tbuckley/cabot-search huggingface dataset:
Abstract 13551: RhoA Mediates Pressure-Induced Endothelial Hyperpermeability
Authors: Andreia Z Chignalia, Joao Carvalho-de-Souza, Evgeny Zemskov, Stephen M Black
Journal: Circulation (2021)

Pulmonary edema is a severe complication of heart failure. It is often caused by the abrupt increase in lung pulmonary capillary pressure that leads to endothelial barrier instability and disruption. The mechanisms whereby high pressure causes pulmonary edema is unresolved. However, eNOS uncoupling and downstream protein nitration may play a role. We have previously shown that eNOS uncoupling, leading to RhoA activation, is key to the development of pulmonary edema in a model of hypertensive heart failure. Herein, we sought to determine if RhoA activation plays a role in pressure-induced pulmonary edema and the molecular mechanisms that govern this process. Human lung microvascular endothelial cells (HLMEC) were exposed to 0cm (control) or 30cm (high pressure) H 2 O pressure for 5 to 60 minutes. Phosphorylation of eNOS at T495 and PKCα activation were assessed by Western blot, RhoA activation and nitration was assessed by ELISA and dot blot assays and endothelial barrier stability was assessed by VE-cadherin staining. The effects of pressure on barrier function were assessed by transendothelial electrical resistance (TEER). High hydrostatic pressure induced PKCα activation (1.42±0.2 vs 0.8±0.05 control, p=0.029; N=5) and the phosphorylation of eNOS at T495 (1.6±0.1 vs 0.62±0.08 control; p=0.0319; N=3), which was used as a correlation to eNOS uncoupling. This was associated with increased RhoA activity (0.009±0.001 vs. 0.005±0.001 control; p=0.0247; N=5), RhoA nitration (2.1±0.4 vs 1.0±0.02 control, p=0.0511; N=4) and VE-cadherin internalization. HLMEC exposed to control and high pressure conditions were transferred to gold electrodes (ECIS assay) to monitor TEER as indices of barrier recovery. High pressure caused a delay in barrier recovery and a decrease in the maximum TEER after 24 hours (0.952±0.16 vs 1.55±.019 control; p=0.0412; N=4). Fasudil, a Rho inhibitor, mitigated the effects of pressure on barrier recovery (1.996±0.79 vs 0.968±0.44 pressure; p&lt;0.0001; N=4). Altogether, these findings suggest that pressure induces endothelial barrier disruption via PKCα-mediated eNOS uncoupling and subsequent activation of RhoA. This may be important in conditions in which pulmonary pressure can increase abruptly, including heart failure.
Abstract 9528: Apical Resection in Newborn Pig Hearts Extends the Regenerative Window of Cardiomyocyte
Authors: Yuji Nakada, Yang Zhou, Wuming Gong, Erik Skie, Eric Y Zhang, Thanh Nguyen, Yuhua Wei, Meng Zhao, Wangping Chen, Jiacheng Sun, Jake Y Chen, Greg P Walcott, Daniel J Garry, Jianyi Zhang
Journal: Circulation (2021)

Background: The neonatal porcine heart possesses proliferative cardiomyocyte capacity to recover heart function and structure after an acute myocardial injury during two days of birth. In this study, we have extended the myocardial regenerative window to postnatal day 28 (P28) by a double injury pig model (AR P1 MI P28 ), which performed apical resection at P1 (AR P1 ) followed by LAD ligation at P28 (MI P28 ). However, the molecular mechanism of regenerative window extension is unknown. Methods: The AR P1 MI P28 hearts showed no visible sign of myocardial damage or malfunction 4 weeks after LAD ligation. The nuclear RNA contents were isolated from hearts that received none, singe, and double injury hearts. They performed single nuclei RNA-seq to characterize the gene-expression profile of the AR P1 MI P28 in cardiomyocytes. Results: Gene-expression profiles revealed that regenerating AR P1 MI P28 hearts contained different subpopulations of cardiomyocytes early after 2 nd injury. Louvain clustering identified the six cardiomyocyte clusters (CM1-CM6). The CM6, CM3, and CM2 clusters have mainly comprised fetal (92.4%), CTL-P1 (95.7%), and CTL-P56 (96.2%) cardiomyocytes. In contrast, the CM1 cluster has comprised heterogeneous cardiomyocyte groups from all other animal groups, including less than 1% of fetal and CTL-P1 cardiomyocytes. The CM5 and CM4 clusters have mainly comprised AR P1 MI P28 -P35 (double injury hearts harvested at P35) cardiomyocytes, 97.8% and 68.6%, respectively. Sparse modeling analysis revealed that AR and MI injury, both alone and in combination, appeared to extend the regenerative capacity of cardiomyocytes and perturb cardiomyocyte maturation. Conclusion: We have demonstrated that the unique CM5 cluster appeared only after the 2 nd injury of AR P1 MI P28 -P35 hearts. This cell cluster was characterized by a highly expressed isoenzyme of the glycolytic enzyme pyruvate kinase M2 (Pkm2) and skeletal muscle filamentous gene Nebulin. Transient expression of the CM5 cluster induces by the AR P1 might contribute to the sustained remuscularization and myocardial function recovery following an acute MI in large mammals.
