tbuckley/cabot-search huggingface dataset:
5'-Monophosphate-activated protein kinase (AMPK) improves autophagic activity in diabetes and diabetic complications
Authors: Fan Yao, Ming Zhang, Li Chen
Journal: Acta Pharmaceutica Sinica B (2015)

Diabetes mellitus (DM), an endocrine disorder, will be one of the leading causes of death world-wide in about two decades. Cellular injuries and disorders of energy metabolism are two key factors in the pathogenesis of diabetes, which also become the important causes for the process of diabetic complications. AMPK is a key enzyme in maintaining metabolic homeostasis and has been implicated in the activation of autophagy in distinct tissues. An increasing number of researchers have confirmed that autophagy is a potential factor to affect or induce diabetes and its complications nowadays, which could remove cytotoxic proteins and dysfunctional organelles. This review will summarize the regulation of autophagy and AMPK in diabetes and its complications, and explore how AMPK stimulates autophagy in different diabetic syndromes. A deeper understanding of the regulation and activity of AMPK in autophagy would enhance its development as a promising therapeutic target for diabetes treatment.
Abstract 331: The Effects of the Rate of Post-resuscitation Rewarming following Hypothermia on Outcomes of CPR in a Rat Model
Authors: Xiaoye Lu, Linhao Ma, Shijie Sun, Wanchun Tang, Jeifeng Xu
Journal: Circulation (2013)

Background: Both clinical and laboratory studies have demonstrated that mild therapeutic hypothermia(TH) following CPR improves myocardial and neurologic outcomes of cardiac arrest. However, the optimal rewarming strategy following TH remains to be explored. The present study investigated the optimal rewarming rate following TH in a rat model of CPR. Methods and Results: Four groups of SD rats were randomized: 1) Control; 2) rewarming rate at 2°C/h; 3) rewarming rate at 1°C/h ; 4) rewarming rate at 0.5°C/h. VF was induced and untreated for 8 mins; defibrillation was attempted after 8 mins of CPR. The body temperature of the controls were maintained at 37±0.2°C throughout the experiment; For 2°C/h, 1°C/h and 0.5°C/h groups, rapid cooling was started with the aid of ice packs at the beginning of CPR. Upon reaching the target temperature of 33±0.2°C, the temperature was maintained with the aid of a cooling blanket until 4hrs after resuscitation. The rewarming was then initiated at the rate of 2.0°C, 1.0 °C or 0.5 °C per hour respectively until the body temperature reached 37±0.2 °C,which maintained at 37±0.2 °C for 6 hrs in 2 °C/h group, 4 hrs in 1 °C/h group, and 0 hours in 0.5 °C/h group. Blood samples were drawn at baseline, PR4, 6, 8, 10 and 12hrs for the measurements . Blood temperature was significantly decreased in the TH groups from CPR to PR 4hrs. Significantly better CO, EF, MPI and reduced neurological scores, longer duration of survival were observed in 1°C/hr and 0.5°C/hr groups. The increased serum levels of TnI, IL-6 and TNF-α was partly attenuated in 1°C/hr and 0.5°C/hr groups when compared with control and 2°C/hr groups. Conclusions: The present study demonstrated that the severity of myocardial, cerebral injuries and inflammatory reaction after CPR were reduced when mild TH was applied. A rewarming rate at 0.5-1°C/h did not alter the beneficial effects of TH. However, a rapid rewarming rate at 2°C/h abolished the beneficial effects of TH.
Abstract 11488: MicroRNA-141 is a Novel Regulator of BMP-2-Mediated Calcification in Aortic Stenosis
Authors: Bobby Yanagawa, Fina Lovren, Yi Pan, Nandini Gupta, Mark Peterson, Adrian Quan, Subodh Verma
Journal: Circulation (2011)

Bone morphogenic protein 2 (BMP-2) is a major regulator of aortic valve calcification and understanding its molecular regulation may uncover novel treatment approaches to limit calcific aortic sten...
Epigenetic silencing of DOC-2/hDAB-2 in nasopharyngeal carcinoma
Authors: Joseph Kwong, Kwok-Wai Lo, Samuel C. Mok, Yin-Ling Chan, Wing-Ki Hung, Dolly P. Huang
Journal: Cancer Research (2004)

