tbuckley/cabot-search huggingface dataset:
Blood Cholesterol and Coronary Heart Disease: Changing Perspectives
Authors: Norman J Temple, Alexander R P Walker
Journal: Journal of the Royal Society of Medicine (1994)

There has been much controversy concerning the value of efforts to reduce blood cholesterol levels. In this contribution, the risks and benefits of interventions are discussed. Lowering cholesterol level by drugs is not recommended except in a small minority of subjects at very high risk of coronary heart disease (CHD), since it causes an excess of non-CHD deaths. Dietary intervention, by contrast, is safe. However, for it to be effective it must be sufficiently vigorous to achieve a drop in blood cholesterol of at least 6%, though considerably more is preferable. This action should be part of a more general effort aimed at the prevention of all Western diseases based on changes in lifestyle.
Abstract 3487: A novel role of transient receptor potential vanilloid type 2 (TRPV2) for augmentation of chemotherapeutic drug efficacy in triple-negative breast cancer
Authors: Mohamad M. Elbaz, Mohd W. Nasser, Helong Zhao, Ramesh K. Ganju
Journal: Cancer Research (2015)

Abstract Transient receptor potential vanilloid type 2 (TRPV2) is a non-selective cation channel that is triggered by agonists like cannabidiol (CBD). Chemotherapeutic drugs such as doxorubicin (DOX) and paclitaxel (PAC) are routinely used for treatment of Triple negative breast cancer (TNBC) patients however, these drugs are usually resisted and show limited efficacy and more side effects at higher doses. In the present study, we analyzed the ability of TRPV2 activation in enhancing the chemotherapeutic efficacy in TNBC cells. Interestingly, we found that TRPV2 is significantly up regulated in primary and metastatic breast tumor tissues compared to normal breast tissues using tissue microarray analysis. In addition, using publically available Kaplan Miere Plotter datasets, we found that estrogen receptor (ER) negative patients with higher TRPV2 expression levels and committed to anti-tumor chemotherapy have significantly higher survival than patients committed to anti-tumor chemotherapy but have lower TRPV2 expression levels. Our in vitro studies showed that TNBC cells subjected to combination treatment of CBD and DOX show enhanced proliferation inhibition compared to cells treated with DOX only . Analysis of molecular mechanisms showed higher levels of cleaved PARP and cleaved Caspase-3 in combination treatment compared to Dox alone. Further studies revealed that CBD activates more uptake of DOX into TNBC cells. This increased uptake was abrogated upon treatment with specific TRPV2 blocker. Furthermore, TRPV2 blocker inhibited the increased levels of cleaved PARP and cleaved caspase-3 in the combination treatment. By using two orthotopic mouse model, we showed that mice treated with CBD in combination with doxorubicin have significantly less tumor weight, fewer Ki67 and CD31 positive cells, and significantly higher level of cleaved caspase 3 and cleaved PARP compared to the mice treated with CBD or DOX alone. This study suggests the use of TRPV2 agonists as an adjuvant therapy to improve the anti-tumor chemotherapeutic efficacy especially in TNBC patients. Citation Format: Mohamad M. Elbaz, Mohd W. Nasser, Helong Zhao, Ramesh K. Ganju. A novel role of transient receptor potential vanilloid type 2 (TRPV2) for augmentation of chemotherapeutic drug efficacy in triple-negative 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 3487. doi:10.1158/1538-7445.AM2015-3487
Abstract 11102: Fibroblast Growth Factor-2 Attenuates Human Cardiac Fibroblast-Mediated Extracellular Matrix Remodeling
Authors: Daniyil A Svystonyuk, Janet M Ngu, Holly E Mewhort, David G Guzzardi, Brodie D Lipon, Daniel S Park, Darrell D Belke, Guoqi Teng, Paul W Fedak
Journal: Circulation (2014)

