tbuckley/cabot-search huggingface dataset:
Abstract 12102: The Racial Disparity Among Congenital Heart Disease Patients Post Surgery: A Meta-Analysis
Authors: Vikash Jaiswal, Ananya Arora, Novonil Deb, Muhammad Hanif, Song Peng Ang, Yusra Nasir, Akash Jaiswal
Journal: Circulation (2023)

Background: Congenital heart disease (CHD), the most prevalent congenital disorder in newborns, is a leading cause of infant mortality. Mortality rates have declined over time with advancements in knowledge and management approaches. Despite these advancements, studies on racial disparities in CHD surgical mortality have yielded inconclusive results. Objective: We aim to evaluate the disparity among the clinical outcomes post-CHD surgery. Methods: A comprehensive literature search was conducted on PubMed, Embase, and Scopus utilizing predefined MeSH terms coupled with Boolean operators "AND" and "OR." The search strategy included the terms "congenital heart disease" AND "racial disparity" OR "minorities" OR "Black" OR "White" AND "mortality." Our meta-analysis sought observational studies published from inception until 10th March 2023 reporting post-surgical incidence of mortality in Black and White patients with CHD. Results: We identified 5 studies, including 79616 patients with CHD. Of these, 15124 Black patients and 64492 White patients (20% vs. 80%) underwent CHD surgery. All included patients were less than 18 years of age with a definitive diagnosis of CHD. The mean length of hospital stay was (11.5 vs. 10.10) days, respectively. The pooled analysis showed that Black patients with CHD have significantly higher odds of postoperative mortality (OR, 1.46(95%CI: 1.31-1.62), P&lt;0.001) with low heterogeneity across the studies. Conclusion: This very first meta-analysis shows that Black patients are at increased risk of mortality post-CHD surgery compared to White patients.
Fallen Leaves
Authors: Charles K. Morris
Journal: JAMA (2023)

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Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy
Authors: Yue Zhang, Jingwen Gao, Na Li, Peng Xu, Shimeng Qu, Jinqian Cheng, Mingrui Wang, Xueru Li, Yaheng Song, Fan Xiao, Xinyu Yang, Jihong Liu, Hao Hong, Ronghao Mu, Xiaotian Li, Youmei Wang, Hui Xu, Yuan Xie, Tianming Gao, Guangji Wang, Jiye Aa
Journal: Acta Pharmaceutica Sinica B (2023)

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.
FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis
Authors: Zhifeng Huang, Tongtong Pan, Liang Xu, Lu Shi, Xiong Ma, Liya Zhou, Luyao Wang, Jiaojiao Wang, Guoqing Zhu, Dazhi Chen, Lingtao Song, Xiaomin Pan, Xiaodong Wang, Xiaokun Li, Yongde Luo, Yongping Chen
Journal: Acta Pharmaceutica Sinica B (2023)

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKKβ) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.
Identification of RP11‐770J1.4 as immune‐related lncRNA regulating the CTXN1–cGAS–STING axis in histologically lower‐grade glioma
Authors: Qiyuan Zhuang, Chaxian Liu, Yihan Hu, Ying Liu, Yingying Lyu, Yuheng Liao, Liang Chen, Hui Yang, Ying Mao
Journal: MedComm (2023)

Human gliomas are lethal brain cancers. Emerging evidence revealed the regulatory role of long noncoding RNAs (lncRNAs) in tumors. Here, we performed a comprehensive analysis of the expression profiles of RNAs in histologically lower-grade glioma (LGG). Enrichment analysis revealed that glioma is influenced by immune-related signatures. Survival analysis further established the close correlation between network features and glioma prognosis. Subsequent experiments showed lncRNA RP11-770J1.4 regulates
Cross-linking breast tumor transcriptomic states and tissue histology
Authors: Muhammad Dawood, Mark Eastwood, Mostafa Jahanifar, Lawrence Young, Asa Ben-Hur, Kim Branson, Louise Jones, Nasir Rajpoot, Fayyaz ul Amir Afsar Minhas
Journal: Cell Reports Medicine (2023)

Identification of the gene expression state of a cancer patient from routine pathology imaging and characterization of its phenotypic effects have significant clinical and therapeutic implications. However, prediction of expression of individual genes from whole slide images (WSIs) is challenging due to co-dependent or correlated expression of multiple genes. Here, we use a purely data-driven approach to first identify groups of genes with co-dependent expression and then predict their status from WSIs using a bespoke graph neural network. These gene groups allow us to capture the gene expression state of a patient with a small number of binary variables that are biologically meaningful and carry histopathological insights for clinical and therapeutic use cases. Prediction of gene expression state based on these gene groups allows associating histological phenotypes (cellular composition, mitotic counts, grading, etc.) with underlying gene expression patterns and opens avenues for gaining biological insights from routine pathology imaging directly.
PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition
Authors: Yang Li, Lacey E. Dobrolecki, Christina Sallas, Xudong Zhang, Travis D. Kerr, Deepa Bisht, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L. Mendillo, Yiling Lu, Collene R. Jeter, Guang Peng, Jinsong Liu, Shannon N. Westin, Anil K. Sood, Michael T. Lewis, Jishnu Das, S. Stephen Yi, Mark T. Bedford, Daniel J. McGrail, Nidhi Sahni
Journal: Cell Reports Medicine (2023)

