tbuckley/cabot-search huggingface dataset:
Length Dependence of Tension Generation in Rat Skinned Cardiac Muscle
Authors: NorioFukuda, DaisukeSasaki, Shin’ichiIshiwata, SatoshiKurihara
Journal: Circulation (2001)

Background At the basis of the Frank-Starling mechanism is the intrinsic ability of cardiac muscle to produce active tension in response to stretch. Titin, a giant filamentous molecule involved in passive tension development, is intimately associated with the thick filament in the sarcomere. Titin may therefore contribute to active tension development by modulating the thick filament structure when the muscle is elongated. Methods and Results Rat skinned right ventricular trabeculae were used. Passive tension at a sarcomere length (SL) of 2.0 to 2.4 μm was decreased after treatment of the preparation with trypsin (0.25 μg/mL) for 13 minutes in the relaxed state at 20°C. This mild trypsin treatment degraded titin without affecting other major contractile proteins. The sarcomere structure was little affected by brief contractions in the trypsin-treated preparations. When SL was adjusted to the slack SL (1.9 μm), active tension was unaffected by trypsin under partial (pCa 5.55) and maximal (pCa 4.8) activati...
A chimpanzee serotype-based adenoviral vector as vaccine for CEA
Authors: Daniela Peruzzi, Agostino Cirillo, Bruni Bruno Ercole, Annalisa Meola, Alfredo Nicosia, Riccardo Cortese, Gennaro Ciliberto, Stefano Colloca, Nicola La Monica, Luigi Aurisicchio
Journal: Cancer Research (2006)

1399   Adenovirus (Ad) is an attractive vector for genetic vaccine development for its capability to infect several tissues and antigen presenting cells. This property is impaired by pre-existing immunity to the human adenoviruses in most of human population. For this reason, use of uncommon alternative Ad serotypes could overcome this problem. Recently, chimpanzee Ad vectors have been shown to be efficient delivery tools for vaccination protocols. To verify the immunogenic potency of a chimp Ad vector to vaccinate hosts, an E1,E3 deleted recombinant Ad based on the chimpanzee serotype 3 (chAd3) was engineered to express human carcinoembryonic antigen (CEA) protein. ChAd3-CEA was tested in CEA.Tg mice that express human CEA with a tissue distribution similar to that of humans. CEA.Tg mice were intramuscularly immunized with chAd3-CEA and expression of human CEA was monitored in the serum. Development of a CEA-specific CD8 +  T cell response was observed after a single injection and it was comparable in terms of efficacy and kinetics to that of mice immunized with a similar vector based on human serotype 5 (Ad5-CEA) expressing the same transgene. Importantly, the capability of chAd3-CEA to elicit the immune response against CEA was not abrogated in animals pre-exposed to human wt Ad5 and works as booster of immunity elicited by other Ad vectors. In conclusion, our data show that this novel chimp Ad based vaccine vector is able to induce an immune response comparable to Ad5 human serotype and, importantly to break tolerance to a tumor antigen. Moreover, ChAd3 presents the advantage to overcome pre-existing immunity and work in conjunction with Ad vaccines based on common human serotypes.
Heme Oxygenase-1 Inhibits Atherogenesis in Watanabe Heritable Hyperlipidemic Rabbits
Authors: KazunobuIshikawa, DaisukeSugawara, JunGoto, YasuyukiWatanabe, KeiichiKawamura, MasashiShiomi, HiroyukiItabe, YukioMaruyama
Journal: Circulation (2001)

Background Heme oxygenase-1 (HO-1) is proposed to have a variety of adaptive responses against oxidative stress. To examine the function of HO-1 against atherogenesis in vivo, we observed the effects of HO-1 inhibition on atherosclerotic lesion formation in Watanabe heritable hyperlipidemic rabbits (WHHL). Methods and Results During 4 weeks of a 1% cholesterol diet, intravenous injections of Sn-protoporphyrin IX to inhibit HO-1 (S group, n=10) and saline as a control (C group, n=10) were given to 3-month-old WHHL rabbits. The percentages of en face atherosclerotic lesion areas in total descending aorta by Sudan IV staining (EFA) and the ratio of intima to media in microscopic atherosclerotic lesions in the ascending aortas (I/M) were calculated. Two different quantitative methods revealed significantly greater atherosclerotic lesions in the S group than the C group (EFA, P<0.001; I/M, P<0.005). HO-1 expression in atherosclerotic lesions was confirmed by Northern blot and immunohistochemical analyses. The ...
α- and β-Adrenergic Pathways Differentially Regulate Cell Type–Specific Apoptosis in Rat Cardiac Myocytes
Authors: EriIwai-Kanai, KojiHasegawa, MakotoAraki, TsuyoshiKakita, TatsuyaMorimoto, ShigetakeSasayama
Journal: Circulation (1999)

