tbuckley/cabot-search huggingface dataset:
AMP-Activated Protein Kinase Inhibits Angiotensin II–Stimulated Vascular Smooth Muscle Cell Proliferation
Authors: DaisukeNagata, RyoTakeda, MasatakaSata, HiroshiSatonaka, EtsuSuzuki, TetsuoNagano, YasunobuHirata
Journal: Circulation (2004)

Background— AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that works as a metabolic sensor of cellular ATP levels. Here, we investigated whether AMPK signaling has a role in the regulation of the angiotensin II (Ang II)-induced proliferation signal in rat vascular smooth muscle cells (VSMCs). Methods and Results— Aminoimidazole-4-carboxamide-1-β-ribofuranoside (AICAR) activated AMPK in rat VSMCs and inhibited Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation but not that of p38 MAPK or Akt/PKB. Although Ang II activated AMPK, this activation was significantly inhibited by catalase, N-acetylcysteine, and diphenyleneiodonium chloride, an NADPH oxidase inhibitor. Moreover, the observation that AMPK was activated by H2O2 suggests that AMPK is redox sensitive. The Ang II type 1 receptor antagonist valsartan but not the Ang II type 2 receptor antagonist PD123319 significantly inhibited Ang II-induced AMPK activation, suggesting that Ang II-induced AMPK activatio...
Abstract 5491: Blocking acyl-CoAs synthesis inhibits prostate cancer progression
Authors: Houjian Cai, Yongjie Ma
Journal: Cancer Research (2018)

Abstract Fatty acid metabolism is essential for the biogenesis of cellular components and ATP production to sustain proliferation of cancer cells. Bioconversion of exogenous or de novo synthesized fatty acids to their corresponding fatty acyl-CoAs, which is required for the fatty acids to participate in metabolic processes, is catalyzed by long chain fatty acyl-CoA synthetases (ACSLs). However, the influence of individual ACSL isoforms on the progression of prostate cancer remains unknown. The goal of this study is to analyze how ACSLs regulates the biosynthesis of acyl-CoAs, thereby prostate cancer progression. In this study, lentivirus carrying shRNA of ACSL1 was constructed and produced in house. Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR) were measured by Seahorse. The amount of protein and acyl-CoAs was analyzed by immunoblotting and LC-MS/MS, respectively. Additionally, the amount of triglyceride and neutral lipid were measured by gas Chromatography and Oil red O staining. TCGA database was also used for analysis of ACSL1 expression levels in different stages of prostate cancer. Finally, inhibition of cell proliferation, migration, invasion assays and cell cycle analysis were examined in numerous cancer cells. Prostate xenograft tumor models were applied for in vivo studies. Prostate tumor tissue array was utilized for the analysis of ACSL1 expression. Based on the systematic analysis on the correlation of ACSL expression levels and the amount of intracellular acyl-CoAs, we demonstrate that expression levels of ACSL1 were significantly associated with the levels of a variety of acyl-CoAs, and were elevated in human prostate tumors. ACSL1 increased the biosynthesis of fatty acyl-CoAs including C16:0-, C18:0-, C18:1- and C18:2-CoA, triglycerides and lipid accumulation in cancer cells. In addition, ACSL1 modulated mitochondrial respiration through regulation of carnitine palmitoyltransferase 1A (CPT1A) activity. Knockdown of ACSL1 expression inhibited the cell cycle, and suppressed the proliferation and migration of prostate cancer cells in vitro, and growth of prostate xenograft tumors in vivo. Our study demonstrates ACSL1 plays an important role in prostate tumor progression. Our results provide a therapeutic strategy of targeting fatty acid metabolism for the treatment of prostate cancer. Citation Format: Houjian Cai, Yongjie Ma. Blocking acyl-CoAs synthesis inhibits prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5491.
Abstract 1533: CD4+ T cells reprogram tumor metabolism and drive oxidative stress-induced tumor destruction
Authors: Gang Zhou, Tsadik Habtetsion, Zhi-Chun Ding
Journal: Cancer Research (2018)