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.
Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies
Authors: Zheng Zhang, Caroline Markmann, Ming Yu, Divyansh Agarwal, Susan Rostami, Wei Wang, Chengyang Liu, Huiwu Zhao, Trini Ochoa, Kalpana Parvathaneni, Xiaoming Xu, Eric Li, Vanessa Gonzalez, Roman Khadka, Jennifer Hoffmann, James J. Knox, John Scholler, Brooke Marcellus, David Allman, Joseph A. Fraietta, Benjamin Samelson-Jones, Michael C. Milone, Dimitri Monos, Alfred L. Garfall, Ali Naji, Vijay G. Bhoj
Journal: Cell Reports Medicine (2023)

Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation. We find that treatment of allo-sensitized hosts with CAR T cells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent islet allografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.
Single-cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia
Authors: Oto Inoue, Chiaki Goten, Daiki Hashimuko, Kosei Yamaguchi, Yusuke Takeda, Ayano Nomura, Hiroshi Ootsuji, Shinichiro Takashima, Kenji Iino, Hirofumi Takemura, Manasi Halurkar, Hee-Woong Lim, Vivian Hwa, Joan Sanchez-Gurmaches, Soichiro Usui, Masayuki Takamura
Journal: Cell Reports Medicine (2023)

Therapeutic angiogenesis using mesenchymal stem/stromal cell grafts have shown modest and controversial effects in preventing amputation for patients with critical limb ischemia. Through single-cell transcriptomic analysis of human tissues, we identify CD271+ progenitors specifically from subcutaneous adipose tissue (AT) as having the most prominent pro-angiogenic gene profile distinct from other stem cell populations. AT-CD271+ progenitors demonstrate robust in vivo angiogenic capacity over conventional adipose stromal cell grafts, characterized by long-term engraftment, augmented tissue regeneration, and significant recovery of blood flow in a xenograft model of limb ischemia. Mechanistically, the angiogenic capacity of CD271+ progenitors is dependent on functional CD271 and mTOR signaling. Notably, the number and angiogenic capacity of CD271+ progenitors are strikingly reduced in insulin-resistant donors. Our study highlights the identification of AT-CD271+ progenitors with in vivo superior efficacy for limb ischemia. Furthermore, we showcase comprehensive single-cell transcriptomics strategies for identification of suitable grafts for cell therapy.
Dapagliflozin protects against chronic heart failure in mice by inhibiting macrophage-mediated inflammation, independent of SGLT2
Authors: Qingqing Wu, Qi Yao, Tongtong Hu, Jiabin Yu, Kebing Jiang, Ying Wan, Qizhu Tang
Journal: Cell Reports Medicine (2023)

The specific mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitor in heart failure (HF) needs to be elucidated. In this study, we use SGLT2-global-knockout (KO) mice to assess the mechanism of SGLT2 inhibitor on HF. Dapagliflozin ameliorates both myocardial infarction (MI)- and transverse aortic constriction (TAC)-induced HF. Global SGLT2 deficiency does not exert protection against adverse remodeling in both MI- and TAC-induced HF models. Dapagliflozin blurs MI- and TAC-induced HF phenotypes in SGLT2-KO mice. Dapagliflozin causes major changes in cardiac fibrosis and inflammation. Based on single-cell RNA sequencing, dapagliflozin causes significant differences in the gene expression profile of macrophages and fibroblasts. Moreover, dapagliflozin directly inhibits macrophage inflammation, thereby suppressing cardiac fibroblasts activation. The cardio-protection of dapagliflozin is blurred in mice treated with a C-C chemokine receptor type 2 antagonist. Taken together, the protective effects of dapagliflozin against HF are independent of SGLT2, and macrophage inhibition is the main target of dapagliflozin against HF.
Advances in methods for tRNA sequencing and quantification
Authors: Nigam H. Padhiar, Upendra Katneni, Anton A. Komar, Yuri Motorin, Chava Kimchi-Sarfaty
Journal: Trends in Genetics (2023)

In the past decade tRNA sequencing (tRNA-seq) has attracted considerable attention as an important tool for the development of novel approaches to quantify highly modified tRNA species and to propel tRNA research aimed at understanding the cellular physiology and disease and development of tRNA-based therapeutics. Many methods are available to quantify tRNA abundance while accounting for modifications and tRNA charging/acylation. Advances in both library preparation methods and bioinformatic workflows have enabled developments in next-generation sequencing (NGS) workflows. Other approaches forgo NGS applications in favor of hybridization-based approaches. In this review we provide a brief comparative overview of various tRNA quantification approaches, focusing on the advantages and disadvantages of these methods, which together facilitate reliable tRNA quantification.
Needle biopsy accelerates pro-metastatic changes and systemic dissemination in breast cancer: Implications for mortality by surgery delay
Authors: Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John F. Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka
Journal: Cell Reports Medicine (2023)