Background—The apoptosis of cardiac myocytes may play a role in the development of heart failure. Norepinephrine is one of the factors activated in heart failure and can induce myocardial cell apoptosis in culture. However, it is unknown if α- and β-adrenergic pathways coordinately or differentially regulate apoptosis and if this apoptotic pathway uses common or cell type–specific apoptotic signals. Methods and Results—We stimulated cultured neonatal rat cardiac myocytes with an α1-adrenergic agonist (PE, phenylephrine), a β-adrenergic agonist (isoproterenol [Iso]) or a membrane-permeable cAMP analogue (8-Br-cAMP) in serum-free conditions for 48 hours. Iso and 8-Br-cAMP markedly increased the number of TUNEL-positive cells (%TUNEL-positive nuclei >40%) compared with saline stimulation (<10%). DNA fragmentation was also confirmed by ladder formation in agarose gels. Apoptotic myocytes were characterized by cell shrinkage and nuclear condensation, consistent with morphological features of apoptosis. The Iso...
Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases
Authors: HiroakiMatsubara
Journal: Circulation Research (1998)

Abstract—Since the discovery of nonpeptidic ligands, the receptors for angiotensin (Ang) II have been classified into 2 subtypes (Ang II type 1 receptor [AT1-R] and Ang II type 2 receptor [AT2-R]). AT1-R mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetus. Its expression is very low in the cardiovascular system of the adult. The expression of AT2-R can be modulated by pathological states associated with tissue remodeling or inflammation. In failing hearts or neointima formation after vascular injury, AT2-R is reexpressed in cells proliferating in interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular matrix proteins, resulting in attenuation of the tissue remodeling. An extreme form of cell growth inhibition ends in programmed cell death, and this process, which is initiated by the withdrawal of growth factors, is also enhanced by AT2-R. Cardiac myocyte- or vascular ...
Integrating comprehensive point of care and preemptive pharmacogenomic testing for patients with gastrointestinal malignancies.
Authors: Caren Hughes, Candice Baldeo, Jessica M Rodgers, Ashton Ritter, Tyler Koep, Erica Schnettler, Pashtoon Murtaza Kasi
Journal: Journal of Clinical Oncology (2018)

e18935 Background: Pharmacogenomic testing can have important implications for patients with gastrointestinal cancers. It may help prevent severe adverse drug reactions resulting in emergency room visits and hospital admissions. It may also help predict responses to not only chemotherapy drugs but also to supportive care medications. The main barrier has been the widespread adoption and integration into practice. The goal of our study was to report on the feasibility and results of integrating a comprehensive pharmacogenomic test into clinical practice. Methods: As a quality improvement initiative, we integrated the use of OneOme RightMed pharmacogenomic comprehensive test, which reports on 23 genes of interest. We limited initial testing to patients with colorectal cancer. Results: 61 patients took the RightMed pharmacogenomic comprehensive test from November 2017 to January 2018. Table 1 outlines the number (%) of variants in UGT1A1 and the DPYD-genes alongside the CYP450 genes. Results were available within 3-5 days of testing for most patients and were integrated into treatment decision making. Pharmacists provided electronic consults to provide patient-specific medication management recommendations. Conclusions: Real-time point of care and preemptive comprehensive pharmacogenomic testing can be integrated into practice for cancer patients given faster turnaround and low cost. Pharmacist-driven, patient specific medication management consults add further value given the number of genes/drugs. Table 1: CYP450, UGT1A1, and DPYD metabolizer frequency in colorectal cancer patients Gene PM and IM-PM IM and NM-IM NM RM UM CYP2D6 4 (6%) 29 (48%) 25 (41%) 0 3 (5%) CYP2C19 2 (3%) 14 (23%) 25 (41%) 17 (28%) 3 (5%) CYP2C9 0 25 (41%) 36 (59%) 0 0 CYP2B6 6 (9%) 21 (35%) 31 (51%) 3 (5%) 0 CYP1A2 0 0 5 (8%) 56 (92%)^ 0 CYP3A4 0 4 (6%) 57 (94%) 0 0 CYP3A5 51 (84%) 5 (8%) 5 (8%) 0 0 Normal Intermediate Poor UGT1A1 *1/*1 29 (48%) *1/*28 27 (44%) *28/*28 5 (8%) DPYD *1/*1 58 (95%) *1/*n† 3 (5%) PM = Poor Metabolizer; IM = Intermediate Metabolizer; NM = Normal Metabolizer; RM = Rapid Metabolizer; UM = Ultrarapid metabolizer. ^In the case of CYP1A2, Rapid Metabolizer refers to inducible phenotypes. †The RightMed
Increase doctors pay award to boost morale, says BMA
Authors: Abi Rimmer
Journal: BMJ (2018)

