tbuckley/cabot-search huggingface dataset:
Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability
Authors: Maarten A.J. De Smet, Alessio Lissoni, Timur Nezlobinsky, Nan Wang, Eef Dries, Marta Pérez-Hernández, Xianming Lin, Matthew Amoni, Tim Vervliet, Katja Witschas, Eli Rothenberg, Geert Bultynck, Rainer Schulz, Alexander V. Panfilov, Mario Delmar, Karin R. Sipido, Luc Leybaert
Journal: Journal of Clinical Investigation (2021)

Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic Ca2+ release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic Ca2+ release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel Ca2+ entry and coupling to Ca2+ release microdomains at the intercalated disc, resulting in enhanced Ca2+ dynamics. Hemichannel opening furthermore contributed to delayed afterdepolarizations and triggered action potentials. In single cardiomyocytes, cardiomyocyte cell pairs, and arterially perfused tissue wedges from failing human hearts, increased hemichannel activity contributed to electrical instability compared with nonfailing rejected donor hearts. We conclude that microdomain coupling between Cx43 hemichannels and Ca2+ release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure.
Cost-effectiveness of Community-Based Depression Interventions for Rural and Urban Adults With Type 2 Diabetes: Projections From Program ACTIVE (Adults Coming Together to Increase Vital Exercise) II
Authors: Shihchen Kuo, Wen Ye, Mary de Groot, Chandan Saha, Jay H. Shubrook, W. Guyton Hornsby, Yegan Pillay, Kieren J. Mather, William H. Herman
Journal: Diabetes Care (2021)

We estimated the cost-effectiveness of the Program ACTIVE (Adults Coming Together to Increase Vital Exercise) II community-based exercise (EXER), cognitive behavioral therapy (CBT), and EXER+CBT interventions in adults with type 2 diabetes and depression relative to usual care (UC) and each other.Data were integrated into the Michigan Model for Diabetes to estimate cost and health outcomes over a 10-year simulation time horizon from the health care sector and societal perspectives, discounting costs and benefits at 3% annually. Primary outcome was cost per quality-adjusted life-year (QALY) gained.From the health care sector perspective, the EXER intervention strategy saved $313 (USD) per patient and produced 0.38 more QALY (cost saving), the CBT intervention strategy cost $596 more and gained 0.29 more QALY ($2,058/QALY), and the EXER+CBT intervention strategy cost $403 more and gained 0.69 more QALY ($585/QALY) compared with UC. Both EXER and EXER+CBT interventions dominated the CBT intervention. Compared with EXER, the EXER+CBT intervention strategy cost $716 more and gained 0.31 more QALY ($2,323/QALY). From the societal perspective, compared with UC, the EXER intervention strategy saved $126 (cost saving), the CBT intervention strategy cost $2,838/QALY, and the EXER+CBT intervention strategy cost $1,167/QALY. Both EXER and EXER+CBT interventions still dominated the CBT intervention. In comparison with EXER, the EXER+CBT intervention strategy cost $3,021/QALY. Results were robust in sensitivity analyses.All three Program ACTIVE II interventions represented a good value for money compared with UC. The EXER+CBT intervention was highly cost-effective or cost saving compared with the CBT or EXER interventions.
Molecular characterization of invasive serogroup B Neisseria meningitidis isolates from Spain during 2015–2018: Evolution of the vaccine antigen factor H binding protein (FHbp)
Authors: Raquel Abad, Cristina García-Amil, Carmen Navarro, Elena Martín, Ariadna Martín-Díaz, Julio A Vázquez
Journal: Journal of Infection (2021)

