Discovery of BIO-8169─A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation.

Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

Skull base surgery for malignant tumors: The 2nd international collaborative study (1995-2015).

BACKGROUND: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. PATIENTS AND METHODS: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. RESULTS: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. CONCLUSION: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

Comparison of the Effect of Pericapsular Nerve Group Block Combined with Lateral Femoral Cutaneous Nerve Block and Fascia Iliaca Compartment Block in Patients Undergoing Hip Arthroscopy Under General Anesthesia: A Randomized, Double-Blind Trial.

Purpose: Patients undergoing arthroscopic hip surgery (AHS) require good analgesia and early rehabilitation after surgery, and there is no consensus on the optimal nerve block. We aimed to compare the efficacy of the pericapsular nerve group (PENG) block with lateral femoral cutaneous nerve (LFCN) block compared to fascia iliaca compartment block (FICB) in patients with AHS. Patients and Methods: A total of 80 patients receiving AHS under general anesthesia were randomized to receive either FICB (group F) or PENG block in combination with LFCN block (group P). The primary outcomes were the rate of quadriceps weakness after block on the afflicted side, as well as muscle strength grading and pain score after block, and the quality of recovery on the second postoperative day. Results: Compared with group F, group P had a lower incidence of quadriceps weakness 48 h after block (76.9% vs 28.2%, P < 0.001), and had less impact on muscle strength grade and lower static pain score at 6, 12, 18, 24, 36, and 48 h after block (P < 0.001), and a lower dynamic pain score at 6 and 12 h after block in group P (p < 0.05). The quality of recovery on the second postoperative day improved (p < 0.05). Conclusion: In comparison to FICB, PENG block in combination with LFCN block can affect less quadriceps muscle strength and reduce the use of postoperative analgesics, which is beneficial for the postoperative recovery of AHS patients.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

l-thyroxine attenuates extracellular Hsp90α-induced vascular endothelial calcification in diabetes mellitus, as revealed by parallel metabolic profiles.

BACKGROUND AND AIMS: Diabetic atherosclerotic vascular disease is characterized by extensive vascular calcification. However, an elevated blood glucose level alone does not explain this pathogenesis. We investigated the metabolic markers underlying diabetic atherosclerosis and whether extracellular Hsp90α (eHsp90α) triggers vascular endothelial calcification in this particular metabolic environment. METHODS: A parallel human/animal model metabolomics approach was used. We analyzed 40 serum samples collected from 24 patients with atherosclerosis and from the STZ-induced ApoE-/- mouse model. A multivariate statistical analysis of the data was performed, and mouse aortic tissue was collected for the assessment of plaque formation. In vitro, the effects of eHsp90α on endothelial cell calcification were assessed by serum analysis, Western blotting and immunoelectron microscopy. RESULTS: Diabetic ApoE-/- mice showed more severe plaque lesions and calcification damage. Stearamide, oleamide, l-thyroxine, l-homocitrulline and l-citrulline are biomarkers of diabetic ASVD; l-thyroxine was downregulated in both groups, and the thyroid sensitivity index was correlated with serum Hsp90α concentration. In vitro studies showed that eHsp90α increased Runx2 expression in endothelial cells through the LRP1 receptor. l-thyroxine reduced the increase in Runx2 levels caused by eHsp90α and affected the distribution and expression of LRP1 through hydrogen bonding with glutamine at position 1054 in the extracellular segment of LRP1. CONCLUSIONS: This study provides a mechanistic link between characteristic serum metabolites and diabetic atherosclerosis and thus offers new insight into the role of extracellular Hsp90α in promoting vascular calcification.

