tbuckley/cabot-search huggingface dataset:
lncRNA Neat1 regulates neuronal dysfunction post-sepsis via stabilization of hemoglobin subunit beta
Authors: Yan Wu, Pengfei Li, Liu Liu, Andrew J. Goodwin, Perry V. Halushka, Tetsuro Hirose, Shinichi Nakagawa, Jiliang Zhou, Meng Liu, Hongkuan Fan
Journal: Molecular Therapy (2022)

Sepsis-associated encephalopathy (SAE) is characterized by acute and diffuse brain dysfunction and correlates with long-term cognitive impairments with no targeted therapy. We used a mouse model of sepsis-related cognitive impairment to examine the role of lncRNA nuclear enriched abundant transcript 1 (Neat1) in SAE. We observed that Neat1 expression was increased in neuronal cells from septic mice and that it directly interacts with hemoglobin subunit beta (Hbb), preventing its degradation. The Neat1/Hbb axis suppressed postsynaptic density protein 95 (PSD-95) levels and decreased dendritic spine density. Neat1 knockout mice exhibited decreased Hbb levels, which resulted in increased PSD-95 levels, increased neuronal dendritic spine density, and decreased anxiety and memory impairment. Neat1 silencing via the antisense oligonucleotide GapmeR ameliorated anxiety-like behavior and cognitive impairment post-sepsis. In conclusion, we uncovered a previously unknown mechanism of the Neat1/Hbb axis in regulating neuronal dysfunction, which may lead to a novel treatment strategy for SAE. Sepsis-associated encephalopathy (SAE) is characterized by acute and diffuse brain dysfunction and correlates with long-term cognitive impairments with no targeted therapy. We used a mouse model of sepsis-related cognitive impairment to examine the role of lncRNA nuclear enriched abundant transcript 1 (Neat1) in SAE. We observed that Neat1 expression was increased in neuronal cells from septic mice and that it directly interacts with hemoglobin subunit beta (Hbb), preventing its degradation. The Neat1/Hbb axis suppressed postsynaptic density protein 95 (PSD-95) levels and decreased dendritic spine density. Neat1 knockout mice exhibited decreased Hbb levels, which resulted in increased PSD-95 levels, increased neuronal dendritic spine density, and decreased anxiety and memory impairment. Neat1 silencing via the antisense oligonucleotide GapmeR ameliorated anxiety-like behavior and cognitive impairment post-sepsis. In conclusion, we uncovered a previously unknown mechanism of the Neat1/Hbb axis in regulating neuronal dysfunction, which may lead to a novel treatment strategy for SAE.
Abstract P4-04-01: β2-adrenergic receptor signaling regulates metabolic pathways critical for the function of myeloid-derived suppressor cells
Authors: Hemn Mohammadpour
Journal: Cancer Research (2022)

Abstract Summary Nerve-driven chronic adrenergic stress can suppress anti-tumor immunity. However, details are still missing or poorly understood. Catecholamines (epinephrine, norepinephrine) released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type including myeloid derived suppressor cells (MDSCs). MDSCs are increasingly recognized as critical players in tumor immunology because, in addition to their fundamental roles in suppressing effector NK cells, CD8+ T cells and CD4+ T cells, they also play a direct role in tumor growth, differentiation and metastasis. Recently, we have shown that β2 adrenergic receptor signaling activated by chronic stress increases the immunosuppressive function of MDSCs, but the precise mechanisms remain unresolved. Building upon our earlier work, we now have discovered that the beta-2 adrenergic receptor (β2-AR) stress pathway drives the immune suppressive activity of MDSCs through altering their metabolism. First, we found that the expression of surface β2-AR on MDSCs increases with tumor growth in 4T1 breast cancer model and patients with breast cancer. We also found that β2-AR signaling decreases glycolysis, while increasing oxidative phosphorylation and fatty acid oxidation (FAO). β2-AR signaling also increased mitochondrial intensity and mitochondrial potential of MDSCs both in vitro and in vivo. β2-AR signaling in MDSCs also increased the expression of Carnitine Palmitoyltransferase 1A (CPT1A) necessary for the FAO-mediated immunosuppressive function of MDSCs. Blocking CPT1A using etomoxir decreased tumor growth and immunosuppressive function of MDSCs in Wild Type (WT) mice but not β2-AR-/- mice or severe combined immunodeficient mice (SCID) mice. Moreover, we found that β2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2 in both mouse MDSCs and. PBMCs derived MDSCs. Together, our data reveal that stress-driven β2-AR signaling is an important physiological determinant that regulates key metabolic pathways in MDSCs enabling their immunosuppressive function. These data reveal a major, physiologically relevant role for nervous activity and adrenergic stress in MDSC-tumor biology. Keywords: β2 adrenergic receptor, stress, MDSC, Metabolism, Breast Cancer, Citation Format: Hemn Mohammadpour. β2-adrenergic receptor signaling regulates metabolic pathways critical for the function of myeloid-derived suppressor cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-01.