Studies of meningococcal genetic population structure, including the potential associations between surface proteins variants and clonal complexes, are important to understand how new protein MenB vaccines might impact in specific scenarios. With the aim to analyze the diversity of Spanish invasive MenB strains, and genetic variability of the fHbp vaccine antigen, all MenB isolates received at National Reference Laboratory (NRL) from 2015 to 2018 were molecularly characterized.Material and methods108, 103, 87 and 112 invasive MenB strains isolated during 2015–2018, respectively, were received at NRL. The strains were whole genome sequenced, and porA, fetA, MLST and fHbp variability was analyzed. Potential impact on MenB vaccines coverage was also assessed.ResultsA total of 42, 38 and 3 different FHbp subfamily A, B and A/B hybrid peptides, respectively, were found. FHbp subfamily A peptides were harboured by most of the strains (65.9%), being the most prevalent peptide 45 which was associated with genosubtype 22,14 and cc213. FHbp subfamily B peptides were harboured by 32.4% of the strains, and 6 strains harbouring subfamily A/B hybrid peptides were also found.The 64.15% of the strains showed FHbp variants “exact-match” or “cross-reactive” to the FHbp variants included in rLP2086 vaccine according to hSBA assays in the rLP2086 clinical development, and 15.85% showed FHbp peptides defined as predictors of FHbp-coverage for 4CMenB vaccine by gMATS.ConclusionsDue to invasive meningococcal strains temporal variability (eg prevalence of the cc213 increased from 3.6% in 2007 to 33% in 2018) affecting to the presence and distribution of the vaccine antigens, continuous detailed meningococcal surveillance and monitoring of the vaccine antigens is needed to determine the degree and durability of coverage provided by these protein vaccine.
Longitudinal whole-exome sequencing of cell-free DNA for tracking the co-evolutionary tumor and immune evasion dynamics: longitudinal data from a single patient
Authors: R.K. Hastings, M.R. Openshaw, M. Vazquez, A.B. Moreno-Cardenas, D. Fernandez-Garcia, L. Martinson, K. Kulbicki, L. Primrose, D.S. Guttery, K. Page, B. Toghill, C. Richards, A. Thomas, J. Tabernero, R.C. Coombes, S. Ahmed, R.A. Toledo, J.A. Shaw
Journal: Annals of Oncology (2021)
Abstract PD8-05: Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer
Authors: Svasti Haricharan, Nindo Punturi, Sinem Seker, Vaishnavi Devarakonda, Rashi Kalra, Ching-Hui Chen, Aloran Mazumder, Shungqiang Li, Tina Primeau, Matthew Ellis, Shyam Kavuri
Journal: Cancer Research (2021)

Abstract Estrogen receptor positive (ER+) breast cancer is a leading cause of cancer-related death globally. Resistance to standard of care endocrine treatment occurs in at least 30% of ER+ breast cancer patients resulting in ~40,000 deaths every year in the US alone. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance of ER+ breast cancer that is HER2- at diagnosis. However, clinical trials of pan-HER inhibitors in ER+/HER2- patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of MLH1, a principal mismatch repair gene, causally activates HER2 in ER+/HER2- breast cancer upon endocrine treatment. Additionally, we show that HER2 activation is indispensable for endocrine treatment resistant growth of MLH1-defective cells in vitro and in vivo. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment in multiple experimental models including patient-derived xenograft tumors. Patient data from multiple clinical datasets (TCGA, METABRIC, Alliance (Z1031) and E-GEOD-28826) supports an association between MLH1 loss, HER2 upregulation, and sensitivity to trastuzumab in endocrine treatment-resistant ER+/HER2- patients. These results provide strong evidence that MLH1 could serve as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine drugs and HER2 inhibitors in endocrine treatment-resistant ER+/HER2- breast cancer patients. Implications of this study extend beyond breast cancer to Lynch Syndrome cancers. Citation Format: Svasti Haricharan, Nindo Punturi, Sinem Seker, Vaishnavi Devarakonda, Rashi Kalra, Ching-Hui Chen, Aloran Mazumder, Shungqiang Li, Tina Primeau, Matthew Ellis, Shyam Kavuri. Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-05.
MEK Inhibition Remodels the Immune Landscape of Mutant <i>KRAS</i> Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors
Authors: Bin Yang, Xi Li, Yu Fu, Ensong Guo, Youqiong Ye, Fuxia Li, Si Liu, Rourou Xiao, Chen Liu, Funian Lu, Jia Huang, Tianyu Qin, Leng Han, Guang Peng, Gordon B. Mills, Chaoyang Sun, Gang Chen
Journal: Cancer Research (2021)