The BMA has called on the government to increase the pay award proposed for doctors in England after a survey found that 74% of the profession thought it was highly unacceptable.

In July, the government announced a one year pay rise of 1.5% for consultants, 2% for trainees, 3% for specialty doctors, and a backdated …
Abstract 2845: The mechanisms of resistance to temozolomide in glioma cells
Authors: Shigeo Ohba, Yuichi Hirose
Journal: Cancer Research (2018)

Abstract Glioblastoma is one of the most aggressive tumor in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). One of the reasons of the worse prognosis of the tumor is the acquisition of resistance to TMZ in glioma cells. TMZ is a DNA-methylating agent. TMZ-induced O6-methylguanine adducts, in the absence of repair by O6-methylguanine DNA methyltransferase (MGMT), mispair with thymine during the next DNA replication cycle, leading to futile DNA mismatch repair (MMR) by the MMR system, formation of double strand breaks (DSBs) and eventual cell death of glioma cells. Several mechanisms have been proposed about the acquisition of resistance to TMZ in glioblastomas, such as changes of expression of MGMT, MMR, nucleotide excision repair and homologous recombination (HR). To clarify the mechanisms of resistance to TMZ and to find the way to overcome the resistance to TMZ, several clones of U251 cells resistant to TMZ were obtained and analyzed. FACS analyses showed several patterns of cell cycle distributions of the cells treated with TMZ. #3 resistant clone showed G2 arrest at day3 after TMZ exposure and this arrest was abrogated sooner compared to the G2 arrest of parental U251. TMZ did not induce G2 arrest in #8 resistant clone. Consistent with the results, TMZ-induced DSBs in #3 resistant cells were rapidly disappeared compared to those in U251 cells, and the DSBs were least induced by TMZ in #8 resistant cells. The expression of MGMT was not found in U251 parental cells, #3 cells nor #8 cells, which mean MGMT was not associated with the resistance to TMZ in those cells. The protein levels of MSH6, which was associated with MMR, was reduced in #8 cells. The inhibitor of PLK1 or PARP reduced the cell growth independent of MMR. The ability of HR was increased in #3 resistant clone. By suppression of Rad51, which was major factor associated with HR, the resistant #3 clone was re-sensitized to TMZ, however #8 was not. These results suggested that inhibition of HR may be a viable means to resensitize some kinds of temozolomide-resistant gliomas to TMZ. Citation Format: Shigeo Ohba, Yuichi Hirose. The mechanisms of resistance to temozolomide in glioma cells [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 2845.
Abstract 14356: Flexibility and Contact Force: Improvements of the Next Generation Irrigated Gold-Tip Ablation Catheter for Remote Magnetic Navigation
Authors: Georg Noelker, Stephan Molatta, Dieter Horstkotte, Klaus-Jürgen Gutleben
Journal: Circulation (2016)