4182   DOC-2/hDAB2 is a signal transduction molecule which involved in multiple signaling pathways, such as Ras/MAPK pathway, ILK signaling pathway and gp300/megalin signal transduction pathway. Recent studies demonstrated that DOC-2/hDAB2 is down-regulated in ovarian, prostate, pancreatic, colorectal cancers and choriocarcinoma. When  DOC-2/hDAB2  was transfected into the ovarian carcinoma cell line, the stable transfectants showed significant reduced growth rate and ability to form tumors in nude mice. The data suggested that  DOC-2/hDAB2  is a tumor suppressor, and a potent growth inhibitor in human cancers. The aim of this study is to examine aberrant expression of  DOC-2/hDAB2  and the mechanism that down-regulate  DOC-2/hDAB2  in nasopharyngeal carcinoma (NPC). Real-time quantitative RT-PCR was applied to examine mRNA expression of  DOC-2/hDAB2  in 5 NPC cell lines, 3 NPC xenografts, an immortalized normal nasopharyngeal epithelial cell line and 2 normal nasopharyngeal epithelial outgrowth cultures. The methylation status of  DOC-2/hDAB2  promoter was investigated by genomic bisulfite sequencing and methylation-specific PCR (MSP). Doc2/hDAB2 protein expression was determined by immunohistochemistry in primary NPC. Among NPC cell lines and xenografts, loss of  DOC-2/hDAB2  transcript was detected in three EBV positive NPC lines (C666-1, X666 and X2117). Dense methylation of  DOC-2/hDAB2  5’ CpG islands was also detected in these three lines. However, methylation was not observed in  DOC-2/hDAB2  expressed NPC cell lines, xenografts and normal nasopharyngeal epithelial cells. When treating the  DOC-2/hDAB2  negative NPC cell line (C666-1) with 5-aza-2’-deoxycytidine, re-activation of  DOC-2/hDAB2  expression was observed. In addition,  DOC-2/hDAB2  promoter hypermethylation was detected in 14 of 20 (70%) primary NPC tumors by MSP. Furthermore, Doc2/hDAB2 protein expression was absent in 8 of 15 (53%) primary tumors. The correlation between the immunostaining of Doc2/hDab2 and the methylation status of  DOC2/hDAB2  5’ CpG islands in primary NPC will be evaluated. These results strongly suggested that promoter hypermethylation is one of the major mechanisms for down-regulation of  DOC-2/hDAB2  in NPC. Frequent inactivation of  DOC-2/hDAB2  implied that it is a candidate tumor suppressor gene of NPC. In conclusion, signal transduction molecule  DOC-2/hDAB2  silenced in NPC by promoter hypermethylation was found. We believe that multiple signal transduction pathways were disrupted in NPC through the elimination of DOC-2/hDAB2 in normal nasopharyngeal epithelial cells.
The effect of the copper transporters ATP7A and ATP7B on the cytotoxicity and cellular pharmacology of JM-118
Authors: Goli Samimi, Stephen B. Howell
Journal: Cancer Research (2005)