Molecular probes targeting HER2 PET/CT and their application in advanced breast cancer.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer cases are among the most aggressive breast tumor subtypes. Accurately assessing HER2 expression status is vital to determining whether patients will benefit from targeted anti-HER2 treatment. HER2-targeted positron emission tomography (PET/CT) is noninvasive, enabling the real-time evaluation of breast cancer patient HER2 status with accuracy. METHODS: We summarize the research progress of PET/CT targeting HER2 in breast cancer, focusing on PET/CT molecular probes targeting HER2 and their clinical application in the management of advanced breast cancer. RESULTS: At present, a variety of different HER2 targeted molecular probes for PET/CT imaging have been developed, including nucleolin-labeled antibodies, antibody fragments, nanobodies, and peptides of various affinities, among others. HER2-targeted PET/CT can relatively accurately evaluate HER2 expression status in advanced breast cancer patients. It has good performance in the early detection of small HER2-positive lesions, evaluation of HER2 status in lesions that cannot be readily biopsied, evaluation of the heterogeneity of multiple metastases, identification of lesions with altered HER2 status, and evaluation of the efficacy of anti-HER2 drugs. CONCLUSION: HER2-targeted PET/CT offers a promising noninvasive approach for real-time assessment of HER2 status，which can be guide targeted treatment for HER2-positive breast cancer patients. Future prospective clinical studies will be invaluable for fully evaluating the importance of HER2-targeted molecular imaging in the management of breast cancer.

Effects of Remifentanil Gradual Withdrawal Combined with Postoperative Infusion on Postoperative Hyperalgesia in Patients Undergoing Laparoscopic hysterectomy: A Factorial Design, Double-Blind, Randomized Controlled Trial.

Background: Remifentanil-induced hyperalgesia (RIH) increases the risk of persistent postoperative pain, making early postoperative analgesic therapy ineffective and affecting postoperative patient satisfaction. This study aimed to verify the effects of gradual withdrawal of remifentanil combined with postoperative pump infusion of remifentanil on postoperative hyperalgesia and pain in patients undergoing laparoscopic hysterectomy. Methods: This trial was a factorial design, double-blind, randomized controlled trial. Patients undergoing laparoscopic hysterectomy were randomly allocated to the control group, postoperative pump infusion of remifentanil group, gradual withdrawal of remifentanil group, or gradual withdrawal plus postoperative pump infusion of remifentanil group (n = 35 each). The primary outcome was postoperative mechanical pain thresholds in the medial forearm. The secondary outcomes included postoperative mechanical pain thresholds around the incision, pain numeric rating scale scores, analgesic utilization, awakening agitation or sedation scores, a 15-item quality of recovery survey, and postoperative complications. Results: Gradual withdrawal of remifentanil significantly increased postoperative pain thresholds versus abrupt discontinuation (P < 0.05), whereas postoperative infusion did not show significant differences compared to the absence of infusion (P > 0.05). The combined gradual withdrawal and postoperative infusion group exhibited the highest thresholds and had the lowest postoperative pain scores and analgesic requirements as well as the highest quality of recovery scores (P < 0.05). No significant differences were observed for agitation scores, sedation scores, or complication rates (P > 0.05). Conclusion: The novel combined gradual withdrawal and postoperative infusion of remifentanil uniquely attenuates postoperative hyperalgesia, pain severity, analgesic necessity, and improves recovery quality after laparoscopic hysterectomy.

Safety and efficacy of dexmedetomidine vs. midazolam in complex gastrointestinal endoscopy: A systematic review and meta-analysis.

OBJECTIVE: This study aims to perform a meta-analysis to evaluate the safety and efficacy of dexmedetomidine versus midazolam for complex digestive endoscopy procedures, with the goal of offering comprehensive clinical evidence. METHODS: Following predefined inclusion criteria, five databases were systematically searched, with a focus on identifying randomized controlled trials (RCTs) that compared the administration of dexmedetomidine and midazolam during complex digestive endoscopy procedures. The statistical software Stata 15.1 was employed for meticulous data analysis. RESULTS: Sixteen RCTs were encompassed, involving a total of 1218 patients. In comparison to the midazolam group, dexmedetomidine administration was associated with a reduced risk of respiratory depression (RR=0.25, 95 %CI: 0.11-0.56) and hypoxemia (RR=0.22, 95 %CI: 0.12-0.39). Additionally, the dexmedetomidine group exhibited lower incidence rates of choking (RR=0.27, 95 %CI: 0.16-0.47), physical movement (RR=0.16, 95 %CI: 0.09-0.27), and postoperative nausea and vomiting (RR=0.56,95 %CI: 0.34-0.92). Patients and endoscopists in the dexmedetomidine group reported higher levels of satisfaction (patient satisfaction: SMD=0.73, 95 %CI: 0.26-1.21; endoscopist satisfaction: SMD=0.84, 95 %CI: 0.24-1.44). The incidence of hypotension and anesthesia recovery time did not significantly differ between the two groups (hypotension: RR=1.73,95 %CI:0.94-3.20; anesthesia recovery time: SMD=0.02, 95 %Cl: 0.44-0.49). It is noteworthy that the administration of dexmedetomidine was associated with a significant increase in the incidence of bradycardia in patients. CONCLUSION: Compared to midazolam, dexmedetomidine exhibits a favorable safety profile for use in complex gastrointestinal endoscopy by significantly reducing the risk of respiratory depression and hypoxemia. Despite this, dexmedetomidine is associated with a higher incidence of bradycardia. These findings underscore the need for further research through larger, multi-center studies to thoroughly investigate dexmedetomidine's safety and efficacy.