Abstract Mutant KRAS tumors are associated with poor outcomes, at least in part, due to decreased therapeutic sensitivity. Here, we show that KRAS mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors (PARPi) and immune checkpoint blockade with anti–PD-L1 antibodies. In mutant KRAS tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation, and CD8+ T-cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration, in part, by inhibiting IL6 and GMCSF production. Importantly, addition of MEKi to PARPi and anti–PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. This study provides the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti–PD-L1 combination in clinical trials of mutant KRAS tumors. Significance: This study provides key insights into the potential for using MEKi combined with PARPi and anti–PD-L1 for the treatment of all mutant KRAS tumors.
Cost-effectiveness of Atezolizumab Plus Bevacizumab vs Sorafenib as First-Line Treatment of Unresectable Hepatocellular Carcinoma
Authors: Dan Su, Bin Wu, Lizheng Shi
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Treatment with atezolizumab plus bevacizumab may prolong overall survival among patients with unresectable hepatocellular carcinoma. However, to our knowledge, the cost-effectiveness of using this high-priced therapy for this indication is currently unknown. <h3>Objective</h3> To evaluate the cost-effectiveness of atezolizumab plus bevacizumab to treat unresectable hepatocellular carcinoma from the US payer perspective. <h3>Design, Setting, and Participants</h3> This economic evaluation used a partitioned survival model consisting of 3 discrete health states to assess the cost-effectiveness of treatment of hepatocellular carcinoma with atezolizumab plus bevacizumab vs sorafenib. The characteristics of patients in the model were similar to patients in a phase 3, open-label randomized clinical trial (IMbrave150) who had unresectable hepatocellular carcinoma and had not previously received systemic treatment. Key clinical data were generated from the IMbrave150 trial conducted between March 15, 2018, and January 30, 2019, and cost and health preference data were collected from the literature. <h3>Main Outcomes and Measures</h3> Costs, quality-adjusted life-years (QALYs), incremental cost-utility ratios, incremental net health benefits, and incremental net monetary benefits were calculated for the 2 treatment strategies. Subgroup, 1-way sensitivity, and probabilistic sensitivity analyses were performed. <h3>Results</h3> Treatment of hepatocellular carcinoma with atezolizumab plus bevacizumab added 0.530 QALYs and resulted in an incremental cost of $89 807 compared with sorafenib therapy, which had an incremental cost-utility ratio of $169 223 per QALY gained. The incremental net health benefit was −0.068 QALYs, and the incremental net monetary benefit was −$10 202 at a willingness-to-pay threshold of $150 000/QALY. The probabilistic sensitivity analysis indicated that treatment with atezolizumab plus bevacizumab achieved a 35% probability of cost-effectiveness at a threshold of $150 000/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the hazard ratio of overall survival. The subgroup analysis found that treatment with atezolizumab plus bevacizumab was associated with preferred incremental net health benefits in several subgroups, including patients with hepatitis B and C. <h3>Conclusions and Relevance</h3> Atezolizumab plus bevacizumab treatment is unlikely to be a cost-effective option compared with sorafenib for patients with unresectable hepatocellular carcinoma. Reducing the prices of atezolizumab and bevacizumab may improve cost-effectiveness. The economic outcomes also may be improved by tailoring treatments based on individual patient factors.
Malignant gastric hyperplastic polyp: endoscopic features of the demarcated malignant component.
Authors: Pierre Lafeuille, Christine Chambon-Augoyard, Marie Napoléon, Paul Bonniaud, Thomas Lambin, Emmanuel Forté, Mathieu Pioche
Journal: Endoscopy (2021)

Gastric hyperplastic polyps are associated with a risk of neoplastic transformation reaching 10 % in a previous study by our team. In this work, retrospectively including 145 gastric hyperplastic polyps, a higher risk of neoplastic changes was associated with a lesion size over 25 mm [1]. Nevertheless, the neoplastic component was never predicted by the endoscopic examination before the resection but discovered either on the biopsy samples or on the resected specimen.
Abstract 16533: Carotid Vasa Vasorum Density Measured in vivo by Contrast-Enhanced Ultrasound is Associated with Acute Coronary Events
Authors: Benjamin J Sprague, Robert Grande, Flordeliza Villanueva
Journal: Circulation (2012)