4110  Satraplatin is the first orally available platinum chemotherapeutic drug. This drug is of interest in that it has potent in vitro growth inhibitory activity and a favorable clinical toxicity profile compared to cisplatin. However, because satraplatin is rapidly metabolized in vitro, it is more relevant to study the cellular pharmacology of its most active metabolite, JM-118. In an effort to identify specific characteristics of JM-118 that distinguish it from cisplatin, we examined the effects of expression of the copper transporters ATP7A and ATP7B on the sensitivity to and cellular pharmacology of JM-118. Studies were performed in human Menkes disease fibroblasts (Me32a cells) that do not express either transporter and sublines molecularly engineered to express either human ATP7A (MeMNK cells) or murine ATP7B (MeWND cells). Expression of either ATP7A or ATP7B rendered the cells resistant to cisplatin and JM-118 treatment. For MeMNK cells, the average growth ratio versus Me32a cells following 72 hr exposure to 10 μM drug was 2.5 ± 0.5 for DDP and 2.9 ± 0.2 for JM-118. For MeWND cells, the average growth ratio versus Me32a cells following 72 hr exposure to 10 μM drug was 2.1 ± 0.9 for DDP and 2.8 ± 0.8 for JM-118. Interestingly, resistance to these drugs was accompanied by an increase rather than a decrease in whole cell platinum accumulation in MeMNK and MeWND cells following 24 hr exposure to physiologically relevant concentrations of cisplatin or JM-118. For MeMNK cells, the average fold increase versus Me32a cells following 24 hr exposure to 2 μM drug was 2.1 ± 0.3 for DDP and 2.7 ± 0.7 for JM-118. For MeWND, the average fold increase versus Me32a cells following 24 hr exposure to 2 μM drug was 1.8 ± 0.3 for DDP and 2.8 ± 0.5 for JM-118. Examination of platinum content in DNA revealed marginally lower platinum levels in cisplatin-treated MeMNK and MeWND cells compared to treated Me32a cells; uptake following 24 hr exposure to 2 μM drug in MeMNK cells was 0.7 ± 0.1 of that in the Me32a cells and in MeWND was 0.8 ± 0.1 of that in the Me32a cells. In contrast, examination of platinum content in DNA revealed significantly increased platinum levels in JM-118 treated MeMNK and MeWND cells compared to treated Me32a cells; the average fold increase versus Me32a cells following 24 hr exposure to 2 μM drug was 1.5 ± 0.1 for MeMNK and 1.5 ± 0.2 for MeWND. We conclude that ATP7A and ATP7B play a role in the regulation of sensitivity to JM-118, and that JM-118 is sequestered differently from cisplatin by these copper efflux transporters, a cellular pharmacologic characteristic that clearly distinguishes JM-118 from cisplatin. This work is supported by a research contract from GPC Biotech.
CD28 Mutations in Peripheral T-Cell Lymphomagenesis and Progression
Authors: Joseph Rohr, Shuangping Guo, Dongdong Hu, Alyssa Bouska, Randy D. Gascoyne, Andreas Rosenwald, Peter Simone, Weiwei Zhang, Wenming Xiao, Chao Wang, Kai Fu, Timothy C. Greiner, Dennis D. Weisenburger, Julie M. Vose, Louis M. Staudt, Francoise Berger, Gloria Borgstahl, Simon Davis, Timothy McKeithan, Javeed Iqbal, Wing-Chung (John) Chan
Journal: Blood (2014)
Correlation of Clinical and Molecular Response to Imatinib in Polycythemia Vera (PV) Patients with Bone Marrow Morphologic and Immunophenotypic Changes.
Authors: Elizabeth Hyjek, Amy Chadburn, Nicholas C.P. Cross, Amy V. Jones, Su-Chieh P. Sun, Susan Mathew, April Chiu, April Young, D.M. Knowles, Richard T. Silver
Journal: Blood (2006)
Progress Toward Interrupting Indigenous Measles Transmission—Region of the Americas, January 1999-September 2000
Authors: H. S. Izurieta, L. Venczel, P. Carrasco, G. Tambini, C. Castillo, M. Landaverde, M. Brana, C. A. de Quadros, Z. Garib, C. Pedreira, R. Quiroga, O. Barrezueta, A. M. Desormeaux, F. Laender, J. Dobbins, J. André, E. Luna, L. Brondi, M. C. Quixadá, S. Parise, C. Segatto, R. Prevots, I. Micelli, J. Vilosio, V. Dietz
Journal: JAMA (2000)