Abstract 13809: Gender Based Difference in Outcomes of Myocardial Injury in COVID-19 Positive Patients in Low to Middle Income Country
Authors: ghufran adnan, Ihsan Ullah, Osman Faheem, Maria Khan, Awais Farhad, Intisar Ahmed
Journal: Circulation (2021)

Introduction: Myocardial injury is associated with poor outcomes in COVID-19 positive patients. We have limited data about gender-based differences, in terms of outcomes in COVID-19 associated myocardial injury, especially from low to middle income country. Hypothesis: Myocardial injury in COVID-19 positive patients has the same impact on outcomes in either gender. Methods: We prospectively collected data of patients admitted with COVID 19 (nasopharyngeal PCR positive) and myocardial injury (hsTrop I&gt;99th percentile) at Aga Khan University Hospital (AKUH), Karachi, Pakistan from 26 Feburary’2020 to 26 November’2020. Both genders were compared in terms of presentation, complications, and mortality. Calculations were done separately for each variable between two groups keeping the significant criteria of p-value less than or equal to 0.05. Result: Among 171 patients fulfilling inclusion criteria, 28.07% (n=48) were female and 72% (n=123) were male. Baseline demographics demonstrated that hypertension was significantly high among females as compared to male patients (87.5% Female vs 65% Male, p=0.004). During the hospital stay, the need for supplemental oxygen, Noninvasive ventilation, and mechanical ventilation was significantly higher in males compared to females. A statistically non-significant trend towards increased mortality was noted in males. Conclusion: Our study signifies that COVID-19 associated myocardial injury in males is associated with worse hospital course as compare to females. The length of hospital stay, complications such as ARDS, and requirement of invasive and non-invasive ventilatory support were higher in males as compared to females. Further studies evaluating the cause of disparate hospital course based on gender are warranted
Surgeon Perception That Opioids Are Not Needed for Young Children Postoperatively
Authors: Emre Ilhan, Julia M. Hush
Journal: JAMA Surgery (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Disparities in stage at diagnosis for five common cancers in China: a multicentre, hospital-based, observational study
Authors: Hongmei Zeng, Xianhui Ran, Lan An, Rongshou Zheng, Siwei Zhang, John S Ji, Yawei Zhang, Wanqing Chen, Wenqiang Wei, Jie He
Journal: The Lancet Public Health (2021)

Stage information is crucial for cancer care and essential to improve polices for cancer control. However, the distribution of stage at diagnosis for common cancers in China is not well known. We aimed to identify the distribution and factors associated with stage at diagnosis for five major cancers in China.In this multicentre, hospital-based, observational study, we included 23 hospitals in 12 provinces from China. We focused on cancers of the lung, stomach, oesophagus, colorectum, and female breast, and using electronic medical records at the individual level from the local hospitals, and cancer registration records from population-based cancer registries, identified diagnoses made between Jan 1, 2016, and Dec 31, 2017. We collected information on sociodemographic characteristics, lifestyle factors, insurance types, and stage at diagnosis. We analysed the prevalence of late-stage (stages III-IV) cancer cases overall, by sex, and by geographical region. We used logistic regression to identify the factors that were associated with late stage at diagnosis. We further compared these estimates with