tbuckley/cabot-search huggingface dataset:
Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa
Authors: Alonso Sánchez-Cruz, Beatriz Villarejo-Zori, Miguel Marchena, Josefa Zaldivar-Díez, Valle Palomo, Carmen Gil, Ignacio Lizasoain, Pedro de la Villa, Ana Martínez, Enrique J. de la Rosa, Catalina Hernández-Sánchez
Journal: Molecular Neurodegeneration (2018)

Retinitis pigmentosa (RP) is a group of hereditary retinal neurodegenerative conditions characterized by primary dysfunction and death of photoreceptor cells, resulting in visual loss and, eventually, blindness. To date, no effective therapies have been transferred to clinic. Given the diverse genetic etiology of RP, targeting common cellular and molecular retinal alterations has emerged as a potential therapeutic strategy. Using the Pde6b rd10/rd10 mouse model of RP, we investigated the effects of daily intraperitoneal administration of VP3.15, a small-molecule heterocyclic GSK-3 inhibitor. Gene expression was analyzed by quantitative PCR and protein expression and phosphorylation by Western blot. Photoreceptor preservation was evaluated by histological analysis and visual function was assessed by electroretinography. In rd10 retinas, increased expression of pro-inflammatory markers and reactive gliosis coincided with the early stages of retinal degeneration. Compared with wild-type controls, GSK-3β expression (mRNA and protein) remained unchanged during the retinal degeneration period. However, levels of GSK-3βSer9 and its regulator AktSer473 were increased in rd10 versus wild-type retinas. In vivo administration of VP3.15 reduced photoreceptor cell loss and preserved visual function. This neuroprotective effect was accompanied by a decrease in the expression of neuroinflammatory markers. These results provide proof of concept of the therapeutic potential of VP3.15 for the treatment of retinal neurodegenerative conditions in general, and RP in particular.
NCCN Guidelines Updates: Prostate Cancer and Prostate Cancer Early Detection
Authors: Peter H. Carroll, James L. Mohler
Journal: Journal of the National Comprehensive Cancer Network (2018)

Peter H. Carroll, MD, MPH, and James L. Mohler, MD, updated attendees on what is new in the 2018 NCCN Guidelines for Prostate Cancer Early Detection and for Prostate Cancer, respectively. Their presentations touched on new screening recommendations, shared decision-making, risk stratification, the role of genomic and molecular testing, active surveillance, and newer systemic treatments.
Trudeau calls for inquiry after Canadian doctor is shot in Gaza
Authors: Owen Dyer
Journal: BMJ (2018)

The Canadian prime minister, Justin Trudeau, has called for an independent investigation after a Canadian doctor was shot by an Israeli sniper on the worst day of violence in Gaza for years.

“We are appalled that Dr Tarek Loubani, a Canadian citizen, is among the wounded—along with so many unarmed people, including civilians, members of the media, first responders, and children,” Trudeau said.

“Reported use of excessive force and live ammunition …
PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity
Authors: Anusara Daenthanasanmak, Yongxia Wu, Supinya Iamsawat, Hung D. Nguyen, David Bastian, MengMeng Zhang, M. Hanief Sofi, Shilpak Chatterjee, Elizabeth G. Hill, Shikhar Mehrotra, Andrew S. Kraft, Xue-Zhong Yu
Journal: Journal of Clinical Investigation (2018)

