tbuckley/cabot-search huggingface dataset:
Reduced presynaptic vesicle stores mediate cellular and network plasticity defects in an early-stage mouse model of Alzheimer’s disease
Authors: Shreaya Chakroborty, Evan S. Hill, Daniel T. Christian, Rosalind Helfrich, Shannon Riley, Corinne Schneider, Nicolas Kapecki, Sarah Mustaly-Kalimi, Figen A. Seiler, Daniel A. Peterson, Anthony R. West, Barbara M. Vertel, William N. Frost, Grace E. Stutzmann
Journal: Molecular Neurodegeneration (2019)

Identifying effective strategies to prevent memory loss in AD has eluded researchers to date, and likely reflects insufficient understanding of early pathogenic mechanisms directly affecting memory encoding. As synaptic loss best correlates with memory loss in AD, refocusing efforts to identify factors driving synaptic impairments may provide the critical insight needed to advance the field. In this study, we reveal a previously undescribed cascade of events underlying pre and postsynaptic hippocampal signaling deficits linked to cognitive decline in AD. These profound alterations in synaptic plasticity, intracellular Ca2+ signaling, and network propagation are observed in 3–4 month old 3xTg-AD mice, an age which does not yet show overt histopathology or major behavioral deficits. In this study, we examined hippocampal synaptic structure and function from the ultrastructural level to the network level using a range of techniques including electron microscopy (EM), patch clamp and field potential electrophysiology, synaptic immunolabeling, spine morphology analyses, 2-photon Ca2+ imaging, and voltage-sensitive dye-based imaging of hippocampal network function in 3–4 month old 3xTg-AD and age/background strain control mice. In 3xTg-AD mice, short-term plasticity at the CA1-CA3 Schaffer collateral synapse is profoundly impaired; this has broader implications for setting long-term plasticity thresholds. Alterations in spontaneous vesicle release and paired-pulse facilitation implicated presynaptic signaling abnormalities, and EM analysis revealed a reduction in the ready-releasable and reserve pools of presynaptic vesicles in CA3 terminals; this is an entirely new finding in the field. Concurrently, increased synaptically-evoked Ca2+ in CA1 spines triggered by LTP-inducing tetani is further enhanced during PTP and E-LTP epochs, and is accompanied by impaired synaptic structure and spine morphology. Notably, vesicle stores, synaptic structure and short-term plasticity are restored by normalizing intracellular Ca2+ signaling in the AD mice. These findings suggest the Ca2+ dyshomeostasis within synaptic compartments has an early and fundamental role in driving synaptic pathophysiology in early stages of AD, and may thus reflect a foundational disease feature driving later cognitive impairment. The overall significance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic vesicle stores, synaptic plasticity, and network propagation, which directly impact memory encoding.
Abstract P382: Association of Passive Smoking Status to Endothelial Vascular Function Among General Japanese Women
Authors: Aya Kadota, Keiko Kondo, Takashi Hisamatsu, Itsuko Miyazawa, Akira Fujiyoshi, Hirotsugu Ueshima, Katsuyuki Miura
Journal: Circulation (2019)

Objective: Passive smoking was reported to impair endothelial vascular function in an acute phase. However, studies regarding the vascular effect of passive smoking status among general population are still scarce. We investigated the association of passive smoking status to endothelial vascular function among general Japanese women. Methods: Study participants were 243 Japanese women who had never smoked, and aged 69 to 85 years randomly selected from Kusatsu City, Japan. Using self-administered questionnaire, passive smoking status and passive smoking hour per week at recent 1 year and those of 20 years ago were obtained. They were classified into 4 groups (never, past, current; &lt;2 hours/week, ≥2 hours/week). Endothelial vascular function was assessed with reactive hyperemia index (RHI) using Endo-PAT2000 (itamar-medical). RHI ≤1.67 were defined as low RHI. Age adjusted means of RHI according to passive smoking status was estimated. Simple liner regression analysis tested the association between RHI and traditional atherosclerotic risk factors such as age, body mass index (BMI), systolic and diastolic blood pressure, heart rate, lipids, fasting blood glucose and hemoglobin A1c. Age and multivariable adjusted odd’s ratios and 95% confidence intervals (OR, 95%CI) of passive smoking status for low RHI were estimated using logistic regression. Variables which showed statistical significant association to RHI in simple liner regression were adjusted. Results: Distribution of passive smoking status was; never 42.4%, past 42.0%, current &lt;2 hours/week 6.5%, ≥2 hours/week 9.1%. Low RHI was confirmed in 41.2% of study participants. Age adjusted means of RHI did not differ significantly by smoking status (Age adjusted mean ± SD of RHI; never 1.94 ± 0.06, past 1.88 ± 0.06, current &lt;2 hours/week 1.85 ± 0.15, ≥2 hours/week 2.15 ± 0.13, p=0.270). In simple liner regression analysis, BMI, diastolic blood pressure, heart rate and fasting glucose showed statistical significant association to RHI, and these variables were adjusted in multivariable adjusted logistic regression model. In logistic regression analyses, significant association of passive smoking status to low RHI was not confirmed [Age adjusted OR (95%CI); never (reference), past 1.00 (0.57-1.75), current &lt;2 hours/week 1.45 (0.50-4.23), ≥2 hours/week 0.66 (0.25-1.76), multivariable adjusted OR (95%CI); never (reference), past 1.02 (0.57-1.82), current &lt;2 hours/week 1.72 (0.57-5.21), ≥2 hours/week 0.61 (0.22-1.73)]. Conclusion: Passive smoking status was not associated to endothelial vascular function assessed with RHI among general Japanese women. Further investigation is still required.
Abstract P099: Heart Rate Variability Differences Between Green and Suburban Walking: A Pilot Crossover Study
Authors: Zachary C Pope, Junia N Brito, Nathan R Mitchell, Ingrid E Schneider, Teresa H Horton, Mark A Pereira
Journal: Circulation (2019)