Single-cell and multi-omics analyses highlight cancer-associated fibroblasts-induced immune evasion and epithelial mesenchymal transition for smoking bladder cancer.

Tobacco carcinogens are recognized as critical hazard factors for bladder tumorigenesis, affecting the prognosis of patients through aromatic amines components. However, the specific function of tobacco carcinogens and systematic assessment models in the prognosis of bladder cancer remains poorly elucidated. We retrieved bladder cancer specific tobacco carcinogens-related genes from Comparative Toxicogenomic Database, our Nanjing Bladder Cancer cohort and TCGA database. Gene×Gene interaction method was utilized to establish a prognostic signature. Integrative assessment of immunogenomics, tumor microenvironments and single-cell RNA-sequencing were performed to illustrate the internal relations of key events from different levels. Finally, we comprehensively identified 33 essential tobacco carcinogens-related genes to construct a novel prognostic signature, and found that high-risk patients were characterized by significantly worse overall survival (HR=2.25; Plog-rank < 0.01). Single-cell RNA-sequencing and multi-omics analysis demonstrated that cancer-associated fibroblasts mediated the crosstalk between epithelial-mesenchymal transition progression and immune evasion. Moreover, an adverse outcome pathway framework was established to facilitate our understanding to the tobacco carcinogens-triggered bladder tumorigenesis. Our study systematically provided immune microenvironmental alternations for smoking-induced adverse survival outcomes in bladder cancer. These findings facilitated the integrative multi-omics insights into risk assessment and toxic mechanisms of tobacco carcinogens.

Cigarette smoking combined with genetic variation regulates the m6A methylation of CRNKL1 and is associated with bladder cancer risk.

Cigarette smoking was known to accelerate the occurrence and development of bladder cancer by regulating RNA modification. However, the association between the combination of cigarette smoking and RNA modification-related single nucleotide polymorphisms (RNAm-SNPs) and bladder cancer risk remains unclear. In this study, 1681 participants, including 580 cases and 1101 controls, were recruited for genetic association analysis. In total, 1 287 990 RNAm-SNPs involving nine RNA modifications (m6A, m1A, m6Am, 2'-O-Me, m5C, m7G, A-to-I, m5U, and pseudouridine modification) were obtained from the RMVar database. The interactive effect of cigarette smoking and RNAm-SNPs on bladder cancer risk was assessed through joint analysis. The susceptibility analysis revealed that 89 RNAm-SNPs involving m6A, m1A, and A-to-I modifications were associated with bladder cancer risk. Among them, m6A-related rs2273058 in CRNKL1 was associated with bladder cancer risk (odds ratios (OR) = 1.35, padj = 1.78 × 10-4), and CRNKL1 expression was increased in bladder cancer patients (p = 0.035). Cigarette smoking combined with the A allele of rs2273058 increased bladder cancer risk compared with nonsmokers with the G allele of rs2273058 (OR = 2.40, padj = 3.11 × 10-9). Mechanistically, the A allele of rs2273058 endowed CRNKL1 with an additional m6A motif, facilitating recognition by m6A reader IGF2BP1, thereby promoting CRNKL1 expression under cigarette smoking (r = 0.142, p = 0.017). Moreover, elevated CRNKL1 expression may accelerate cell cycle and proliferation, thereby increasing bladder cancer risk. In summary, our study demonstrated that cigarette smoking combined with RNAm-SNPs contributes to bladder cancer risk, which provides a potential target for bladder cancer prevention.