PIM kinase family members play a crucial role in promoting cell survival and proliferation via phosphorylation of their target substrates. In this study, we investigated the role of the PIM kinases with respect to T cell responses in transplantation and tumor immunity. We found that the PIM-2 isoform negatively regulated T cell responses to alloantigen, in contrast to the PIM-1 and PIM-3 isoforms, which acted as positive regulators. T cells deficient in PIM-2 demonstrated increased T cell differentiation toward Th1 subset, proliferation, and migration to target organs after allogeneic bone marrow transplantation, resulting in dramatically accelerated graft-versus-host disease (GVHD) severity. Restoration of PIM-2 expression markedly attenuated the pathogenicity of PIM-2-deficient T cells to induce GVHD. On the other hand, mice deficient in PIM-2 readily rejected syngeneic tumor, which was primarily dependent on CD8+ T cells. Furthermore, silencing PIM-2 in polyclonal or antigen-specific CD8+ T cells substantially enhanced their antitumor response in adoptive T cell immunotherapy. We conclude that PIM-2 kinase plays a prominent role in suppressing T cell responses, and provide a strong rationale to target PIM-2 for cancer immunotherapy.
Deterioration of Regional Lung Strain and Inflammation during Early Lung Injury
Authors: Gabriel C. Motta-Ribeiro, Soshi Hashimoto, Tilo Winkler, Rebecca M. Baron, Kira Grogg, Luís F. S. C. Paula, Arnoldo Santos, Congli Zeng, Kathryn Hibbert, Robert S. Harris, Ednan Bajwa, Marcos F. Vidal Melo
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

The contribution of aeration heterogeneity to lung injury during early mechanical ventilation of uninjured lungs is unknown.To test the hypotheses that a strategy consistent with clinical practice does not protect from worsening in lung strains during the first 24 hours of ventilation of initially normal lungs exposed to mild systemic endotoxemia in supine versus prone position, and that local neutrophilic inflammation is associated with local strain and blood volume at global strains below a proposed injurious threshold.Voxel-level aeration and tidal strain were assessed by computed tomography in sheep ventilated with low Vt and positive end-expiratory pressure while receiving intravenous endotoxin. Regional inflammation and blood volume were estimated from 2-deoxy-2-[(18)F]fluoro-d-glucose (18F-FDG) positron emission tomography.Spatial heterogeneity of aeration and strain increased only in supine lungs (P < 0.001), with higher strains and atelectasis than prone at 24 hours. Absolute strains were lower than those considered globally injurious. Strains redistributed to higher aeration areas as lung injury progressed in supine lungs. At 24 hours, tissue-normalized 18F-FDG uptake increased more in atelectatic and moderately high-aeration regions (>70%) than in normally aerated regions (P < 0.01), with differential mechanistically relevant regional gene expression. 18F-FDG phosphorylation rate was associated with strain and blood volume. Imaging findings were confirmed in ventilated patients with sepsis.Mechanical ventilation consistent with clinical practice did not generate excessive regional strain in heterogeneously aerated supine lungs. However, it allowed worsening of spatial strain distribution in these lungs, associated with increased inflammation. Our results support the implementation of early aeration homogenization in normal lungs.
Abstract 15063: Association of Global Longitudinal Strain With Outcomes in Patients Who Develop Significant Tricuspid Regurgitation After Pacemaker/Defibrillator Implantation
Authors: Alaa Alashi, Amjad Abdallah, Amgad Mentias, Mohamad Kanj, Oussama Wazni, Bruce Lindsay, Zoran B Popovic, Brian P Griffin, Milind Y Desai
Journal: Circulation (2016)