Introduction: Heart rate variability (HRV) assesses the sympathetic and parasympathetic innervation of the heart. Lower HRV indicates greater sympathetic tone and is associated with adverse cardiovascular outcomes. During exercise, factors like activity intensity influence HRV. Yet, an environment’s inherent anxiety-/stress-promoting characteristics may also affect HRV. Hypothesis: Given nature’s calming characteristics, we hypothesized green (i.e., nature-based) walking would promote higher HRV and less HRV reduction than suburban walking. Methods: Twenty-four middle-aged adults (20 female; 49.3 ± 6.7 yrs; BMI: 30.7 ± 7.9 kg/m 2 ) participated in this nine-week crossover study comprised of once-weekly 50-minute moderate-intensity walking sessions. Participants walked for three weeks in each of two treatment conditions: (1) green walking: nature-based walking on trails of local arboretum; and (2) suburban walking: walking on sidewalks of a local suburb’s downtown area. Half were assigned to suburban walking in the first treatment period, and half completed green walking first. A two-week washout separated treatments. The Zephyr BioHarness 3 assessed HRV—reported as standard deviations of normal-to-normal RR intervals in milliseconds (ms) while also tracking activity intensity. For analysis, walks were split into 15-minute intra-walk phases with the first, second, and third phases representing each walk’s beginning, middle, and end. Five-minute pre- and post-walk sitting phases for HRV were also created. Linear mixed models with repeated measures evaluated HRV phase differences between treatments and HRV change between phases by treatment. Results: Lower HRV was observed during the pre-walk sitting phase in the green (56.5 ms) vs. the suburban walking treatment (62.4 ms; p = 0.04); however, a sequence effect was present ( p = 0.02). Due to lower walking intensity during green walking (0.31 g vs. 0.27 g; p &lt; 0.01), activity intensity was a covariate in all intra-walk analyses. Intra-walk phase analyses revealed higher green vs. suburban walking HRV during the second (29.1 ms vs. 24.2 ms, respectively; p &lt; 0.01) and third (33.9 ms vs. 23.8 ms, respectively; p = 0.03) phases. Further, less HRV reduction was seen between the first and second intra-walk phases during green (-7.6 ms) vs. suburban walking (-12.4 ms; p = 0.05). Between-treatment HRV differences were not found for the post-walk sitting phase. No sequence effects were observed for the intra-walk or post-walk phases. Finally, no carryover effects were observed—suggesting adequate washout between treatments. Conclusions: Green walking elicits higher HRV and less HRV reduction vs. suburban walking. Activity intensity did not explain these observations. Fully powered longer-term trials should rigorously evaluate green walking’s potential anxiety-/stress-reducing characteristics.
Determining androgen inactivation status in prostate cancer by [<sup>18</sup>F] DHT PET.
Authors: Ziqi Zhu, Yoon-Mi Chung, Olga Sergeeva, Vladimir Kepe, Michael Berk, Jianneng Li, Hyun-Kyung Ko, Zhenfei Li, Marianne Petro, Frank DiFilippo, Zhenghong Lee, Nima Sharifi
Journal: Journal of Clinical Oncology (2019)