data from the USA using the Surveillance, Epidemiology, and End Results database.We included 52 103 eligible patients. Among 41 671 patients with known stage at diagnosis, 22 009 (52·8%) were diagnosed with late-stage cancer. The proportion of late-stage cases was higher in men and boys than in women and girls (14 084 [64·1%] of 21 973 vs 7925 [40·2%] of 19 698 patients; diagnosed at stages III-IV; adjusted odds ratio [OR] 1·3, 95% CI 1·2-1·5). There is a persistent diagnostic disparity between rural and urban areas (adjusted OR 1·2, 1·1-1·4). Patients with the new rural cooperative medical scheme insurance had a significantly higher risk of late-stage diagnosis compared with patients with urban insurance (adjusted OR 1·4, 1·1-1·9). By specific cancer type, sex and rural-urban disparities were the largest in lung cancer. Compared with the USA, our study patients had a higher percentage of stage II-IV breast cancer (72·4% in China vs 48·8% in the USA), lung cancer (82·7% in China vs 74·7% in the USA), and colorectal cancer (84·8% in China vs 75·9% in the USA).The disparities of cancer diagnosis within China, and between China and the USA, indicate an urgent need for early detection of cancer in China.National Key R&D Programme of China, Major State Basic Innovation Programme of the Chinese Academy of Medical Sciences, and National Natural Science Fund.
FLGS-02. What is the role of intraoperative MRI when performing a high-grade glioma resection using 5-ALA? A single center series reporting extent of resection of contrast-enhancing tumor and FLAIR signal abnormality with clinical outcomes
Authors: Rasheed Zakaria, Sujit Prabhu
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Use of intraoperative MRI (iMRI) and 5-ALA together is poorly investigated although both appear individually superior to standard resection alone in meta-analyses. METHODS We identified 54 patients who underwent 5-ALA guided resection of an intracranial high-grade glioma. Intraoperative ultrasound and frameless stereotactic neuronavigation with tractography were used in all cases. iMRI was selectively used in 33 cases. MRI scans were used to measure extent of resection (EOR) of T1-weighted contrast enhancing (T1WCE) tumor and FLAIR signal abnormality. Clinical data were collected prospectively and survival data retrospectively. RESULTS The mean EOR of T1WCE tumor was 93.7% (range 38 – 100%) with mean residual volume of 2.2 cc. The mean EOR of FLAIR signal abnormality was 59% (range 15–100%) with mean residual volume of 35.7 cc. Compared to using 5-ALA alone, using iMRI+5-ALA did not reduce the volume of residual T1WCE tumor (Mann-Whitney U, p = 0.557) and no more patients achieved complete resection (14/21 vs. 24/33, Chi-Square, p = 0.634). The volume of residual FLAIR signal abnormality was no different (Mann-Whitney U, p= 0.081) but more patients in the 5-ALA+iMRI group achieved resection of &amp;gt;53.21% of the FLAIR signal abnormality, which is known to be a predictor of improved prognosis (20/31 vs 5/21, Chi-Square, p = 0.004*). There was no difference in new neurological deficits at 30 days (Fisher’s exact test, p=0.549). Median OS was 14.3 months and median PFS was 5.2 months. There were no significant differences in OS or PFS between patients operated with iMRI in addition to 5-ALA. CONCLUSIONS 5-ALA and iMRI both assist in safely maximizing EOR when combined with adjuncts such as awake craniotomy and cortical/subcortical mapping. The role and interaction of these two technologies needs further study to understand whether they are additive and what their influence on clinical outcomes is.
Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis–Interstitial Lung Disease: Open-Label Extension of a Phase 3 Randomized Controlled Trial
Authors: Dinesh Khanna, Celia J. F. Lin, Daniel E. Furst, Bridget Wagner, Mauro Zucchetto, Ganesh Raghu, Fernando J. Martinez, Jonathan Goldin, Jeffrey Siegel, Christopher P. Denton
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Tocilizumab, an anti-IL-6 receptor antibody, had no statistically significant effect on skin sclerosis but preserved lung function over 48 weeks in patients with early systemic sclerosis (SSc)-associated interstitial lung disease (ILD) in a phase 3 randomized controlled trial. Objectives: Assess long-term safety and efficacy of tocilizumab. Methods: Adults with diffuse cutaneous SSc for ⩽60 months and elevated acute-phase reactants, including those with ILD, received weekly placebo or tocilizumab 162 mg subcutaneously in the 48-week, double-blind period and then open-label tocilizumab from Weeks 48 to 96 (placebo-tocilizumab; continuous-tocilizumab). Measurements and Main Results: Eighty-two of 107 patients in the placebo-tocilizumab group and 85 of 105 patients in the continuous-tocilizumab group completed 96 weeks. Mean age and disease duration were 48 years and 23 months; high-resolution computed tomography revealed ILD in 61%. Mean (95% confidence interval [CI]) change in modified Rodnan skin score from baseline to week 96 was -8.4 (-10.0 to -6.8) for placebo-tocilizumab and -9.6 (-10.9 to -8.4) for continuous-tocilizumab. Mean (95% CI) change in FVC (percent predicted) from baseline to week 96 was -3.3 (-5.1 to -1.5) for placebo-tocilizumab and -0.5 (-2.4 to 1.3) for continuous-tocilizumab among completers and, in a post hoc analysis, -4.1 (-6.7 to -1.6) and -0.6 (-3.1 to 2.0), respectively, among completers with ILD (mean [95% CI] change from Weeks 48 to 96: 0.9 [-0.8 to 2.7] and -0.4 [-2.3 to 1.5], respectively). Rates per 100 patient-years of serious adverse events from Weeks 48 to 96 were 14.8 for placebo-tocilizumab and 15.8 for continuous-tocilizumab. Conclusions: Tocilizumab preserved lung function, slowing decline in FVC, in patients with SSc, including those with ILD. Long-term safety was consistent with the known safety profile of tocilizumab. Clinical trial registered with www.clinicaltrials.gov (NCT02453256).
STEM-26. BLOOD-TUMOR BARRIER IS COMPOSED OF MECHANOSENSING TUMOR CELLS THAT MASK THERAPEUTIC VULNERABILITY
Authors: Ali Momin, Xin Chen, Gousiyi Wang, Xian Wang, Hyun-Kee Min, Wenkun Dou, Zheyuan Gong, Jade Chan, Yuki Chen, Kelly Veerasammy, Weifan Dong, Jerry Fan, Adam Fekete, Zhengchao Dou, Malini Hu, Parnian Pardis, Sachin Kumar, Kyle Juraschka, Laura Donovan, Peter Dirks, Michael D Taylor, Lu-Yang Wang, Chi-chung Hui, Rinat Abzalimov, Ye He, Yu Sun, Xuejun Li, Xi Huang
Journal: Neuro-Oncology (2021)

Abstract Two major obstacles in brain cancer treatment are the blood-tumor barrier (BTB), which restricts delivery of most therapeutic agents, and the quiescent brain tumor-initiating cells (BTICs), which evade cell cycle-targeting chemotherapy. Mechanosensation, the transduction of mechanical cues into cellular signaling, underlies physiological processes such as touch, pain, proprioception, hearing, respiration, epithelial homeostasis, and vascular and lymphatic development. We report that medulloblastoma (MB) BTICs are mechanosensing, a property conferred by force-activated ion channel Piezo2. In contrast to the prevailing view that astrocytes function as a physical barrier in BTB, BTICs project endfeet to ensheathe capillaries. MB develops a tissue stiffness gradient as a function of distance to capillaries. Piezo2 senses substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion at BTIC growth cones, which allow BTICs to mechanically interact with their substrate and sequester β-Catenin to prevent WNT/β-Catenin signaling in BTICs. Our single cell analysis uncovers a two-branched BTIC trajectory that progresses from a deep quiescent state to two cycling states. Tumor cell-specific Piezo2 knockout reverses the off-on WNT/β-Catenin signaling states in BTICs and endothelial cells, collapses the BTB, reduces quiescence depth of BTICs, and markedly enhances MB response to chemotherapy. Our study reveals that BTICs co-opt astrocytic mechanism to contribute to the BTB and provides the first evidence that BTB depends on mechanochemical signaling to mask tumor chemosensitivity. Targeting Piezo2 addresses BTB and BTIC properties that underlie therapy failures in brain cancer.