Background:  Development of significant tricuspid regurgitation (TR) following pacemaker/internal defibrillator (PPM/ICD) implantation, due to leaflet perforation or lack of coaptation, is occasionally observed. Global longitudinal strain (GLS) on echocardiography is a sensitive marker of regional myocardial mechanics. In a group of patients who developed significant TR, following PPM/ICD implantation, we sought to assess whether left (LV) & right ventricular (RV) GLS is independently associated with mortality.   Methods:  We studied 237 consecutive patients (age 64±13 years, 70% men) with    Results:  Mean baseline STS score, LV ejection fraction (LVEF), RV systolic pressure (RVSP), LV-GLS & RV-GLS were 11±11%, 27±12%, 36±10 mm Hg, -9.9±3% & -15.5±5%. 24% had 1, 43% had 2 and 33% had 3-chamber PPM/ICD. 54 % had ischemic cardiomyopathy. Mean follow-up RVSP, LV and RV-GLS (at 2 years after PPM/ICD implantation) were 36±10 mm Hg, -9.3±4% & -11.4±4%. At 6±3 years of follow-up, 3% underwent tricuspid repair/replacement, while 5% had heart transplantation and 64% died. Results of multivariate Cox Proportional Hazard analysis for long-term mortality are shown in Figure A. Survival curves separated on basis of baseline RV-GLS better or worse than median (-16%) are shown in Figure B.   Conclusion:  High-risk patients who develop ≥3+ TR following PPM/ICD implantation have a high rate of mortality & worse baseline & follow-up RV-GLS (but not LV-GLS) are independently associated with long-term mortality. No causality between post PPM/ICD TR & mortality is established & there is need for prospective confirmation.
Randomized Trial Comparing Open Radical Cystectomy and Robot-assisted Laparoscopic Radical Cystectomy: Oncologic Outcomes
Authors: Bernard H. Bochner, Guido Dalbagni, Karim H. Marzouk, Daniel D. Sjoberg, Justin Lee, Sheri M. Donat, Jonathan A. Coleman, Andrew Vickers, Harry W. Herr, Vincent P. Laudone
Journal: European Urology (2018)
Timing of surgery following neoadjuvant chemoradiation in rectal cancer: A retrospective analysis from an academic medical center.
Authors: Justin Chau, Seth Maliske, Daniel James Berg, Sudershan Bhatia, Andrew Bellizzi, John Byrn, Timothy Ginader, Varun Monga
Journal: Journal of Clinical Oncology (2018)

702 Background: Neoadjuvant chemoradiotherapy has been proven to achieve decreased local recurrence in rectal cancer with lower toxicity but data confirming the optimal timing of surgery following neoadjuvant cares is less robust. Methods: The University of Iowa Cancer Registry was queried to identify all patients with rectal cancer between 2000-2012. Individual records were reviewed for all patients with Stage II-III disease who received neoadjuvant chemoradiation. Primary endpoints were time interval from last day of chemoradiation to surgery (TI) and overall survival (OS). Secondary endpoints included hospital length of stay following surgery (LOS), intraoperative blood loss (BL), and major postoperative complication including infection, anastomotic failure, and thromboembolic event. Patient characteristics such as personal and family history of malignancy were studied, and treatment regimens including chemotherapy type, radiation technique and quality of resection were also compared. All postoperative pathology slides were reviewed for completeness of resection by a single pathologist. Univariate logistic regression analyses were used to study the association between TI and OS to help define the optimal interval. Results: 88 patients were identified with Stage II and III rectal cancer after imaging and endoscopic study. There was no significant association between OS and TI when comparing less than 8 weeks to greater than 8 weeks (p = 0.14) or when considering TI as a continuous variable (p = 0.99). There was no significant association between TI and surgical complications including BL (p = 0.60) or LOS (median = 7.00 days, p = 0.06), though patients undergoing pelvic exenteration experienced notably longer LOS (n = 4, mean 24.25 days, max 60 days). Conclusions: Our findings indicate that overall survival is not significantly impacted by longer intervals between chemoradiation and surgery. The incidence of major postoperative complication was rare but cost patients and the healthcare provider significant resources; thus, our results implicate potential benefits to treating some Stage II and III rectal cancers solely with chemoradiotherapy.
Influence of Aortic Dilation on the Regional Aortic Stiffness of Bicuspid Aortic Valve Assessed by 4-Dimensional Flow Cardiac Magnetic Resonance
Authors: Andrea Guala, Jose Rodriguez-Palomares, Lydia Dux-Santoy, Gisela Teixido-Tura, Giuliana Maldonado, Laura Galian, Marina Huguet, Filipa Valente, Laura Gutiérrez, Teresa González-Alujas, Kevin M. Johnson, Oliver Wieben, Augusto Sao Avilés, David Garcia-Dorado, Arturo Evangelista
Journal: JACC. Cardiovascular imaging (2018)
Abstract 9885: Exercise Enhances Vascular Protective Effects of HMG-CoA Inhibitor Statins in Mice at Advanced Age
Authors: Xian Wu Cheng, Lina Hu, Haiying Jiang, Aiko Inoue, Hongxian Wu, Limei Piao, Kenji Okumura, Toyoaki Murohara, Masafumi Kuzuya
Journal: Circulation (2015)

