KLF4 Inhibits the Activation of Human Hepatic Stellate Cell In Vitro.

OBJECTIVE: Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis. Early-stage liver fibrosis is reversible and intimately associated with the state of HSCs. Kruppel-like factor 4 (KLF4) plays a pivotal role in a wide array of physiological and pathological processes. This study aimed to investigate the effect of KLF4 on the proliferation, apoptosis and phenotype of quiescent HSCs METHODS: We designed a KLF4 lentiviral vector and a KLF4 siRNA lentiviral vector, to upregulate and silence KLF4 expression in human HSC LX-2 cells via transfection. Cell proliferation was assessed using the CCK-8 assay. Flow cytometry was used to detect the cell cycle distribution and apoptosis rate. Western blotting was used to determine the levels of some quiescence and activation markers of HSCs RESULTS: Overexpression of KLF4 significantly increased the levels of E-cadherin and ZO-1, which are quiescent HSC markers, while significantly decreased the levels of N-cadherin and a-SMA, known activated HSC markers. In contrast, cell proliferation and apoptosis rates were elevated in LX-2 cells in which KLF4 expression was silenced CONCLUSION: KLF4 inhibits the proliferation and activation of human LX-2 HSCs. It might be a key regulatory protein in the maintenance of HSC quiescence and may serve as a target for the inhibition of hepatic fibrosis.

Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study.

Background: Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods: A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results: Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion: Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

Fisetin enhances cisplatin sensitivity in renal cell carcinoma via the CDK6/PI3K/Akt/mTOR signaling pathway.

Cisplatin resistance is ubiquitous among patients with renal cell carcinoma (RCC). The present study assessed the role of fisetin in regulating cisplatin sensitivity and increasing the efficacy of chemotherapy for patients with RCC. Cell Counting Kit-8 and colony formation assays were used to assess the proliferation of RCC cells after fisetin and cisplatin treatment. The mRNA expression levels of cyclin-dependent kinase (CDK)6 were evaluated using reverse transcription-quantitative PCR. The expression levels of CDK6 and key proteins of the PI3K/Akt/mTOR signaling pathway were assessed using western blotting. The present study demonstrated that fisetin inhibited the proliferation and colony-forming ability of RCC cells, and induced apoptosis and cell cycle arrest in a dose-dependent manner. Additionally, fisetin enhanced the antineoplastic effects of cisplatin, as demonstrated by the increase in proliferation inhibition and apoptosis promotion after fisetin and cisplatin combination treatment. Furthermore, fisetin regulated the PI3K/Akt/mTOR signaling pathway through CDK6 inhibition, which enhanced cisplatin sensitivity. Overexpression of CDK6 neutralized the positive effects of fisetin on the improvement of cisplatin sensitivity in RCC cells. In conclusion, fisetin may enhance the sensitivity of RCC cells to cisplatin via the CDK6/PI3K/Akt/mTOR signaling pathway.

A pan-cancer analysis of the prognosis and immune infiltration of eEF1A2 and its potential function in thyroid carcinoma.

Purpose: Eukaryotic translation elongation factor 1α2 (eEF1A2) promotes tumour progression in various cancers. We performed a pan-cancer analysis of eEF1A2 and explored its role in thyroid carcinoma (THCA). Methods: Databases from The Cancer Genome Atlas (TCGA), the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and the Human Protein Atlas (HPA) were used to investigate the differential expression of eEF1A2 in pan-cancer. The pathological stage, prognostic characteristics, tumour microenvironment (TME), tumour mutational burden (TMB), and microsatellite instability (MSI) were analysed in diverse tumours with different expression levels of eEF1A2. The expression levels in papillary thyroid carcinoma (PTC) and its specific role in cell proliferation, migration, invasion, and cell glycolysis in PTC cells were verified by quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry, cell counting kit-8, colony formation, wound healing, Transwell assay, and lactate acid and glucose assays.Results:eEF1A2 was differentially expressed in various malignant tumour tissues compared to control tissues and was associated with poor pathological stage and prognosis in most types of tumours. Moreover, eEF1A2 expression closely correlated with the infiltration of immunosuppressive cells, TMB, and MSI in some tumour types. Expression of eEF1A2 in PTC is higher than the para-carcinoma, and eEF1A2 downregulation suppressed TPC-1 and BCPAP cell proliferation, migration, invasion, and glycolysis. Conclusion: Our study suggests that the expression of eEF1A2 is related to the prognosis and immune infiltration of some tumours and may be a predictor of prognosis and immunotherapy. eEF1A2 could promote malignant behaviour of PTC cells.