Introduction: Remote magnetic navigation (RMN) has been proven safe and effective in ablation of arrhythmias. While for manual ablation new irrigation technologies are established in clinical practice , basic design of RMN catheters remained unchanged after initial improvements. Furthermore, distribution and strength of magnets in so far available products seem to be arbitrary and are unsatisfying in terms of flexibility and contact force (CF). For the development of a novel RMN catheter incorporating most recent irrigation technology, all aspects for a new mechanical catheter design were investigated with special focus on CF and flexibility. Hypothesis: Improvements in flexibility and contact force can be achieved by a newly designed magnetic ablation catheter. Methods: 13 different prototypes with various combinations of magnetic volume, magnet position and shaft design all equipped with an irrigated gold-tip were compared to 2 commercially available catheters in an experimental set-up (at 37°C). For CF...
Abstract 5928: Suicide gene therapy of ovarian cancer
Authors: Obeid M. Malekshah, Siddik Sarkar, Arash Hatefi
Journal: Cancer Research (2018)

Abstract Purpose: The objective of this study was to develop a gene directed enzyme prodrug therapy (GDEPT) method that can effectively kill both differentiating and cancer stem-like cells (CSCs) in ovarian cancer. Methods: Ovarian cancer cell lines including A2780, A2780-Cis, SKOV-3, OVCAR-3 and OVASC-1 (malignant cells from ascitic fluid of an ovarian cancer patient) were examined to identify the most drug resistant one. Various chemotherapeutic drugs which are used for suicide gene therapy were tested to identify one that is the most effective against ovarian cancer cells. These include 6-Methylpurine, 5-Fluorouracil, and SN-38. Cisplatin was used as a standard of care control. The anticancer activities of the drugs were studied by a cell toxicity assay and clonogenic assay. Flow cytometry was performed to study surface stem markers, such as CD133, CXCR4, HER2. ALDH1 activity in ovarian cancer cells was studied by ALDH assay kit. The ability of the most effective enzyme/prodrug system to kill drug resistant ovarian cancer cells was studied by a cell viability assay. Results: The results of in vitro dose-response experiments on various ovarian cancer cells showed that SN-38 was the most efficient drug with IC50 in a range of 10 -100 nM, in comparison to 10-500 μM range of all other selected active drugs. OVASC-1 and OVCAR-3 cell lines showed a higher resistance to drug therapy as compared with other cell lines. It was observed that these two cell lines have a higher number of drug resistant cancer cells in their populations. It was also observed that CSCs are strongly associated with resistance to chemotherapy. ALDH assay, clonogenic assay and sphere formation assay showed a direct correlation between the therapy resistance and the percentage of CSCs. OVASC-1 cells in comparison to the other cell lines were found to be a suitable model for therapy resistant studies. After treatment by 100 nM SN-38, no visible colonies of Ascites were observed. Adipose-derived stem cells (ADSCs) were genetically modified to express Carboxylesterase-2 (CE2) and thus could convert CPT-11 to its active form (SN-38). Using this enzyme/prodrug system an effective eradication of highly resistant OVASC-1 ovarian cancer cells was demonstrated. Conclusions: Our findings suggest that Carboxylesterase/CPT-11 enzyme/prodrug system is the most effective GDEPT method against highly drug resistant ovarian cancer cells. Citation Format: Obeid M. Malekshah, Siddik Sarkar, Arash Hatefi. Suicide gene therapy of ovarian cancer [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 5928.
Abstract MP77: Will the World Health Organization’s “25 x 25” Goal Be Achieved? An Ecologic Time Trend Analysis of Relative and Absolute Premature Mortality Risk Due to Non-Communicable, Chronic Diseases
Authors: AbigailBaldridge, JayPandit, MarkHuffman
Journal: Circulation (2014)

Objectives: To evaluate country-level time trends (1994-2011) in premature (30-69 years) mortality from non-communicable, chronic diseases (NCDs), including cardiovascular diseases, and to create forward projections to 2025 to evaluate the WHO’s goal of reducing the risk of premature mortality from NCDs by 25% by 2025. Methods: Using publicly available data from the WHO Mortality Database, we created annual estimates of risk of premature (30-69 years) NCD mortality (1994-2011). The sample included data from all countries reporting NCD mortality data from ≥2 years (n=116) and all countries reporting population estimates over the same years (n=135). We matched these datasets by country, year, division, administrative grouping and sex to reach a final sample of 60 countries (193 WHO Member States, 2011). We used ordinary least squares and log-linear Poisson regression models stratified by sex to evaluate the annual change in risk of premature mortality. We then created forward projections through 2025 using ...
Gaza shootings: an orthopaedic crisis and mass disability
Authors: Nafiz Abu-Shaban
Journal: BMJ (2018)