Abstract The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal cancer. By conducting metabolic profiling on resected tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) along with increased oxidative DNA damages. We further demonstrate that T cell-derived TNFα can synergize with chemotherapy to drive heightened oxidative stress and tumor cell death. Reduction of oxidative stress, by neutralizing TNFα or scavenging ROS, antagonized the therapeutic effects of adoptive T-cell therapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effect of T-cell transfer. Furthermore, T cell-induced oxidative stress in tumor was observed in several different tumor models. These findings imply that tumor redox modulation represents an important mechanism underlying the efficacy of adoptive immunotherapy. Citation Format: Gang Zhou, Tsadik Habtetsion, Zhi-Chun Ding. CD4+ T cells reprogram tumor metabolism and drive oxidative stress-induced tumor destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1533.
Abstract 11474: Deficiency of Senescence Marker Protein-30 Impairs Collateral Growth by Supressing Nitric Oxide Bioactivity Under Ischemia
Authors: HiroyukiYamauchi, Shu-ichiSaitoh, TakashiOwada, YasuchikaTakeishi
Journal: Circulation (2014)

Aging impairs collateral growth under ischemia and reduces the expression of VEGF, however the exact mechanism is unclear. Senescence marker protein-30 (SMP30) decreases with aging. Mice with SMP30 deficiency, a model of aging, have a short lifespan with increased oxidant stress. To elucidate the effect of SMP30 on ischemia-induced collateral growth, we examined the recovery of cutaneous blood flow (CBF) after femoral artery ligation by laser Doppler imaging in mice. Recoveries of CBF and tissue capillary density were suppressed in SMP30 knockout (KO) mice compared to those of wild type (WT) mice (Figure). Acetylcholine (ACh, 1 μM)-induced NO generation, total thiol and reduced glutathione (GSH) levels in aorta of SMP30 KO mice were lower than those of WT mice (NO: 2.6±4.5 vs. 86.2±9.2 nM; total thiol: 6.3±1.6 vs. 33.2±4.6 nmol/mg/protein; GSH: 5.1±0.8 vs. 18.6±2.1 nmol/mg/protein; P<0.01, respectively). Superoxide generation and NADPH oxidase activity were greater in aorta of SMP30 KO mice compared to th...
Developing institutions for cancer care in low-income and middle-income countries: from cancer units to comprehensive cancer centres
Authors: Bhawna Sirohi, Kalipso Chalkidou, C S Pramesh, Benjamin O Anderson, Patrick Loeher, Omar El Dewachi, Omar Shamieh, Shailesh V Shrikhande, R Venkataramanan, Groesbeck Parham, Mulindi Mwanahamuntu, Tim Eden, Audrey Tsunoda, Arnie Purushotham, Susannah Stanway, Goura K Rath, Richard Sullivan
Journal: The Lancet Oncology (2018)
Abstract 3825: INCAGN02390, a novel antagonist antibody that targets the co-inhibitory receptor TIM-3
Authors: Jeremy Waight, Priyadarshini Iyer, Ekaterina Breous-Nystrom, Christina Riordan, Mark Findeis, Dennis Underwood, Joseph Connolly, Michele Sanicola-Nadel, Horacio Nastri, Peggy Scherle, Gregory Hollis, Reid Huber, Robert Stein, Mark van Dijk, Nicholas S. Wilson
Journal: Cancer Research (2018)

Abstract Unprecedented rates of durable clinical responses have been observed for antibody-based therapeutics targeting immune checkpoint proteins such as cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1). Nonetheless, a significant number of patients experience de novo resistance or relapse due to adaptive resistance mechanisms. T-cell immunoglobulin and mucin domain containing-3 (TIM-3) is an inhibitory receptor involved in immune tolerance often co-opted by tumors to prevent successful antitumor responses. Accordingly, TIM-3 is frequently expressed on myeloid and so-called exhausted T and NK cells within the tumor microenvironment. Targeting the TIM-3 pathway in preclinical models has provided additional rationale for pharmacologic modulation of this axis in cancer patients. INCAGN02390 is a novel and fully human Fc-engineered IgG1κ antibody developed to antagonize the TIM-3 pathway for the treatment of human malignancies. INCAGN02390 forms a high-affinity interaction with TIM-3, occluding access to the CC'-FG binding cleft and blocking phosphatidylserine binding. In addition, INCAGN02390 elicits rapid receptor internalization, potentially obviating interactions with other described or undescribed ligands. INCAGN02390 also enhances IFN-γ production from T cells undergoing tonic TCR stimulation when combined with PD-1 blockade. Finally, to demonstrate combinatorial potential, we show potent antitumor activity of an anti-mouse TIM-3 antibody in concert with other checkpoint antibodies in vivo. In summary, these data support assessment of INCAGN02390 in patients with advanced or metastatic solid tumors. Citation Format: Jeremy Waight, Priyadarshini Iyer, Ekaterina Breous-Nystrom, Christina Riordan, Mark Findeis, Dennis Underwood, Joseph Connolly, Michele Sanicola-Nadel, Horacio Nastri, Peggy Scherle, Gregory Hollis, Reid Huber, Robert Stein, Mark van Dijk, Nicholas S. Wilson. INCAGN02390, a novel antagonist antibody that targets the co-inhibitory receptor TIM-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3825.
Abstract P137: Examining the Effect of the Accumulation of Physical Activity on Blood Pressure in a Physical Activity Intervention for Community Dwelling Older Adults
Authors: Kelsie M Full, Katie Crist, Suneeta Godbole, Jacqueline Kerr
Journal: Circulation (2016)