A comprehensive predictive model for radiation-induced brain injury in risk stratification and personalized radiotherapy of nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Radiation-induced brain injury (RBI) is a severe radiotoxicity for nasopharyngeal carcinoma (NPC) patients, greatly affecting their long-term life quality and survival. We aim to establish a comprehensive predictive model including clinical factors and newly developed genetic variants to improve the precision of RBI risk stratification. MATERIALS AND METHODS: By performing a large registry-based retrospective study with magnetic resonance imaging follow-up on RBI development, we conducted a genome-wide association study and developed a polygenic risk score (PRS) for RBI in 1189 NPC patients who underwent intensity-modulated radiotherapy. We proposed a tolerance dose scheme for temporal lobe radiation based on the risk predicted by PRS. Additionally, we established a nomogram by combining PRS and clinical factors for RBI risk prediction. RESULTS: The 38-SNP PRS could effectively identify high-risk individuals of RBI (P = 1.42 × 10-34). Based on genetic risk calculation, the recommended tolerance doses of temporal lobes should be 57.6 Gy for individuals in the top 10 % PRS subgroup and 68.1 Gy for individuals in the bottom 50 % PRS. Notably, individuals with high genetic risk (PRS > P50) and receiving high radiation dose in the temporal lobes (D0.5CC > 65 Gy) had an approximate 50-fold risk over individuals with low PRS and receiving low radiation dose (HR = 50.09, 95 %CI = 24.27-103.35), showing an additive joint effect (Pinteraction < 0.001). By combining PRS with clinical factors including age, tumor stage, and radiation dose of temporal lobes, the predictive accuracy was significantly improved with C-index increased from 0.78 to 0.85 (P = 1.63 × 10-2). CONCLUSIONS: The PRS, together with clinical factors, could improve RBI risk stratification and implies personalized radiotherapy.

The interaction and mediation effects between the host genetic factors and Epstein-Barr virus VCA-IgA in the risk of nasopharyngeal carcinoma.

Previous studies have demonstrated strong associations between host genetic factors and Epstein-Barr virus (EBV) VCA-IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific interplay between host genetics and EBV VCA-IgA on NPC risk is not well understood. In this two-stage case-control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome-wide association study-derived polygenic risk score [PRS]) and EBV VCA-IgA antibody level in the NPC risk. We employed a four-way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA-IgA. We consistently found a significant interaction between the PRS and EBV VCA-IgA on NPC risk (discovery population: synergy index [SI] = 2.39, 95% confidence interval [CI] = 1.85-3.10; replication population: SI = 3.10, 95% CI = 2.17-4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA-IgA antibody. We also observed an obvious dose-response relationship between the PRS and EBV VCA-IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic-EBV interaction, while the risk effects mediated by EBV VCA-IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA-IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.

Laparoscopic vs open radical resection in management of gallbladder carcinoma: A systematic review and meta-analysis.

BACKGROUND: Radical resection offers the only hope for the long-term survival of patients with gallbladder carcinoma (GBC) above the T1b stage. However, whether it should be performed under laparoscopy for GBC is still controversial. AIM: To compare laparoscopic radical resection (LRR) with traditional open radical resection (ORR) in managing GBC. METHODS: A comprehensive search of online databases, including Medline (PubMed), Cochrane Library, and Web of Science, was conducted to identify comparative studies involving LRR and ORR in GBCs till March 2023. A meta-analysis was subsequently performed. RESULTS: A total of 18 retrospective studies were identified. In the long-term prognosis, the LRR group was comparable with the ORR group in terms of overall survival and tumor-free survival (TFS). LRR showed superiority in terms of TFS in the T2/tumor-node-metastasis (TNM) Ⅱ stage subgroup vs the ORR group (P = 0.04). In the short-term prognosis, the LRR group had superiority over the ORR group in the postoperative length of stay (POLS) (P < 0.001). The sensitivity analysis showed that all pooled results were robust. CONCLUSION: The meta-analysis results show that LRR is not inferior to ORR in all measured outcomes and is even superior in the TFS of patients with stage T2/TNM Ⅱ disease and POLS. Surgeons with sufficient laparoscopic experience can perform LRR as an alternative surgical strategy to ORR.

