Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS: We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

The deubiquitinase USP28 maintains the expression of the transcription factor MYCN and is essential in neuroblastoma cells.

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk NB patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of NB cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN NB cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for NB with or without MYCN amplification/overexpression.

Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation.

BACKGROUND: Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown. METHODS: We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence. RESULTS: Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway. CONCLUSIONS: We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.

Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T-cell acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T-ALL cases. Ubiquitin-specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T-ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T-ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T-ALL with or without mutant NOTCH1.

Retrospective assessment of neoadjuvant camrelizumab combined with induction chemotherapy: efficacy in laryngeal preservation for advanced hypopharyngeal and laryngeal squamous cell carcinoma.

BACKGROUND: Hypopharyngeal and laryngeal squamous cell carcinoma (SCC) account for 25-30% of head and neck SCC. Total laryngectomy, while effective, compromises the quality of life. Immune checkpoint inhibitors such as Camrelizumab offer potential in laryngeal preservation. The study investigated Camrelizumab combined with TP regimen as a neoadjuvant therapy for laryngeal preservation in advanced hypopharyngeal and laryngeal SCC. METHODS: A retrospective study was conducted at Sun Yat-sen University Cancer Center on patients diagnosed with locally advanced SCC of the hypopharynx and larynx from October 1, 2019, to October 25, 2022. The efficacy of a first-line treatment combining Camrelizumab (200 mg) and TP regimen (Albumin-bound paclitaxel at 260 mg/m2 and Cisplatin at 60 mg/m2) was evaluated using RECIST 1.1 criteria. Outcomes included overall survival (OS), progression-free survival (PFS), laryngectomy-free survival (LFS), and response rates. RESULTS: Of the 71 included patients, the median age was 60.7 years. Post the first-line treatment, 90.1% demonstrated an overall response. The one-year and two-year OS rates were 91.5% and 84.3%, respectively. One-year and two-year PFS rates were 92.9% and 83.9%, respectively, with LFS at 85.6% and 73.2%. The initial T4 stage as significantly associated with reduced OS and LFS. Skin reaction was the predominant adverse event. CONCLUSION: The Camrelizumab-TP regimen demonstrated promising results for advanced hypopharyngeal/laryngeal SCC patients, exhibiting high response rates, OS, and LFS, positioning it as a potential primary option for laryngeal preservation. Further comprehensive, randomized controlled studies are imperative to validate these initial observations and elucidate the regimen's full clinical efficacy in optimizing laryngeal outcomes.

Integrated analysis of transcriptome and small RNAome reveals regulatory network of rapid and long-term response to heat stress in Rhododendron moulmainense.

MAIN CONCLUSION: The post-transcriptional gene regulatory pathway and small RNA pathway play important roles in regulating the rapid and long-term response of Rhododendron moulmainense to high-temperature stress. The Rhododendron plays an important role in maintaining ecological balance. However, it is difficult to domesticate for use in urban ecosystems due to their strict optimum growth temperature condition, and its evolution and adaptation are little known. Here, we combined transcriptome and small RNAome to reveal the rapid response and long-term adaptability regulation strategies in Rhododendron moulmainense under high-temperature stress. The post-transcriptional gene regulatory pathway plays important roles in stress response, in which the protein folding pathway is rapidly induced at 4 h after heat stress, and alternative splicing plays an important role in regulating gene expression at 7 days after heat stress. The chloroplasts oxidative damage is the main factor inhibiting photosynthesis efficiency. Through WGCNA analysis, we identified gene association patterns and potential key regulatory genes responsible for maintaining the ROS steady-state under heat stress. Finally, we found that the sRNA synthesis pathway is induced under heat stress. Combined with small RNAome, we found that more miRNAs are significantly changed under long-term heat stress. Furthermore, MYBs might play a central role in target gene interaction network of differentially expressed miRNAs in R. moulmainense under heat stress. MYBs are closely related to ABA, consistently, ABA synthesis and signaling pathways are significantly inhibited, and the change in stomatal aperture is not obvious under heat stress. Taken together, we gained valuable insights into the transplantation and long-term conservation domestication of Rhododendron, and provide genetic resources for genetic modification and molecular breeding to improve heat resistance in Rhododendron.

