tbuckley/cabot-search huggingface dataset:
Abstract 1197: Selenium-binding protein 1-mediated tumor suppression is associated with alterations of lipid/glucose metabolic pathways in vivo
Authors: Qi Ying, Emmanuel Ansong, Alan M. Diamond, Zhaoxin Lu, Xiaomei Bie, Wancai Yang
Journal: Cancer Research (2015)

Abstract Selenium-binding protein 1 (SBP1) is significantly decreased in most of human cancers including liver, prostate, breast, lung and colorectal cancers, and the decreased SBP1 is associated with poor clinical outcomes and recurrence, showing a tumor suppressor role. However, the underlying mechanisms are still unclear. In this study, we constructed a doxycycline inducible SBP1 plasmid (pRetroX-Tight- Pur-SBP1) and established a stable colorectal cancer cell line HCT116-TetSBP1, then injected the HCT116-TetSBP1 cell line into BALB/c CD-1 Nu female mice subcutaneously on the right flank, the control cell line HCT116-Act was injected in the left flank. The mice was supplied with Doxycycline (200 μg/mL) in drinking water. Four weeks after injection, the tumors from both sides were isolated and the weight (gm) and volume (mm3) of tumors were determined. Tumors were stored at -80°C until used for immunoblot and isobaric tags for relative and absolute quantitation (iTRAQ) analysis. We found that induction of SBP1 showed significant inhibition of cancer cell growth and metastasis in mice. iTRAQ analysis showed 132 differentially expressed proteins in response to SBP1 induction, among them, 53 proteins were upregulated and 79 proteins were downregulated. Importantly, many of the differentially altered proteins were associated with lipid/glucose metabolism. Although all seven proteins related to glucose metabolism (GAA, GAPDH, ALDH2, Thioredoxin, ENO3, UGDH and Lumican) were downregulated by SBP1 induction, thirteen lipid metabolism-related proteins act differentially on SBP1-medited signal transduction (five proteins were upregulated: DKK1, HSP60, DHCR7, ANXA4 and AGPAT5, and eight proteins were downregulated: LPCAT2, GPX5, GAPDH, NME2, ALDH2, BPIFA3, PPIA and FABP4). Bioinformatic analysis showed that these proteins were involved in Glycolysis, MAPK, Wnt, NF-kB, NOTCH and epithelial-mesenchymal transition (EMT) signaling pathways. Taken together, our results have revealed a novel mechanism that SBP1-mediated cancer inhibition is through altering lipid/glucose metabolic signaling pathways. Note: This abstract was not presented at the meeting. Citation Format: Qi Ying, Emmanuel Ansong, Alan M. Diamond, Zhaoxin Lu, Xiaomei Bie, Wancai Yang. Selenium-binding protein 1-mediated tumor suppression is associated with alterations of lipid/glucose metabolic pathways in vivo. [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 1197. doi:10.1158/1538-7445.AM2015-1197
Double Serine Phosphorylation of P47(Phox) At 303-304 is Critical for Acute Tnf alpha-Induced Ros Production but Not for Mapk Activation in Endothelial Cells
Authors: Lei Teng, Jian-Mei Li
Journal: Circulation (2011)

p47phox is a major regulatory subunit of Nox2 enzyme, which by generating superoxide plays important role in TNFα-induced endothelial dysfunction. The p47phox has several serines clustered within t...
Abstract 3238: Financial Impact to Hospitals of Changing Medicare Payment Policy for Avoidable Complications Associated with Cardiovascular Admissions
Authors: Matthew R Reynolds, Aaron D Kugelmass, Phillip P Brown, Steven D Culler, April W Simon
Journal: Circulation (2008)