Disitamab Vedotin plus anti-PD-1 antibody show good efficacy in refractory primary urethral cancer with low HER2 expression: a case report.

Primary urethral carcinoma (PUC) has a low incidence, but with high aggressiveness. Most of the patients are found in late stage, with poor prognosis. At present, chemotherapy is still the main treatment for metastatic PUC, but it has limited effect. Here, we report a case of metastatic PUC with low HER2 expression that developed disease progression after multiline therapy including chemotherapy, programmed death-1 (PD-1) inhibitors and multi-targeted receptor tyrosine kinase (RTK) inhibitor. After receiving Disitamab Vedotin(a novel antibody drug conjugate, ADC) and toripalimab (a PD-1 inhibitor), the patient achieved persistent PR, and the PFS exceeded 12 months up to now. Our report indicates that, despite the patient of metastatic PUC has low expression of HER2, it is still possible to benefit from Disitamab Vedotin combined with PD-1 inhibitor, which may reverse the drug resistance of PD-1 inhibitor and chemotherapy to a certain extent. But larger sample studies are needed to determine the efficacy of this treatment strategy and its impact on survival.

Integrative transcriptomic and metabolomic analysis in mice reveals the mechanism by which ginseng stem-leaf saponins enhance mucosal immunity induced by a porcine epidemic diarrhea virus vaccination.

Porcine epidemic diarrhea virus (PEDV) is a main cause of severe enteric disease in piglets, leading to millions of dollars lost annually in the global pig industry. Parenteral vaccination is limited in generating sufficient mucosal immunity, which is crucial for early defense against PEDV. Here, we orally administered ginseng stem-leaf saponins (GSLS) to mice before parenteral vaccination and found that GSLS significantly enhanced the phagocytosis of dendritic cells, promoted the activities of CD4+ T cells and increased PEDV-specific IgA antibodies in the intestinal mucosa. Transcriptomic results showed that the altered genes following GSLS treatment were mostly related to the immune response and metabolism. In addition, integrated analysis of the transcriptome and metabolome revealed that the mechanism by which GSLS enhances mucosal immunity may be associated with progesterone-related pathways. Further studies are needed to explore the detailed molecular mechanisms.

The pseudokinase MLKL contributes to host defense against Streptococcus pluranimalium infection by mediating NLRP3 inflammasome activation and extracellular trap formation.

Host innate immunity plays a pivotal role in the early detection and neutralization of invading pathogens. Here, we show that pseudokinase mixed lineage kinase-like protein (MLKL) is required for host defence against Streptococcus pluranimalium infection by enhancing NLRP3 inflammasome activation and extracellular trap formation. Notably, Mlkl deficiency leads to increased mortality, increased bacterial colonization, severe destruction of organ architecture, and elevated inflammatory cell infiltration in murine models of S. pluranimalium pulmonary and systemic infection. In vivo and in vitro data provided evidence that potassium efflux-dependent NLRP3 inflammasome signalling downstream of active MLKL confers host protection against S. pluranimalium infection and initiates bacterial killing and clearance. Moreover, Mlkl deficiency results in defects in extracellular trap-mediated bactericidal activity. In summary, this study revealed that MLKL mediates the host defence response to S. pluranimalium, and suggests that MLKL is a potential drug target for preventing and controlling pathogen infection.

Neonatal resuscitation workshop for trainees in standardized medical residency training-a pilot practice in Shenzhen, China.

Background: Neonatal resuscitation is an important skillset for clinicians attending deliveries. Accredited neonatal resuscitation training is not obligatory in most training centers of standardized medical residency programs before 2022 in China. We investigated the feasibility and effectiveness of neonatal resuscitation simulation training (neo-RST) in residents in Shenzhen, China. Methods: Four two-day neo-RST workshops were conducted in the University of Hong Kong-Shenzhen Hospital and Shenzhen Health Capacity Building and Continuing Education Center in 2020-2021. The workshops had Neonatal Resuscitation Program (NRP)® update, skill stations and simulation practice with debriefing. Each participant had the integrated skill station assessment (ISSA) at the end of workshop. Participants of workshops included residents of different disciplines and health care providers (HCPs) of neonatal and obstetrical departments. We compared demographic characteristics, neonatal resuscitation knowledge before training, ISSA overall and categorical scores on skill sets between residents and HCPs. Results: In 2020-2021, 4 neo-RST workshops were conducted with 48 residents and 48 HCPs. The residents group had less working experience, less prior experience in neo-RST and lower neonatal resuscitation knowledge scores than those of HCPs group. After the workshop, residents had higher overall ISSA score than that of HCPs group (90.2 ± 5.9 vs. 86.3 ± 6.6%, P = 0.003, respectively). There was no significant difference in the numbers of participants scored <80% in residents and HCPs group (3 [6.3%] vs. 7 [14.6%], respectively). Regarding the categorical scores, residents scored significantly higher in preparation, ventilation, crisis resource management and behavioral skills but lower in appropriate oxygen use, when compared with the HCPs. Conclusion: Neo-RST for residents is feasible with promising short-term educational outcomes. Neo-RST could be implemented in standardized medical residency programs in China.

