ß2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function.

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of ß2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders.

SLC11A1 promotes kidney renal clear cell carcinoma (KIRC) progression by remodeling the tumor microenvironment.

Kidney renal clear cell carcinoma (KIRC) is a highly immune-infiltrated kidney cancer with the highest mortality rate and the greatest potential for invasion and metastasis. Solute carrier family 11 member1 (SLC11A1) is a phagosomal membrane protein located in monocytes and plays a role in innate immunity, autoimmune diseases, and infection, but its expression and biological role in KIRC is still unknown. In this study, we sought to investigate the potential value of SLC11A1 according to tumor growth and immune response in KIRC. TIMER and UALCAN database was used to analyze the expression feature and prognostic significance of SLC11A1 and its correlation with immune-related biomarkers in KIRC. Proliferation, migration, and invasion were measured using colony formation, EdU, and transwell assays. Role of SLC11A1 on KIRC tumor growth was examined by the xenograft tumor model in vivo. Effects of KIRC cells on macrophage polarization and the proliferation and apoptosis of CD8+ T cells were analyzed using flow cytometry assays. Herein, SLC11A1 was highly expressed in KIRC tissues and cell lines. SLC11A1 downregulation repressed KIRC cell proliferation, migration, invasion, macrophage, and lymphocyte immunity in vitro, as well as hindered tumor growth in vivo. SLC11A1 is significantly correlated with immune cell infiltration and immune-related biomarkers. In KIRC patients, SLC11A1 is highly expressed and positively correlated with the immune-related factors CCL2 and PD-L1. SLC11A1 induced CCL2 and PD-L1 expression, thereby activating the JAK/STAT3 pathway. SLC11A1 deficiency constrained KIRC cell malignant phenotypes and immune response via regulating CCL2 and PD-L1-mediated JAK/STAT3 pathway, providing a promising therapeutic target for KIRC treatment.

The SARS-CoV-2 nucleocapsid protein suppresses innate immunity by remodeling stress granules to atypical foci.

Viruses deploy multiple strategies to suppress the host innate immune response to facilitate viral replication and pathogenesis. Typical G3BP1+ stress granules (SGs) are usually formed in host cells after virus infection to restrain viral translation and to stimulate innate immunity. Thus, viruses have evolved various mechanisms to inhibit SGs or to repurpose SG components such as G3BP1. Previous studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inhibited host immunity during the early stage of COVID-19. However, the precise mechanism is not yet well understood. Here we showed that the SARS-CoV-2 nucleocapsid (SARS2-N) protein suppressed the double-stranded RNA (dsRNA)-induced innate immune response, concomitant with inhibition of SGs and the induction of atypical SARS2-N+ /G3BP1+ foci (N+ foci). The SARS2-N protein-induced formation of N+ foci was dependent on the ability of its ITFG motif to hijack G3BP1, which contributed to suppress the innate immune response. Importantly, SARS2-N protein facilitated viral replication by inducing the formation of N+ foci. Viral mutations within SARS2-N protein that impair the formation of N+ foci are associated with the inability of the SARS2-N protein to suppress the immune response. Taken together, our study has revealed a novel mechanism by which SARS-CoV-2 suppresses the innate immune response via induction of atypical N+ foci. We think that this is a critical strategy for viral pathogenesis and has potential therapeutic implications.

Label-free Colorimetric Detection of Viral RNA Based on Clustered Regularly Interspaced Short Palindromic Repeats and Gold Nanoparticles with a Portable Device.

Viral infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are some of the most dangerous threats to humans. SARS-CoV-2 has caused a global pandemic, highlighting the unprecedented demand for rapid and portable diagnostic methods. To meet these requirements, we designed a label-free colorimetric platform that combines the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) 12a system for naked-eye detection (named LFP). This method utilizes reverse transcription loop-mediated isothermal amplification (RT-LAMP) and the trans-cleavage activity of the CRISPR/Cas12a system to increase the sensitivity and specificity of the reaction. This platform can detect as few as 4 copies/µL of RNA and produces no false positive results when tested against the influenza virus. To better meet the requirements of point-of-care (POC) detection, we developed a portable device that can be applied in resource-poor and densely populated regions. The LFP assay holds great potential for application in resource-limited settings, and the label-free gold nanoparticle (AuNPs) probe can reduce costs, making it suitable for large-scale screening. We expect that the LFP assay will be promising for the POC screening of COVID-19.