Objective:  CMS has proposed 17 avoidable complications (AVC) that will no longer result in incremental hospital reimbursement. This analysis identifies AVC rates among 5 types of cardiovascular procedures and calculates the financial impact to hospitals of this payment policy.   Methods:  This retrospective study examined MedPar Files from 2006 to identify all hospital admissions where a Medicare Beneficiary (MB) underwent CABG, cardiac valve surgery, PCI, ICD implant, or PPM implant. The study population consists of 823,097 admissions. ICD-9-CM codes reported by CMS were used to identify MB experiencing AVC. Two measures of financial impact were calculated:   difference in hospital length of stay between MB who did and did not experience the AVC; and  the potential financial loss (average reimbursement of those who didn’t experience an AVC - average cost of those MB who experienced the AVC).   Findings:  The table reports the number of complications and financial impact for AVC where more than 0.2% of MB undergoing a cardiovascular procedure experienced the complication. This table indicates that the incidence of AVC is below 2.5% for all complications except septicemia among MB undergoing CABG and Cardiac Valve Surgery. Average length-of-stay (LOS) increased among MB experiencing AVC by more than 10 days for all but 9 of the 35 possible procedure/complication combinations reported. The financial impact of an AVC varied from a low of -$1,373 per event (iatrogenic pneumothorax among valve admissions) to a high of -$58,215 per event (ventilator-associated pneumonia among valve admissions).   Conclusions:  The relatively low rates for most of CMS’s proposed AVC will limit the impact of this payment policy change on Medicare expenditures for cardiovascular procedures. However, the financial impact on individual hospitals may be significant if they have multiple patients experience AVCs.
Abstract 3103: A Cardiopulmonary Exercise Testing Score for Predicting Risk in Patients with Heart Failure
Authors: Jonathan Myers, Ross Arena, Daniel Bensimhon, Joshua Abella, Leon Hsu, Paul Chase, Marco Guazzi, Mary Ann Peberdy
Journal: Circulation (2007)

Background. Cardiopulmonary exercise test (CPX) responses, including markers of ventilatory inefficiency (eg. the VE/VCO 2 slope and oxygen uptake efficiency slope [OUES]), and hemodynamic responses, such as heart rate recovery (HRR) and chronotropic incompetence (CRI) predict outcomes in patients with heart failure (HF). However, multivariate risk models integrating the full range of CPX variables have not been fully explored. Methods: 710 HF patients (568 male/142 female, mean age 56±13 years, EF 33±14%) underwent CPX and were followed for major cardiac events (death, transplant, LVAD implantation) for a mean of 29± 25 months. The age-adjusted prognostic power of peak VO 2 , VE/VCO 2 slope, OUES (VO 2 = a log 10 VE + b), resting end-tidal CO 2 pressure (PetCO 2 ), HRR, and CRI were determined using Cox proportional hazards, optimal cutpoints were determined, the variables were weighted, and a multivariate score was derived. Results. There were 111 composite outcomes. Multivariately, only CRI was not a significant predictor of risk. The VE/VCO 2 slope (≥ 34) was the strongest predictor, and was attributed a relative weight of 7, with weighted scores for abnormal HRR (≤6 beats at 1 min), OUES (&gt;1.4), PetCO2 (&lt;33mmHg), and peak VO 2 (≤14 ml/kg/min) having scores of 5, 3, 3, and 2, respectively. A Kaplan-Meier curve illustrating the incremental scores is presented in the figure ; a score &gt;15 was associated with an annual mortality rate of 26% and a relative risk of 15. Conclusion . A score using CPX responses provides a simple and integrated method that powerfully predicts outcomes in patients with HF.
Abstract 18375: A Luminal Calcium Sensing Deficient Mutation of the Cardiac Ryanodine Receptor Diminishes Stress-Induced Ventricular Tachycardias in Calsequestrin Null Mice
Authors: Jingqun Zhang, Ang Guo, Andrea Koop, Qiang Zhou, Long-Sheng Song, S.R. Wayne Chen
Journal: Circulation (2011)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with syncope and sudden cardiac death. Naturally occurring mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin (CASQ2) have been linked to CPVT. The sarcoplasmic reticulum (SR) calcium content and the sensitivity of RyR2 to activation by luminal calcium are some of the key factors determining the propensity for Store Overload Induced Calcium Release (SOICR) and SOICR-evoked VTs. We have recently found that the residue E4782 located in the helix bundle crossing (the ion gate) of the RyR2 calcium release channel acts as a SR store calcium sensor responsible for luminal calcium regulation of RyR2 and SOICR. Interestingly, we found that E4782Q mutation completely protected against SOCR-evoked VTs in a CPVT mouse model harboring the disease-causing RyR2 mutation R4496C. In this present study, we determined whether the E4782Q mutation is capable of rescuing the VT phenotype of the CASQ2 null mice, another mouse model of CPVT. We bred E4872Q+/- mice with the CASQ2 null mice to produce CASQ2-/- or CASQ2+/- with or without the heterozygous E4872Q mutation. After the injection of epinephrine (1.6mg/kg) and caffeine (120mg/kg), CASQ2-/- / E4872Q-/- and CASQ2+/- / E4872Q -/- mice showed long lasting VTs during 30-min of ECG recording (83% and 33%, respectively). On the other hand, CASQ2-/- / E4872Q+/- and CASQ2+/- / E4872Q -/- displayed little or no VTs (6.5% and 0.8%, respectively, p &lt; 0.001, when compared with CASQ2-/- / E4872Q -/-, and CASQ2+/- /E4872Q -/-, n=7~9, for each group). Thus, the E4872Q mutation nearly completely rescued the CPVT phenotype in CASQ2 null mice. These observations indicate that targeting the luminal calcium sensor of the RyR2 calcium release channel represents a new and promising therapeutic strategy for treating CPVT and other calcium mediated cardiac arrhythmias.
Abstract 10589: Examination of the Food and Drug Administration Black Box Warning for Statins and Cognitive Dysfunction
Authors: Frances M Sahebzamani, Cindy L Munro, Ocsar C Marroquin, David M Diamond, Kevin E Kip
Journal: Circulation (2013)

