tbuckley/cabot-search huggingface dataset:
A new hypothesis for Parkinson’s disease pathogenesis: GTPase-p38 MAPK signaling and autophagy as convergence points of etiology and genomics
Authors: Julia Obergasteiger, Giulia Frapporti, Peter P. Pramstaller, Andrew A. Hicks, Mattia Volta
Journal: Molecular Neurodegeneration (2018)

The combination of genetics and genomics in Parkinson´s disease has recently begun to unveil molecular mechanisms possibly underlying disease onset and progression. In particular, catabolic processes such as autophagy have been increasingly gaining relevance as post-mortem evidence and experimental models suggested a participation in neurodegeneration and alpha-synuclein Lewy body pathology. In addition, familial Parkinson´s disease linked to LRRK2 and alpha-synuclein provided stronger correlation between etiology and alterations in autophagy. More detailed cellular pathways are proposed and genetic risk factors that associate with idiopathic Parkinson´s disease provide further clues in dissecting contributions of single players. Nevertheless, the fine-tuning of these processes remains elusive, as the initial stages of the pathways are not yet clarified.In this review, we collect literature evidence pointing to autophagy as the common, downstream target of Parkinsonian dysfunctions and augment current knowledge on the factors that direct the subsequent steps. Cell and molecular biology evidence indicate that p38 signaling underlies neurodegeneration and autoptic observations suggest a participation in neuropathology. Moreover, alpha-synuclein and LRRK2 also appear involved in the p38 pathway with additional roles in the regulation of GTPase signaling. Small GTPases are critical modulators of p38 activation and thus, their functional interaction with aSyn and LRRK2 could explain much of the detailed mechanics of autophagy in Parkinson´s disease.We propose a novel hypothesis for a more comprehensive working model where autophagy is controlled by upstream pathways, such as GTPase-p38, that have been so far underexplored in this context. In addition, etiological factors (LRRK2, alpha-synuclein) and risk loci might also combine in this common mechanism, providing a powerful experimental setting to dissect the cause of both familial and idiopathic disease.
Evaluation of Myocardial Cell Damage by In-111-Monoclonal Antimyosin Antibodies in Patients Under Chronic Tricyclic Antidepressant Drug Treatment
Authors: VicensMartí, ManelBallester, ClaudiUdina, IgnasiCarrió, EnricAlvarez, DamiàObrador, GuillemPons-Lladó
Journal: Circulation (1995)

Background The capability of chronic tricyclic antidepressant drug (TAD) treatment to elicit myocardial damage has been a subject of debate. Lack of an adequate noninvasive method to detect such damage has prevented an in-depth study. Methods and Results A prospective study with In-111-monoclonal antimyosin antibodies was undertaken in a series of 21 young patients with major depression on TADs and a control group of 19 healthy subjects. A heart-to-lung ratio (HLR) of antimyosin uptake was used to discriminate normal from abnormal scans. HLR in healthy subjects was 1.39±0.08. Patients on imipramine (HLR, 1.41±0.09) or clomipramine (HLR, 1.44±0.06) showed normal studies. Those under amitriptyline had a higher HLR (1.58±0.12) compared with nonamitriptyline or normal groups (P<.05). None of the 15 patients on imipramine or clomipramine showed abnormal HLR, while 3 of 6 on amitriptyline did (P<.01). In these 3 patients, uptake decreased or disappeared after drug withdrawal. Ejection fraction was normal in eve...
Abstract 17095: Clinical Characteristics and Short-term Outcomes of Aortic Disease Patients With Cardiovascular Shock: Results From the Shock Registry of the Japanese Circulation Society
Authors: Yasuyuki Tsujita, Yasuji Doi, Toshiaki Kadokami, Hirohide Matsuura, Ryuichirou Imai, Takamichi Miyamoto, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao
Journal: Circulation (2015)