An azole fungicide climbazole damages the gut-brain axis in the grass carp.

Azole antifungal climbazole has frequently been detected in aquatic environments and shows various effects in fish. However, the underlying mechanism of toxicity through the gut-brain axis of climbazole is unclear. Here, we investigated the effects of climbazole at environmental concentrations on the microbiota-intestine-brain axis in grass carp via histopathological observation, gene expression and biochemical analyses, and high-throughput sequencing of the 16 S rRNA. Results showed that exposure to 0.2 to 20 µg/L climbazole for 42 days significantly disrupted gut microbiota and caused brain neurotoxicity in grass carp. In this study, there was an alteration in the phylum and genus compositions in the gut microbiota following climbazole treatment, including reducing Fusobacteria (e.g., Cetobacterium) and increasing Actinobacteria (e.g., Nocardia). Climbazole disrupted intestinal microbial abundance, leading to increased levels of lipopolysaccharide and tumor necrosis factor-alpha in the gut, serum, and brain. They passed through the impaired intestinal barrier into the circulation and caused the destruction of the blood-brain barrier through the gut-brain axis, allowing them into the brain. In the brain, climbazole activated the nuclear factor kappaB pathway to increase inflammation, and suppressed the E2-related factor 2 pathway to produce oxidative damage, resulting in apoptosis, which promoted neuroinflammation and neuronal death. Besides, our results suggested that this neurotoxicity was caused by the breakdown of the microbiota-gut-brain axis, mediated by reduced concentrations of dopamine, short chain fatty acids, and intestinal microbial activity induced by climbazole.

Association study between SNPs in MST1 and MST2 genes and H. pylori infection as well as non-cardia gastric carcinogenesis.

Introduction Gastric cancer (GC) remains a global health challenge, and H. pylori infection is a main risk factor for non-cardia GC. The present study aimed to investigate the association between single nucleotide polymorphisms (SNPs) in Mammalian sterile 20-like kinase 1 (MST1) and MST2, Helicobacter pylori (H. pylori) infection, and the risk of non-cardia gastric cancer (GC). Methods A case-control study was conducted using enzyme-linked immunosorbent assay (ELISA) and Taqman method to detect the titer of anti-H. pylori antibody in normal human serum and genotype 9 SNPs of MST1 and MST2 genes among 808 samples. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between SNPs and H. pylori infection, as well as the risk of non-cardia gastric cancer in codominant, dominant, overdominant, recessive, and log-additive genetic models. Haplotypes were constructed using the Haploview 4.2 software. Results The CC genotype of MST2 SNP rs10955176 was associated with a reduced risk of H. pylori infection compared to the TT+CT genotype. None of other SNPs were associated with H. pylori infection. The TT genotype of MST2 SNP rs7827435 was associated with a reduced risk of non-cardia gastric cancer compared to the AA+AT genotype. None of the SNPs were associated with non-cardia gastric cancer. There were no associations between haplotypes and H. pylori infection or the risk of non-cardia gastric cancer. Conclusions The CC genotype of rs10955176 and the TT genotype of rs7827435 may serve as protective factors against H. pylori infection and non-cardia gastric cancer risk, respectively.

PM2.5-derived exosomal long noncoding RNA PAET participates in childhood asthma by enhancing DNA damage via m6A-dependent OXPHOS regulation.