191 Background: Castration-resistant prostate cancer occurs in part due to increased tumor tissue testosterone (T) and dihydrotestosterone (DHT) that sustain tumor growth. T and DHT are converted to inactive T- and DHT-glucuronide (T/DHT-G) by uridine 5'-diphospho-glucuronosyltransferase family genes (UGT2B15 and UGT2B17) in glucuronidation-competent cells and excreted, but not in glucuronidation-deficient cells. Thus, low glucuronidation activity enables prostate tumors to preserve androgens, which increases hormone treatment resistance and may be detectable by functional imaging. Methods: We knocked out (KO) UGT2B15 and 17 in LNCaP cells and tested the DHT retention rate in the cell lines by pulse-chase using [ 3 H]DHT as a probe. Free and DHT-G retention rates were separately determined after 5 to 60 min. To increase the signal difference between control and KO cells, we screened several ATP-binding cassette transporter inhibitors to block DHT-G excretion. We performed [ 18 F]DHT PET/CT in castrated mice having a control and a KO xenograft on contralateral flanks ( n = 3). The ratio of the standard uptake value (SUV) in control to KO xenografts in each mouse was calculated. To increase the ratio between control and KO tumors, 50µg cyclosporin A (CSA) was injected 30 min before injecting [ 18 F]DHT. Results: After 5 minutes of chase, control cells retained twice the DHT of KO cells. In control cells, 50%-70% DHT was glucuronidated. Almost no DHT-G was detected in KO cells, and free DHT was similar to control. Of the inhibitors, only CSA increased DHT-G (but not free DHT) in control cells, resulting in a 3-4-fold increase in overall signal. In vivo PET/CT showed control xenografts had higher peak SUV but also a higher elution rate. CSA increased the SUV ratio by 1.5-2. Conclusions: We developed a PET/CT modality to detect androgen inactivation in a prostate cancer xenograft model. Androgen-glucuronidation-proficient tumors give off a stronger signal that is increased by ATP transporter inhibition. Our method can provide a noninvasive means of determining androgen metabolism status and therefore could possibly predict effectiveness of potential therapies in a subgroup of tumors predisposed to androgen deprivation resistance.
Abstract P077: Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Outcomes in Black Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Recent Cardiovascular Outcome Trials
Authors: Efstratios Koutroumpakis, Heinrich Taegtmeyer, David Aguilar
Journal: Circulation (2019)

Introduction: The prevalence of type 2 diabetes mellitus (T2DM) is higher in black individuals than non-Hispanic white individuals. Recent cardiovascular (CV) outcome trials have demonstrated CV benefit of glucagon-like peptide 1 (GLP-1) receptor agonists in patients with T2DM and high CV risk. Whether the benefit seen in the overall trial population extends to the subgroup of black individuals is not known given the limited sample size. Methods: We performed a meta-analysis of randomized CV outcome trials published after the issuance of Food and Drug Administration Guidance on antihyperglycemic medications in 2008. Results: Five trials assessing the CV benefit of GLP-1 receptor agonists in T2DM were identified (ELIXA, LEADER, SUSTAIN-6, EXSCEL, and HARMONY). ELIXA was excluded given the different primary outcome studied and the lack of complete outcome data by race. The four trials included in this meta-analysis enrolled 36,852 individuals, including 2,101 black participants (6%). The prevalence of black patients in the individual clinical trials ranged from 2% in the HARMONY trial to 8% in the LEADER trial. The composite primary outcome of CV death, non-fatal MI, or non-fatal stroke was recorded in 114 out of 1,031 black patients (11%) treated with a GLP-1 analogue compared to 136/1070 (13%) treated with placebo (Hazard Ratio 0.96, 95% Confidence Interval 0.57-1.62). The test for heterogeneity was significant (p=0.04). Conclusions: Despite the high prevalence of T2DM in black individuals, they remain underrepresented in the clinical trials assessing the effect of GLP-1 receptor agonists on CV outcomes in T2DM. The results of this meta-analysis suggest heterogeneity in the studies that have been performed to date. Future studies are needed to confirm the benefit of GLP-1 receptor agonists in black individuals with T2DM and high CV risk. Figure: Hazard ratios of cardiovascular death, non-fatal MI, or non-fatal stroke in black patients with diabetes type 2 treated with a glucagon-like peptide-1 analogue versus placebo
Abstract MP51: Sleep Characteristics and Adverse Social Exposures Elevate Blood Pressure in Young Black Females
Authors: Jewel Scott, Susan Silva, Leigh Ann Simmons
Journal: Circulation (2019)