Background: High blood pressure is one of the most common health conditions experienced by US older adults. Hypertension leads to heart disease, CVD incidence, stroke, and death. In older adults, community based physical activity (PA) interventions have been shown to significantly decrease systolic and diastolic blood pressure. The American Heart Association Physical Activity Guidelines recommend that adults accumulate at least 150 minutes of moderate-vigorous intensity physical activity (MVPA) per week in order to obtain substantial health benefits. It is not clear whether accumulation of total minutes of physical activity is more important for significant changes in cardiovascular health, including reductions in blood pressure levels, or whether the intensity of the physical activity is important. New physical activity assessment techniques allow us to assess daily minutes of intensity outside of the clinic environment. Study Objectives: The objective of this study was to assess the effects of total accumulation of PA, independent of time spent in MVPA, on changes in blood pressure in older adults participating in a 6-month physical activity intervention. Methods: Study data are from a multilevel physical activity intervention (MIPARC) for older adults. Residents over the age of 65 years (N=307, mean age 84) were recruited from 11 retirement communities in San Diego. Study evaluation included collection of blood pressure measures and 6 day hip-worn accelerometry data. Change in blood pressure (dependent variable) and PA (intensity and total) from baseline to 6 months and 6 months to 12 months were examined. To account for within person and within group clustering, hierarchical longitudinal mixed effect models were used. Results: Increases in total PA counts was related to significant decreases in systolic blood pressure over the 12-month intervention period, after adjusting for minutes of time spent in MVPA (p&lt;.005). Conclusions: Evidence is mixed on the intensity of PA needed for older adults to experience significant health benefits, including reducing blood pressure. The results of this study suggest that for older adults, the total accumulation of PA at any intensity, is more important than PA at moderate to vigorous intensities. These findings have important implications for the design of PA interventions and PA prescriptions for older adults. More research is needed in older adult populations to examine if MVPA is beneficial to older adults, or if the relationship varies by an individual’s cardiovascular health.
Abstract 11819: The Impact of Peripheral Artery Disease Assessed by Ankle-Brachial Index on Endothelial Dysfunction and Risk of In-Stent Restenosis After Percutaneous Coronary Intervention
Authors: NaohiroKomura, KenichiTsujita, KenshiYamanaga, KenjiSakamoto, TakashiMiyazaki, NoriakiTabata, MasanobuIshii, TomonoriAkasaka, YuichiroArima, TakamichiOno, SunaoKojima, ShinjiTayama, KoichiKaikita, SeijiHokimoto, KiyoshiHibi, KazuoKimura, SatoshiUmemura, HisaoOgawa
Journal: Circulation (2014)

Introduction: Although drug-eluting stent (DES) has been gradually replacing the bare-metal stent (BMS), the problem of in-stent restenosis (ISR) remains unresolved. Peripheral artery disease (PAD), defined as a decreased ankle-brachial index (ABI), is a risk factor for cardiovascular disease. However, to our knowledge, no studies have assessed the relationship between PAD and ISR after percutaneous coronary intervention (PCI). Hypothesis: We assessed the hypothesis whether ABI at PCI could predict occurrence of ISR. Methods: ABI and reactive hyperemia index (RHI) assessed by peripheral arterial tonometry were checked before PCI and at follow-up (F/U) angiography in 246 consecutive patients who had successful PCI. Patients were categorized according to their ABI values (PAD: ABI≦0.9, borderline: 0.9<ABI<1.0, normal: 1.0≦ABI). F/U angiography was performed at 6 and 9 months after PCI with BMS and DES, respectively. ISR was defined as percent diameter stenosis greater than 50% at F/U angiography. Results: W...
Abstract 16943: Obesity Moderates the Relationship Between Depressive Symptoms and Diet Quality in Overweight and Obese Adults in Rural Kentucky
Authors: Demetrius A Abshire, Terry A Lennie, Misook L Chung, Martha J Biddle, Debra K Moser
Journal: Circulation (2015)