Synthesis of Multisubstituted 2,3-Allenamides via Palladium-Catalyzed Carbonylation of Propargylic Esters.

2,3-Allenamides are an important class of unsaturated group-substituted carbonyl compounds. A palladium-catalyzed aminocarbonylation of propargyl acetates with amines for the synthesized tri-/tetrasubstituted 2,3-allenamides has been developed. A broad range of tri-/tetrasubstituted 2,3-allenamides have been prepared from propargyl acetates in good to excellent yields. The reaction featured mild reaction conditions and good functional group tolerance. The applicability of this methodology was further highlighted by the late-stage modification of several natural products and pharmaceuticals.

Cooperative Cu/Pd-Catalyzed 1,5-Boroacylation of Cyclopropyl-Substituted Alkylidenecyclopropanes.

A Cu/Pd-cocatalyzed 1,5-boroacylation of cyclopropyl-substituted ACPs with B2pin2 and acid chlorides has been developed. Using cyclopropyl-substituted ACPs as the starting material, a broad range of 1,5-boroacylated products with multiple functional groups was prepared in good yields with excellent regio- and stereoselectively. Both aromatic and aliphatic acid chlorides were tolerated in this reaction.

CircSOD2: Disruption of intestinal mucosal barrier function in ulcerative colitis by regulating the miR-378g/Snail1 axis.

BACKGROUND AND AIM: Circular RNA (circRNA) has been found to mediate ulcerative colitis (UC) progression by regulating intestinal mucosal barrier function. However, the role of circSOD2 in UC process and its underlying molecular mechanism still need to be further elucidated. METHODS: Lipopolysaccharide (LPS)-induced Caco2 cells were used to mimic UC cell models. CircSOD2, miR-378g, and Snail1 levels were determined by quantitative real-time PCR. Cell viability was detected using MTT assay, and inflammatory cytokine levels were measured using ELISA. The intestinal mucosal barrier function was evaluated by testing transepithelial electrical resistance and fluorescein isothiocyanate (FITC)-dextran permeability. Snail1 and tight junction-related markers (Zo-1 and Claudin2) protein levels were examined using western blot. The interaction between miR-378g and circSOD2 or Snail1 was confirmed by dual-luciferase reporter assay. Dextran sulfate sodium (DSS) was used to induce UC rat models in vivo. RESULTS: CircSOD2 was overexpressed in UC patients, and its knockdown significantly increased cell viability, transepithelial electrical resistance, and tight junction-related protein expression, while reduced inflammation cytokine levels and the permeability of FITC-dextran in LPS-induced Caco2 cells. In terms of mechanism, circSOD2 sponged miR-378g to positively regulate Snail1 expression. MiR-378g inhibitor reversed the effect of circSOD2 knockdown on intestinal mucosal barrier injury and Snail1 expression in LPS-induced Caco2 cells. In DSS-induced UC rat models, circSOD2 knockdown also could repair the intestinal mucosal barrier injury through regulating miR-378g/Snail1 axis. CONCLUSION: CircSOD2 could destroy intestinal mucosal barrier function in LPS-induced Caco2 cells and DSS-induced UC rats by miR-378g/Snail1 axis.

Developing a Prognostic Model for Primary Biliary Cholangitis Based on a Random Survival Forest Model.

