tbuckley/cabot-search huggingface dataset:
Molecular Variant of Angiotensinogen Gene Is Associated With Coronary Atherosclerosis
Authors: TomoakiIshigami, SatoshiUmemura, TamioIwamoto, KouichiTamura, KiyoshiHibi, SatoshiYamaguchi, NobuoNyuui, KazuoKimura, NaomichiMiyazaki, MasaoIshii
Journal: Circulation (1995)

Background A positive association was previously reported between angiotensin-converting enzyme (ACE) gene polymorphism and several cardiovascular diseases, such as myocardial infarction, left ventricular hypertrophy, and restenosis after percutaneous transluminal coronary angioplasty. Plasma ACE activity and carotid-wall thickening measured by ultrasonography were related, and it was postulated that long-term exposure to high levels of plasma ACE could be involved in structural changes of the arterial wall. In addition, angiotensinogen gene mutation was recently reported to be associated with essential hypertension and preeclampsia. There exists a possibility that the renin-angiotensin system plays an important role in the progress of cardiovascular diseases in humans. Therefore, we examined the association between the molecular variant of the angiotensinogen gene and coronary atherosclerosis. Methods and Results This study included 82 patients who had coronary atherosclerosis and 160 control subjects; a...
Abstract 2543: Concurrent chemotherapy and temozolomide-resistant CAR-T immunotherapy enhances glioblastoma clearance in experimental animals
Authors: Sadhak Sengupta, Mansour Gergi, Prajna Guha, Sudarshana Sengupta, Richard P. Junghans, Prakash Sampath
Journal: Cancer Research (2018)

Abstract Dismal long-term progression-free survival of glioblastoma (GBM) patients, who are concurrently treated with radiation and chemotherapy, demands development of alternative strategies for management of this disease. Recent clinical success of chimeric antigen receptors expressing T cells (CAR-T) in GBM patients, interest in tumor-directed immunotherapy has been reinvigorated. However as per standard care, immunotherapy must be concurrent with or following the standard care protocol for glioma therapy, which includes Temozolomide (TMZ) chemotherapy. Concurrent chemotherapy with TMZ reduces the efficacy of adoptive T cell immunotherapy by inducing severe lymphopenia, while post-chemotherapy treatment minimizes the window of opportunity for effective immunotherapy, because of inherent tumor heterogeneity resulting in an altered antigenic profile in recurrent GBMs. To address this, we have created a TMZ-resistant CAR-T cell directed against IL13Rα2+ GBM tumors by introducing a mutated O6-methylguanine-DNA methyltransferase (MGMT) moiety in the existing IL13CAR backbone. This specific mutation in MGMT (P140KMGMT) blocks the interaction of TMZ to MGMT and therefore protects the rapidly proliferating anti-GBM CAR-T cells from TMZ-induced lymphopenia. Activated P140KMGMT-IL13CAR-T cells were protected from TMZ-induced cytotoxicity in vitro without any loss of anti-tumor effects of these modified CAR-T cells. Experimental xenograft animals treated with P140KMGMT-IL13CAR-T cells and concurrent TMZ therapy showed 2-fold increase in median survival over groups that were treated with TMZ alone, and 2.8-fold increase in overall survival over groups that were treated with TMZ-sensitive second generation IL13CAR-T cells and concurrent TMZ. These encouraging results point us strongly in the direction of developing this CAR-T technology towards a promising future of concurrent chemotherapy and immunotherapy of GBM. Citation Format: Sadhak Sengupta, Mansour Gergi, Prajna Guha, Sudarshana Sengupta, Richard P. Junghans, Prakash Sampath. Concurrent chemotherapy and temozolomide-resistant CAR-T immunotherapy enhances glioblastoma clearance in experimental animals [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 2543.
Percutaneous Transluminal Septal Myocardial Ablation in Hypertrophic Obstructive Cardiomyopathy
Authors: LotharFaber, HubertSeggewiss, UlrichGleichmann
Journal: Circulation (1998)