Background: The mortality rate of aortic disease patients with cardiovascular shock (CVS) is still high. We examined the factors related to short-term outcomes of aortic disease patients with CVS. Methods: The Japanese Circulation Society Shock Registry was a prospective, observational, multi-center (83 institutions), cohort study that enrolled 980 patients presenting with CVS when transported to the emergency room between May 2012 and June 2014. Of those, 82 aortic dissection (AD) and 63 aortic aneurysm (AA) patients were enrolled in this study. Because each institution used a different D-dimer kit, adjusted D-dimer levels were calculated by dividing the measured D-dimer value by the upper limit of the normal range of the kit. Results: The mean age was 76 years and 52% were male. The 30-day mortality rate was 46% (AD, 39%; AA, 56%). In AD, Stanford type A accounted for 95% and surgical intervention was performed in 68%. In AA, 24% were thoracic; 6%, thoracoabdominal; 69%, abdominal AA, and surgical intervention was performed in 57%. In AD, adjusted D-dimer levels on admission of non-survivors were significantly higher than those of survivors [median (interquartile range): 75.6 (19.5-229.4) vs. 25.8 (8.0-61.3) arbitrary units, respectively; P=0.01]. In AD, surgical intervention, a transferred case, absence of aortic rupture, and low D-dimer levels (adjusted D-dimer &lt; 33.2 arbitrary units, which was the median value) were associated with the 30-day survival. In AA, surgical intervention, a transferred case, higher consciousness level, higher systolic blood pressure, and abdominal AA were associated with 30-day survival. Cox proportional hazards analysis indicated that surgical intervention (hazard ratio 0.14; 95%CI, 0.049-0.40; P&lt;0.001) and low D-dimer level (hazard ratio 0.21; 95%CI, 0.067-0.57; P&lt;0.001) were independent predictors of 30-day survival in AD, and surgical intervention (hazard ratio 0.087; 95%CI, 0.023-0.28; P&lt;0.001) was an independent predictor of 30-days survival in AA. Conclusions: Surgical intervention was the only method to improve short-term outcomes of aortic disease patients with CVS. In AD, lower D-dimer level was associated with more favorable short-term outcomes regardless of surgical intervention.
Comparing the Efficacy and Safety of a Novel Monophasic Waveform Delivered by the Passive Implantable Atrial Defibrillator With Biphasic Waveforms in Cardioversion of Atrial Fibrillation
Authors: GaneshManoharan, NoelEvans, DesmondAllen, JohnAnderson, JenniferAdgey
Journal: Circulation (2004)

Background— The passive implantable atrial defibrillator (PIAD) (with no battery or discharging capacitor and powered transcutaneously by radio-frequency energy) delivering a novel monophasic low-tilt waveform is more efficacious than the standard monophasic waveform at atrial defibrillation. Standard biphasic (STB) waveforms, however, are more efficacious and safer than monophasic waveforms. This study compared the efficacy and safety of the PIAD waveform with biphasic waveforms. Methods and Results— Sustained atrial fibrillation (AF) was induced by rapid atrial pacing. Cardioversion was attempted via 2 atrial defibrillation leads. The efficacy of the PIAD was compared with 3 biphasic waveforms (standard, single rounded, and double rounded) at varying voltage settings in 10 pigs. After a synchronized shock, hemodynamic changes between the PIAD, standard biphasic, and monophasic waveforms were compared at 1.5 and 3.0 J in 12 pigs. Myocardial injury (biochemical and histological) after ten 5-J PIAD shocks ...
Abstract 1394: Resistance to BET inhibitor leads to new therapeutic vulnerabilities in castration resistant prostate cancer
Authors: Aishwarya S. Pawar, Irfan A. Asangani
Journal: Cancer Research (2018)