Peptidome-wide association analysis of Epstein-Barr virus identifies epitope repertoires associated with nasopharyngeal carcinoma.

Human leukocyte antigen (HLA) molecules are essential for presenting Epstein-Barr virus (EBV) antigens and are closely related to nasopharyngeal carcinoma (NPC). This study aims to systematically investigate the association between HLA-bound EBV peptides and NPC risk through in silico HLA-peptide binding prediction. A total of 455 NPC patients and 463 healthy individuals in NPC endemic areas were recruited, and HLA-target sequencing was performed. HLA-peptide binding prediction for EBV, followed by peptidome-wide logistic regression and motif analysis, was applied. Binding affinity changes for EBV peptides carrying high-risk mutations were analyzed. We found that NPC-associated EBV peptides were significantly enriched in immunogenic proteins and core linkage disequilibrium (LD) proteins related to evolution, especially those binding HLA-A alleles (p = 3.10 × 10-4 for immunogenic proteins and p = 8.10 × 10-5 for core LD proteins related to evolution). These peptides were clustered and showed binding motifs of HLA supertypes, among which supertype A02 presented an NPC-risk effect (padj = 3.77 × 10-4 ) and supertype A03 presented an NPC-protective effect (padj = 4.89 × 10-4 ). Moreover, a decreased binding affinity toward risk HLA supertype A02 was observed for the peptide carrying the NPC-risk mutation BNRF1 V1222I (p = 0.0078), and an increased binding affinity toward protective HLA supertype A03 was observed for the peptide carrying the NPC-risk mutation BALF2 I613V (p = 0.022). This study revealed the distinct preference of EBV peptides for binding HLA supertypes, which may contribute to shaping EBV population structure and be involved in NPC development.

High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma.

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

Improved neonatal outcomes by multidisciplinary simulation-a contemporary practice in the demonstration area of China.

Background: Simulation-based training improves neonatal resuscitation and decreases perinatal mortality in low- and middle-income countries. Interdisciplinary in-situ simulation may promote quality care in neonatal resuscitation. However, there is limited information regarding the effect of multidisciplinary in-situ simulation training (MIST) on neonatal outcomes. We aimed to investigate the impact of MIST on neonatal resuscitation in reducing the incidence of neonatal asphyxia and related morbidities. Methods: Weekly MIST on neonatal resuscitation has been conducted through neonatal and obstetrical collaboration at the University of Hong Kong-Shenzhen Hospital, China, since 2019. Each simulation was facilitated by two instructors and performed by three health care providers from obstetric and neonatal intensive care units, followed by a debriefing of the participants and several designated observers. The incidence of neonatal asphyxia, severe asphyxia, hypoxic-ischemic encephalopathy (HIE), and meconium aspiration syndrome (MAS) before (2017-2018) and after (2019-2020) the commencement of weekly MIST were analyzed. Results: There were 81 simulation cases including the resuscitation of preterm neonates of different gestational ages, perinatal distress, meconium-stained amniotic fluid, and congenital heart disease with 1,503 participant counts (225 active participants). The respective incidence of neonatal asphyxia, severe asphyxia, HIE, and MAS decreased significantly after MIST (0.64%, 0.06%, 0.01%, and 0.09% vs. 0.84%, 0.14%, 0.10%, and 0.19%, respectively, all P < 0.05). Conclusions: Weekly MIST on neonatal resuscitation decreased the incidence of neonatal asphyxia, severe asphyxia, HIE, and MAS. Implementation of regular resuscitation simulation training is feasible and may improve the quality of neonatal resuscitation with better neonatal outcomes in low- and middle-income countries.