Background—Percutaneous transluminal septal myocardial ablation (PTSMA) has been introduced as an alternative procedure for reducing the left ventricular outflow tract gradient (LVOTG) in hypertrophic obstructive cardiomyopathy. We report on the acute and mid-term results in 91 symptomatic patients with respect to intraprocedural myocardial contrast echocardiography (MCE). Methods and Results—PTSMA was intended for 46 women and 45 men (54.1±15.5 years). In 2 patients, the intervention could not be completed. In the first 30 patients the target vessel was determined by probatory balloon occlusion alone and in the remainder by additional intraprocedural MCE. Resting LVOTG was reduced from 73.8±35.4 to 16.6±18.1 and nostextrasystolic LVOTG from 149.3±42.5 to 61.9±43.0 mm Hg (P<0.0001 each). In 10 (11%) patients, permanent DDD pacemaker implantation was necessary. Two (2%) patients died, 1 from ventricular fibrillation associated with treatment for chronic obstructive pulmonary disease after 9 days and 1 from...
Abstract 5441: Regulation of AKT phosphorylation by GSK3β and PTEN to control chemoresistance in breast cancer
Authors: Chunyi Gao, Guohua Wang, Zhenglin Jiang
Journal: Cancer Research (2018)

Abstract Background Chemotherapy is an important element in the treatment paradigm for breast cancers. However, the resistance of cancer cells to chemotherapeutic agents frequently results in the subsequent recurrence and metastasis. AKT phosphorylation is highly expressed or over-expressed in chemoresistant tumor samples. However, the precise molecular mechanism involved in AKT phosphorylation-related chemoresistance in breast cancer remains unknown. The aim of the present study was to assess whether the role of AKT phosphorylation in the cell viability and chemoresistance of breast cancer. Methodology/Principal Findings We developed two taxol resisted breast cancer cells: TAX Resis HepG2 and TAX Resis HepG2 SMMC7721. Western blot and immunofluorescence analysis indicated that glycogen synthase kinase 3 beta (GSK3β), phosphorylated phosphatase and tension homologue (p-PTEN) and phosphorylation of AKT (p-AKT) were highly expressed in taxol resisted HepG2 and SMMC7721 cells. The increase of GSK3β phosphorylated and inactivated PTEN, thereby enhanced phosphatidylinositide 3-kinases (PI3K)/Akt signaling. The increase in GSK3β, p-PTEN and p-AKT was associated with cell viability by MTT assay. Annexin-V-PI assay and transwell analysis were indicated that GSK3β knockdown with lentiviral shRNA (shRNA-GSK3β) promoted the apoptosis and suppressed the migration ability of Taxol resisted HepG2 and SMMC7721 cells, and both effects were reversed by activating p-AKT via PTEN inhibitor bpV(pic). Conclusions In conclusion, AKT phosphorylation manipulated by GSK3β and PTEN were correlated with cell viability, migration and apoptosis in Taxol resisted HepG2 and SMMC7721 cells, which may promote chemoresistance of breast cancer. Furthermore, functions of GSK3β can modulate cell viability via the PTEN/PI3K/Akt signaling pathway and induce chemoresistance, serving as a valuable molecular target for treatment of breast cancer. Citation Format: Chunyi Gao, Guohua Wang, Zhenglin Jiang. Regulation of AKT phosphorylation by GSK3β and PTEN to control chemoresistance 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 5441.
Isolated Congenital Complete Atrioventricular Block in Adult Life
Authors: MagnusMichaëlsson, AndersJonzon, TomasRiesenfeld
Journal: Circulation (1995)

Background The prognosis of congenital complete atrioventricular block (CCHB) is usually considered favorable in adults. This belief is based on studies comprising a limited number of patients and with rather short observation times. In the present study, the natural history of the disease was investigated by a prospective follow-up through decades of adult life of patients with a large group having well-defined CCHB without structural heart disease. Methods and Results The diagnostic criteria of CCHB proposed by Yater were applied. Patients registered as having CCHB in 1964, supplemented by younger patients all without symptoms during their first 15 years of life, were selected. The study was limited to patients with isolated, complete, permanent block. An interview was conducted with all patients and clinical follow-up data obtained. There were finally 102 patients, 61 women and 41 men. In November 1994, the time of observation, after the age of 15 years in survivors, was between 7 and 30 years. The mea...
Association of Left Ventricular Global Longitudinal Strain With Asymptomatic Severe Aortic Stenosis
Authors: E. Mara Vollema, Tadafumi Sugimoto, Mylène Shen, Lionel Tastet, Arnold C. T. Ng, Rachid Abou, Nina Ajmone Marsan, Bart Mertens, Raluca Dulgheru, Patrizio Lancellotti, Marie-Annick Clavel, Philippe Pibarot, Philippe Genereux, Martin B. Leon, Victoria Delgado, Jeroen J. Bax
Journal: JAMA Cardiology (2018)