Sevoflurane inhibits the malignant behavior of nasopharyngeal carcinoma cells by regulating mitochondrial membrane potential.

This study aims to determine the effect of sevoflurane (Sev) on nasopharyngeal carcinoma (NPC) in malignant behavior and mitochondrial membrane potential (MMP). NPC cells (5-8F and CNE2) were exposed to Sev at different concentrations and then tested for proliferation by CCK-8 and colony formation assays, apoptosis by flow cytometry, and invasion and migration by Transwell assays. In addition, the Warburg effect was examined by measurements of glucose consumption, lactic acid production, and adenosine triphosphate (ATP). Mitochondrial function was evaluated by reactive oxygen species (ROS) production, oxidative stress-related indexes, and mitochondrial membrane potential. Sev suppressed 5-8F and CNE2 cell proliferation, invasion, and migration, and enhanced apoptosis. Moreover, Sev dampened the Warburg effect by reducing glucose consumption, lactic acid production, and ATP, as well as decreasing hexokinase 2 and pyruvate kinases type M2 protein expressions. Also, Sev induced ROS production and malondialdehyde content and reduced superoxide and glutathione peroxidase levels. Finally, Sev caused damage to mitochondrial homeostasis through induction of cleaved caspase-3, cleaved caspase-9, and cytochrome c protein expression and reduction of MMP. Sev inhibits the malignant behavior of NPC cells by regulating MMP.

Stress Granule Core Protein-Derived Peptides Inhibit Assembly of Stress Granules and Improve Sorafenib Sensitivity in Cancer Cells.

Upon a variety of environmental stresses, eukaryotic cells usually recruit translational stalled mRNAs and RNA-binding proteins to form cytoplasmic condensates known as stress granules (SGs), which minimize stress-induced damage and promote stress adaptation and cell survival. SGs are hijacked by cancer cells to promote cell survival and are consequently involved in the development of anticancer drug resistance. However, the design and application of chemical compounds targeting SGs to improve anticancer drug efficacy have rarely been studied. Here, we developed two types of SG inhibitory peptides (SIPs) derived from SG core proteins Caprin1 and USP10 and fused with cell-penetrating peptides to generate TAT-SIP-C1/2 and SIP-U1-Antp, respectively. We obtained 11 SG-inducing anticancer compounds from cell-based screens and explored the potential application of SIPs in overcoming resistance to the SG-inducing anticancer drug sorafenib. We found that SIPs increased the sensitivity of HeLa cells to sorafenib via the disruption of SGs. Therefore, anticancer drugs which are competent to induce SGs could be combined with SIPs to sensitize cancer cells, which might provide a novel therapeutic strategy to alleviate anticancer drug resistance.

Research Progress on the Role and Mechanism of IL-37 in Liver Diseases.

Cytokines are important components of the immune system that can predict or influence the development of liver diseases. IL-37, a new member of the IL-1 cytokine family, exerts potent anti-inflammatory and immunosuppressive effects inside and outside cells. IL-37 expression differs before and after liver lesions, suggesting that it is associated with liver disease; however, its mechanism of action remains unclear. This article mainly reviews the biological characteristics of IL-37, which inhibits hepatitis, liver injury, and liver fibrosis by inhibiting inflammation, and inhibits the development of hepatocellular carcinoma (HCC) by regulating the immune microenvironment. Based on additional evidence, combining IL-37 with liver disease markers for diagnosis and treatment can achieve more significant effects, suggesting that IL-37 can be developed into a powerful tool for the clinical adjuvant treatment of liver diseases, especially HCC.

Gonadal transcriptomes reveal sex-biased expression genes associated with sex determination and differentiation in red-tail catfish (Hemibagrus wyckioides).