Increased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE2/EP2 feedforward loop, which favors M2 polarization and its associated pro-metastatic changes but are abrogated by oral treatment with COX-2 or EP2 inhibitors in estrogen-receptor-positive (ER+) syngeneic mouse tumor models. Therefore, we conclude that needle biopsy of ER+ BC provokes progressive pro-metastatic changes, which may explain the mortality risk posed by surgery delay after diagnosis.
NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy
Authors: Laura Hurtado-Navarro, Ernesto José Cuenca-Zamora, Lurdes Zamora, Beatriz Bellosillo, Esperanza Such, Eva Soler-Espejo, Helios Martínez-Banaclocha, Jesús M. Hernández-Rivas, Javier Marco-Ayala, Laura Martínez-Alarcón, Lola Linares-Latorre, Sara García-Ávila, Paula Amat-Martínez, Teresa González, Montserrat Arnan, Helena Pomares-Marín, Gonzalo Carreño-Tarragona, Tzu Hua Chen-Liang, María T. Herranz, Carlos García-Palenciano, María Luz Morales, Andrés Jerez, María L. Lozano, Raúl Teruel-Montoya, Pablo Pelegrín, Francisca Ferrer-Marín
Journal: Cell Reports Medicine (2023)

Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.
FLT3L-dependent dendritic cells control tumor immunity by modulating Treg and NK cell homeostasis
Authors: Paul Régnier, Mathias Vetillard, Adèle Bansard, Eméranne Pierre, Xinyue Li, Nicolas Cagnard, Emmanuel L. Gautier, Pierre Guermonprez, Bénédicte Manoury, Katrina Podsypanina, Guillaume Darrasse-Jèze
Journal: Cell Reports Medicine (2023)

FLT3-L-dependent classical dendritic cells (cDCs) recruit anti-tumor and tumor-protecting lymphocytes. We evaluate cancer growth in mice with low, normal, or high levels of cDCs. Paradoxically, both low or high numbers of cDCs improve survival in mice with melanoma. In low cDC context, tumors are restrained by the adaptive immune system through influx of effector T cells and depletion of Tregs and NK cells. High cDC numbers favor the innate anti-tumor response, with massive recruitment of activated NK cells, despite high Treg infiltration. Anti CTLA-4 but not anti PD-1 therapy synergizes with FLT3-L therapy in the cDC
MEFV variants are a predisposing factor for generalized pustular psoriasis
Authors: Takenori Yoshikawa, Takuya Takeichi, Kazuki Nishida, Yumiko Kobayashi, Hozumi Sano, Akitaka Shibata, Haruka Koizumi, Reiko Tsutsumi, Ryo Fukaura, Masahiro Hayashi, Akiko Imanishi, Kenta Nakamura, Yasutomo Mikoshiba, Eisaku Ogawa, Shinya Sano, Manao Kinoshita, Takashi Okamoto, Reiko Kageyama, Yuko Sano, Sakae Kaneko, Jun Aoi, Toshihide Hara, Yaei Togawa, Mari Kishibe, Yuichi Yoshida, Hiroaki Yagi, Tetsuya Honda, Kazumitsu Sugiura, Shigetoshi Sano, Tamio Suzuki, Tomoo Ogi, Yoshinao Muro, Masashi Akiyama
Journal: Journal of the American Academy of Dermatology (2023)
Abstract 11969: Association Between Blood Lead Levels and Silent Myocardial Infarction in the General Population
Authors: Mohamed A Mostafa, Mohammed A Abuessa, Mai Soliman, Muhammad I Ahmad, Elsayed Z Soliman
Journal: Circulation (2023)

Background: While the connection between environmental lead exposure and cardiovascular disease (CVD) is well-known, the association with silent myocardial infarction (SMI) remains unexplored. Aims: Our objective was to examine if there is a connection between higher blood lead levels (BLL) and increased prevalence of SMI in the general population. Methods: This analysis included 7,283 (mean age 56.1±2.52 years, 52.5% women, 49.8% Whites) participants from the Third National Health and Nutrition Examination Survey who were free of CVD. Graphite furnace atomic absorption spectrophotometry was used to measure blood lead levels (BLL). SMI was defined as the presence of electrocardiographic evidence of myocardial infarction (MI) without a prior history of MI. Multivariable logistic regression analysis was used to examine the cross-sectional association between baseline BLL and SMI. Results: Participants with higher levels of BLL had a higher prevalence of SMI (SMI prevalence 0.4%, 0.9% and 2.4% across BLL tertiles). In a multivariable-adjusted model, the highest BLL tertile was associated with over three times the odds of SMI compared to the first tertile, with an odds ratio of 3.42 (95% CI: 1.76-6.63). There was a 9% increase in the odds of SMI for every 1 μg/dL increase in BLL (Table). This association was consistent across subgroups stratified by median age, sex, and race. Conclusion: Higher BLL levels are associated with a higher likelihood of SMI in the general US population. These results underscore the ongoing need for efforts to minimize lead exposure among the general public.