<h3>Importance</h3> The optimal timing to operate in patients with asymptomatic severe aortic stenosis (AS) remains controversial. Left ventricular global longitudinal strain (LV GLS) may help to identify patients who might benefit from undergoing earlier aortic valve replacement. <h3>Objective</h3> To investigate the prevalence of impaired LV GLS, the natural course of LV GLS, and its prognostic implications in patients with asymptomatic severe AS with preserved left ventricular ejection fraction (LVEF). <h3>Design, Setting, and Participants</h3> This registry-based study included the institutional registries of 3 large tertiary referral centers and 220 patients with asymptomatic severe AS and preserved LVEF (&gt;50%) who were matched for age and sex with 220 controls without structural heart disease. The echocardiograms of patients and controls were performed between 1998 and 2017. <h3>Exposures</h3> Both clinical and echocardiographic data were assessed retrospectively. Severe AS was defined by an indexed aortic valve area less than 0.6 cm<sup>2</sup>/m<sup>2</sup>. Left ventricular global longitudinal strain was evaluated on transthoracic echocardiography using speckle tracking imaging. <h3>Main Outcomes and Measures</h3> The prevalence of impaired LV GLS, the natural course of LV GLS, and the association of impaired LV GLS with symptom onset and the need for aortic valve intervention. <h3>Results</h3> Two hundred twenty patients (mean [SD] age, 68 [13] years; 126 men [57%]) were included. Despite comparable LVEF, LV GLS was significantly impaired in patients with asymptomatic severe AS compared with age- and sex-matched controls without AS (mean [SD] LV GLS, −17.9% [2.5%] vs −19.6% [2.1%];<i>P</i> &lt; .001). After a median follow-up of 12 (interquartile range, 7-23) months, mean (SD) LV GLS significantly deteriorated (−18.0% [2.6%] to −16.3% [2.8%];<i>P</i> &lt; .001) while LVEF remained unchanged. Patients with impaired LV GLS at baseline (&gt;−18.2%) showed a higher risk for developing symptoms (<i>P</i> = .02) and needing aortic valve intervention (<i>P</i> = .03) at follow-up compared with patients with more preserved LV GLS (≤−18.2%). <h3>Conclusions and Relevance</h3> Subclinical myocardial dysfunction that is characterized by impaired LV GLS is often present in patients with asymptomatic severe AS with preserved LVEF. Left ventricular global longitudinal strain further deteriorates over time and impaired LV GLS at baseline is associated with an increased risk for progression to the symptomatic stage and the need for aortic valve intervention.
Abstract OT1-1-11: DETECT III - A multicenter, randomized, phase III trial to compare standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells
Authors: N de Gregorio, F Schochter, C Melcher, C Hagenbeck, TWP Friedl, B Jäger, BK Rack, V Müller, PA Fasching, W Janni, T Fehm
Journal: Cancer Research (2013)