BACKGROUND: Red-tail catfish (Hemibagrus wyckioides) is an important commercially farmed catfish in southern China. Males of red-tail catfish grow faster than females, suggesting that all-male catfish will produce more significant economic benefits in aquaculture practice. However, little research has been reported on sex determination and gonadal development in red-tail catfish. RESULTS: In this study, we performed the first transcriptomic analysis of male and female gonads at four developmental stages at 10, 18, 30, and 48 days post hatching (dph) using RNA-seq technology. A total of 23,588 genes were screened in 24 sequenced samples, of which 28, 213, 636, and 1381 differentially expressed genes (DEGs) were detected at four developmental stages, respectively. Seven candidate genes of sex determination and differentiation were further identified. Real-time quantitative PCR (RT-qPCR) further confirmed that anti-Mullerian hormone (amh), growth differentiation factor 6a (gdf6a), testis-specific gene antigen 10 (tsga10), and cytochrome P450 family 17 subfamily A (cyp17a) were highly expressed mainly in the male, while cytochrome P450 family 19 subfamily A polypeptide 1b (cyp19a1b), forkhead box L2 (foxl2), and hydroxysteroid 17-beta dehydrogenase 1 (hsd17b1) were highly expressed in the female. The KEGG pathway enrichment data showed that these identified DEGs were mainly involved in steroid hormone biosynthesis and TGF-ß signaling pathways. CONCLUSIONS: Based on RNA-seq data of gonads at the early developmental stages, seven DEGs shared by the four developmental stages were identified, among which amh and gdf6a may be the male-biased expression genes, while foxl2, cyp19a1b and hsd17b1 may be the female-biased expression genes in red-tail catfish. Our study will provide crucial genetic information for the research on sex control in red-tail catfish, as well as for exploring the evolutionary processes of sex determination mechanisms in fish.

Neuro-immune crosstalk in depressive symptoms of multiple sclerosis.

Depressive disorders can occur in up to 50% of people with multiple sclerosis in their lifetime. If left untreated, comorbid major depressive disorders may not spontaneously remit and is associated with an increased morbidity and mortality. Conversely, epidemiological evidence supports increased psychiatric visit as a significant prodromal event prior to diagnosis of MS. Are there common molecular pathways that contribute to the co-development of MS and psychiatric illnesses? We discuss immune cells that are dysregulated in MS and how such dysregulation can induce or protect against depressive symptoms. This is not meant to be a comprehensive review of all molecular pathways but rather a framework to guide future investigations of immune responses in depressed versus euthymic people with MS. Currently, there is weak evidence supporting the use of antidepressant medication in comorbid MS patients. It is our hope that by better understanding the neuroimmune crosstalk in the context of depression in MS, we can enhance the potential for future therapeutic options.

Sponge-Like Porous-Conductive Polymer Coating for Ultrastable Silicon Anodes in Lithium-Ion Batteries.

Urgent calls for reversible cycling performance of silicon (Si) requires an efficient solution to maintain the silicon-electrolyte interface stable. Herein, a conductive biphenyl-polyoxadiazole (bPOD) layer is coated on Si particles to enhance the electrochemical process and prolong the cells lifespan. The conformal bPOD coatings are mixed ionicelectronic conductors, which not only inhibit the infinite growth of solid electrolyte interphase (SEI) but also endow electrodes with outstanding ion/electrons transport capacity. The superior 3D porous structure in the continuous phase allows the bPOD layers to act like a sponge to buffer volume variation, resulting in high structural stability. The in situ polymerized bPOD coating and it-driven thin LiF-rich SEI layer remarkably improve the lithium storage performance of Si anodes, showing a high reversible specific capacity of 1600 mAh g-1 even after 500 cycles at 1 A g-1 along with excellent rate capacity of over 1500 mAh g-1 at 3 A g-1 . It should be noticed that a long cycle life of 800 cycles with 1065 mAh g-1 at 3 A g-1 can also be achieved with a capacity retention of more than 80%. Therefore,  we  believe this unique polymer coating design paves the way for the widespread adoption of next-generation lithium-ion batteries.

Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study.

BACKGROUND: Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. METHODS: Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. RESULTS: Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45-0.59), and decreased HOMA-IR (ß = - 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06-1.15), and decreased HOMA-B (ß = - 0.04, SE = 0.01, P = 4.52 × 10-5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. CONCLUSIONS: This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

Evaluating the Clinical Utility of a Long-Read Sequencing-Based Approach in Prenatal Diagnosis of Thalassemia.