Background: In 2012, the U.S. Food and Drug Administration (FDA) mandated black box warnings for all statin drugs for possible adverse effects on cognitive performance including memory loss, amnesi...
Abstract 347: eNOS Deficiency Ameliorates Vascular Remodeling Induced by Periadventitial Injury in SOD1 Knock-Out Mice
Authors: Keiichiro Kataoka, Masaya Fukuda, Eiichiro Yamamoto, Taishi Nakamura, Hisao Ogawa, Shokei Kim-Mitsuyama
Journal: Circulation (2007)

Background: Copper/zinc SOD (SOD1) is a major enzyme which deactivates superoxide radicals (O2−), and endothelial nitric oxide synthase (eNOS) synthesizes nitric oxide (NO) in endothelial cells. Reduction of each enzyme can increase oxidative stress, leading to cardiovascular dysfunction. Herein, we established SOD1 and eNOS double deficient mice, and examined their physiological and pathological cardiovascular phenotypes to clarify the function of eNOS in cardiovascular system in the case of SOD1 deficiency. Methods and Results: SOD1 deficient mice (SOD-KO) were crossbred with eNOS deficient mice (eNOS-KO), and SOD1 and eNOS double-deficient mice (Do-KO) were established. Do-KO had significantly higher blood pressure (BP) than SOD-KO (129.6 ± 4.7 vs. 102.1 ± 1.2 mmHg, p&lt;0.0001). Do-KO had significantly higher heart weights than SOD-KO (3.12 ± 0.09 vs. 2.89 ± 0.03 mg/g, p&lt;0.01). Relaxation of carotid arteries due to acetylcholine was mildly impaired in SOD-KO when compared with wild type mice (WT), while relaxation to acetylcholine was completely ablated in Do-KO. These data indicated that targeted ablation of eNOS in SOD-KO impaired their vascular relaxation, and caused hypertension. Next, we examined vascular remodeling induced by periadventitial cuff-injuries. Four weeks after cuff replacement, marked neointimal formation was induced in SOD-KO; however, eNOS deficiency in SOD-KO ameliorated the vascular remodeling of SOD-KO, and significantly decreased the ratio of intimal to medial areas (1.23 ± 0.23 vs. 2.23 ± 0.38, p&lt;0.05). This data shows that eNOS enhances the vascular remodeling of SOD-KO caused by cuff injury. NO and O2− react to form the strong oxidant peroxynitrite, which is involved in vascular injury. The levels of 3-nitrotyrosine, a marker of peroxynitrite generation, were significantly elevated in the injured arteries of SOD-KO, while their elevation were attenuated in Do-KO. This indicates that NO derived from eNOS enhances the peroxynitrite formation in injured arteries of SOD-KO, so that vascular remodeling may be markedly enhanced. Conclusion: Our results demonstrate that peroxynitrite, generated from O2− and eNOS derived-NO, plays a key role in vascular remodeling induced by periadventitial injury.
The proteasome inhibitor bortezomib inhibits tumor cell growth and induces apoptosis by activating the cJUN NH2-terminal kinase (JNK) pathway in pancreatic cancer
Authors: Steffan T. Nawrocki, David J. McConkey
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4005 