TEMPORAL TRENDS AND PREDICTORS OF INTRACRANIAL HEMORRHAGE IN PATIENTS UNDERGOING CATHETER DIRECTED THROMBOLYSIS FOR DEEP VEIN THROMBOSIS IN THE UNITED STATES: INSIGHTS FROM THE NATIONAL READMISSIONS DATABASE
Authors: Muhammad Umar Khalid, Irfan Shafi, Maninder Singh, Vladimir Lakhter, Riyaz Bashir
Journal: Journal of the American College of Cardiology (2022)
Broad-spectrum and powerful neutralization of bacterial toxins by erythroliposomes with the help of macrophage uptake and degradation
Authors: Chunying Liu, Shuangrong Ruan, Ying He, Xuejing Li, Yuefei Zhu, Honglan Wang, Hanwei Huang, Zhiqing Pang
Journal: Acta Pharmaceutica Sinica B (2022)

Anti-virulence strategy has been considered as one of the most promising approaches to combat drug-resistant bacterial infections. Pore-forming toxins (PFTs) are the largest class of bacterial toxins, inflicting their virulence effect through creating pores on the cell membrane. However, current solutions for eliminating PFTs are mostly designed based on their molecular structure, requiring customized design for different interactions. In the present study, we employed erythroliposome (denoted as RM-PL), a biomimetic platform constructed by artificial lipid membranes and natural erythrocyte membranes, to neutralize different hemolytic PFTs regardless of their molecular structure. When tested with model PFTs, including α-hemolysin, listeriolysin O, and streptolysin O, RM-PL could completely inhibit toxin-induced hemolysis in a concentration-dependent manner. In vivo studies further confirmed that RM-PL could efficiently neutralize various toxins and save animals' lives without causing damage to organs or tissues. In addition, we explored the underlying mechanisms of this efficient detoxification ability and found that it was mainly macrophages in the spleen and the liver that took up RM-PL-absorbed toxins through a variety of endocytosis pathways and digested them in lysosomes. In summary, the biomimetic RM-PL presented a promising system for broad-spectrum and powerful toxin neutralization with a mechanism of lysosome-mediated toxin degradation.
