-1β (IL-1β) is closely involved in liver disorders. IL-1β produces nitric oxide (NO) in vascular smooth muscle cells and relaxes vascular smooth muscle via cyclic guanosine 3′,5′-monophosphate (cGMP). In this study, we evaluated the relaxing effect of IL-1β on cultured Ito cells. Ito cells were isolated from the livers of male Wistar rats and cultured for 24 hours. Immunolocalization of inducible nitric oxide synthase (iNOS) and cGMP and intensity of fluorescence of cGMP were examined using a confocal laser microscope. Ito cells were treated with 0, 200, and 1,000 pmol/L IL-1β, and the intracellular cGMP concentration was measured after 12 hours. Moreover, Ito cells treated with 200 and 1,000 pmol/L IL-1β and not treated with IL-1β were observed over 12 hours, and the area of the same Ito cell was compared before and after the addition of IL-1β. Next, effects of N G -monomethyl-L-arginine (L-NMMA) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) on Ito cell relaxation by IL-1β treatment were examined. In Ito cells, immunofluorescence of iNOS was observed, and fluorescent intensity of cGMP increased after addition of IL-1β. Intracellular cGMP concentration increased dose-dependently after addition of IL-1β. Cell area significantly increased in the IL-1β-treated group compared with the untreated group. Relaxation of Ito cells by IL-1β treatment was inhibited by L-NMMA in a dose-dependent manner, but was enhanced by SNAP. These results indicate that IL-1β produces NO in cultured Ito cells and relaxes the cells via cGMP.
Diazoxide causes early activation of cardiac sarcolemmal KATP channels during metabolic inhibition by an indirect mechanism
Authors: G Rodrigo
Journal: Cardiovascular Research (2003)

We have used isolated myocytes to investigate the effects of diazoxide on sarcolemmal KATP channel (sarcoKATP) activity and action potential failure during metabolic inhibition, and the role of these channels in protection of functional recovery on reperfusion.Isolated adult rat ventricular myocytes were exposed to metabolic inhibition (NaCN and iodoacetate) and reperfusion. Functional recovery was assessed from the ability of cells to contract on electrical stimulation and to recover calcium homeostasis, measured with fura-2. Action potentials and KATP currents were measured using patch clamp.Pretreatment with diazoxide (100 microM, 5 min) increased the proportion of cells that recovered contractile function after MI and reperfusion from 16.8 +/- 2.4% to 65.0 +/- 2.2% (p<0.001) and the proportion of cells in which [Ca2+]i recovered to <250 nM. Pretreatment also accelerated action potential and contractile failure during MI. In cell-attached patches, MI activated sarcoKATP channels after 224 +/- 11 s, and diazoxide pretreatment decreased this to 145 +/- 24 s (p<0.01). However, diazoxide present in the patch pipette did not accelerate sarcoKATP channel activation. Intracellular Mg2+ rose earlier in diazoxide-pretreated cells. The sarcoKATP blocker HMR 1883 delayed action potential failure and reduced diazoxide protection.Diazoxide pretreatment increases recovery of function and [Ca2+]i following reperfusion. Protection is coupled with early action potential failure, due to early activation of sarcoKATP channels during metabolic inhibition (MI), which is likely to involve an indirect effect of diazoxide.
Recombinant Human Erythropoietin and Overall Survival in Cancer Patients: Results of a Comprehensive Meta-analysis
Authors: J. Bohlius, S. Langensiepen, G. Schwarzer, J. Seidenfeld, M. Piper, C. Bennett, A. Engert
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: Anemia associated with cancer and cancer therapy is an important clinical and economic factor in the treatment of malignant diseases. Methods: We conducted a systematic literature review to assess the efficacy of erythropoietin to prevent or treat anemia in cancer patients with regard to red blood cell transfusions, hematologic response, adverse events, and overall survival. We searched the Cochrane Library, Medline, EMBASE, and other databases for relevant articles published from January 1985 to December 2001. We included all randomized controlled trials that compared the use of recombinant human erythropoietin (plus transfusion, if needed) with no erythropoietin treatment (plus transfusion, if needed). Relative risks (RRs) and 95% confidence intervals (CIs) were calculated under a fixed-effects model. Clinical and statistical heterogeneity were examined with sensitivity analyses and meta-regression. Statistical tests for effect estimates were two-sided. Results: We identified 27 trials involving 3287 adult patients. Patients treated with erythropoietin had a lower relative risk of having a blood transfusion than untreated patients (RR = 0.67, 95% CI = 0.62 to 0.73). Erythropoietin-treated patients with baseline hemoglobin levels lower than 10 g/dL were more likely to have a hematologic response than untreated patients (RR = 3.60, 95% CI = 3.07 to 4.23). The relative risk for thromboembolic complications after erythropoietin treatment was not statistically significantly increased (RR = 1.58, 95% CI = 0.94 to 2.66) compared with that of untreated patients. There is suggestive but inconclusive evidence that erythropoietin may improve overall survival (adjusted data: hazard ratio [HR] = 0.81, 95% CI = 0.67 to 0.99; unadjusted data: HR = 0.84, 95% CI = 0.69 to 1.02). Conclusions: Erythropoietin treatment may reduce the risk for blood transfusions and improve hematologic response in cancer patients. However, our favorable survival outcome is in contrast to two large (N = 351 and 939) recently published randomized controlled trials in which erythropoietin-treated patients had statistically significantly worse survival than untreated patients. Possible reasons for the disparity with our results include differences in study population and design, higher target hemoglobin levels and higher risk of thromboembolic complications, and concerns that erythropoietin may stimulate tumor growth.
Endogenous Osteonectin/SPARC/BM-40 Expression Inhibits MDA-MB-231 Breast Cancer Cell Metastasis
Authors: Jennifer E. Koblinski, Benjamin R. Kaplan-Singer, Sherilyn J. VanOsdol, Michael Wu, Jean A. Engbring, Songlin Wang, Corinne M. Goldsmith, John T. Piper, Jaroslav G. Vostal, John F. Harms, Danny R. Welch, Hynda K. Kleinman
Journal: Cancer Research (2005)