Background: Although depressive symptoms have been linked to poor diet quality, little is known about this relationship among overweight and obese adults in rural Kentucky where rates of cardiovascular disease (CVD) are high. Identifying the impact of depressive symptoms on diet quality by obesity status may aid in identifying those at highest risk for CVD due to poor dietary habits. Purpose: To determine if obesity moderates the association between depressive symptoms and diet quality in overweight and obese rural adults at high risk for CVD. Methods: Rural adults in Kentucky (n=948; age=53±15; 73% female; 96% Caucasian; body mass index [BMI]=34±7; 67% obese) completed an assessment of depressive symptoms using the 9-item Patient Health Questionnaire and diet quality using a food frequency questionnaire that generated the 2005 Healthy Eating Index score. They were grouped into overweight (BMI 25-29.99kg/m 2 ) and obese (BMI ≥30kg/m 2 ) groups. Multiple linear regression was used to determine the moderation effect by entering the interaction term of depressive symptoms and obesity level. Results: Depressive symptom scores were higher in obese adults than overweight adults (5.9 ± 4.8 vs. 4.6 ± 4.1, p&lt;0.001). Depressive symptoms predicted poor diet quality (B= -0.618, p&lt;0.001, R 2 =0.019). The interaction between depressive symptoms and obesity status was significant (Figure 1) in predicting diet quality and indicated the relationship between depressive symptoms and poor diet quality was stronger in the overweight group than obese group. Conclusion: Although obese rural Kentuckians have more depressive symptoms, the negative impact of depressive symptoms on diet quality is stronger among those who are overweight. Treating depressive symptoms may facilitate healthy eating in this population, particularly those who are overweight.
Abstract 19344: Involvement of Mitochondrial Permeability Transition Pore (mPTP) in Cardiac Arrhythmias: Evidence From Cyclophilin D Knockout Mice
Authors: Richard Gordan, Nadezhda Fefelova, Zhenhang Zhao, Lai-Hua Xie
Journal: Circulation (2015)

Our previous studies have demonstrated that mitochondrial membrane potential ( ΔΨ m ) dissipation leads to mitochondrial Ca efflux via the mitochondrial permeability transition pore (mPTP), and consequently promotes spontaneous Ca waves (CaW) in isolated cardiomyocytes. In the present study, we have used a genetic mouse model which lacks cyclophilin D (CypD KO), a necessary regulator for mPTP opening, to assess the cardioprotective effect of mPTP inhibition on cellular CaWs, Ca alternans, and whole-heart inducible arrhythmias. Ventricular myocytes were isolated from wild type (WT) and CypD KO mice. Tetramethylrhodamine (TMRM) was used as an indicator of ΔΨ m. Mitochondrial calcein release was used as the index of mPTP opening. Cytosolic Ca was imaged using Fluo-4-AM. Spontaneous CaWs were induced in the presence of 4mM external Ca. The protonophore FCCP was used to depolarize Δ Ψ m . FCCP caused Δ Ψ m depolarization to the same extent in both WT and CypD KO myocytes, however, CypD KO cells exhibited significantly less mPTP opening than WT cells (p &lt; 0.05). Consistent with these results, treatment with FCCP caused significant increases in WT CaW rate but no increase in CypD KO CaW rate. These results were further confirmed by treating WT cells with the mPTP blocker cyclosporin A (CsA). Furthermore, occurrence of Ca alternans after treatment with FCCP and programmed stimulation was observed in a significantly higher number of WT cells (11 of 13), than in WT cells treated with CsA (2 of 8; p &lt; 0.05) or CypD KO cells (2 of 10; p &lt; 0.01). At the whole-heart level, pseudo-Lead II ECGs were recorded from ex vivo, Langendorff-perfused WT and CypD KO hearts, and the incidences of T-wave alternans (a precursor of lethal arrhythimas) and arrhythmias induced by programmed S 1 -S 2 stimulation were compared. We observed T-wave alternans in 5 of 7 WT hearts, but none in 5 CypD KO hearts (p &lt; 0.05) and in only 1 of 6 WT hearts treated with CsA (p &lt;0.05). Consistent with these results, WT hearts exhibited a significantly higher average arrhythmia score than CypD KO (p &lt;0.01) or WT hearts treated with CsA (p &lt; 0.01). In conclusion, CypD deficiency-induced mPTP inhibition attenuates CaWs and Ca alternans during mitochondrial depolarization, and thereby protects against arrhythmogenesis in the heart.
Adenosine Diphosphate–Induced Platelet Aggregation Is Associated With P2Y12 Gene Sequence Variations in Healthy Subjects
Authors: PierreFontana, AnnabelleDupont, SophieGandrille, ChristillaBachelot-Loza, Jean-LucReny, MartineAiach, PascaleGaussem
Journal: Circulation (2003)