Background: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease with few effective treatments and a poor prognosis, and its incidence is on the rise. There is an urgent need for more targeted treatment strategies to accurately identify high-risk patients. The use of stochastic survival forest models in machine learning is an innovative approach to constructing a prognostic model for PBC that can improve the prognosis by identifying high-risk patients for targeted treatment. Method: Based on the inclusion and exclusion criteria, the clinical data and follow-up data of patients diagnosed with PBC-associated cirrhosis between January 2011 and December 2021 at Taizhou Hospital of Zhejiang Province were retrospectively collected and analyzed. Data analyses and random survival forest model construction were based on the R language. Result: Through a Cox univariate regression analysis of 90 included samples and 46 variables, 17 variables with p-values <0.1 were selected for initial model construction. The out-of-bag (OOB) performance error was 0.2094, and K-fold cross-validation yielded an internal validation C-index of 0.8182. Through model selection, cholinesterase, bile acid, the white blood cell count, total bilirubin, and albumin were chosen for the final predictive model, with a final OOB performance error of 0.2002 and C-index of 0.7805. Using the final model, patients were stratified into high- and low-risk groups, which showed significant differences with a P value <0.0001. The area under the curve was used to evaluate the predictive ability for patients in the first, third, and fifth years, with respective results of 0.9595, 0.8898, and 0.9088. Conclusion: The present study constructed a prognostic model for PBC-associated cirrhosis patients using a random survival forest model, which accurately stratified patients into low- and high-risk groups. Treatment strategies can thus be more targeted, leading to improved outcomes for high-risk patients.

A deep learning-powered diagnostic model for acute pancreatitis.

BACKGROUND: Acute pancreatitis is one of the most common diseases requiring emergency surgery. Rapid and accurate recognition of acute pancreatitis can help improve clinical outcomes. This study aimed to develop a deep learning-powered diagnostic model for acute pancreatitis. MATERIALS AND METHODS: In this investigation, we enrolled a cohort of 190 patients with acute pancreatitis who were admitted to Sichuan Provincial People's Hospital between January 2020 and December 2021. Abdominal computed tomography (CT) scans were obtained from both patients with acute pancreatitis and healthy individuals. Our model was constructed using two modules: (1) the acute pancreatitis classifier module; (2) the pancreatitis lesion segmentation module. Each model's performance was assessed based on precision, recall rate, F1-score, Area Under the Curve (AUC), loss rate, frequency-weighted accuracy (fwavacc), and Mean Intersection over Union (MIOU). RESULTS: Upon admission, significant variations were observed between patients with mild and severe acute pancreatitis in inflammatory indexes, liver, and kidney function indicators, as well as coagulation parameters. The acute pancreatitis classifier module exhibited commendable diagnostic efficacy, showing an impressive AUC of 0.993 (95%CI: 0.978-0.999) in the test set (comprising healthy examination patients vs. those with acute pancreatitis, P < 0.001) and an AUC of 0.850 (95%CI: 0.790-0.898) in the external validation set (healthy examination patients vs. patients with acute pancreatitis, P < 0.001). Furthermore, the acute pancreatitis lesion segmentation module demonstrated exceptional performance in the validation set. For pancreas segmentation, peripancreatic inflammatory exudation, peripancreatic effusion, and peripancreatic abscess necrosis, the MIOU values were 86.02 (84.52, 87.20), 61.81 (56.25, 64.83), 57.73 (49.90, 68.23), and 66.36 (55.08, 72.12), respectively. These findings underscore the robustness and reliability of the developed models in accurately characterizing and assessing acute pancreatitis. CONCLUSION: The diagnostic model for acute pancreatitis, driven by deep learning, exhibits excellent efficacy in accurately evaluating the severity of the condition. TRIAL REGISTRATION: This is a retrospective study.

Extracorporeal vs. conventional CPR for out-of-hospital cardiac arrest: A systematic review and meta-analysis.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) remains a significant cause of mortality and morbidity worldwide. Extracorporeal cardiopulmonary resuscitation (ECPR) is a potential intervention for OHCA, but its effectiveness compared to conventional cardiopulmonary resuscitation (CCPR) needs further evaluation. METHOD: We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, and ClinicalTrials.gov for relevant studies from January 2010 to March 2023. Pooled meta-analysis was performed to investigate any potential association between ECPR and improved survival and neurological outcomes. RESULTS: This systematic review and meta-analysis included two randomized controlled trials enrolling 162 participants and 10 observational cohort studies enrolling 4507 participants. The pooled meta-analysis demonstrated that compared to CCRP, ECPR did not improve survival and neurological outcomes at 180 days following OHCA (RR: 3.39, 95% CI: 0.79 to 14.64; RR: 2.35, 95% CI: 0.97 to 5.67). While a beneficial effect of ECPR was obtained regarding 30-day survival and neurological outcomes. Furthermore, ECPR was associated with a higher risk of bleeding complications. Subgroup analysis showed that ECPR was prominently beneficial when exclusively initiated in the emergency department. Additional post-resuscitation treatments did not significantly impact the efficacy of ECPR on 180-day survival with favorable neurological outcomes. CONCLUSIONS: There is no high-quality evidence supporting the superiority of ECPR over CCPR in terms of survival and neurological outcomes in OHCA patients. However, due to the potential for bias, heterogeneity among studies, and inconsistency in practice, the non-significant results do not preclude the potential benefits of ECPR. Further high-quality research is warranted to optimize ECPR practice and provide more generalizable evidence. Clinical trial registration PROSPERO, https://www.crd.york.ac.uk/prospero/, registry number: CRD42023402211.