Introduction: The prevalence of hypertension (HTN) in Black females is 46%, which is higher than males and other females in the United States. Among Black females, HTN develops at younger ages and often is more difficult to treat. Research suggests that sleep quality and quantity may have sex- and race-specific implications for CV health. Further, sleep characteristics may be a behavioral response to adverse social exposures (e.g., discrimination, financial stress), and this response may be amplified among young adults. Hypothesis: We assessed the hypothesis that sleep characteristics and adverse social exposures may contribute to elevated blood pressure in Black women. Methods: Participants included 634 Black females who participated in the National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative study of youth in the U.S. initially enrolled between 7 th -12 th grades and followed over 2.5 decades. Adverse social exposures included child abuse, discrimination, perceived stress, social isolation, and subjective social status. Self-reported sleep characteristics included measures of duration, latency, continuity, and snoring. Applying 2018 AHA guidelines, participants were classified as having elevated BP (&gt;120/80) or not in early adulthood (age 24-32 years). Bivariate and multivariable logistic regression was used to evaluate the influence of social exposures, sleep characteristics, and their interactions on elevated BP. Results: Despite a mean age of 28.9 years, 58% (374 of 634) of the sample had elevated BP. In bivariate analyses, lack of sleep continuity, snoring, less social isolation, and less perceived stress predicted elevated BP, but sleep duration and latency did not. Multivariable analyses that adjusted for demographics, BMI, and depression indicated that elevated BP was associated with snoring (OR 1.458, p=0.03), frequent awakening (OR 1.904, p=0.0005), less social isolation (OR 0.691, p=0.05), and lower perceived stress (OR 0.646, p=0.02). Interactions between sleep characteristics and social exposures were insignificant in predicting elevated BP. Conclusions: Sleep characteristics may represent a key risk factor for HTN that could be addressed in targeted interventions beginning in adolescence. Given the unexpected inverse relationship between social isolation, perceived stress, and elevated BP, future research should examine how current paradigms and measures of social connectedness and stress may need to be adapted to better elucidate the impact of these factors on Black women’s long-term CV health.
Abstract 11485: New Metrics of Postoperative Mechanical Ventilation Duration After Congenital Heart Surgery Reveal Variation Across Hospitals
Authors: Michael Gaies, David Werho, Nancy Ghanayem, Sarah Tabbutt, John Costello, Mark Scheurer, Sara K Pasquali, Janet Donohue, Wenying Zhang, Mousumi Banerjee, Steven Schwartz
Journal: Circulation (2016)

Background: Pediatric cardiac surgical programs aim to limit duration of postoperative mechanical ventilation (POMV) to reduce complications and hospital stay. Measuring casemix-adjusted duration of POMV across hospitals might elucidate differential performance and identify improvement opportunities. Methods: All surgical hospitalizations in the Pediatric Cardiac Critical Care Consortium (PC 4 ) clinical registry from 10/2013-8/2015 were used to create a model predicting casemix-adjusted total duration of POMV using zero-inflated negative binomial regression and validated with 1000 bootstrap samples. From the model we developed metrics based on observed-to-expected POMV: early extubation success/failure, POMV reduction, and total hours of POMV saved/lost ( Table 1 ). We ranked hospitals on each metric (1-15, 1=best) and calculated an average ranking across metrics to identify high and low performing hospitals. Results: The cohort included 4739 hospitalizations from 15 hospitals: 53% were infants and 22% had high complexity surgery. The final model included age, weight-for-age z-score, prematurity, pre-operative MV, extracardiac anomalies, procedure complexity, and bypass time. The model was well-calibrated to predict mean duration of POMV for groups of patients. Table 1 displays the range and median of hospital rates on each of the four metrics, demonstrating variation across the group. The average ranks across these POMV duration metrics suggested two positive outlying hospitals (average rank across all 4 metrics = 1.75) and five hospitals with consistently lower performance (average 8.75-11.25). Conclusions: We developed novel casemix-adjusted metrics of hospital performance to limit duration of POMV following pediatric cardiac surgery, and identified wide variation in relative performance across centers. These metrics may suggest opportunities for improvement when evaluated in context with other perioperative quality measures.
Validation of MSKCC pre-prostatectomy nomogram in men who undergo MRI-targeted prostate biopsy prior to radical prostatectomy.
Authors: Zachary A Glaser, Jennifer Gordetsky, Sejong Bae, Jeffrey Nix, Kristin K Porter, Soroush Rais-Bahrami
Journal: Journal of Clinical Oncology (2019)