BACKGROUND: After MI, elevation of profibrotic transforming growth factor-β1 (TGF-β1) results in myofibroblast-mediated matrix remodeling and progression of heart failure. In this study, we examined the effects of fibroblast growth factor (FGF-2) on human cardiac fibroblast (CF) mediated extracellular matrix (ECM) remodeling. METHOD/RESULTS: Human CF from atrial or ventricular heart biopsies were seeded into 3D collagen matrices. Myofibroblast activation was functionally assessed by the extent of matrix contraction. As compared to baseline myofibroblast activity, FGF-2 attenuated TGF-β1 mediated myofibroblast activation in both atrial (1.06±0.09 versus 1.17±0.09, P<0.0001) and ventricular fibroblasts (1.12±0.04 vs. 1.51±0.27, P<0.05). New collagen synthesis was assessed by 3H-proline incorporation. Fibroblasts treated with TGF-β1 had increased collagen synthesis while FGF-2 reduced collagen synthesis (P<0.05). ECM dysregulation was investigated by in situ zymography. TGF-β1 increased total protease activi...
The STICH Trial (Surgical Treatment for Ischemic Heart Failure)
Authors: Peter Carson, John Wertheimer, Alan Miller, Christopher M. O'Connor, Ileana L. Pina, Craig Selzman, Carla Sueta, Lilin She, Deborah Greene, Kerry L. Lee, Robert H. Jones, Eric J. Velazquez
Journal: JACC Heart Failure (2013)
Abstract 3223: Dietary Pattern, Metabolic Syndrome and Left Ventricular Systolic Dysfunction - The Multi-Ethnic Study of Atherosclerosis
Authors: Longjian Liu, Jennifer A Nettleton, Alain G Bertoni, David A Bluemke, Joao A Lima, Moyses Szklo
Journal: Circulation (2008)

Little is known about the association between dietary patterns and left ventricular (LV) function. We assessed the hypothesis that dietary patterns may influence LV function via pathways related to metabolic dysfunction. With a cross-sectional study design, using reduced rank regression (RRR), dietary patterns that maximally explained variation in metabolic syndrome (MetSyn) components (waist circumference, serum triglycerides, fasting glucose, HDL cholesterol, SBP, and DBP) were identified. We used magnetic resonance imaging to assess LV ejection fraction (LVEF), LV mass, and stroke volume. LV mass and stroke volume were adjusted for body surface area (m 2 ). Insulin resistance (IR) was estimated using HOMA-IR method. A total of 4574 (M: 2173, F: 2401) White, African American, Hispanic and Chinese adults aged 45– 84 and free of clinical cardiovascular disease were included in these analyses. After adjusting for age, sex, and race/ethnicity, scores on the primary dietary pattern (RRR1) were positively correlated with intake of added fats, processed meats, and cheeses, and negatively correlated with vegetable, soy, wine, green/black tea, and fish intake. With adjustment for demographics, lifestyle factors, and anti-hypertensive drug use, means for LV mass increased across quintiles of RRR1 scores, and means for LVEF and stroke volume decreased across quintiles of RRR1 scores. Multiple linear regression analyses indicated that each one unit increase in RRR1 score (i.e. toward high-fat food intake) was associated with 0.32 g/m 2 (95%CI: 0.05–0.69 g/m 2 ) increase in LV mass, and with 0.26 % (−0.44 ~ − 0.08 %) and 0.28 ml/m 2 (−0.52~ −0.05, ml/m 2 ) decreases in LVEF and stroke volume, respectively. The associations remained significant after adjustment for IR alone, but were not significant after adjustment for all MetSyn components. A dietary pattern characterized by high intakes of added fats, meats, and cheese and low intakes of vegetables, soy and fish, as indicative of variation in MetSyn components, was significantly associated with unfavorable LV function. The result supports the hypothesis that the influence of dietary pattern on LV function may be through a pathway related to metabolic dysfunction.
Antimigratory and antimetastatic activity of novel anti-Rac nucleoside compounds in a mouse mammary carcinoma model
Authors: Pablo Lorenzano Menna, Alejandra Zinni, Luis Iglesias, Adolfo Irribarren, Daniel Alonso, Daniel Gomez
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5640 