The 26S proteasome is a primary component of the cell’s protein degradation machinery and is responsible for the degradation of most cellular proteins. The rapid elimination of targeted proteins is key to the activation or repression of many cellular processes, including cell cycle progression and apoptosis. The importance of the proteasome in regulating cell growth, survival, and metastasis of cancer cells makes it an attractive therapeutic target. Pancreatic cancer is the fourth most common cause of cancer-related death in the United States. Treatment with gemcitabine has demonstrated improvements in response rates, but median survival for patients with metastatic disease continues to be poor. Therefore, novel, more effective therapies are clearly needed for the treatment of pancreatic cancer. Bortezomib, formerly known as PS-341, is a boronic acid dipeptide derivative that is a selective and potent inhibitor of the proteasome. We examined the antitumor activity of bortezomib in two pancreatic cancer cell lines, MiaPaCa-2 and L3.6pl. Bortezomib was determined to be a potent inhibitor of cell cycle progression by stabilizing p21 and p27 in both cell lines. Drug treatment also resulted in inhibition of the kinases, cdk1 and cdk2. Clonogenic and MTT assays demonstrated that bortezomib effectively reduced tumor cell viability. Orthotopic models of both pancreatic cancer cell lines were utilized to examine the growth effects of bortezomib in vivo . Tumor weight and volume were reduced in both models. This reduction in tumor burden was associated with decreased proliferating cell nuclear antigen (PCNA) expression. The ability of bortezomib to inhibit tumor cell proliferation likely contributes to the anticancer properties of the drug. Bortezomib was also determined to induce apoptosis as measured by propidium iodide staining and FACS analysis and activation of caspase-3. Bortezomib treatment led to the activation of the cJUN NH2-terminal kinase (JNK) pathway. Inhibition of JNK activation by SP600125 abrogated cell death, suggesting that activation of the JNK pathway is essential for bortezomib-induced apoptosis. Similarly, inhibition of caspase-3 activity also prevented apoptosis induced by bortezomib. Therefore, bortezomib has cytostatic and cytotoxic effects, both of which contribute to the drug’s antineoplastic properties. The efficacy of bortezomib at inducing apoptosis in pancreatic cancer cells in vitro and in vivo warrants further investigation of bortezomib for the treatment of pancreatic cancer.
Autoantibody Epitope Mapping By Hydrogen-Deuterium Exchange Mass Spectrometry at Nearly Single Amino Acid Residue Resolution Reveals Novel Exosites on ADAMTS13 Critical for Substrate Recognition and Mechanism of Autoimmune Thrombotic Thrombocytopenic Purpura
Authors: Veronica C. Casina, Wenbing Hu, Hayley A. Hanby, Brandy Pickens, Leland Mayne, Eric Ostertag, Stephen Kacir, Don L. Siegel, S. Walter Englander, X. Long Zheng
Journal: Blood (2014)
Abstract 1258: The unfolded protein response may contribute to racial disparity in endocrine responsiveness in breast cancer
Authors: Ahreej E. Eltayeb, Diane M. Demas, Robert Clarke, Ayesha N. Shajahan-Haq
Journal: Cancer Research (2015)