Abstract BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration resistant prostate cancer (CRPC) cells. Bromodomain and extraterminal protein (BET) inhibitors displace BRD4 protein from chromatin, resulting in the inhibition of oncogenic transcriptional programs. Several BET inhibitors (BETi) are in phase I clinical trials for a variety of malignancies including CRPC. Here we describe a general mechanism of acquired resistance to BETi due to modulation of cellular pathways that are amenable to targeted therapies in CRPC cells. BETi resistant CRPC cells displayed cross resistance to a variety of BETi in the absence of gatekeeper mutations or persistent drug pump activation. Resistant cells exhibited reduced chromatin bound BRD4, and were less sensitive to Proteolysis Targeting Chimeric (PROTAC) -mediated degradation or genetic knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR-signaling due to CDK9-mediated serine-81 phosphorylation of AR, with a consequent increase in sensitivity to CDK9 inhibitors and anti-androgens in BETi resistant cells. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DNA damage response (DDR) genes was observed due to the loss of BRD4 from their proximal promoter regions in the resistant cells, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy in CRPC. However, data showing the reactivation of AR-signaling and increased DNA damage in the BETi resistant cells provide unique opportunities for combination therapies in managing CRPC. Citation Format: Aishwarya S. Pawar, Irfan A. Asangani. Resistance to BET inhibitor leads to new therapeutic vulnerabilities in castration resistant prostate 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 1394.
Abstract 217: Effect of Amiodarone with Therapeutic Hypothermia on Arrhythmia Substrates During Global Myocardial Ischemia
Authors: Shalen Kouk, Lance D Wilson, Joseph S Piktel
Journal: Circulation (2013)

Background: The effect of therapeutic hypothermia (TH) after cardiac arrest on susceptibility to arrhythmias is not well understood. We have shown that TH has a beneficial effect on reentrant substrates for ischemia-induced arrhythmias by limiting decreases in conduction velocity (CV) and attenuating increases in transmural dispersion of repolarization (DOR). As amiodarone is utilized during TH, it is important to understand the effect of TH and amiodarone on arrhythmia substrates during ischemia. Our hypothesis is that amiodarone worsens the antiarrhythmic effect of TH during global ischemia. To test this hypothesis, a model of no flow global ischemia in the canine wedge preparation was used to study the effects of ischemia on all cell types spanning the transmural wall. Methods: Optical action potentials were recorded transmurally with high spatial (1 mm), temporal (.5 ms) and voltage (.5mv) resolution. Amiodarone (5microM) was used at both 36oC (control, CTAmio n=4) and 32oC (THAmio, n=4) during 15 min of no flow global ischemia and compared to controls (CT=7, TH=6). Action potential duration (APD), DOR, and CV were measured for all conditions. Programmed electrical stimulation (PES) was performed to assess for ischemia-induced arrhythmias and compared to prior controls (CT, n=5, TH, n=4). Results: At baseline, TH prolonged APD in both THAmio and TH, but there was no difference between DOR and CV. At 15 minutes of ischemia, DOR increased in the THAmio group compared to TH (34±3 ms to 79±9 ms vs. 25±3 to 37±7 ms, p=.04). There was a trend towards worsening ischemia-induced conduction slowing in the THAmio group vs TH, but not significant (39±4 to 24±3 cm/s vs 44±2 to 35±3 cm/s, p=.06). There was no difference under control temperature of CTAmio vs CT for CV, DOR, or APD. PES induced arrhythmias in 2/4 in the CTAmio group vs. 0/4 in THAmio group (compared to 3/5 in CT group, 1/4 in TH group). Conclusions: Amiodarone worsens the beneficial effect of TH on ischemia-induced DOR, but does not worsen susceptibility to arrhythmias. Further study in translatable models of ischemia-induced cardiac arrest is warranted to assess the effect of ACLS pharmacology on arrhythmias with the increased use of TH.
Impact of Practice-Based Management of Pulmonary Artery Pressures in 2000 Patients Implanted With the CardioMEMS Sensor
Authors: J. Thomas Heywood, Rita Jermyn, David Shavelle, William T. Abraham, Arvind Bhimaraj, Kunjan Bhatt, Fareed Sheikh, Eric Eichorn, Sumant Lamba, Rupinder Bharmi, Rahul Agarwal, Charisma Kumar, Lynne W. Stevenson
Journal: Circulation (2017)