14 Background: The Memorial Sloan Kettering Cancer Center (MSKCC) Pre-Prostatectomy nomogram is a widely used resource using clinical factors to predict the likelihood of adverse pathology at radical prostatectomy. The increasing adoption of magnetic resonance imaging (MRI) and MRI-targeted biopsy (TB) permits optimized detection of clinically-significant cancer over systematic biopsy sampling alone. We aim to validate the prognostic utility of the MSKCC Pre-Prostatectomy nomogram with TB pathology results. Methods: Men who underwent systematic extended-sextant prostate biopsy (SB) followed by MRI TB who later underwent radical prostatectomy at our institution were included. Patient information was entered into the MSKCC Pre-Prostatectomy nomogram using five biopsy reporting schemes (SB alone, TB alone reported each of two ways (individual core (IC) technique or aggregate cores (AG) technique combining cores from a single MRI targeted lesion), and SB with TB combined with TB reported by both IC and AG methods. The likelihood of extracapsular extension (EPE), lymph node involvement (LNI), and seminal vesicle invasion (SVI) as predicted by the nomogram for each biopsy reporting schema were compared to radical prostatectomy pathology. Results: We identified 63 men from January 2014 to November 2017. On ROC analysis, IC-TB, AG-TB, SB plus IC-TB, and SB plus AG-TB exhibited similar, if not improved, AUC compared to SB alone in predicting EPE (0.671, 0.674, 0.658, and 0.6613 versus 0.6085). For LNI, superior AUC was observed for AG-TB (0.647) compared to IC-TB (0.571) and SB alone (0.524) Equivocal SVI prediction was observed for SB plus IC-TB compared to SB alone (0.727 versus 0.733). Conclusions: Using TB pathology results either alone or combined with SB pathology results for the MSKCC Pre-Prostatectomy nomogram appears comparable, if not improved, in prognosticating adverse pathologic features on radical prostatectomy compared to using SB core data alone from which the nomogram was developed.
The role of the gastrectomy on survival in metastatic gastric cancer patients: A multicenter study of Anatolian Society of Medical Oncology (ASMO).
Authors: Ozan Yazici, Nuriye Ozdemir, Ayse Ocak Duran, Serkan Menekse, Mehmet Ali Nahit Sendur, Halit Karaca, Gamze Goksel, Erkan Arpaci, Tulay Eren, Ilhan Hacibekiroglu, Irem Bilgetekin, Turgut Kacan, Metin Ozkan, Sercan Aksoy, Asude Aksoy, Nurullah Zengin
Journal: Journal of Clinical Oncology (2015)

e15052 Background: In cancer patients by decreasing the tumor load the duration of survival could be prolonged.During last decades, the positive impact of gastric resection on survival of advanced gastric cancer (AGC) patients were reported.This study was aimed to investigate the role of surgical resection of primary tumor on overall survival in AGC patients at the time of diagnosis. Methods: A total of 488 AGC patients treated between December 2003 and April 2014 were retrospectively evaluated.The data obtained from 9different institutions in Turkey. The patients included in operated group whose primary tumor was resected at the time of diagnosis, who had peroperatively detected metastasis (n = 236). The patients whose primary tumor were not resected, were included in non-operated group (n = 252). Results: Median follow-up of this study was 9 (1-80) months.The median progression free survival (PFS) in operated and non-operated group were 10 (95% CI, 8.69 -11.30) and 6 (95% CI, 5.37 - 6.62) months, respectively (p < 0.001). The overall survival (OS) in operated and non-operated groups were 14 months (95% CI, 12.07 - 15.92) and 9 (95% CI, 8.05 - 9.94) months, respectively (p < 0.001). In the subgroup analyses of operated group, median OS of the patients who had RO resection compared to R1-2 resection was 21 (95% CI, 17.98 - 24.02) and 11 (95% CI, 9.33 - 12.66) months, respectively (p = 0.001). In multivariate analysis histologic grade, European Cooperative Oncology Group (ECOG) performance status and operation had significant effect on PFS (p < 0.05). ECOG performance status with HR: 0.57 (95% CI, 0.42 - 0.78) and operation with HR:0.61 (95% CI, 0.45 - 0.83) had significant effect on OS (p < 0.001 and p = 0.002, respectively). In operated group; ECOG, gender and date of diagnosis were independent factors indicating the patients mostly benefited from gastrectomy. (p = 0.001, p = 0.01 and p = 0.01, respectively). Conclusions: The patients diagnosed in recent years, females and patients with good performance status were mostly benefited from gastrectomy. These results suggesting a subpopulation of AGC patients could be benefited from gastrectomy at the time of diagnosis.