Introduction: Regulatory T cells (Treg) have been shown to be immune suppressors of inflammatory actions. Given that exercise or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, protect vascular tissue to stress in young animals and humans, we aimed to clarify the potential effect of swimming training (ST) to enhance the beneficial effects of statins and the cellular mechanism of the effect of statins on vascular actions in response to ischemia in mice at advanced age. Methods and Results: Aged (24 months) mice underwent hindlimb ischemic surgery. On operative day 1, the mice were randomly assigned to three groups treated with either vehicle, pitavastatin (PiS: 1 mg/kg/day; given by oral gavage every day), or PiS with swimming training (PiS-ST 1 hour/day) for 14 days. PiS treatment increased the levels of GATA3 and p-GATA6 proteins and interleukin-10 and CD206 (M2 macrophage marker) genes, whereas it suppressed the levels of p-STAT4 and tumor necrosis factor-1α proteins and C-X-C motif chemokine 10, monocyte chemotactic protein-1, gp91phox and CD40 (M1 macrophage marker) genes as well as macrophage infiltration of the ischemic muscles. PiS also reduced circulating numbers of CD4+ and CD8+ T cells and enhanced circulating CD4+/CD25+ T cells and CD31+/c-Kit+ EPCs. Moreover, EC apoptosis of the ischemic muscles ware lower in PiS-treated mice than in that of control mice. PiS improved blood flow recovery and capillary density. Interestingly, ST was found to enhance PiS-mediated beneficial actions. Conclusion: The statin-mediated beneficial effects are likely attributable, at least in part, to improvement of Treg-mediated inflammation and immune action and EC apoptosis; in addition, ST appears to enhance the vasculoprotective effects of statins, suggesting that a combination of statin and ST could be effective for the clinical treatment of cardiovascular disease in advanced age.
Association of Burden of Atrial Fibrillation With Risk of Ischemic Stroke in Adults With Paroxysmal Atrial Fibrillation
Authors: Alan S. Go, Kristi Reynolds, Jingrong Yang, Nigel Gupta, Judith Lenane, Sue Hee Sung, Teresa N. Harrison, Taylor I. Liu, Matthew D. Solomon
Journal: JAMA Cardiology (2018)