Associations between child abuse and neglect, and dento-alveolar injuries in a Children's hospital population.

BACKGROUND/AIM: The purpose of this study was to identify social variables common to children with dento-alveolar trauma (DAT) and child abuse and neglect (CAN) in a large children's hospital population. METHODS: Emergency department data from an urban trauma Level 1 children's hospital were queried between December 02, 2017 and September 30, 2022 to identify children with both DAT and CAN. Patients with DAT and CAN were compared to DAT-only children in a case-control study design. Descriptive statistics were used to report characteristics of children in case and control groups. Chi-Squared and Fisher's exact tests were used to compare cases and controls. The level of significance was set at p ≤ .05. RESULTS: In total, 14 children who had DAT and CAN reported simultaneously comprised the case group. A total of 42 children with DAT-only, age/sex matched with cases, comprised the control group. Mean (SD) age of cases was 10.4 (±4) and controls was 10.1 (±3.9) years-old. Eight cases (57.1%) and 24 controls (57.1%) were female. No statistical differences (p = .05) were present for language, race, insurance coverage, parental custody, legal guardianship, and type of residence for cases versus controls. Five (35.7%) cases had a special need versus 4 (9.5%) controls and was statistically different (p = .03). Nine (64.3%) cases had behavioral problems versus 13 (31%) controls (p = .05). Cases were more likely to have facial injuries than controls (74.3 vs. 31%), however no significant differences were present for total number of injured teeth, head injury or neck injury between cases and controls. In half of cases, the perpetrator reported was the sibling. CONCLUSIONS: Demographics did not predict CAN in children with dental injuries. Sibling violence should be considered in suspected CAN children.

The changing profile of infective endocarditis: A multi-year retrospective study for dentists.

BACKGROUND: Infective endocarditis (IE) has high morbidity and mortality and is often attributed to dental procedures. AIM: This study characterized variables related to paediatric IE in a paediatric hospital cohort. DESIGN: A retrospective review of medical records, from January 1, 2008, to January 1, 2020, to examine demographic, medical and dental history, and risk factors associated with children diagnosed with IE at Nationwide Children's Hospital. RESULTS: Of the 242 patients who were admitted with tentative IE diagnoses, 67 met the inclusion criteria: 46 (69%) had underlying cardiac conditions and 21 (31%) had not. One-third had an infection with S. aureus and viridans streptococci. Age was significantly associated with intracardiac devices in children with IE. Mean hospitalization was 25 days, and the mortality was 6 (9%); 41(61%) required surgery for causative defects, and 24 (32%) had dental consultation during admission. CONCLUSION: Although cardiac-related conditions were present in most cases, IE occurred in patients without cardiac factors.

[Clinicians' Practice and Opinions on Sedation Therapy in End-Stage Patients].