This report summarizes the measles control strategies implemented  by the Pan American Health Organization (PAHO) in countries  situated in the Region of the Americas.  A three-part vaccination  strategy for interrupting indigenous measles transmission was  recommended by PAHO.  These include: 1) a one-time nationwide   campaign targeting all persons aged 1-14 years; 2)  routine  vaccination among 1-year-olds; and 3)  nationwide  campaigns conducted every 4 years  targeting all children of 41 countries in the region.  Moreover  39 of 41 countries in the regions conducted catch-up campaigns  during 1989-95 follow-up campaigns since 1994 and routine  keep-up coverage increased from 80% in 1994 to 91% in 1999.   Overall the PAHO measles control strategies have made important  progress in suppressing measles transmission.  Moreover dedicated  health care personnel resources and political support have  intensified the success.
Decreased expression of 14-3-3 sigma is a prognostic factor in human epithelial ovarian cancer: Its correlation with aberrant DNA methylation
Authors: Jun-Ichi Akahira, Takashi Suzuki, Kiyoshi Ito, Takuya Moriya, Hironobu Sasano, Nobuo Yaegashi
Journal: Cancer Research (2004)

4982    Objective:  14-3-3 sigma, one isoform of the 14-3-3 family, plays a crucial role in the G2 checkpoint by sequestering Cdc2-cyclin B1 in the cytoplasm and the expression is frequently lost in human cancers. In this study, we examined the promoter methylation status and expression of 14-3-3 sigma, and evaluated its clinical significance in epithelial ovarian cancer.  Materials and Methods:  Twelve ovarian cancer cell lines, 2 ovarian surface epithelial cell lines, 8 normal, 8 benign, 12 borderline, and 102 ovarian cancer tissues were examined. Methylation specific PCR (MSP), quantitative RT-PCR, immunoblotting, and immunohistochemistry were employed to evaluate methylation status and expression of 14-3-3 sigma gene and protein.  Results:  Among the 12 ovarian cancer cell lines, the presence of methylated band was detected in 7 cell lines, 2 of which were together with unmethylated bands. Both of OSE cells were negative for methylated bands. By quantitative RT-PCR analysis, median values of relative 14-3-3 sigma gene expression in cancers with methylation (3.27) were significantly lower than those without methylation (16.4)(p  2cm, high serum CA125, high Ki-67 LI, and positive p53 immunoreactivity. In univariate analysis, 14-3-3 sigma immunoreactivity, age, performance status, grade, stage, residual tumor, and Ki-67 were significantly associated with overall survival. Negative 14-3-3 sigma cases were significantly worse overall survival and disease free survival (p=0.0058 and 0.002, respectively). In multivariate analysis, stage and residual tumor turned out to be independent prognostic factors.  Conclusion:  Our findings suggest that 14-3-3 sigma is inactivated mainly by aberrant DNA methylation and it may play an important role in the pathogenesis of epithelial ovarian cancer.
Identification of transcriptional programs regulated by p63 in primary epithelial cells
Authors: Chris Barton, Deborah Mays, Carmen Perez, Jennifer Pietenpol
Journal: Cancer Research (2008)

4408  p63, a p53 homologue, is required for normal development of stratified and glandular epithelia such as the skin, breast, and prostate. Along with a developmental role, p63 is often overexpressed in squamous epithelial cancers as a result of genomic amplification. To discover transcriptional programs regulated by p63 in epithelial cells, we have carried out whole genome chromatin immunoprecipitation (ChIP) to identify genomic loci bound by p63 in normal human epidermal keratinocytes (NHEK). From this dataset, we sequenced over 5,000 candidate binding sites for p63, representing 2,879 candidate target genes. These genes group into several enriched ontological classes, with “tissue development,” “cell-cell signaling/interaction,” and “cell morphology,” representing the most significant matches. Parallel microarray analysis following RNAi-mediated p63 depletion in NHEKs identified 86 genes that were present in our ChIP dataset and also displayed significant transcriptional changes following p63 knockdown. Chromatin immunoprecipitation (ChIP) validated a number of the candidate genes such as CALML5, BDKRB1, FOSL2, IL1A, ITGA6, NRG1, and RAB38 as direct transcriptional targets of p63 in human keratinocytes. Further, these target genes are regulated during calcium-induced differentiation of keratinocytes, a process known to result in down-regulation of p63. Further, using our expression analyses, we derived a p63 gene “signature” that we used to query the Connectivity Map (Lamb, et al., 2006) to identify perturbagens or drugs that would modulate either endogenous levels of p63 and/or epithelial cell differentiation. In addition to a number of molecules known to modulate keratinocyte differentiation, this approach identified other drugs able to modulate p63 expression in human keratinocytes. Thus, the use of newly identified target genes aided in the discovery of small molecules capable of modulating the expression of p63. Future use of this approach carries the potential to identify drugs or small compounds that may act to treat specific cancers and/or skin diseases that are driven by the deregulation of the p63 signaling pathway.  Lamb et al., The Connectivity Map: using gene expression signatures to connect small molecules, genes, and disease. Science. (2006) 313(5795):1929-35.
Chemoimmunotherapy for Chronic Lymphocytic Leukemia
Authors: Valentin Goede, Kirsten Fischer, Michael Hallek
Journal: New England Journal of Medicine (2014)