Enhancement of nucleus pulposus repair by glycoengineered adipose-derived mesenchymal cells
Authors: Liwei Ying, Chengzhen Liang, Yujie Zhang, Jingkai Wang, Chenggui Wang, Kaishun Xia, Kesi Shi, Chao Yu, Biao Yang, Haibin Xu, Yuang Zhang, Jiawei Shu, Xianpeng Huang, Hongyuan Xing, Fangcai Li, Xiaopeng Zhou, Qixin Chen
Journal: Biomaterials (2022)
Improving the Model for End‐Stage Liver Disease with sodium by incorporating kidney dysfunction types
Authors: Giuseppe Cullaro, Elizabeth C. Verna, Charles E. McCulloch, Jennifer C. Lai
Journal: Hepatology (2022)

Abstract Background and Aims We investigated the impact of the inclusion of kidney dysfunction type on the discrimination and calibration of the Model for End‐Stage Liver Disease with sodium (MELD‐Na‐KT) score. Approach and Results We included all adults listed for ≥90 days without exception points from January 1, 2008, through December 31, 2018. We defined kidney dysfunction types as follows: acute kidney disease (AKD; an increase of ≥0.3 mg/dL or ≥50% in serum creatinine in the last 7 days or fewer than 72 days of hemodialysis), chronic kidney disease (CKD; an estimated glomerular filtration rate &lt;60 ml/min/1.73 m 2 for 90 days or ≥72 days of hemodialysis), AKD on CKD (met both definitions), or none (met neither definition). We then developed and validated a multivariable survival model with follow‐up beginning at the first assessment after 90 days from waitlist registration and ending at the time of death, waitlist removal, or 90 days from enrollment in this study. The predictor variables were MELD‐Na and the derived MELD‐Na‐KT model. In the derivation cohort, kidney dysfunction type was significantly associated with waitlist mortality after controlling for MELD‐Na. There was a significant linear interaction between kidney dysfunction type and MELD‐Na score. In the validation cohort, we saw an improvement in the discrimination of the model with an increase in the c‐index from 0.76 with MELD‐Na to 0.78 with MELD‐Na‐KT ( p = 0.002) and a net reclassification index of 10.8% (95% CI, 1.9%–11.4%). The newly derived MELD‐Na‐KT model had lower Brier scores (MELD‐Na‐KT 0.042 vs. MELD‐Na 0.053). Conclusions This study demonstrates the feasibility and the potential for objectively defined kidney dysfunction types to enhance the prognostication of waitlist mortality provided by the MELD‐Na score.
MULTICOMPONENT GERIATRIC INTERVENTION TO DE-FRAIL HOSPITALIZED OLDER ADULTS WITH CARDIOVASCULAR DISEASE: SUBSTUDY OF THE TARGET-EFT RANDOMIZED CLINICAL TRIAL
Authors: Fayeza Ahmad, Rosie Fountotos, Neetika Bharaj, Haroon Munir, Kiana Hagerty, Mojdeh Hedjazi, John Marsala, Lawrence G. Rudski, Michael Goldfarb, Jonathan Afilalo
Journal: Journal of the American College of Cardiology (2022)
Human iPS cell-derived cartilaginous tissue spatially and functionally replaces nucleus pulposus
Authors: Takashi Kamatani, Hiroki Hagizawa, Seido Yarimitsu, Miho Morioka, Saeko Koyamatsu, Michihiko Sugimoto, Joe Kodama, Junko Yamane, Hiroyuki Ishiguro, Shigeyuki Shichino, Kuniya Abe, Wataru Fujibuchi, Hiromichi Fujie, Takashi Kaito, Noriyuki Tsumaki
Journal: Biomaterials (2022)

The loss of nucleus pulposus (NP) precedes the intervertebral disk (IVD) degeneration that causes back pain. Here, we demonstrate that the implantation of human iPS cell-derived cartilaginous tissue (hiPS-Cart) restores this loss by replacing lost NP spatially and functionally. NP cells consist of notochordal NP cells and chondrocyte-like NP cells. Single cell RNA sequencing (scRNA-seq) analysis revealed that cells in hiPS-Cart corresponded to chondrocyte-like NP cells but not to notochordal NP cells. The implantation of hiPS-Cart into a nuclectomized space of IVD in nude rats prevented the degeneration of the IVD and preserved its mechanical properties. hiPS-Cart survived and occupied the nuclectomized space for at least six months after implantation, indicating spatial and functional replacement of lost NP by hiPS-Cart. Further scRNA-seq analysis revealed that hiPS-Cart cells changed their profile after implantation, differentiating into two lineages that are metabolically distinct from each other. However, post-implanted hiPS-Cart cells corresponded to chondrocyte-like NP cells only and did not develop into notochordal NP cells, suggesting that chondrocyte-like NP cells are nearly sufficient for NP function. The data collectively indicate that hiPS-Cart is a candidate implant for regenerating NP spatially and functionally and preventing IVD degeneration.