Early Oral Administration of Ginseng Stem-Leaf Saponins Enhances the Peyer's Patch-Dependent Maternal IgA Antibody Response to a PEDV Inactivated Vaccine in Mice, with Gut Microbiota Involvement.

Neonatal piglets during the first week of life are highly susceptible to porcine epidemic diarrhoea virus (PEDV) infection, with mortality rates reaching 80-100%. Passive lactogenic immunity remains the most effective way to protect neonates from infection. Although safe, inactivated vaccines provide little or no passive protection. Here, we administered ginseng stem-leaf saponins (GSLS) to mice before parenteral immunization with an inactivated PEDV vaccine to investigate the effect of GSLS on the gut-mammary gland (MG)-secretory IgA axis. Early oral GSLS administration potently increased PEDV-specific IgA plasma cell generation in the intestine, facilitated intestinal IgA plasma cell migration to the MG by enhancing the chemokine receptor (CCR)10-chemokine ligand (CCL)28 interaction, and ultimately promoted specific IgA secretion into milk, which was dependent on Peyer's patches (PPs). Additionally, GSLS improved the gut microbiota composition, especially increasing probiotic abundance, and these microflora members promoted the GSLS-enhanced gut-MG-secretory IgA axis response and were regulated by PPs. In summary, our findings highlight the potential of GSLS as an oral adjuvant for PEDV-inactivated vaccines and provide an attractive vaccination strategy for lactogenic immunity induction in sows. Further studies are required to evaluate the mucosal immune enhancement efficacy of GSLS in pigs.

G Protein-Coupled Receptor 120 Mediates Host Defense against Clostridium perfringens Infection through Regulating NOD-like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation.

Clostridium perfringens is a major cause of infectious foodborne disease, frequently associated with the consumption of raw and undercooked food. Despite intensive studies on clarifying C. perfringens pathogenesis, the molecular mechanisms of host-pathogen interactions remain poorly understood. In soft tissue and mucosal infection models, Gpr120-/- mice, G protein-coupled receptor 120 (GPR120), are more susceptible to C. perfringens infection. Gpr120 deficiency leads to a low survival rate (30 and 10%, p < 0.01), more bacterial loads in the muscle (2.26 × 108 ± 2.08 × 108 CFUs/g, p < 0.01), duodenum (2.80 × 107 ± 1.61 × 107 CFUs/g, p < 0.01), cecum (2.50 × 108 ± 2.05 × 108 CFUs/g, p < 0.01), and MLN (1.23 × 106 ± 8.06 × 105 CFUs/g, p < 0.01), less IL-18 production in the muscle (8.54 × 103 ± 1.20 × 103 pg/g, p < 0.01), duodenum (3.34 × 103 ± 2.46 × 102 pg/g, p < 0.01), and cecum (3.81 × 103 ± 5.29 × 102 pg/g, p < 0.01), and severe organ injury. Obviously, GPR120 facilitates IL-18 production and pathogen control via potassium efflux-dependent NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling. Mechanistically, GPR120 interaction with NLRP3 potentiates the NLRP3 inflammasome assembly. Thus, this study uncovers a novel role of GPR120 in host protection and reveals that GPR120 may be a potential therapeutic target for limiting pathogen infection.

Association of Critical Value With 28-Day Mortality After Cardiac Surgery.

OBJECTIVE: The emergence of critical values gives a warning to the medical safety of hospitalized patients, especially Cardiosurgery Intensive Care Unit (CSICU) patients. The aim of this study was to investigate the association between early postoperative critical values and the prognosis of patients after cardiac surgery. METHODS: Clinical data of the patients were obtained from the Cardiac Critical Care Clinical Database of the Cardiovascular Intensive Care Unit of Nanjing First Hospital. A total of 1,598 consecutive patients undergoing cardiac surgery were enrolled in this retrospective cohort study, during the period from July 2019 to December 2020. According to whether critical value occurred within 7 days after cardiac surgery, patients were divided into two groups: the critical value group and control group. COX regression and survival analysis were performed to analyze the clinical data of the two groups. The area under the receiver operating characteristic curve (ROC) was used to assess the critical value's predictive value and determine the optimal cutoff value. RESULTS: With patients in the critical value group, the 28-day mortality after cardiac surgery was 21.98%, significantly higher than that of the control group (P < 0.05). Logistic regression analysis revealed the APACHE II score (Adjusted HR-1.11, 95% CI-1.043-1.185) and critical value group (Adjusted HR-13.57, 95% CI-6.714-27.435 ) were independent predictors of 28-day mortality after cardiac surgery. The ROC curve showed that the critical value case model (AUC = 0.748 ± 0.052, P < 0.05) could effectively predict the 28-day mortality, and the optimum cutoff was 1 case (sensitivity 52.63%, specificity 95.70%). CONCLUSIONS: One or more reported cases of critical values in the early postoperative period could be an independent risk factor for 28-day mortality in patients undergoing cardiac surgery. The predictive model based on critical value might be effective in clinical therapy and risk stratification.