Background— The adenosine diphosphate (ADP) receptor P2Y12 plays a pivotal role in platelet aggregation, as demonstrated by the benefit conferred by its blockade in patients with cardiovascular disease. Some studies have shown interindividual differences in ADP-induced platelet aggregation responses ex vivo, but the mechanisms underlying this variability are unknown. Methods and Results— We examined ADP-induced platelet aggregation responses in 98 healthy volunteers, and we identified 2 phenotypic groups of subjects with high and low responsiveness to 2 μmol/L ADP. This prompted us to screen the recently identified Gi-coupled ADP receptor gene P2Y12 for sequence variations. Among the 5 frequent polymorphisms thus identified, 4 were in total linkage disequilibrium, determining haplotypes H1 and H2, with respective allelic frequencies of 0.86 and 0.14. The number of H2 alleles was associated with the maximal aggregation response to ADP in the overall study population (P=0.007). Downregulation of the platele...
Interaction between human serum albumin and cholesterol-grafted polyglutamate as the potential carriers of protein drugs
Authors: Xiangxue Lyu, Qiufen Zhang, Dehai Liang, Yanbin Huang
Journal: Acta Pharmaceutica Sinica B (2018)

Currently there is no successful platform technology for the sustained release of protein drugs. It seems inevitable to specifically develop new materials for such purpose, and hence the understanding of protein–material interactions is highly desirable. In this study, we synthesized cholesterol-grafted polyglutamate (PGA-g-Chol) as a hydrophobically-modified polypeptide, and thoroughly characterized its interaction with a model protein (human serum albumin) in the aqueous solution by using circular dichroism, fluorescence methods, and light scattering. With the protein concentration fixed at 5 μmol/L, adding PGA-g-Chol polymers into the solution resulted in continuous blue shift of the protein fluorescence (from 339 to 332 nm), until the polymer molar concentration reached the same value as the protein. In contrast, the un-modified polyglutamate polymers apparently neither affected the protein microenvironment nor formed aggregates. Based on the experimental data, we proposed a physical picture for such protein–polymer systems, where the polymer first bind with the protein in a 1:1 molar ratio via a fraction of their hydrophobic pendant cholesterol resides along the polymer chain. In this protein/polymer complex, there are excess unbound cholesterol residues. As the polymer concentration increases, the polymers form multi-polymer aggregates around 200 nm in diameter via the same hydrophobic cholesterol residues. The protein/polymer complex also participate in the aggregation via their excess cholesterol residues, and consequently the proteins are encapsulated into the nanoparticles. The encapsulation was also found to increase the thermal stability of the model protein.
Ethical criteria for developing medical interventions in a for-profit world
Authors: Francis P Crawley
Journal: BMJ (2018)

Parker and colleagues call for the World Health Organization to revise its ethical criteria for drug promotion.1 Rather than revise criteria that have proven to have little effect for 30 years, WHO might consider directly addressing the medical and patient communities rather than for-profit industries.

As long as the much needed innovation and development of drugs and other …
Abstract 11066: Acute Efficacy of Systemic to Pulmonary Arterial Collateral Embolization
Authors: Yoav Dori, Andrew C Glatz, Brian D Hanna, Matthew J. Gillespie,, Matthew A Harris, Marc S. Keller, Mark A Fogel, Jonathan J Rome, Kevin K Whitehead
Journal: Circulation (2012)

Yoav Dori, 2012 Finalist and Presenting Author