The Rho family of small GTPases includes at least 23 molecules with structural and functional relation to Ras oncoprotein. In the last years many evidences have been accumulated about the role of Rho-GTPases in malignant transformation and tumorigenesis. Previously, we have demonstrated that β2-chimaerin, a specific Rac1 inhibitor, is a key modulator of tumor invasion and metastasis in the highly aggressive F3II mouse mammary carcinoma model (Lorenzano Menna et al. Cancer Res. 63: 2284-91, 2003). The central aim of this work was to evaluate the antitumor properties of small organic compounds with high affinity for the nucleoside binding site of the Rho-GTPase Rac1. A panel of guanosine and inosine analogs was designed and synthesized using chemo-enzymatic methodologies. In vitro antitumor activity of compounds in log-phase growing F3II cells was studied by a colorimetric method, and the IC50 values were calculated. Effect on tumor cell migration was examined by the wound assay on confluent F3II monolayers. Rac activity was evaluated using the pull-down assay followed by Western blot. To study the effects of compounds on formation and growth of blood-borne metastasis, 2 x 105 F3II viable cells were injected into the lateral tail vein of syngeneic Balb/c mice and surface lung nodules were measured 21 days later. Compounds designated N-101 (acylguanosine), N-104 (6-chloro-acylpurine riboside) and N-205 (acylguanosine) showed cytostatic activity with IC50 values in the low micromolar range, while other compounds tested had no relevant inhibitory activity on mammary tumor cells. N-101, N-104 and N-205 inhibited F3II cell migration at doses of 1-10 µM, without cytotoxic effects. Furthermore, the antimigratory effect was associated with a dose-dependent decrease of intracellular Rac-GTP levels. Daily treatment with intraperitoneal doses of 5 mg/kg of N-205 was well tolerated in female mice, and significantly reduced the number of metastatic lung nodules. Our results demonstrated the antitumor properties of novel anti-Rac nucleoside analogs in a preclinical animal model, suggesting their potential utility in breast cancer treatment.
Particles in the Air: The Enigma of Urban Air Pollution
Authors: Anthony Seaton
Journal: Journal of the Royal Society of Medicine (1996)

As British cities grew during the Industrial Revolution, so they became increasingly polluted by the smoke from factory and domestic coal combustion. During winter time, episodes of temperature inversion kept the smoke close to ground level and gave rise to the famous smogs of the first half of this century, culminating in the London smog of December 1952, which was associated with some 4000 excess deaths in 1 weekl. Knowledge of an association between cold weather and excess deaths was not new, meteorologists having studied it from the middle of the nineteenth century2, but in the early twentieth century it became apparent that cold alone did not explain the excess and that the concurrence of fogs was a likely additional factor3. The 1952 message that air pollution is bad for you, delivered so close to Parliament itself, had a dramatic effect and smoke control in towns and cities was enforced by the Clean Air Act of 1956. The pioneering Medical Research Council (MRC) air pollution unit was also set up at St Bartholomew's Hospital Medical School under Professor Pat Lawther and an important series of studies of the interactions of air pollutants and health, notably by Lawther and Waller, began4. This was the heyday of the 'English disease', chronic bronchitis, and the researchers concentrated (understandably) on the lung as a target for pollutants. They did, however, recognize that deaths during these episodes were often from heart disease. The legislation was so successful that smoke and sulphur dioxide concentrations in our cities fell progressively through the following three decades, and the MRC unit was eventually closed, its work apparently done. Why the excess deaths occurred has never convincingly been explained but it has been assumed that air pollution episodes, acting as the grim reaper, harvest those who, on account of severe heart or lung disease, are about to die. The closure of the MRC unit occurred at a time of rapid increase in the numbers of vehicles on our roads. As the smokey chimneys disappeared, so the streets filled with cars and lorries and their attendant exhaust fumes and gases. This increase in motor vehicles has accelerated, although fortunately there has not been a corresponding rise in air pollutants because engine and fuel technology has to date kept pace. However, the fall in air pollutants has been checked and the centres of some cities have again become unpleasant places to live in or to pass through during large parts of the day. In appropriate weather conditions, episodes of quite severe air pollution have started to return, although the constituents are not the same as those associated with the urban smogs of earlier years. And epidemiologists have once again shown associations between modem air pollution, disease and death5-7.
Shiga-like toxin-1 receptor on human breast cancer, lymphoma, and myeloma and absence from CD34(+) hematopoietic stem cells: implications for ex vivo tumor purging and autologous stem cell transplantation.
Authors: E.C. LaCasse, M.R. Bray, B. Patterson, W.-M. Lim, S. Perampalam, L. G. Radvanyi, A. Keating, A.K. Stewart, R. Buckstein, J.S. Sandhu, N. Miller, D. Banerjee, D. Singh, A.R. Belch, L.M. Pilarski, J. Gariépy
Journal: Blood (1999)
Abstract B112: Transcriptome analysis in pancreatic cancer reveals a tumor suppressor function for HNF1A
Authors: Jason W. Hoskins, Marta Flandez, Jinping Jia, Hemang Parikh, Irene Collins, Mickey Emmanuel, Abdisamad Ibrahim, Wenming Xiao, John Powell, Nuria Malats, Gloria M. Petersen, Fransisco X. Real, Laufey T. Amundadottir
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDAC), as with all cancer, is driven by dysregulation of genetic programs due to accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. Holistic views of perturbations in gene expression networks could illuminate key regulators and pathways for this highly lethal cancer. Toward this end, we performed massively-parallel mRNA-sequencing in normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples as well as pancreatic cancer cell lines (n = 9), and determined differential gene expression (DE) patterns. Sub-network enrichment analyses of all expressed genes based on magnitude of DE identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in our pancreatic tumor samples (median P = 7.56 x 10-7, median rank = 1, range = 1-25). To explore the effect of HNF1A expression in pancreatic tumor-derived cells we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines. Induction of HNF1A overexpression caused severe growth inhibition (5.3-fold, P = 4.5x10-5 for MIA PaCa-2 clones; 7.2-fold, P = 2.2x10-5 for PANC-1 clones), and G0/G1 cell cycle arrest. This was accompanied by down-regulation of 49 out of 84 assayed cell cycle genes, while only 1 displayed increased expression. These data, combined with HNF1A’s direct regulation of pancreatic development and homeostasis genes (i.e. PDX1, PTF1A and NR5A2), suggest it may be an important tumor suppressor in pancreatic cells. Citation Format: Jason W. Hoskins, Marta Flandez, Jinping Jia, Hemang Parikh, Irene Collins, Mickey Emmanuel, Abdisamad Ibrahim, Wenming Xiao, John Powell, Nuria Malats, Gloria M. Petersen, Fransisco X. Real, Laufey T. Amundadottir. Transcriptome analysis in pancreatic cancer reveals a tumor suppressor function for HNF1A. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B112.
Dual treatment possibilities with S179D prolactin and physiological levels of 1,25 dihydroxy vitamin D3
Authors: Wei Wu, Ameae M. Walker
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4870 