Elevated pulmonary artery (PA) pressures in patients with heart failure are associated with a high risk for hospitalization and mortality. Recent clinical trial evidence demonstrated a direct relationship between lowering remotely monitored PA pressures and heart failure hospitalization risk reduction with a novel implantable PA pressure monitoring system (CardioMEMS HF System, St. Jude Medical). This study examines PA pressure changes in the first 2000 US patients implanted in general practice use.Deidentified data from the remote monitoring Merlin.net (St. Jude Medical) database were used to examine PA pressure trends from the first consecutive 2000 patients with at least 6 months of follow-up. Changes in PA pressures were evaluated with an area under the curve methodology to estimate the total sum increase or decrease in pressures (mm Hg-day) during the follow-up period relative to the baseline pressure. As a reference, the PA pressure trends were compared with the historic CHAMPION clinical trial (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association [NYHA] Functional Class III Heart Failure Patients). The area under the curve results are presented as mean±2 SE, and P values comparing the area under the curve of the general-use cohort with outcomes in the CHAMPION trial were computed by the t test with equal variance.Patients were on average 70±12 years old; 60% were male; 34% had preserved ejection fraction; and patients were followed up for an average of 333±125 days. At implantation, the mean PA pressure for the general-use patients was 34.9±10.2 mm Hg compared with 31.3±10.9 mm Hg for CHAMPION treatment and 32.0±10.5 mm Hg for CHAMPION control groups. The general-use patients had an area under the curve of -32.8 mm Hg-day at the 1-month time mark, -156.2 mm Hg-day at the 3-month time mark, and -434.0 mm Hg-day after 6 months of hemodynamic guided care, which was significantly lower than the treatment group in the CHAMPION trial. Patients consistently transmitted pressure information with a median of 1.27 days between transmissions after 6 months.The first 2000 general-use patients managed with hemodynamic-guided heart failure care had higher PA pressures at baseline and experienced greater reduction in PA pressure over time compared with the pivotal CHAMPION clinical trial. These data demonstrate that general use of implantable hemodynamic technology in a nontrial setting leads to significant lowering of PA pressures.
Noninvasive Assessment of Significant Left Anterior Descending Coronary Artery Stenosis by Coronary Flow Velocity Reserve With Transthoracic Color Doppler Echocardiography
Authors: TakeshiHozumi, KiyoshiYoshida, YumikoOgata, TakashiAkasaka, YoshioAsami, TsutomuTakagi, ShigefumiMorioka
Journal: Circulation (1998)

Background—Coronary flow reserve has been considered an important diagnostic index of the functional significance of coronary artery stenosis. With Doppler technique, it has been assessed as the ratio of hyperemic to basal coronary flow velocity (coronary flow velocity reserve [CFVR]) by invasive or semiinvasive methods with a Doppler catheter, a Doppler guide wire, and a transesophageal Doppler echocardiographic probe. Recent technological advancement in transthoracic Doppler echocardiography (TTDE) provides measurement of coronary flow velocity in the distal portion of the left anterior descending coronary artery (LAD) and may be useful in the noninvasive CFVR measurement. The purpose of this study was to evaluate the value of CFVR determined by TTDE for the assessment of significant LAD stenosis. Methods and Results—We studied 36 patients who underwent coronary angiography for the assessment of coronary artery disease. The study population consisted of 12 patients with significant LAD stenosis (group A...
Abstract 4395: KP-1339 (IT-139) induces the hallmarks of immunogenic cell death in a colon cancer 3D model in vitro
Authors: Debora Wernitznig, Giorgia Del Favero, Konstantinos Kiakos, Nathalie Harrer, Herwig Machat, Doris Marko, Michael Jakupec, Wolfgang Sommergruber, Bernhard K. Keppler
Journal: Cancer Research (2018)