Abstract Skeletal metastases occur with high incidence in patients with breast cancer and cause long-term skeletal morbidity. Osteonectin (SPARC, BM-40) is a bone matrix factor that is an in vitro chemoattractant for breast and prostate cancer cells. Increased expression of osteonectin is found in malignant breast tumors. We infected MDA-231 breast cancer cells with an adenovirus expressing osteonectin to examine the role of osteonectin expression in breast cancer cells and its effect on metastasis, in particular to bone. Expression of osteonectin did not affect MDA-231 cell proliferation, apoptosis, migration, cell aggregation, or protease cleavage of collagen IV. However, in vitro invasion of these osteonectin-infected cells through Matrigel and colony formation on Matrigel was decreased. Interestingly, high osteonectin expression in MDA-231 cells inhibited metastasis in a dose-dependent manner to many different organs including bone. The reduction in metastasis may be due to decreased platelet-tumor cell aggregation, because exogenous osteonectin inhibited platelet aggregation in vitro and the high osteonectin expression in MDA-231 cells reduced tumor cell-induced thrombocytopenia in vivo compared with control-infected cells. These studies suggest that high endogenous expression of osteonectin in breast cancer cells may reduce metastasis via reduced invasive activity and reduced tumor cell-platelet aggregation.
Genetic Polymorphisms in Vitamin D Receptor <i>VDR/RXRA</i> Influence the Likelihood of Colon Adenoma Recurrence
Authors: Jan B. Egan, Patricia A. Thompson, Erin L. Ashbeck, David V. Conti, David Duggan, Elizabeth Hibler, Peter W. Jurutka, Elizabeth C. LeRoy, María Elena Martínez, David Mount, Elizabeth T. Jacobs
Journal: Cancer Research (2010)

Abstract Low circulating levels of vitamin D affect colorectal cancer risk. The biological actions of the hormonal form of vitamin D, 1,25(OH)2D3, are mediated by the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptors (RXR). Using a single nucleotide polymorphism (SNP) tagging approach, we assessed the association between genetic variations in RXRA and VDR and odds of recurrent (metachronous) colorectal neoplasia in a pooled population of two studies. A total of 32 tag SNPs in RXRA and 42 in VDR were analyzed in 1,439 participants. A gene-level association was observed for RXRA and any (P = 0.04) or proximal (P = 0.03) metachronous neoplasia. No gene-level associations were observed for VDR, nor was any single SNP in VDR related to any metachronous adenoma after correction for multiple comparisons. In contrast, the association between RXRA SNP rs7861779 and proximal metachronous neoplasia was of borderline statistical significance [odds ratio (OR), 0.68; 95% confidence interval (95% CI), 0.53-0.86; unadjusted P = 0.001; adjusted P = 0.06], including when observed independently in each individual study. Haplotypes within linkage blocks of RXRA support an ∼30% reduction in odds of metachronous neoplasia arising in the proximal colon among carriers of specific haplotypes, which was strongest (ORproximal, 0.67; 95% CI, 0.52–0.86) for carriers of a CGGGCA haplotype (rs1805352, rs3132297, rs3132296, rs3118529, rs3118536, and rs7861779). Our results indicate that allelic variation in RXRA affects metachronous colorectal neoplasia, perhaps of particular importance in the development of proximal lesions. Cancer Res; 70(4); 1496–504