S179D prolactin (PRL) is a molecular mimic of human phosphorylated PRL. It was originally developed as a PRL antagonist since the naturally phosphorylated form had that activity. Since both prostate and mammary epithelium use unmodified PRL as an autocrine growth factor, we reasoned that blockade of this autocrine growth loop might be beneficial in the treatment of prostate and breast adenocarcinomas. Indeed, S179D PRL has been shown to inhibit growth of human prostate and breast cancer cells in vitro (1,2), growth of human prostate tumors in nude mice (1) and growth of normal mammary glands during pregnancy in both rats and mice (3,4). However, continued analysis of the mechanism of action of S179D PRL has demonstrated that it is not just a simple blocker of the actions of unmodified PRL, but a molecule that exerts a good deal of its anti-tumor activities through other means. Of interest in the current study is its ability to synergize with 1,25 dihydroxy vitamin D3 (D3) to cause apoptotic cell death. Synergy between D3 and other apoptosis-inducing molecules is not uncommon. What is uncommon is our finding that S179D PRL sensitizes human prostate cancer cells to physiological concentrations of D3. Thus there exists the very real possibility of dual therapy without concern about the hypercalcemic side effects of pharmacological doses of D3 (frequently 10 nM) otherwise required to produce human cancer cell apoptosis. In order to investigate the effect of dual therapy at the cellular level, human prostate cancer cell lines, DU145 and PC3, were incubated under conditions where either S179D PRL or D3 had little or no effect on their own. Parameters measured after a 3-day treatment included viable cell number, levels of the cell cycle regulatory protein, p21, amount of the vitamin D receptor (VDR), and DNA degradation. In all instances, the combination produced synergy, with 94% of cells either not grown or killed in 10nM S179D PRL and 160 picomolar D3. The same conditions tripled p21 levels, doubled VDR levels and promoted its nuclear translocation, and produced DNA laddering typical of apoptotic internucleosomal cleavage. These data support the idea that dual therapy with S179D PRL and D3 has the potential to be very efficacious in vivo. Supported by NIDDK 61005.
Abstract 228: Glutathione S-transferase P-dependent Glutathiolation of Oxidized Aldose Reductase in the Ischemic Heart; a Novel Mechanism of Reversible Redox Signaling?
Authors: Karin Kaiserova, Daniel J Conklin, Aruni Bhatnagar
Journal: Circulation (2008)

Aldose reductase (AR) is a stress-responsive enzyme reducing glucose and aldehydes derived from lipid peroxides generated during increased oxidative stress. We have recently reported that ischemia ...
Abstract 16578: Scalable, Reproducible, and Economical Method for Producing Cardiomyocytes From Human Induced Pluripotent Stem Cells
Authors: Masamichi Ito, Ryoko Takizawa, Natsumi Igarashi, Megumi Naito, Issei Komuro, Atsuhiko Naito
Journal: Circulation (2014)

Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes are considered to be a promising tool for various purposes, e.g. regenerative medicine, drug discovery, and safety pharmacology. Many researchers have reported various protocols for inducing cardiac differentiation from hiPSC. For above-mentioned purposes, ideal protocol for cardiac differentiation should be scalable (3D-culture preferred), inexpensive (use of small molecule preferred), and highly reproducible (defined factor preferred).  Here, we report an innovative protocol of cardiac differentiation, which is based on widely used protocol from Gordon Keller’s lab that uses various cytokines in a 3D-culture system (Yang L et al. Nature 2008). In the new protocol, costs for inducing cardiac differentiation was reduced by 96% with improved differentiation efficiency and high interclonal reproducibility.  According to our previous report (Naito AT et al. PNAS 2006), we tested whether appropriate activation and inhibition of Wnt signaling can replace the cytokines used for cardiac differentiation. We found that activator of Wnt signaling can by itself replace the cytokine that was used for mesoderm induction (Activin A and BMP). Although inhibitor of Wnt signaling alone could not replace the cytokines that was used after mesoderm induction (Dkk-1, bFGF, and VEGF), robust cardiac differentiation was observed when Wnt inhibitor was used in combination with inhibitor of Tgfb signaling and a steroid hormone. We have also developed a differentiation medium that is consisted of defined and inexpensive factors. The total cost for inducing cardiac differentiation was cut from 1,376,250 yen (~$13,762) to 57,150 yen (~$571) in a 1L scale. Our new protocol and culture medium would dramatically reduce the cost for producing cardiomyocytes from iPSCs and would promote utilization of iPSC-derived cardiomyocytes for regenerative medicine, drug discovery and safety pharmacology.
Abstract 655: Paradoxical Reduction in Glycosylation Sensitizes the Diabetic Heart to Mitochondrial Permeability Transition
Authors: Lewis J Watson, Gladys A Ngoh, Yanqing Zhu, Ashley L Campbell, Yu-Ting Xuan, Steven P Jones
Journal: Circulation (2007)

Hexosamine biosynthesis, an accessory pathway for glucose metabolism, culminates in the formation of UDP-GlcNAc, which is the monosaccharide donor for the post-translational modification, O-linked beta-N-acetylglucosamine (O-GlcNAc). Augmented hexosamine biosynthesis has been implicated in the pathogenesis of diabetes in many peripheral tissues. Yet, glucose transporters in cardiac myocytes are predominantly insulin dependent, thereby limiting intracellular glucose availability in diabetic cardiac myocytes. Driven by such paradoxes, we hypothesized that unlike other tissues, intracellular O-GlcNAc signaling would actually be reduced in diabetic hearts. HPLC revealed a 24% reduction in UDP-GlcNAc levels in db/db diabetic (2.2 +/−0.5 nmol) compared to nondiabetic (2.9 +/−0.5 nmol) mouse hearts. Immunoblots showed a reduced expression of O-GlcNAc transferase (61 +/−14% of nondiabetic), which is the enzyme that adds the O-GlcNAc modification to proteins, and reduced O-GlcNAc levels (86 +/−8% of nondiabetic) in diabetic hearts (n = 8/group). We recently reported an interaction between O-GlcNAc signaling and mitochondrial-controlled cell death and, accordingly, evaluated the sensitivity to mitochondrial permeability transition pore (mPTP) formation here. Cardiac mitochondria from diabetic hearts were more sensitive to calcium-induced mitochondrial swelling (138 +/−15% of nondiabetic) compared with mitochondria from nondiabetics (n = 3/group). Because diabetes is multi-faceted, we distilled the system to one variable, reduced O-GlcNAc levels, by injecting additional groups of nondiabetic mice with a drug (TT04) to reduce O-GlcNAc levels, or Vehicle (n =3/group). Cardiac mitochondria from nondiabetic mice with reduced O-GlcNAc levels (TT04) were also more sensitive to calcium-induced swelling (178 +/−12% of Vehicle) than cardiac mitochondria from Vehicle treated mice, thus recapitulating one element of the diabetic phenotype and supporting the idea that reduction of O-GlcNAc levels is sufficient to sensitize cardiac mPTP formation. We conclude that the paradoxical reduction in O-GlcNAc signaling in diabetic hearts may be responsible for heightened sensitivity to cardiac injury, particularly in terms of mPTP formation.