Abstract Background: In metastatic breast cancer (MBC) patients, HER2 status may be subject to change and it has been shown that 20-30% of initially HER2-negative patients have HER2-positive metastases. The discordance of the HER2 status between primary tumor and circulating tumor cells (CTCs) may be an important factor affecting the response to HER2-targeted treatments; however, it is unclear if therapy based on the HER2 status of CTC offers a clinical benefit for patients. Trial Design: DETECT III is a recruiting prospective, multicenter, open-label, two-arm, phase-III study for patients with HER2-negative MBC. Patients with HER2-positve CTCs are randomized to receive either a standard therapy of the physician's choice alone or a standard therapy plus additional HER2-targeted treatment with Lapatinib. Main Eligibility criteria: - Metastatic breast cancer; - HER2-negative primary tumor tissue and/or biopsies from metastatic sites; - Evidence of at least 1 HER2-positive CTC out of 7.5 ml blood; - Indication for systemic treatment - ≥1 lesion evaluable according to RECIST Specific aims: The objective of the DETECT III trial is to estimate the clinical efficacy of standard therapy plus lapatinib as assessed by progression free survival (PFS) in patients with initially HER2-negative MBC and HER2-positive CTCs. Additional research will be performed on CTC dynamic and characteristics. Present accrual and target accrual: The DETECT III – trial started February 2012 and has analyzed so far (2013-06-06) 506 patients. We found CTCs in 336 (66.4%) patients (median 7 CTCs, range 1-35078). 67 of these patients (19.9%) had at least one HER2 positive CTC. Estimated patient enrollment is 228. Methods: The primary endpoint progression-free survival will be estimated using the Kaplan-Meier method. Prevalence and number of CTCs at various time points as well as the HER2 status of CTCs will be determined using the FDA-approved CellSearch System (Veridex, USA). In addition, different measures of CTC dynamics and their value for evaluating therapy efficacy or as a prognostic tool will be examined in detail by explorative data analyses. Perspectives: The DETECT III-Trail is the first study where treatment is based on phenotypic characteristics of CTCs. If this trial succeeds in proving efficacy of lapatinib in patients with initially HER2-negative primary tumor but HER2-positive CTCs, it may lead to a new strategy for the treatment of metastatic breast cancer. Contact information: nikolaus.de-gregorio@uniklinik-ulm.de. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-11.
Abstract 3192: Aptamers, antibodies and radiotherapy for the treatment of DIPG
Authors: Naiara Martinez-Velez, Miguel Marigil, Javier Aristu, Luis Ramos, Fernando Pastor, Ana Patiño-García, Marc García-Moure, Juan Fueyo, Candelaria Gomez-Manzano, Ricardo Diez-Valle, Sonia Tejada, Marta M. Alonso
Journal: Cancer Research (2018)

Abstract Diffuse intrinsic pontine gliomas (DIPGs) is one of the most aggressive pediatric brain tumors. Radiotherapy (RT) constitute the standard of care of these tumors being its therapeutic effect just palliative. There is plenty of evidence that RT is able to activate immune responses through the induction of immunogenic cell death. However, it also elicits immunosuppressive effects and enforces immunological tolerance. The result is that in DIPGs the RT effect is just transitory. In this context, immune costimulatory or inhibitory molecules with the capability to boost the immune effect of RT could be amenable agents to use in combination to treat DIPGs. Agonist antibodies has been widely used in immunotherapy. Aptamers are high-affinity single-stranded nucleic acid ligands that exhibit remarkable affinity and specificity to their targets, comparable or exceeding that of antibodies. 4-1BB is a major costimulatory receptor promoting the survival and expansion of activated T cells. TIM-3 is a negative regulator of lymphocyte function that is involved in T-cell exhaustion. To this end, we examined the effect of RT in combination with either an agonist 4-1BB antibody or an aptamer against TIM-3. Importantly, both combined treatments showed a safe profile. Moreover, combination treatment of 4-1BB agonist antibody or TIM-3 aptamer with RT resulted in a significant improvement in the median survival of mice bearing DIPG orthotopic tumors when compared with single treatment in around 20 days (P=0.001 and P=0.04, for the combination of RT and 4-1BB or TIM-3,respectively). In addition, both combination led to long-term survivors (90 days). Rechallenge experiments in these animals showed the generation of memory against the tumors in both combined treatment. Mechanistic studies performed on day 16 showed an increase in CD8 effector cells, a decrease in T-regulators Foxp3+ cells and an increase in INF-gamma expression suggesting the triggering of an antitumor-immune response. Our data underscore that combination of RT with immune-boosting strategies for DIPGs are worth exploring. Citation Format: Naiara Martinez-Velez, Miguel Marigil, Javier Aristu, Luis Ramos, Fernando Pastor, Ana Patiño-García, Marc García-Moure, Juan Fueyo, Candelaria Gomez-Manzano, Ricardo Diez-Valle, Sonia Tejada, Marta M. Alonso. Aptamers, antibodies and radiotherapy for the treatment of DIPG [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 3192.
Abstract 14835: The Prevalence of Sleep Disturbance and Its Strong Impact on Depression Symptom in Patients Hospitalized With Cardiovascular Diseases
Authors: Risa Matsuda, Takashi Kohno, Ryoma Fukuoka, Mariko Kondo, Yuichiro Maekawa, Motoaki Sano, Keiichi Fukuda
Journal: Circulation (2015)