Fine particulate matter (PM2.5) is known to enhance DNA damage levels and is involved in respiratory diseases. Exosomes can carry noncoding RNAs, especially long noncoding RNAs (lncRNAs), as regulators of DNA damage, which participate in diseases. However, their role in PM2.5-induced childhood asthma remains unclear. We performed RNA-seq to profile aberrantly expressed exosomal lncRNAs derived from PM2.5-treated human bronchial epithelial (HBE) cell models. The role of exosomal lncRNAs in childhood asthma was determined in a case-control study. The intercellular communication mechanisms of exosomal lncRNA on DNA damage were determined in vitro. Exosomes secreted by PM2.5-treated HBE cells (PM2.5-Exos) could increase the DNA damage levels of recipient HBE cells and promote the expression levels of airway remodeling-related markers in sensitive human bronchial smooth muscle cells (HBSMCs). LncRNA PM2.5-associated exosomal transcript (PAET) was highly expressed in PM2.5-Exos and was associated with PM2.5 exposure in childhood asthma. Mechanistically, exosomal lncRNA PAET promoted methyltransferase-like 3 (METTL3) accumulation by increasing its stability, which stimulated N6-methyladenosine (m6A) modification of cytochrome c oxidase subunit 4I1 (COX4I1), and COX4I1 levels were decreased in a mechanism dependent on the m6A "reader" YTH domain family 3 (YTHDF3). COX4I1 deficiency subsequently disrupted oxidative phosphorylation (OXPHOS), resulting in attenuated adenosine triphosphate (ATP) production and accumulation of reactive oxygen species (ROS), which increased DNA damage levels. This comprehensive study extends the understanding of PM2.5-induced childhood asthma via DNA damage and identifies exosomal lncRNA PAET as a potential target for childhood asthma.

Homologous proteins SAPCD2X1 and SAPCD2 have significantly different carcinogenic capacities in human colorectal cancer cells based on structural prediction and functional verification.

We discussed the expression and biological functions of the SAPCD2X1 protein in the HCT116 CRC cell line by bioinformatics analysis and prediction, and biological function verification. Spatial conformation models of SAPCD2X1 and SAPCD2 were predicted using the threading method, ensemble method, and several other protein structure prediction approaches. The conformational similarity between SAPCD2X1 and SAPCD2 was studied, and their functions were predicted. The biological experiments showed that SAPCD2X1 and SAPCD2 were overexpressed in CRC cells. SAPCD2X1-specific antibodies were prepared. The expressions of SAPCD2X1 and SAPCD2 were localized in cells using the immunofluorescence assay. The SAPCD2 and SAPCD2X1 overexpression models were validated using Western Blot and RT-qPCR. We successfully predicted the structures of the SAPCD2X1 and SAPCD2 proteins, and visualized them using the VDM software. It was predicted that the tertiary structure of SAPCD2X1 changed significantly compared with SAPCD2. Alteration of the biological functions of SAPCD2X1 was also predicted due to the changes in the spatial conformation of the protein. Anti-SAPCD2X1 antibody and SAPCD2X1-EGFP and SAPCD2-EGFP recombinant plasmids were established. The overexpression of the two proteins was induced in HCT116 cells using the recombinant plasmids, and verified by RT-qPCR and Western Blot. Meanwhile, the anti-SAPCD2X1 antibody was proved to have a high specificity. The immunofluorescence assay showed that SAPCD2X1 and SAPCD2 are mainly expressed in the cytoplasm. SAPCD2X1 and SAPCD2 exhibited significantly different biological functions in HCT116 cells. SAPCD2 is a carcinogenic protein, while SAPCD2X1 does not affect the proliferation, invasion, and migration of human CRC HCT116 cells.

Sex differences in serum pigment epithelium-derived factor in healthy individuals.

To investigate sexual dimorphism of serum pigment epithelium-derived factor (PEDF) and its influencing factors in healthy individuals. A total of 162 healthy people (69 males, 93 females) who underwent health examinations in our department were selected. Serum PEDF, estradiol and other metabolic indices were measured, and homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of ß-cell function (HOMA-ß) were calculated to evaluate insulin resistance and ß-cell function, respectively. Subjects were divided into < 50 years and ≥ 50 years groups to explore the sexual dimorphism of serum PEDF in different age groups. We found no statistically significant difference in serum PEDF levels between men and women in total. However, in the group of subjects under 50 years old, men had significantly higher PEDF levels than women (9.32 ±â€…2.07 µg/mL vs 8.24 ±â€…2.29 µg/mL, P < .05), and no sex difference was found in the ≥ 50 years group. In women, serum PEDF levels were significantly higher in subjects aged 50 years and over than in those younger than 50 years of age (9.56 ±â€…3.05 µg/mL vs 8.25 ±â€…2.30 µg/mL, P < .05). In men, there was no significant difference in serum PEDF levels between the 2 age groups. In women, correlation analysis showed that serum PEDF levels were significantly correlated with body mass index, waist circumference, diastolic blood pressure (DBP), 2-h postprandial glucose, fasting and 2-h postprandial insulin, HOMA-ß, HOMA-IR, aminotransferase, triacylglycerol, and estradiol. Elevated triacylglycerol and aminotransferase and decreased estradiol were significant predictors of increased PEDF concentrations in women. There is sexual dimorphism in circulating PEDF levels, which may be related to estrogen status.