Objective To investigate clinicians' practice and opinions on sedation therapy in end-stage patients at Peking Union Medical College Hospital. Methods From August,2022 to April,2023,an online questionnaire survey was conducted among clinicians involved in end-stage patient management. Results A total of 205 questionnaires were distributed,with an effective response rate of 56.1%.Among the clinicians,55.7% of them had experience of applying sedation therapy in end-stage patients;85.2% of clinicians believed that sedation could relieve the suffering of terminal patients from physical refractory symptoms;75.7% of clinicians considered that sedation therapy could be used to relieve agony from psycho-existential distress.Most clinicians had concerns about sedation therapy due to the lack of legal support(86.1%)and the lack of understanding of patients or families(59.1%).The majority (90.4%) of clinicians were willing to receive training on palliative sedation. Conclusions A majority of clinicians agree that sedation therapy could relieve the physical distress and psycho-existential distress in end-stage patients.However,most clinicians have concerns about the application of sedation therapy due to the lack of legal support.It is necessary to enhance the training on palliative sedation.

The deubiquitinase USP28 stabilizes the expression of RecQ family helicases and maintains the viability of triple negative breast cancer cells.

Triple-negative breast cancer (TNBC) lacks significant expression of the estrogen receptor, the progesterone receptor, and of human epidermal growth factor receptor. It is the most aggressive and malignant of all breast cancers, and for which, there are currently no effective targeted therapies. We have shown previously that the RecQ helicase family member RECQL5 is essential for the proliferation and survival of TNBC cells; however, the mechanism of its involvement in cell viability has not been shown. Here, we report that the expression of RecQ family helicases, including RECQL5, is regulated by the deubiquitinase USP28. We found using genetic depletion or a small molecule inhibitor that like RECQL5, USP28 is also essential for TNBC cells to proliferate in vitro and in vivo. Compromising the function of USP28 by shRNA knockdown or the inhibitor caused TNBC cells to arrest in S/G2 phases, concurrent with DNA-damage checkpoint activation. We further showed that the small molecule inhibitor of USP28 displayed anti-tumor activity against xenografts derived from TNBC cells. Our results suggest that USP28 could be a potential therapeutic target for triple negative breast cancer.

Identifying patterns of reported findings on long-term cardiac complications of COVID-19: a systematic review and meta-analysis.

INTRODUCTION: Prior reviews synthesized findings of studies on long-term cardiac complications of COVID-19. However, the reporting and methodological quality of these studies has not been systematically evaluated. Here, we conducted a systematic review and meta-analysis on long-term cardiac complications of COVID-19 and examined patterns of reported findings by study quality and characteristics. METHODS: We searched for studies examining long-term cardiac complications of COVID-19 that persisted for 4 weeks and over. A customized Newcastle-Ottawa scale (NOS) was used to evaluate the quality of included studies. Meta-analysis was performed to generate prevalence estimates of long-term cardiac complications across studies. Stratified analyses were further conducted to examine the prevalence of each complication by study quality and characteristics. The GRADE approach was used to determine the level of evidence for complications included in the meta-analysis. RESULTS: A total number of 150 studies describing 57 long-term cardiac complications were included in this review, and 137 studies reporting 17 complications were included in the meta-analysis. Only 25.3% (n = 38) of studies were of high quality based on the NOS quality assessment. Chest pain and arrhythmia were the most widely examined long-term complications. When disregarding study quality and characteristics, summary prevalence estimates for chest and arrhythmia were 9.79% (95% CI 7.24-13.11) and 8.22% (95% CI 6.46-10.40), respectively. However, stratified analyses showed that studies with low-quality scores, small sample sizes, unsystematic sampling methods, and cross-sectional design were more likely to report a higher prevalence of complications. For example, the prevalence of chest pain was 22.17% (95% CI 14.40-32.55), 11.08% (95% CI 8.65-14.09), and 3.89% (95% CI 2.49-6.03) in studies of low, medium, and high quality, respectively. Similar patterns were observed for arrhythmia and other less examined long-term cardiac complications. CONCLUSION: There is a wide spectrum of long-term cardiac complications of COVID-19. Reported findings from previous studies are strongly related to study quality, sample sizes, sampling methods, and designs, underscoring the need for high-quality epidemiologic studies to characterize these complications and understand their etiology.

Neuropilin-1 Facilitates Pseudorabies Virus Replication and Viral Glycoprotein B Promotes Its Degradation in a Furin-Dependent Manner.