<h3>Importance</h3> Atrial fibrillation is a potent risk factor for stroke, but whether the burden of atrial fibrillation in patients with paroxysmal atrial fibrillation independently influences the risk of thromboembolism remains controversial. <h3>Objective</h3> To determine if the burden of atrial fibrillation characterized using noninvasive, continuous ambulatory monitoring is associated with the risk of ischemic stroke or arterial thromboembolism in adults with paroxysmal atrial fibrillation. <h3>Design, Setting, and Participants</h3> This retrospective cohort study conducted from October 2011 and October 2016 at 2 large integrated health care delivery systems used an extended continuous cardiac monitoring system to identify adults who were found to have paroxysmal atrial fibrillation on 14-day continuous ambulatory electrocardiographic monitoring. <h3>Exposures</h3> The burden of atrial fibrillation was defined as the percentage of analyzable wear time in atrial fibrillation or flutter during the up to 14-day monitoring period. <h3>Main Outcomes and Measures</h3> Ischemic stroke and other arterial thromboembolic events occurring while patients were not taking anticoagulation were identified through November 2016 using electronic medical records and were validated by manual review. We evaluated the association of the burden of atrial fibrillation with thromboembolism while not taking anticoagulation after adjusting for the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) or CHA<sub>2</sub>DS<sub>2</sub>-VASc stroke risk scores. <h3>Results</h3> Among 1965 adults with paroxysmal atrial fibrillation, the mean (SD) age was 69 (11.8) years, 880 (45%) were women, 496 (25%) were persons of color, the median ATRIA stroke risk score was 4 (interquartile range [IQR], 2-7), and the median CHA<sub>2</sub>DS<sub>2</sub>-VASc score was 3 (IQR, 1-4). The median burden of atrial fibrillation was 4.4% (IQR ,1.1%-17.23%). Patients with a higher burden of atrial fibrillation were less likely to be women or of Hispanic ethnicity, but had more prior cardioversion attempts compared with those who had a lower burden. After adjusting for either ATRIA or CHA<sub>2</sub>DS<sub>2</sub>-VASc stroke risk scores, the highest tertile of atrial fibrillation burden (≥11.4%) was associated with a more than 3-fold higher adjusted rate of thromboembolism while not taking anticoagulants (adjusted hazard ratios, 3.13 [95% CI, 1.50-6.56] and 3.16 [95% CI, 1.51-6.62], respectively) compared with the combined lower 2 tertiles of atrial fibrillation burden. Results were consistent across demographic and clinical subgroups. <h3>Conclusions and Relevance</h3> A greater burden of atrial fibrillation is associated with a higher risk of ischemic stroke independent of known stroke risk factors in adults with paroxysmal atrial fibrillation.
Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial
Authors: Richard J Russell, Latifa Chachi, J Mark FitzGerald, Vibeke Backer, Ronald Olivenstein, Ingrid L Titlestad, Charlotte Suppli Ulrik, Timothy Harrison, Dave Singh, Rekha Chaudhuri, Brian Leaker, Lorcan McGarvey, Salman Siddiqui, Millie Wang, Martin Braddock, Lars H Nordenmark, David Cohen, Himanshu Parikh, Gene Colice, Christopher E Brightling, Michel Laviolette, Tina Skjold, Læge Carl Nielsen, Peter Howarth
Journal: The Lancet Respiratory Medicine (2018)
Pregnancy and oestrogen regulate sinoatrial node calcium homeostasis and accelerate pacemaking
Authors: Nabil El Khoury, Jenna L Ross, Valérie Long, Simon Thibault, Nathalie Ethier, Céline Fiset
Journal: Cardiovascular Research (2018)

During pregnancy, there is a significant increase in heart rate (HR) potentially associated with an increased risk of arrhythmias or exacerbation of pre-existing cardiac conditions endangering both mother and foetus. Calcium homeostasis plays an important role in regulating automaticity of the sinoatrial node (SAN); however, its contribution to the accelerated HR during pregnancy remains unknown. Using murine SAN cells, we showed that pregnancy increased L-type Ca2+ current (ICaL) and CaV1.3 mRNA expression, whereas T-type Ca2+ current (ICaT) and its underlying channel were unchanged. Analysis of SAN intra-cellular Ca2+ oscillations showed that the rate of spontaneous Ca2+ transients was significantly higher in pregnant mice along with a higher mRNA expression of ryanodine receptor. Assessment of supra-ventricular arrhythmias using programmed electrical stimulation protocols on anaesthetized mice revealed higher susceptibility in pregnancy. Of note, the modifications associated with pregnancy were reversible following delivery. Furthermore, chronic administration of 17β-estradiol (E2) to nodal-like human-induced pluripotent stem cell-derived cardiomyocytes (N-hiPSC-CM), control mice, oestrogen-receptor-β knockout (ERKOβ) but not ERKOα mice, accelerated cardiac automaticity, recapitulating the pregnancy phenotype in both mouse and human SAN cell models. Together, these results indicate that pregnancy considerably alters intra-cellular Ca2+ homeostasis sustaining faster HR during pregnancy. Importantly, these changes were dependent on an oestrogen receptor α (ERα) mechanism that resulted in increased ICaL and spontaneous Ca2+ release from the sarcoplasmic reticulum, highlighting a novel role for oestrogen in regulating HR.
Abstract 2431: Global Strain with Speckle Tracking Method is Next Generation Index of Left Ventricular Systolic Function
Authors: Hideaki Kanzaki, Makoto Amaki, Takuya Hasegawa, Takahiro Ohara, Kazuhiko Hashimura, Masafumi Kitakaze
Journal: Circulation (2008)