LncRNA BCCE4 Genetically Enhances the PD-L1/PD-1 Interaction in Smoking-Related Bladder Cancer by Modulating miR-328-3p-USP18 Signaling.

Identification of cancer-associated variants, especially those in functional regions of long noncoding RNAs (lncRNAs), has become an essential task in tumor etiology. However, the genetic function of lncRNA variants involved in bladder cancer susceptibility remains poorly understood. Herein, it is identified that the rs62483508 G > A variant in microRNA response elements (MREs) of lncRNA Bladder cancer Cell Cytoplasm-Enriched abundant transcript 4 (BCCE4) is significantly associated with decreased bladder cancer risk (odds ratio = 0.84, P = 7.33 × 10-8 ) in the Chinese population (3603 cases and 4986 controls) but not in the European population. The protective genetic effect of the rs62483508 A allele is found in smokers or cigarette smoke-related carcinogen 4-aminobiphenyl (4-ABP) exposure. Subsequent biological experiments reveal that the A allele of rs62483508 disrupts the binding affinity of miR-328-3p to facilitate USP18 from miRNA-mediated degradation and thus specifically attenuates the downstream PD-L1/PD-1 interaction. LncRNA BCCE4 is also enriched in exosomes from bladder cancer plasma, tissues, and cells. This comprehensive study clarifies the genetic mechanism of lncRNA BCCE4 in bladder cancer susceptibility and its role in the regulation of the immune response in tumorigenesis. The findings provide a valuable predictor of bladder cancer risk that can facilitate diagnosis and prevention.

The impact of empirical Marshall vein ethanol infusion as a first-choice intraoperative strategy on the long-term outcomes in patients with persistent atrial fibrillation undergoing mitral isthmus ablation.

Background: Marshall vein ethanol infusion (MVEI) as an additional therapy to conventional catheter ablation (CA) has been proved to be efficacious in patients with persistent atrial fibrillation (PeAF). However, whether empirical MVEI could be the first-line strategy in mitral isthmus (MI) ablation has seldom been investigated. Here, we aim to compare the efficacy, safety, and long-term outcomes between provisional and empirical MVEI in PeAF patients undergoing the index MI ablation procedure. Methods: We enrolled 133 patients with PeAF either in the provisional group (n = 38, MVEI was performed when conventional endocardial and/or epicardial ablation procedures were inadequate to achieve bidirectional MI block) or in the empirical group (n = 95, MVEI was performed empirically before MI CA). Results: All of the baseline characteristics were comparable. Less spontaneous or inducible atrial tachycardias (ATs) were encountered in the empirical group of patients (P < 0.001). More epicardial ablations were applied (26.3% vs. 9.5%, P = 0.016) and a higher incidence of CA-facilitated restoration of sinus rhythm was recorded (86.8% vs. 11.7%, P < 0.001) in the provisional group of patients. Although more fluoroscopy time (6.4[4.2, 9.3] vs. 9.5[5.9, 11.6] min, P = 0.019) and radiation exposure (69.0[25.3, 160.2] vs. 122.0[62.5, 234.1] mGy, P = 0.010) were documented in the empirical group with comparable procedure time, less time (455.9 ± 192.2 vs. 366.5 ± 161.3 s, P = 0.038) was consumed to achieve bidirectional MI block during endocardial ablation in the provisional group. Incidences of procedure-related complications were similar between the two groups. During a 16.5 ± 4.4-month follow-up, the empirical group of patients showed a significantly higher rate of freedom from AT recurrence (95.8% vs. 81.6%, log-rank P = 0.003), while the rate of freedom from AF or atrial tachyarrhythmias (combining AF and AT) was similar. Both univariate (HR 0.19, 95% CI 0.05-0.64, P = 0.008) and multivariate (HR 0.25, 95% CI 0.07-0.92, P = 0.037) Cox regression analyses indicated that empirical MVEI was independently associated with lower long-term AT recurrence. Conclusion: Among patients with PeAF who underwent the index MI ablation procedure, empirical MVEI could reduce endocardial MI ablation time and provide greater long-term freedom from AT recurrence.