Abstract P5-01-05: Transcriptional signature of metastatic triple negative breast cancer in humanized mice
Authors: Chun I Yu, Te-Chia Wu, Francesca Menghi, Joshy George, Kyung In Kim, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer with high risk of recurrence and approximately 22% rate of five-year survival when the disease becomes metastatic. Thus, understanding of mechanisms supporting metastatic colonization of distant organs is of critical importance for the development of new therapies and possibly improved outcomes. Syngeneic mouse models suggest the role of innate immune cells, particularly neutrophils, in support of metastatic dissemination of TNBC. However, it is not possible to study human cancer in immunocompetent mice. Furthermore, organoids or other 3D tissue models do not allow investigations of distant organs colonization with metastatic TNBC tumors. Here, we used humanized mice and patient-derived xenograft (PDX) from treatment naïve primary TNBC tumors to investigate the mechanisms that promote metastasis. NSG mice with transgenic expression of human hematopoietic cytokines SCF/GM-CSF/IL-3 were engrafted with human CD34+ hematopoietic progenitor cells (HPCs) to generate humanized (h)NSG-SGM3 mice. All PDX tumors grew after orthotopic implantation at week 8-12. The presence of distant metastasis was determined by macroscopic evaluation of distant organs and further confirmed by E-cadherin and cytokeratin 19 expression using polychromatic immunofluorescence on frozen tissue section. Among ten PDX tumors tested, four did not develop metastasis, four developed only lung metastasis and two developed multi-organ metastases (lung and liver). We find that different TNBC PDX tumors have different metastatic potential. Their metastatic potential is linked with differences in cellular composition and transcriptional signatures at the level of the primary tumor. Interferon Response signature is enriched in primary TNBC PDXs with metastatic potential, while non-metastatic primary tumors display a TNF signature as well as allograft rejection signature. Furthermore, liver metastases were enriched in myeloid transcripts. Thus, our model enables mechanistic and pre-clinical studies of human TNBC metastasis. Citation Format: Chun I Yu, Te-Chia Wu, Francesca Menghi, Joshy George, Kyung In Kim, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka. Transcriptional signature of metastatic triple negative breast cancer in humanized mice [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-05.
Prophylactic Oral Dextrose Gel and Neurosensory Impairment at 2-Year Follow-up of Participants in the hPOD Randomized Trial
Authors: Taygen Edwards, Jane M. Alsweiler, Caroline A. Crowther, Richard Edlin, Greg D. Gamble, Joanne E. Hegarty, Luling Lin, Christopher J. D. McKinlay, Jenny A. Rogers, Benjamin Thompson, Trecia A. Wouldes, Jane E. Harding
Journal: JAMA (2022)

<h3>Importance</h3> Prophylactic oral dextrose gel reduces neonatal hypoglycemia, but later benefits or harms remain unclear. <h3>Objective</h3> To assess the effects on later development of prophylactic dextrose gel for infants born at risk of neonatal hypoglycemia. <h3>Design, Setting, and Participants</h3> Prospective follow-up of a multicenter randomized clinical trial conducted in 18 Australian and New Zealand hospitals from January 2015 to May 2019. Participants were late preterm or term at-risk infants; those randomized in 9 New Zealand centers (n = 1359) were included and followed up between January 2017 and July 2021. <h3>Interventions</h3> Infants were randomized to prophylactic 40% dextrose (n = 681) or placebo (n = 678) gel, 0.5 mL/kg, massaged into the buccal mucosa 1 hour after birth. <h3>Main Outcomes and Measures</h3> The primary outcome of this follow-up study was neurosensory impairment at 2 years' corrected age. There were 44 secondary outcomes, including cognitive, language, and motor