Background: Coronary artery adventitial vasa vasorum (VV) proliferation is a feature of the “vulnerable” plaques (VP) that cause acute coronary syndromes (ACS). Carotid contrast enhanced ultrasound...
Intra-host variation and evolutionary dynamics of SARS-CoV-2 populations in COVID-19 patients
Authors: Yanqun Wang, Daxi Wang, Lu Zhang, Wanying Sun, Zhaoyong Zhang, Weijun Chen, Airu Zhu, Yongbo Huang, Fei Xiao, Jinxiu Yao, Mian Gan, Fang Li, Ling Luo, Xiaofang Huang, Yanjun Zhang, Sook-san Wong, Xinyi Cheng, Jingkai Ji, Zhihua Ou, Minfeng Xiao, Min Li, Jiandong Li, Peidi Ren, Ziqing Deng, Huanzi Zhong, Xun Xu, Tie Song, Chris Ka Pun Mok, Malik Peiris, Nanshan Zhong, Jingxian Zhao, Yimin Li, Junhua Li, Jincun Zhao
Journal: Genome Medicine (2021)

Since early February 2021, the causative agent of COVID-19, SARS-CoV-2, has infected over 104 million people with more than 2 million deaths according to official reports. The key to understanding the biology and virus-host interactions of SARS-CoV-2 requires the knowledge of mutation and evolution of this virus at both inter- and intra-host levels. However, despite quite a few polymorphic sites identified among SARS-CoV-2 populations, intra-host variant spectra and their evolutionary dynamics remain mostly unknown.Using high-throughput sequencing of metatranscriptomic and hybrid captured libraries, we characterized consensus genomes and intra-host single nucleotide variations (iSNVs) of serial samples collected from eight patients with COVID-19. The distribution of iSNVs along the SARS-CoV-2 genome was analyzed and co-occurring iSNVs among COVID-19 patients were identified. We also compared the evolutionary dynamics of SARS-CoV-2 population in the respiratory tract (RT) and gastrointestinal tract (GIT).The 32 consensus genomes revealed the co-existence of different genotypes within the same patient. We further identified 40 intra-host single nucleotide variants (iSNVs). Most (30/40) iSNVs presented in a single patient, while ten iSNVs were found in at least two patients or identical to consensus variants. Comparing allele frequencies of the iSNVs revealed a clear genetic differentiation between intra-host populations from the respiratory tract (RT) and gastrointestinal tract (GIT), mostly driven by bottleneck events during intra-host migrations. Compared to RT populations, the GIT populations showed a better maintenance and rapid development of viral genetic diversity following the suspected intra-host bottlenecks.Our findings here illustrate the intra-host bottlenecks and evolutionary dynamics of SARS-CoV-2 in different anatomic sites and may provide new insights to understand the virus-host interactions of coronaviruses and other RNA viruses.
Abstract PS5-45: The impact of progesterone receptor negativity on oncologic outcomes in estrogen receptor positive breast cancer
Authors: Matthew G Davey, Éanna J Ryan, Padraig J Folan, Niamh O'Halloran, Michael R Boland, Michael Kevin Barry, Karl J Sweeney, Carmel M Malone, Ray J McLaughlin, Michael J Kerin, Aoife J Lowery
Journal: Cancer Research (2021)