Abstract Chemotherapeutic drugs exert their activity by directly killing tumor cells through a variety of cellular targets eventually leading to apoptosis. Apoptosis is regarded as non-inflammatory and non-immunogenic, however, recent data confirm that the induction of damage-associated molecular patterns by dying cancer cells treated with certain chemotherapeutic agents, such as oxaliplatin, lead to their recognition by the immune system, and result in dendritic cell maturation and immune responses, a mechanism described as Immunogenic Cell Death (ICD). The main hallmarks of ICD are: Calreticulin (CRT) exposure on the cell membrane and release of high mobility group box-1 (HMGB-1) and ATP from dying cells. We have recently shown that the mode of action of KP-1339, a clinically investigated ruthenium-based metal complex, involves the enhancement of endoplasmic reticulum stress (ERS) and the induction of apoptosis-like events. We next investigated the ability of KP-1339 to trigger ICD. There is currently no reliable method to study ICD in vitro, and therefore we aimed at a more suitable model that better mimics the tumor microenvironment in comparison to 2D monolayer cultures. For this reason, ICD was assessed in human colorectal cancer HCT-116 3D multicellular spheroids in vitro. We demonstrate that spheroids treated with KP-1339 activate the PERK/Phospho-eIF-2alpha pathway of the ERS, a prerequisite for CRT exposure on the cell membrane. HMGB1 protein levels decrease considerably during a 72 hours drug treatment, as shown by Immunoblotting, suggesting the depletion of the protein. Additionally, treated spheroids released significantly more ATP than untreated controls. Immunofluorescence of cryosections of KP-1339 treated spheroids stained for CRT and HMGB1 confirmed the above observations and, clearly showed the translocation of CRT to the cell membrane. In conclusion, we have established a 3D tumor spheroid model as an alternative to the 2D monolayer cultures to study ICD in vitro. This model more closely resembles the tumor microenvironment and recapitulates relevant aspects of the in vivo situation. We successfully employed this model to demonstrate that the clinically investigated compound KP-1339 triggers the main hallmarks of ICD, which suggests enhanced induction anti-tumor immunity in colorectal cancer. Citation Format: Debora Wernitznig, Giorgia Del Favero, Konstantinos Kiakos, Nathalie Harrer, Herwig Machat, Doris Marko, Michael Jakupec, Wolfgang Sommergruber, Bernhard K. Keppler. KP-1339 (IT-139) induces the hallmarks of immunogenic cell death in a colon cancer 3D model in vitro [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 4395.
Abstract 3477: Metabolic pathway analyses identify proline biosynthesis as a promoter of liver carcinogenesis
Authors: Zhaobing Ding, Russell E. Ericksen, Michael Steckel, Andrea Haegebarth, Sylvia Gruenewald, Weiping Han
Journal: Cancer Research (2018)

Abstract Cancer cells undergo dramatic metabolic reprogramming, largely to meet the requirements of sustained proliferation. These metabolic pathways are tightly regulated by various oncogenes, such as Myc and Ras. However, it has been difficult to directly and effectively inhibit these oncogenic signaling cascades with pharmacological compounds. Therefore, focusing on the downstream metabolic pathways that enable indefinite growth may provide a therapeutic opportunity. To identify metabolic enzymes required for hepatocellular carcinoma (HCC) tumorigenesis, we compared gene expression profiles of normal liver tissue to the Morris Hepatoma and DEN (Diethylnitrosamine)-induced HCC models as well as a liver regeneration model. PYCR1 (Pyrroline-5-Carboxylate Reductase 1), an enzyme in the proline biosynthesis pathway, was identified as one of the top up-regulated genes in the HCC models. An increase in PYCR1 protein levels in tumor samples versus normal liver tissue was confirmed by Western blot. shRNA-mediated knockdown of PYCR1 in HCC cell lines (Huh-7, Hep3B, HepG2 SNU-398, and MH3924a) potently reduced cell proliferation in vitro and tumor growth in vivo. Conversely, overexpression of PYCR1 enhanced the proliferation of Hep3B and AML12 cells. Importantly, PYCR1 expression was not elevated in regenerating tissues, and knockdown in a non-tumorigenic cell line did not influence proliferation. Additional enzymes in the proline biosynthesis pathway were also altered in tumors. For instance, ALDH18A1 was up-regulated and knockdown by shRNA decreased proliferation of human HCC cell lines. Metabolomic analyses suggested that the metabolism of glucose was disrupted in PYCR1 knockdown cells, with reduced fluxes through glycolytic and pentose phosphate pathways. Clinical data demonstrated that PYCR1 expression was increased in HCC, and expression levels correlated with increasing tumor grades and were independent predictors of clinical outcome. Overall, our data suggest that enhanced expression of proline biosynthetic enzymes promotes cell proliferation, and that inhibiting PYCR1 or ALDH18A1 may be a novel therapeutic strategy to target HCC. Citation Format: Zhaobing Ding, Russell E. Ericksen, Michael Steckel, Andrea Haegebarth, Sylvia Gruenewald, Weiping Han. Metabolic pathway analyses identify proline biosynthesis as a promoter of liver carcinogenesis [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 3477.