Abstract About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and depend on estrogen to grow and proliferate. Anti-hormone therapy such as antiestrogens (e.g., Tamoxifen; TAM) are often used to treat ER+ breast tumors but the cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ∼50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. Nonetheless, little is known about the causes of endocrine resistance, and even less is known about the racial disparities that exist for antiestrogen responsiveness among ER+ breast cancer cases. Clinical investigations into ER+ breast cancer cases with similarly treated tumors showed that progression-free survival (PFS) and overall survival (OS) in African-American (AA) women were worse than in European-American (EA) women. The underlying causes of these racial differences within ER+ breast cancers is unknown. One cellular adaptive mechanism that allow endocrine resistant cells to survive antiestrogen treatment is a called the unfolded protein response (UPR) that is initiated within the endoplasmic reticulum caused by a stress stimulus. Cellular stress induced by antiestrogens can trigger the UPR leading to induce a pro-survival response by inhibiting cell death (by apoptosis) and promoting cell survival (by autophagy). Gene expression analysis for ER+ tumors of AA patients show up-regulation of UPR genes such as glucose-regulated protein 78, GRP78 (also known as HSP5A or BiP), activation transcription factor-6 (ATF6) and spliced X-box-protein-1 (XBP1s). Moreover, ER+ breast cancer cell lines derived from tumors of AA patients show increased levels of GRP78, ATF6 and XBP1 compared with cells derived from EA patients. The ER+ breast cancer cell lines derived from tumors of AA patients also show reduced sensitivity to Tamoxifen compared with cells derived from EA patients. Through our study, we will determine how up-regulation of the UPR contribute to the differences noted in anti-hormone therapy in treatment of ER+ breast cancer in AA versus EA women. Therefore, targeting critical pro-survival signaling molecules of the UPR can inhibit endocrine resistance and reduce growth of ER+ breast cancer cells more efficiently and avoid unsuccessful treatment in AA breast cancer patients. Citation Format: Ahreej E. Eltayeb, Diane M. Demas, Robert Clarke, Ayesha N. Shajahan-Haq. The unfolded protein response may contribute to racial disparity in endocrine responsiveness in breast 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 1258. doi:10.1158/1538-7445.AM2015-1258
Angiotensin-converting enzymeinhibitors and angiotensin iireceptor blockers synergistically increasecoronary blood flow in canine ischemic myocardium
Authors: Masafumi Kitakaze, Hiroshi Asanuma, Hiroharu Funaya, Koichi Node, Seiji Takashima, Shoji Sanada, Masanori Asakura, Hisakazu Ogita, Jiyoong Kim, Masatsugu Hori
Journal: Journal of the American College of Cardiology (2002)
Association may not be causal
Authors: Q. D Sandifer, S. Vuilo, G. Crompton
Journal: BMJ (1996)

EDITOR,—P Patel and colleagues report a causal relation between infection with Helicobacter pylori and the presence of ischaemic heart disease.1 We do not believe that this assertion is supported by the evidence.

Firstly, their findings were based on a cross sectional survey, and it is difficult to separate cause and effect from such surveys. This means …
抗抑郁药的起效时间——大部分疗效在头2周显现，而不是传统认为的6周
Authors: 薛海波（译）, 张明园（校）
Journal: BMJ (2007)

最近，由英国国家医疗卫生和临床优化研究所（NICE）制定的指南称：应该给所有的中到重度的抑郁症患者常规提供抗抑郁药治疗，推荐选择性5-羟色胺再摄取抑制剂（SSRI）作为一线治疗药物。NICE指南继续声明：“要告诉病人抗抑郁药起效延迟的情况”。这反映了一种传统的观点，现在要重新考虑这种观点吗？
Substance abuse and cerebral blood flow
Authors: R J Mathew, W H Wilson
Journal: American Journal of Psychiatry (1991)