Background. Myocardial strain is an index of regional function, whereas global left ventricular (LV) systolic function is generally assessed with ejection fraction (EF). Recent development of speckle tracking analysis software allows angle-independent and less time-consuming measurement of whole LV strain. Our objective was to assess whether the method is useful as another index of global LV systolic function. Methods. In 54 patients (LVEF 36±19%, 7–72%), digital gray-scales cine-loops were acquired from the apical 4-, 2-chamber, and long-axis views (GE Vivid7). After defining a region of interest (ROI) by tracing the LV endocardial border with several points at each view, a bull’s eye map was automatically constructed based on longitudinal strain and an averaged value of systolic peak strain was easily determined (EchoPAC Dimension AFI, GE). The strain value multiplied by −1 was used as global strain. Nineteen of the 54 patients underwent dobutamine stress and global strain value was calculated at baseline and during administration of 10 μg/kg/min. Results. Figure at left shows a bull’s eye strain map in a case of anterior myocardial infarction with regional dyskinetic wall motion. The blue area indicates the dyskinetic region. Despite of low dose, dobutamine increased global strain value (from 15.3 ± 5.3 to 17.1 ± 6.0, P &lt;0.001) as well as LVEF. Figure at right shows global strain value was well correlated with LVEF ( r =0.917, P &lt;0.001). Conclusion. Global strain is a new index which reflects the location, severity and extent of myocardial damage in addition to global LV systolic function.
Absence of early HHV‐6 reactivation after cord blood allograft predicts powerful graft‐versus‐tumor effect
Authors: Armin Rashidi, Maryam Ebadi, Bassil Said, Qing Cao, Ryan Shanley, Julie Curtsinger, Nelli Bejanyan, Erica D. Warlick, Jaime S. Green, Claudio G. Brunstein, Jeffrey S. Miller, Daniel J. Weisdorf
Journal: American Journal of Hematology (2018)

Abstract Approximately 75% of cord blood transplant (CBT) recipients experience human herpes virus‐6 (HHV‐6) reactivation. Considering the immunomodulatory effects of HHV‐6, we hypothesized that early HHV‐6 reactivation may influence the risk of relapse of the underlying hematologic malignancy. In 152 CBT recipients with hematological malignancies, we determined the association between HHV‐6 reactivation by day +28 and 2‐year cumulative incidence of relapse. In univariate analysis, the absence of HHV‐6 reactivation ( n = 32) was associated with less relapse (26 [18‐35]% vs. 7 [0‐17]% in groups with vs. without HHV‐6 reactivation, respectively; P = .03). This difference was due to a remarkably low relapse incidence among patients without HHV‐6 reactivation. In multivariable analysis, the absence of HHV‐6 reactivation was associated with less relapse (hazard ratio [95% confidence interval]: 0.2 [0.05‐0.9], P = .03). This association was independent of patient‐, disease‐, and transplant‐related characteristics known to influence the risk of relapse. Natural killer cell and T‐cell reconstitution at day +28 were similar between patients with vs. without HHV‐6 reactivation. Our results suggest that CB allografts not complicated by HHV‐6 reactivation by day +28 have a powerful graft‐versus‐tumor effect. Knowledge about early HHV‐6 reactivation may stratify patients at day +28 into low vs. high relapse risk groups.