composite Bayley-III scores (mean [SD], 100 [15]; higher scores indicate better performance). <h3>Results</h3> Of eligible infants, 1197 (91%) were assessed (581 females [49%]). Neurosensory impairment was not significantly different between the dextrose and placebo gel groups (20.8% vs 18.7%; unadjusted risk difference [RD], 2.09% [95% CI, −2.43% to 6.60%]; adjusted risk ratio [aRR], 1.13 [95% CI, 0.90 to 1.41]). The risk of cognitive and language delay was not significantly different between the dextrose and placebo groups (cognitive: 7.6% vs 5.3%; RD, 2.32% [95% CI, −0.46% to 5.11%]; aRR, 1.40 [95% CI, 0.91 to 2.17]; language: 17.0% vs 14.7%; RD, 2.35% [95% CI, −1.80% to 6.50%]; aRR, 1.19 [95% CI, 0.92 to 1.54]). However, the dextrose gel group had a significantly higher risk of motor delay (2.5% vs 0.7%; RD, 1.81% [95% CI, 0.40% to 3.23%]; aRR, 3.79 [95% CI, 1.27 to 11.32]) and significantly lower composite scores for cognitive (adjusted mean difference [aMD], −1.30 [95% CI, −2.55 to −0.05]), language (aMD, −2.16 [95% CI, −3.86 to −0.46]), and motor (aMD, −1.40 [95% CI, −2.60 to −0.20]) performance. There were no significant differences between groups in the other 27 secondary outcomes. <h3>Conclusions and Relevance</h3> Among late preterm and term infants born at risk of neonatal hypoglycemia, prophylactic oral 40% dextrose gel at 1 hour of age, compared with placebo, resulted in no significant difference in the risk of neurosensory impairment at 2 years' corrected age. However, the study may have been underpowered to detect a small but potentially clinically important increase in risk, and further research including longer-term follow-up is required. <h3>Trial Registration</h3> anzctr.org.au Identifier:ACTRN12614001263684
CARDIAC TAMPONADE AND ACUTE PULMONARY EDEMA DUE TO LUPUS MYOPERICARDITIS AND LUPUS NEPHRITIS REQUIRING URGENT PERICARDIOCENTESIS AND HEMODIALYSIS: A RARE MALIGNANT PRESENTATION OF LUPUS FLARE UP
Authors: Pranav Kumar Sharma, Amar Bhagat, Andrew Aboyme, Fady Ibrahim
Journal: Journal of the American College of Cardiology (2022)
APPROPRIATE INDICATION AND CLINICAL IMPACT OF INHOSPITAL TRANSTHORACIC ECHOCARDIOGRAPHY
Authors: Arnold Mendez Toro, Fabian Andres Sanchez, Ingrid Tatiana Rojas, Oscar Amaris, Guillermo Mora Pabon, Luis Eduardo Silva, Manuel Agustin Paz, Laura Catalina Arcos Medina, Estivalis Geraldine Acosta, Karen Yuliana Ramirez, Andres Felipe linares
Journal: Journal of the American College of Cardiology (2022)
IMPACT OF EARLY DISCHARGE AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT ON PERMANENT PACEMAKER IMPLANTATION RATES: A NATIONWIDE-ANALYSIS
Authors: Ahmed Elzanaty, Ahmed M. Maraey, Mahmoud Khalil, Ahmed Hashim, Ayman Elbadawi, Eman Elsheikh, Hashim Ghoraba
Journal: Journal of the American College of Cardiology (2022)
PRIOR MYOCARDIAL INFARCTION IN WOMEN WITH SIGNS AND SYMPTOMS OF ISCHEMIA AND NO OBSTRUCTIVE CORONARY ARTERIES: A REPORT FROM THE WOMEN’S ISCHEMIA SYNDROME EVALUATION- CORONARY VASCULAR DYSFUNCTION (WISE-CVD) PROJECT
Authors: Breanna Hansen, Galen Cook-Wiens, Chrisandra Shufelt, John W. Petersen, R. David Anderson, Eileen M. Handberg, Daniel S. Berman, Louise Thomson, Carl J. Pepine, C. Noel Bairey Merz, Janet Wei
Journal: Journal of the American College of Cardiology (2022)
Blood exosomes-based targeted delivery of cPLA2 siRNA and metformin to modulate glioblastoma energy metabolism for tailoring personalized therapy
Authors: Qi Zhan, Kaikai Yi, Xiaoteng Cui, Xueping Li, Shixue Yang, Qixue Wang, Chuan Fang, Yanli Tan, Lijie Li, Can Xu, Xubo Yuan, Chunsheng Kang
Journal: Neuro-Oncology (2022)