To the Editor: Goede et al. (March 20 issue)1 report improved outcomes in patients with chronic lymphocytic leukemia (CLL) and coexisting conditions who received obinutuzumab in combination with chlorambucil. This conclusion is flawed because of underdosing of chlorambucil. In Germany, chlorambucil is licensed for treatment of CLL starting at 0.4 mg per kilogram of body weight every other week, with gradual increases in increments of 0.1 mg per kilogram until there is a clinical response or toxicity. The study, however, used a fixed dose of 0.5 mg per kilogram every other week without escalation. The dose escalation of chlorambucil is based on earlier data by Knospe et al.,2 who described a remission rate of 61% among untreated patients with CLL; this rate is higher than the 31.4% rate reported by Goede et al. Knospe and colleagues reported a median maximum dose of 0.90 mg per kilogram (range, 0.40 to 1.83). So far, no other chlorambucil dosing schedule has been shown to be superior. Goede and colleagues cite a study that compared chlorambucil with fludarabine.3 In that study, the planned dose escalation of chlorambucil, starting at 0.4 mg per kilogram, was not performed in most of the patients; thus the median dose was only 0.5 mg per kilogram every other week. The similar progression-free survival among patients in the chlorambucil and fludarabine groups in that study cannot justify the lowering of an established and approved dose regimen. We believe that treating control patients below the therapeutic standard jeopardizes the validity of study results and, moreover, violates rules in the Declaration of Helsinki that a new intervention must be tested against “the best proven intervention.” 4 Jurgen Spehn, M.D.
Abstract 13621: Prospective Study to Evaluate the Accuracy of Aortic Annulus Diameter Measurement: a Comparison of Multi-detector CT versus Two- and Three- Dimensional Echocardiography
Authors: Hiroshi Tsuneyoshi, Tatsuhiko Komiya, Takeshi Shimamoto
Journal: Circulation (2014)

OBJECTIVE:  Accurate preoperative quantification of the aortic annulus diameter is crucial for the success of aortic valve surgery, especially transcatheter aortic valve implantation (TAVI). We conducted this prospective study to compare the accuracy of preoperative aortic annulus measurement to direct measurements taken during open aortic valve surgery.   METHODS:  We enrolled 52 patients who underwent open aortic valve surgery between February 2012 and October 2013. In each case, we used transthoracic two-dimensional echocardiography (2D-TTE), transesophageal three-dimensional echocardiography (3D-TEE), and multi-detector CT (MDCT) to measure the diameter of the aortic annulus. Lab technicians performed the measurements blindly, and then the diameter of the aortic annulus was measured directly at surgery. The results of these intraoperative aortic annulus measurements were not revealed until the study ended in October 2013.   RESULTS:  The results of all three methods presented certain measures of accuracy; however,, none was perfect. Of the three methods, MDCT provided the smallest margin of error when compared to direct measurements taken at surgery. MDCT provided the smallest (95%) probability range (within±1.96SD) for measuring the aortic diameter of all the imaging methods used in this present study. However, the diameter predicted by MDCT was slightly larger (by about 1 mm) than the direct measures taken during surgery.(Figure)   CONCLUSIONS:  MDCT measurements provided the closest agreement in measuring the diameter of the aortic annulus compared to 2D-TTE and 3D-TEE; however, there was fixed positive bias of about 1mm. We may be able to eliminate this bias as we obtain more data from MDCT and compensate accordingly.
Larger studies are needed
Authors: K. S Bhatnagar
Journal: BMJ (1995)