Further to Summerfield and colleagues’ correspondence on the situation in Gaza,12 I respond as head of plastic and reconstructive surgery in the country. The death and injury toll is still rising—as at 18 May, 117 were dead, including 13 children, and 12 271 injured. 6760 have been hospitalised, including 3598 with bullet wounds. Nineteen clearly identified medics have been shot.3

Medecins Sans …
Abstract 15025: Validation of the TRA2°P TIMI50 Risk Score for Predicting Cardiovascular Events in Real World Patients
Authors: Kevin M Chagin, Michael W Kattan, Brent A Williams, Alex Milinovich, Janine M Bauman, Mehul D Patel, Lori D Bash
Journal: Circulation (2016)

Objective: To assess the discrimination of an RCT (TRA2°P TIMI-50) derived risk tool in predicting recurrent cardiovascular events in the real world. Methods: Patients experiencing a myocardial inf...
Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis
Authors: Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage E. Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, Beth A. McCormick
Journal: Journal of Clinical Investigation (2018)

Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen. Knockdown or inhibition of P-gp reduced luminal secretion levels of N-acyl ethanolamine-type endocannabinoids, which correlated with increased neutrophil transmigration in vitro and in vivo. Additionally, loss of CB2, the peripheral cannabinoid receptor, led to increased pathology and neutrophil influx in models of acute intestinal inflammation. These results define a key role for epithelial cells in balancing the constitutive secretion of antiinflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine.
Auscultatory and Phonocardiographic Assessment of Pulmonary Stenosis with Intact Ventricular Septum
Authors: Louisvogelpoel, Velvaschrire
Journal: Circulation (1960)

A clinical and phonocardiographic study has been made on pulmonary and infundibular stenosis with intact ventricular septum, in order to determine the value of auscultation and phonocardiography in assessing the severity of the stenosis. There were 43 cases of pulmonary valve stenosis with intact ventricular septum and 8 cases of infundibular stenosis with intact ventricular septum. The severity of the stenosis, as determined by the right ventricular pressure, was correlated with the duration of right ventricular systole, as determined both by the length of the systolic murmur and the width of splitting of the second heart sound. It was shown that increasingly severe stenosis resulted in progressive lengthening of the murmur in relation to the aortic second sound and delay in pulmonary valve closure. Criteria were defined whereby the severity of the stenosis could be predicted; these proved more accurate than other clinical methods. In mild stenosis (RVP under 60 mm. Hg), the murmur was soft to loud in in...
Abstract 4419: FOXP3 mediated transcriptional regulation of microRNAs in breast cancer
Authors: Wei Liu, Song Gao, Xin Li, Fengpin Hu, Lizhong Wang
Journal: Cancer Research (2018)

Abstract MicroRNAs (miRs) have potential as non-invasive biomarkers, but their relevance as biomarkers is limited by inconsistent results, and their regulatory mechanisms remain elusive. In the present study, our results show that the levels of miR-200c and 141 in tumor cells and in circulation differ for mice and for humans between cases with metastatic breast cancer, cases with localized breast cancer, and healthy female controls. The levels of miR-200c and 141 are low in primary tumor cells but are high in the circulation of patients with metastatic breast cancer. Further, we suggest the potential cell origin of circulating miR-200c and 141 and describe their transcriptional regulation in cultured cells and during tumor progression in animal models of spontaneous breast cancer. These results could provide useful insights in early prediction of tumor metastasis and influence treatment strategies for patients at high risk of developing metastatic breast cancer. Citation Format: Wei Liu, Song Gao, Xin Li, Fengpin Hu, Lizhong Wang. FOXP3 mediated transcriptional regulation of microRNAs in breast cancer [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 4419.