Introduction: There is increasing evidence that sleep disturbance significantly contribute to the development of heart disease. However, sleep disturbance often remains unrecognized and untreated because of barrier to its assessment. The aims of this study were to assess the prevalence of sleep disturbance in cardiovascular patients, and examine its related factors including mental status. Methods and Results: A total of 1087 patients (mean age, 65±15 years; 29% female) hospitalized for a spectrum of cardiovascular diseases in Keio University Hospital were enrolled (coronary artery disease n=348, arrhythmia n=459, heart failure n=81, valvular heart disease n=119, and other n=80). We assessed sleep disturbance using the Pittsburgh Sleep Quality Index (PSQI; mean 5.6±3.3). The sleep disturbance was defined as PSQI&gt;7 (n=256 [24%]). We screened sleep-disordered breathing (SDB) using nocturnal pulse oximetry, a non-invasive method for detecting nocturnal intermittent hypoxia. The prevalence of SDB (3% oxygenation desaturation index&gt;15/hour) was higher in patients with sleep disturbance (33% vs 26%, p=0.02). Sleep disturbance was associated with older age, higher BNP and CRP level, and lower eGFR and albumin level (all p&lt;0.05). Sex, BMI, and the prevalence of hypertension or diabetics mellitus did not differ between patients with sleep disturbances and those without. The patients with sleep disturbance had significantly higher depression (Hospital Anxiety and Depression Scale [HADS]-Depression score; 6.4±3.7 vs 3.7±3.2, p&lt;0.001, PHQ-9; 6.8±4.5 vs 2.7±2.9, p&lt;0.001) and anxiety (HADS-anxiety score; 6.2±3.8 vs 3.6±2.9, p&lt;0.001) symptoms. After adjustment for age, sex, and psychological disturbance, sleep disturbance was associated with heart failure (OR=1.81; P=0.027; 95% CI, 1.06-3.06). Multiple regression analysis revealed that depressive symptom was the most powerful factor related to sleep disturbance (OR=1.2; P&lt;0.0001; 95% CI, 1.12-1.33). Conclusions: Given the high prevalence of sleep disturbances and their strong impact on psychological disturbance, increased efforts should be undertaken for their identification and treatment in patients with cardiovascular diseases, especially in the field of heart failure.
Abstract 2663: CR42-24, a novel colchicine derivative, a therapeutic for bladder cancer
Authors: Clayton Bell, Kyle Potts, Desmond Pink, John Lewis, Jack Tuszynski
Journal: Cancer Research (2018)

Abstract Colchicine is an anti-mitotic drug that targets unpolymerized tubulin, and inhibits microtubule polymerization. It is primarily used to treat gout but has been investigated in numerous clinical trials to treat conditions such as leukemia (ALL), prostate cancer, Behcet's disease, etc.. However, due to its narrow therapeutic window colchicine has had limited clinical translation. A possible approach to reduce general is to produce a derivative with an increased cancer specificity and selectivity by a narrower molecular target selection. Previously, our lab has designed and synthesized a novel colchicine derivative (CR42-24) with a more favorable pharmacological profile compared to colchicine. This was accomplished by designing a structure with an increased affinity for βIII tubulin. βIII tubulin is a β-tubulin isotype that is incorporated into tubulin dimers that make up microtubules. βIII is an excellent target for novel therapies as it has low expression in healthy tissue, is overexpressed in metastatic cancers, and is a clinical marker of poor prognosis. Using cell line screening we demonstrate that CR42-24 is highly toxic to a variety of cancer types with IC50 values at low nanomolar concentrations. More specifically CR42-24 is shown to be highly effective against bladder cancer. Current chemotherapy for bladder cancer is a combination of gemcitabine and cisplatin (Gem/Cis). Although marginally successful, many patients develop resistance to Gem/Cis leaving them with limited options for a second line therapy, thus development of alternative therapies is highly desired. Using in vitro assays we demonstrate that CR42-24 kills aggressive bladder cancer cell types, and is more effective than gemcitabine and cisplatin. Additionally, CR42-24 doubles survival rates of mice with bladder cancer xenografts. We also show that CR42-24 is highly synergistic with other chemotherapies, thereby increasing its therapeutic potential. Through our studies we have shown that CR42-24 is effective in treating aggressive bladder cancer and thus may serve as an alternative or second line therapy. Citation Format: Clayton Bell, Kyle Potts, Desmond Pink, John Lewis, Jack Tuszynski. CR42-24, a novel colchicine derivative, a therapeutic for bladder 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 2663.