This paper reviews acute and chronic effects of drugs of abuse on cerebral blood flow (CBF) and metabolism and their clinical significance. The most important source of information for the review is human research reports published in refereed journals. A few animal studies, book chapters, and abstracts that are especially relevant are also included.In humans, ethanol in small doses produces cerebral vasodilation; higher doses induce cerebral vasoconstriction. Chronic alcoholism is associated with reduced CBF and cerebral metabolism. Sedatives and antianxiety drugs lead to global reduction in CBF and cerebral metabolism. Caffeine, even in small doses, is a potent cerebral vasoconstrictor. Cerebral vasodilation is seen immediately after cigarette smoking, but chronic smokers show global reduction in CBF. Changes in CBF after marijuana smoking are variable; both increases and decreases are seen. Chronic marijuana smoking, however, seems to reduce CBF. Most inhalants and solvents are vasodilators; chronic abuse is accompanied by a decrease in CBF. A number of drugs of abuse, including ethanol, amphetamines, cocaine, nicotine, and caffeine-phenylpropanolamine combinations, increase the risk for stroke. Reduction in CBF associated with chronic use of ethanol, nicotine, inhalants, and solvents is at least partially reversible upon abstinence.Topics for future research include regional brain function, which mediates drug-induced mood changes (euphoria); CBF concomitants of psychological and physiological characteristics that increase addiction potential; changes in CBF that accompany withdrawal syndromes; mechanisms responsible for drug-induced stroke; and effects of functional and organic complications on CBF.
Abstract #DDT01-3: Identification of the p21-activated kinase inhibitor PF-3758309: A key effector of Ras signaling
Authors: Brion Murray
Journal: Cancer Research (2009)

The p21-activated kinase (PAK) family members are key effectors of Rho family GTPases. These small G protein act as regulatory switches that control such cellular processes as motility, proliferation, and cell survival. Some members of this family (such as Cdc42) have been shown to be required for Ras driven tumorigenesis. PAK4 is a key effector for Cdc42 and mediates downstream signals that control cell motility, proliferation and cell survival. To date, PAK4 is the only PAK family member that has been shown to be oncogenic and able to drive anchorage independent growth when activated. PAK4 expression and activity is broadly up-regulated in solid tumors of epithelial origin and the PAK4 gene maps to an amplicon associated with ovarian and pancreatic cancers. The PAK family consists of two sub groups; group I that consists of PAK1,2,3 and group II that consists of PAK4,5,6. Both PAK4 and PAK1 have been shown to be required for Ras driven transformation. PF-3758309 is an ATP-competitive inhibitor of PAK4 kinase domain (Kd = 4.5 nM). In engineered cell assays, PF-3758309 inhibited PAK4 dependent phosphorylation of its substrate GEF-H1 (IC50 = 1 nM). Anchorage-independent growth inhibition is a critical phenotype that has been rigorously associated with PAK4 inhibition. PF-3758309 potently inhibits the anchorage independent growth of HCT116 cells (IC50 = 0.24 nM). PF-3758309 exhibited broad anti-proliferative activity across a panel of 67 cell lines (CRC/pancreatic/NSCLC): 66% IC50  70%TGI at 15-20 mg/kg PO) by PF-3758309: HCT116, A549, MDAMB231, M24met, and Colo205. PK/PD modeling of tumor growth inhibition in the HCT116 model yielded an EC50 = 400 pM (unbound). PF-3758309 is a kinase inhibitor that has been widely profiled biochemically: (146 kinase assays, 74 CEREP assays), cellularly (171 cellular assays), and in vivo (tumor proteomics). By biochemical analysis, PF-3758309 is an inhibitor of PAK1, 4, 5, 6. Broad kinase screening has demonstrated that this is a selective inhibitor with potential additional activities (Src, Fyn, AMPK, CHK). The pharmacodynamic and antitumor effects of PF-3758309 support its evaluation as an anticancer agent.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr DDT01-3.