Abstract BACKGROUND: Estrogen receptor (ER) status provides invaluable prognostic and therapeutic information in breast cancer (BC). When clinical decision making is driven by ER status, the value of assessing progesterone receptor (PgR) status is less certain. AIM: To describe the clinicopathologic features of ER positive (ER+) /PgR negative (PgR-) BC and to determine the effect of PgR negativity on oncologic outcomes in ER+ disease.METHODS: Consecutive female patients with ER+ BC managed in a single institution between 2005-2015 were included. Clinicopathological features of PgR- BC were determined. Factors associated with PgR- disease were assessed using binary logistic regression. Oncological outcome was assessed using Kaplan-Meier curves and Cox regression analysis.RESULTS: 2660 patients were included with a median age of 59.6±13.3 years (21-99). Median follow-up was 97.2 months (3.0-181.2). 2208 cases were PgR+ (83.0%) and 452 were PgR- (17.0%). Being postmenopausal (OR:1.656, 95% Confidence interval (CI):1.249-2.195, P&amp;lt;0.001), presenting with symptoms (OR:1.712, 95% CI:1.302-2.249, P&amp;lt;0.001), invasive ductal subtype (OR:1.514, 95% CI:1.166-1.966, P=0.002) and grade 3 tumours (OR:2.198, 95% CI:1.683-2.870, P&amp;lt;0.001) were all associated with PgR- status. In patients receiving neoadjuvant chemotherapy (n=308), pathological complete response rates were 10.1% (25/247) in patients with PgR+ disease, versus 18.0% in those with PgR- disease (11/61) (P=0.050). PgR negativity independently predicted worse disease-free (HR:1.632, 95%CI:1.209-2.204, P=0.001) and overall survival (OS) (HR:1.774, 95%CI:1.324-2.375, P&amp;lt;0.001), as well as worse OS in ER+/HER2- disease (P=0.004). CONCLUSIONS: In ER+ disease, PgR- tumours have more aggressive clinicopathological features and worse oncological outcomes. Neoadjuvant and adjuvant therapeutic strategies should be tailored according to PgR status. Citation Format: Matthew G Davey, Éanna J Ryan, Padraig J Folan, Niamh O'Halloran, Michael R Boland, Michael Kevin Barry, Karl J Sweeney, Carmel M Malone, Ray J McLaughlin, Michael J Kerin, Aoife J Lowery. The impact of progesterone receptor negativity on oncologic outcomes in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-45.
Prophylactic anticoagulation for patients in hospital with covid-19
Authors: Beverley J Hunt, Erich V De Paula, Claire McLintock, Mert Dumantepe
Journal: BMJ (2021)

Most people with covid-19 have mild disease, but after 5-10 days an important minority develop pneumonia and require hospital admission to treat hypoxia.This group is in a marked prothrombotic state and has high rates of hospital associated venous thromboembolism. 1 Early in the pandemic, deep vein thromboses and high rates of occlusive changes on computed tomography pulmonary angiograms were seen in at least 70% of patients with severe covid-19.Although these were initially thought to be pulmonary emboli, many patients had only isolated segmental and subsegmental changes, probably caused by the in situ thrombosis (termed immunothrombosis) that occurs in all forms of acute respiratory distress syndrome, 2 3 although more commonly with covid-19. 4 5 Randomised controlled trials show that drug based thromboprophylaxis with low molecular weight heparin (LMWH) reduces the risk of hospital associated venous thromboembolism by about 50% in medical and critically ill inpatients. 6 Risk factors that qualify patients for thromboprophylaxis are reduced mobility; acute infective illness, such as pneumonia; and admission for critical care.Thus, adults admitted to hospital with covid-19 pneumonia should automatically receive thromboprophylaxis.
Insights Gained from Single-Cell Analysis of Immune Cells in the Tumor Microenvironment
Authors: Xianwen Ren, Lei Zhang, Yuanyuan Zhang, Ziyi Li, Nathan Siemers, Zemin Zhang
Journal: Annual Review of Immunology (2021)

Understanding tumor immune microenvironments is critical for identifying immune modifiers of cancer progression and developing cancer immunotherapies. Recent applications of single-cell RNA sequencing (scRNA-seq) in dissecting tumor microenvironments have brought important insights into the biology of tumor-infiltrating immune cells, including their heterogeneity, dynamics, and potential roles in both disease progression and response to immune checkpoint inhibitors and other immunotherapies. This review focuses on the advances in knowledge of tumor immune microenvironments acquired from scRNA-seq studies across multiple types of human tumors, with a particular emphasis on the study of phenotypic plasticity and lineage dynamics of immune cells in the tumor environment. We also discuss several imminent questions emerging from scRNA-seq observations and their potential solutions on the horizon.