Pseudorabies virus (PRV), which is extremely infectious and can infect numerous mammals, has a risk of spillover into humans. Virus-host interactions determine viral entry and spreading. Here, we showed that neuropilin-1 (NRP1) significantly potentiates PRV infection. Mechanistically, NRP1 promoted PRV attachment and entry, and enhanced cell-to-cell fusion mediated by viral glycoprotein B (gB), gD, gH, and gL. Furthermore, through in vitro coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) assays, NRP1 was found to physically interact with gB, gD, and gH, and these interactions were C-end Rule (CendR) motif independent, in contrast to currently known viruses. Remarkably, we illustrated that the viral protein gB promotes NRP1 degradation via a lysosome-dependent pathway. We further demonstrate that gB promotes NRP1 degradation in a furin-cleavage-dependent manner. Interestingly, in this study, we generated gB furin cleavage site (FCS)-knockout PRV (Δfurin PRV) and evaluated its pathogenesis; in vivo, we found that Δfurin PRV virulence was significantly attenuated in mice. Together, our findings demonstrated that NRP1 is an important host factor for PRV and that NRP1 may be a potential target for antiviral intervention. IMPORTANCE Recent studies have shown accelerated PRV cross-species spillover and that PRV poses a potential threat to humans. PRV infection in humans always manifests as a high fever, tonic-clonic seizures, and encephalitis. Therefore, understanding the interaction between PRV and host factors may contribute to the development of new antiviral strategies against PRV. NRP1 has been demonstrated to be a receptor for several viruses that harbor CendR, including SARS-CoV-2. However, the relationships between NRP1 and PRV are poorly understood. Here, we found that NRP1 significantly potentiated PRV infection by promoting PRV attachment and enhanced cell-to-cell fusion. For the first time, we demonstrated that gB promotes NRP1 degradation via a lysosome-dependent pathway. Last, in vivo, Δfurin PRV virulence was significantly attenuated in mice. Therefore, NRP1 is an important host factor for PRV, and NRP1 may be a potential target for antiviral drug development.

M-type pyruvate kinase 2 (PKM2) tetramerization alleviates the progression of right ventricle failure by regulating oxidative stress and mitochondrial dynamics.

BACKGROUND: Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. OBJECTIVE: We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. METHOD: We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. RESULTS: We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. CONCLUSION: Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF.

Kidney-type glutaminase is a biomarker for the diagnosis and prognosis of hepatocellular carcinoma: a prospective study.

PURPOSE: The pathological diagnosis and prognosis prediction of hepatocellular carcinoma (HCC) is challenging due to the lack of specific biomarkers. This study aimed to validate the diagnostic and prognostic efficiency of Kidney-type glutaminase (GLS1) for HCC in prospective cohorts with a large sample size. METHODS: A total of 1140 HCC patients were enrolled in our prospective clinical trials. Control cases included 114 nontumour tissues. The registered clinical trial (ChiCTR-DDT-14,005,102, chictr.org.cn) was referred to for the exact protocol. GLS1 immunohistochemistry was performed on the whole tumour section. The diagnostic and prognostic performances of GLS1 was evaluated by the receiver operating characteristic curve and Cox regression model. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and area under the curve of GLS1 for the diagnosis of HCC were 0.746, 0.842, 0.979, 0.249, 0.588, and 0.814, respectively, which could be increased to 0.846, 0.886, 0.987,0.366, 0.732, and 0.921 when combined with glypican 3 (GPC3) and alpha-fetoprotein (AFP), indicating better diagnostic performance. Further, we developed a nomogram with GPC3 and GLS1 for identifying HCC which showed good discrimination and calibration. GLS1 expression was also related with age, T stage, TNM stage, Edmondson-Steiner grade, microvascular invasion, Ki67, VEGFR2, GPC3, and AFP expression in HCC. GLS1 expression was negatively correlated with disease-free survival (P < 0.001) probability of patients with HCC. CONCLUSIONS: It was validated that GLS1 was a sensitive and specific biomarker for pathological diagnosis of HCC and had prognostic value, thus having practical value for clinical application.