Erratum: Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis.

[This corrects the article DOI: 10.1016/j.isci.2022.105121.].

A novel SETD3-ALK fusion in lung adenocarcinoma and sustained clinical response to crizotinib.

OBJECTIVES: Anaplastic lymphoma kinase (ALK) rearrangement is a vital driving mutation in non-small cell lung cancer (NSCLC). ALK rearrangements may involve different breakpoints and multiple fusion partners, presenting different therapeutic responses. There are no standard treatment options for rare ALK rearrangements. Here, we report a case of advanced lung adenocarcinoma (LUAD) harboring a novel SET domain containing 3 (SETD3)-ALK fusion and sensitive to crizotinib, which has not been previously reported. MATERIALS AND METHODS: Molecular and pathological features were confirmed using percutaneous lung biopsy guided by computed tomography (CT), immunohistochemical (IHC) staining and next-generation sequencing (NGS). RESULTS: NGS revealed that a novel SETD3-ALK fusion was detected in the patient with LUAD, and IHC analysis confirmed that this fusion had functional expression. The patient had a progression-free survival (PFS) over 16 months after crizotinib treatment (250 mg b.i.d.), with ongoing clinical response. CONCLUSION: This case introduces a novel and meaningful ALK fusion type in LUAD with sustained sensitivity to crizotinib, providing a reference to the treatment of similar cases with SETD3-ALK fusion in the future.

Association between Left Ventricular Longitudinal Strain (GLS) and Prognosis of the Patients Undergoing Heart Valve Surgery with Preserved Left Ventricular Ejection Fraction.

PURPOSE: Global longitudinal strain (GLS) seems accurate for detecting subclinical myocardial dysfunction. This study aimed to determine the association between GLS and postoperative intensity of inotropic support in the patients undergoing heart valve surgery with preserved left ventricular ejection fraction. METHODS: 74 patients with preserved left ventricular ejection fraction who underwent valve surgery during the period between March 2021 and June 2022 were included in this prospective observational study. Transthoracic echocardiography including strain analysis with speckle tracking was performed before surgery. Patients were stratified according to the left ventricle (LV) GLS: LV-GLS ≥-16% (Impaired GLS group) and LV-GLS <-16% (Normal GLS group). The primary endpoint was postoperative vasoactive inotropic score. A high vasoactive inotropic score (VIS) was defined as a maximum VIS of ≥15 within 24 hours postoperatively. Postoperative adverse events, baseline clinical and echocardiographic data were also recorded. We invested the ability of preoperative GLS in predicting adverse postoperative outcomes, such as prolonged mechanical ventilation and the need for pharmacologic hemodynamic support after cardiac surgery. RESULTS: Seventy-four patients were included and analyzed in this study, including thirty-three in impaired GLS group and forty-one in normal GLS group. In-hospital mortality was 1.27% (1/74). Patients in impaired GLS group were more likely to have prolonged mechanical ventilation (p = 0.041). Multivariable logistic regression analysis revealed that the apical four-chamber view of the left ventricle (A4C)-GLS was significantly associated with high VIS (OR 1.373, p = 0.007). A4C-GLS had a sensitivity of 62.5% and a specificity of 89.66% for predicting high VIS (area under the curve, 0.78). The relationships between GLS and other secondary outcome measures were not statistically significant. The optimal cutoff of A4C-GLS for postoperative high vasoactive inotropic score was -10.85%. CONCLUSION: Preoperative LV dysfunction is an independent risk factor for postoperative high VIS. A4C-GLS may be a reliable tool in predicting high VIS after cardiac surgery. Those patients with impaired contractility were at high risk for elevated inotropic support and prolonged mechanical ventilation after cardiac surgery. These findings suggest an important role for echocardiographic GLS in perioperative assessment of cardiac function in the patients undergoing cardiac surgery.