ITVT-06. Application of artificial intelligence and radiomics for the analysis of intraoperative ultrasound images of brain tumors
Authors: Santiago Cepeda
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Intraoperative ultrasound (ioUS) images of brain tumors contain information that has not yet been exploited. The present work aims to analyze images in both B-mode and strain-elastography using techniques based on artificial intelligence and radiomics. We pretend to assess the capacity for differentiating glioblastomas (GBM) from solitary brain metastases (SBM) and also to assess the ability to predict the overall survival (OS) in GBM. METHODS We performed a retrospective analysis of patients who underwent craniotomy between March 2018 to June 2020 with GBM and SBM diagnoses. Cases with an ioUS study were included. In the first group of patients, an analysis based on deep learning was performed. An existing neural network (Inception V3) was used to classify tumors into GBM and SBM. The models were evaluated using the area under the curve (AUC), classification accuracy, and precision. In the second group, radiomic features from the tumor region were extracted. Radiomic features associated with OS were selected employing univariate correlations. Then, a survival analysis was conducted using Cox regression. RESULTS For the classification task, a total of 36 patients were included. 26 GBM and 10 SBM. Models were built using a total of 812 ultrasound images. For B-mode, AUC and accuracy values ranged from 0.790 to 0.943 and from 72 to 89 % respectively. For elastography, AUC and accuracy values ranged from 0.847 to 0.985 and from 79 to 95 % respectively. Sixteen patients were available for the survival analysis. A total of 52 radiomic features were extracted. Two texture features from B-mode (Conventional mean and GLZLM_SZLGE) and one texture feature from strain-elastography (GLZLM_LZHGE) were significantly associated with OS. CONCLUSIONS Automated processing of ioUS images through deep learning can generate high-precision classification algorithms. Radiomic tumor region features in B-mode and elastography appear to be significantly associated with OS in GBM.
CBIO-24. NF2 LOSS-OF-FUNCTION COOPERATES WITH HYPOXIA TO DRIVE RADIATION RESISTANCE IN GRADE 2 MENINGIOMAS
Authors: Bhuvic Patel, Tatenda Mahlokozera, Hsiang-Chih Lu, Alicia Yang, Diane Mao, Namita Sinha, Sonika Dahiya, Allegra Petti, Akash Patel, Albert Kim
Journal: Neuro-Oncology (2021)

Abstract World health organization grade 2 meningiomas (G2M) are associated with an aggressive natural history characterized by frequent recurrence, resistance to radiation therapy (RT), and poor survival. We and others have shown that intratumoral necrosis is an independent predictor of disease progression in G2Ms treated with RT, suggesting that necrosis is a histopathological biomarker of radiation resistance. However, the mechanisms of radiation resistance in G2M remain unclear and treatment of radioresistant G2M is challenging. We performed genetic sequencing and histopathological analysis of 121 G2Ms and found that NF2 mutations are associated with intratumoral necrosis. To further investigate the relationship between NF2 loss-of-function, necrosis, and radiation resistance, we developed an in vitro model system using the IOMM-Lee meningioma cell line. In clonogenic survival assays, we found that NF2 knockdown under normoxia had little to no effect on radiation resistance compared to control. However, in the setting of hypoxia, NF2 knockdown significantly increased radiation resistance by maintaining cellular proliferation without impacting cell death. To understand the molecular basis of NF2 loss-of-function on radiation resistance, we performed bulk RNA sequencing of cells in our in vitro hypoxia/RT model and 10 patient G2Ms (5 necrotic and 5 non-necrotic tumors). GO and KEGG pathway analysis of the in vitro dataset revealed that NF2 deficiency triggers upregulation of pathways involved in DNA damage repair and cellular proliferation. Integration of differentially expressed genes between the in vitro NF2 loss-of-function model and necrotic patient tumors identified shared upregulation of S100A4, which promotes cell cycle progression, and downregulation of WNK2, a cell proliferation inhibitor. Together, these results suggest NF2 loss-of-function in the setting of hypoxia confers radiation resistance through a transcriptional program that promotes proliferation and DNA repair.