Impact of visceral obesity on infectious complications after resection for colorectal cancer: a retrospective cohort study.

OBJECTIVES: To explore the impact of visceral obesity (VO) measured by preoperative abdominal computed tomography (CT) on postoperative infectious complications for colorectal cancer (CRC) patients and establish a predictive model. METHODS: Patients who underwent resection for colorectal cancer between January 2015 and January 2021 were enrolled in this study. All patients were measured for body mass index (BMI) and visceral fat area (VFA) preoperatively. Infectious complications were compared between the different groups according to BMI and VO categories. Univariate and multivariate logistic regression were used to analyze whether VO was an independent risk factor for postoperative infectious complications. According to the results of logistic regression, six machine learning approaches were used to establish predictive models and perform internal validation. The best-performing model was interpreted by the SHAPley Additive exPlanations value. RESULTS: Approximately 64.81% of 520 patients had VO. VO was significantly connected with postoperative infectious complications (P < 0.001), coronary heart disease (P = 0.004), cerebral infarction (P = 0.001), hypertension (P < 0.001), diabetes (P < 0.001), and fatty liver (P < 0.001). The rates of wound infection (P = 0.048), abdominal or pelvic infection (P = 0.006), and pneumonia (P = 0.008) increased obviously in patients with VO. Compared to the low BMI group, a high BMI was found to be significantly associated with hypertension (P=0.007), fatty liver (P＜0.001), and a higher rate of postoperative infection (P=0.003). The results of logistic regression revealed that VO (OR = 2.01, 95% CI 1.17 ~ 3.48, P = 0.012), operation time ≥ 4 h (OR = 2.52, 95% CI 1.60 ~ 3.97, P < 0.001), smoking (OR = 2.04, 95% CI 1.16 ~ 3.59, P = 0.014), ostomy (OR = 1.65, 95% CI 1.04 ~ 2.61, P = 0.033), and chronic obstructive pulmonary disease (COPD) (OR = 2.23, 95% CI 1.09 ~ 4.57, P = 0.029) were independent risk factors. The light gradient boosting machine (LGBM) model displayed the largest area under the receiver operating characteristic curve (AUC) (0.74, 95% CI 0.68 ~ 0.81). CONCLUSIONS: In this study, VO was superior to BMI in evaluating the influence of obesity on metabolic comorbidities and postoperative infectious complications in colorectal cancer patients.

Correlation between Serum Myosin Light Chain 4 Levels and Recurrence after Radiofrequency Ablation in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia that is harmful to human health. This study aims to explore the relationship between myosin light chain 4 (MYL4) and AF recurrence after radiofrequency ablation (RFA). Patients with AF (n = 85) were enrolled, and healthy subjects (n = 90) with normal sinus rhythm and no previous history of AF were selected as controls. The serum levels of MYL4, transforming growth factor (TGF) -ß1, and procollagen type-I C-terminal propeptide (PICP) were determined. The correlation between MYL4 and atrial fibrosis remodeling indicators (TGF-ß1/PICP) and left atrial diameter (LAD) was analyzed. The influence of MYL4 on AF recurrence after RFA was evaluated, and the independent correlation between them was assessed. Patients with AF and the controls showed no significant differences in age, gender, body mass index, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, white blood cell count, neutrophil/lymphocyte ratio, brain natriuretic peptide, and history of smoking, drinking, hypertension, and diabetes (P > 0.05), but with increased LAD in patients with AF (P < 0.01). Serum MYL4 level was reduced in patients with AF (0.6 ± 0.2) compared with that of controls (0.1 ± 0.6) (P < 0.01), and it was negatively correlated with TGF-ß1, PICP, and LAD (r = -0.2389, P < 0.05; r = -0.5174, P < 0.01; r = -0.3191; P < 0.01). Low levels of MYL4 increased the risk of AF recurrence after RFA (χ2 = 16.64; P < 0.0001). A low MYL4 level in patients with AF showed a poorer prognosis. Serum MYL4 level and AF type were independent risk factors affecting AF recurrence after RFA.