schizophrenia is increased for black people and Asians compared with the local white population in Merton and Wandsworth.There seems, however, to be an additional risk for black people living in Wandsworth.There is a non-significant trend to a slightly increased risk of bipolar affective disorder.As a service driven instrument the long term case register does not have the epidemiological robustness of King and colleagues' study, but we do not consider our findings to be artefacts.The differences among ethnic groups have been stable over five years despite a 47% turnover of people on the register and a 70% change in the consultants making the clinical diagnoses.Furthermore, as mental health services are often considered to be inaccessible to ethnic minorities the long term case register may be expected to underestimate the
Abstract 14053: Development of Hypercholesterolemia-Induced Complex Unstable Atherosclerotic Lesions in a Novel Low Density Lipoprotein Receptor Knockout Pig
Authors: Mitsumasa Sudo, Yuxin Li, Akira Onishi, Seiji Fukushima, Shunichi Suzuki, Daiichiro Fuchimoto, Shoichiro Sembon, Masaki Iwamato, Michiko Hashimoto, Hironori Haruta, Tadateru Takayama, Takafumi Hiro, Taro Matsumoto, Masako Mitsumata, Masahiko Sugitani, Satoshi Saito, Atsushi Hirayama
Journal: Circulation (2012)

Background: Atherosclerotic plaque rupture is the most common cause of acute coronary syndrome, but the detail process of plaque development and rupture is not well known by lack of suitable animal...
Abstract 5280: A polymorphism of VEGFA is associated with susceptibility to extrathyroidal invasion of papillary thyroid cancer
Authors: Young Gyu Eun, Young Chan Lee, Jung-Woo Lee
Journal: Cancer Research (2015)

Abstract Background: Vascular endothelial growth factor A (VEGFA) has pivotal roles in angiogenesis, vascular permeability, vasculogenesis, cellular growth, and cell migration. We investigated whether single nucleotide polymorphisms (SNPs) of the VEGFA gene are associated with the development of papillary thyroid cancer (PTC). We also assessed the relationships between VEGFA SNPs and the clinicopathologic characteristics such as the size of cancers (&amp;lt; 1 cm and ≥ 1 cm), numbers of cancers (unifocality and multifocality), location of cancers (one lobe and both lobe), extrathyroidal invasion (present and absent), and cervical lymph node metastasis (present and absent). Methods: One promoter SNP (rs699947, -2578A/C) and one 5′-untranslation region (5′UTR) SNP (rs2010963, +405C/G) in VEGFA were genotyped using direct sequencing in 94 PTC patients and 213 healthy controls. SNPStats, SNPAnalyzer, Helixtree, and Haploview version 4.2 were used to analyze genetic data. Multiple logistic regression models (codominant, dominant, recessive, and log-additive) were performed to evaluate odds ratios (ORs), 95% confidence intervals (CIs), and p values. Results: Two SNPs of VEGFA were not associated with the development of PTC. Also, haplotypes were not associated with PTC??. However, we found a relationship between the 5′UTR SNP rs2010963 and PTC with the extrathyroidal invasion (p = 0.0060 in codominant model, p = 0.0258 in dominant model, p = 0.0057 in recessive model, and p = 0.0060 in log-additive model). Allele frequencies of rs2010963 were different between the extrathyroidal invasion (-) and extrathyroidal invasion (+) groups (p = 0.0050). In Bonferroni correction, these correlations were also significant except the recessive model. Conclusion: Our results suggest that the 5′UTR SNP rs2010963 (+405C/G) of VEGFA may be associated with susceptibility to extrathyroidal invasion of PTC in Korean population. Note: This abstract was not presented at the meeting. Citation Format: Young Gyu Eun, Young Chan Lee, Jung-Woo Lee. A polymorphism of VEGFA is associated with susceptibility to extrathyroidal invasion of papillary thyroid cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5280. doi:10.1158/1538-7445.AM2015-5280