Abstract Background Targeting glioblastoma (GBM) energy metabolism through multiple metabolic pathways has emerged as an effective therapeutic approach. Dual inhibition of phospholipid and mitochondrial metabolism with cytoplasmic phospholipase A2 (cPLA2) knockdown and metformin treatment could be a potential strategy. However, the strategic prerequisite is to explore a carrier capable of co-delivering the therapeutic combination to cross the blood-brain barrier (BBB) and preferentially accumulate at the GBM site. Methods Blood exosomes (Exos) were selected as the combination delivery carriers. The cellular uptake of Exos and the therapeutic effects of the combination strategy were evaluated in primary GBM cells. In vivo GBM-targeted delivery efficiency and anti-GBM efficacy were tested in a patient-derived xenograft (PDX) model. Results Here, we showed that the Exos-mediated cPLA2 siRNA/metformin combined strategy could regulate GBM energy metabolism for personalized treatment. Genomic analysis and experiments showed that polymerase 1 and transcript release factor (PTRF, a biomarker of GBM) positively regulated the uptake of Exos by GBM cells, confirming the feasibility of the delivery strategy. Further, Exos could co-load cPLA2 siRNA (sicPLA2) and metformin and co-deliver them across the BBB and into GBM tissue. The mitochondrial energy metabolism of GBM was impaired with this combination treatment (Exos-Met/sicPLA2). In the PDX GBM model, systemic administration of Exos-Met/sicPLA2 reduced tumor growth and prolonged survival. Conclusions Our findings demonstrated that Exos-based combined delivery of sicPLA2 and metformin selectively targeted the GBM energy metabolism to achieve antitumor effects, showing its potential as a personalized therapy for GBM patients.
Errors in Abstract and Results
Journal: JAMA Network Open (2022)

Development of a Molecular Assay for Detection and Quantification of the BRAF Variation in Residual Tissue From Thyroid Nodule Fine-Needle Aspiration Biopsy Specimens," 1 published October 6, 2021, there were errors in the 95% CI values in the Abstract and Results sections.This article has been corrected.
CLINICIAN AND ALGORITHM ASSIGNED SCAI SHOCK STAGES IN THE CRITICAL CARE CARDIOLOGY TRIALS NETWORK REGISTRY
Authors: Siddharth Patel, David Berg, Erin Bohula, Jacob Colin Jentzer, Patrick R. Lawler, Jeong-Gun Park, Jason Neil Katz, Sean Van Diepen, David A. Morrow
Journal: Journal of the American College of Cardiology (2022)
Computational Tools and Resources for CRISPR/Cas Genome Editing
Authors: Chao Li, Wen Chu, Rafaqat Ali Gill, Shifei Sang, Yuqin Shi, Xuezhi Hu, Yuting Yang, Qamar U. Zaman, Baohong Zhang
Journal: Genomics Proteomics & Bioinformatics (2022)

The past decade has witnessed a rapid evolution in identifying more versatile clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) nucleases and their functional variants, as well as in developing precise CRISPR/Cas-derived genome editors. The programmable and robust features of the genome editors provide an effective RNA-guided platform for fundamental life science research and subsequent applications in diverse scenarios, including biomedical innovation and targeted crop improvement. One of the most essential principles is to guide alterations in genomic sequences or genes in the intended manner without undesired off-target impacts, which strongly depends on the efficiency and specificity of single guide RNA (sgRNA)-directed recognition of targeted DNA sequences. Recent advances in empirical scoring algorithms and machine learning models have facilitated sgRNA design and off-target prediction. In this review, we first briefly introduce the different features of CRISPR/Cas tools that should be taken into consideration to achieve specific purposes. Secondly, we focus on the computer-assisted tools and resources that are widely used in designing sgRNAs and analyzing CRISPR/Cas-induced on- and off-target mutations. Thirdly, we provide insights into the limitations of available computational tools that would help researchers of this field for further optimization. Lastly, we suggest a simple but effective workflow for choosing and applying web-based resources and tools for CRISPR/Cas genome editing.