BACKGROUND: The aim is to evaluate the clinical utility of a long-read sequencing-based approach termed comprehensive analysis of thalassemia alleles (CATSA) in prenatal diagnosis of thalassemia. METHODS: A total of 278 fetuses from at-risk pregnancies identified in thalassemia carrier screening by PCR-based methods were recruited from 9 hospitals, and PCR-based methods were employed for prenatal diagnosis. CATSA was performed retrospectively and blindly for all 278 fetuses. RESULTS: Among the 278 fetuses, 263 (94.6%) had concordant results and 15 (5.4%) had discordant results between the 2 methods. Of the 15 fetuses, 4 had discordant thalassemia variants within the PCR detection range and 11 had additional variants identified by CATSA. Independent PCR and Sanger sequencing confirmed the CATSA results. In total, CATSA and PCR-based methods correctly detected 206 and 191 fetuses with variants, respectively. Thus, CATSA yielded a 7.9% (15 of 191) increment as compared with PCR-based methods. CATSA also corrected the predicted phenotype in 8 fetuses. Specifically, a PCR-based method showed one fetus had homozygous HBB c.52A > T variants, while CATSA determined the variant was heterozygous, which corrected the predicted phenotype from ß-thalassemia major to trait, potentially impacting the pregnancy outcome. CATSA additionally identified α-globin triplicates in 2 fetuses with the heterozygous HBB c.316-197C > T variant, which corrected the predicted phenotype from ß-thalassemia trait to intermedia and changed the disease prognosis. CONCLUSIONS: CATSA represents a more comprehensive and accurate approach that potentially enables more informed genetic counseling and improved clinical outcomes compared to PCR-based methods.

Current Advances in Genetic Testing for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is one of the most common genetic disorders worldwide, and genetic testing plays a key role in its diagnosis and prevention. The last decade has seen a continuous flow of new methods for SMA genetic testing that, along with traditional approaches, have affected clinical practice patterns to some degree. Targeting different application scenarios and selecting the appropriate technique for genetic testing have become priorities for optimizing the clinical pathway for SMA. In this review, we summarize the latest technological innovations in genetic testing for SMA, including MassArray®, digital PCR (dPCR), next-generation sequencing (NGS), and third-generation sequencing (TGS). Implementation recommendations for rationally choosing different technical strategies in the tertiary prevention of SMA are also explored.

A Pair of Multifunctional Cu(II)-Dy(III) Enantiomers with Zero-Field Single-Molecule Magnet Behaviors, Proton Conduction Properties and Magneto-Optical Faraday Effects.

Multifunctional materials with a coexistence of proton conduction properties, single-molecule magnet (SMM) behaviors and magneto-optical Faraday effects have rarely been reported. Herein, a new pair of Cu(II)-Dy(III) enantiomers, [DyCu2(RR/SS-H2L)2(H2O)4(NO3)2]·(NO3)·(H2O) (R-1 and S-1) (H4L = [RR/SS] -N,N'-bis [3-hydroxysalicylidene] -1,2-cyclohexanediamine), has been designed and prepared using homochiral Schiff-base ligands. R-1 and S-1 contain linear Cu(II)-Dy(III)-Cu(II) trinuclear units and possess 1D stacking channels within their supramolecular networks. R-1 and S-1 display chiral optical activity and strong magneto-optical Faraday effects. Moreover, R-1 shows a zero-field SMM behavior. In addition, R-1 demonstrates humidity- and temperature-dependent proton conductivity with optimal values of 1.34 × 10-4 S·cm-1 under 50 °C and 98% relative humidity (RH), which is related to a 1D extended H-bonded chain constructed by water molecules, nitrate and phenol groups of the RR-H2L ligand.

[Clinical characteristics and prognostic factors of distant metastatic penile cancer].

OBJECTIVE: To investigate the clinical features of distant metastatic penile cancer (DMPC) and the factors influencing its prognosis. METHODS: We searched the Surveillance, Epidemiology and End Results Database for cases of DMPC diagnosed between 2004 and 2019, analyzed their clinical characteristics and the cancer-specific survival (CSS) rates relating to different factors using the Kaplan-Meier method and the differences among the variables by log-rank test. We determined the variables independently associated with CSS by Cox regression analysis. RESULTS: According to the inclusion criteria, 108 cases of DMPC were identified. The patients were mainly married White people, with a median CSS of 9 months, and 1-, 2- and 3-year CSS rates of 36.4%, 17.8% and 13.5%, respectively. Pairwise comparison showed no statistically significant differences in the median overall CSS among the patients in the surgery, chemotherapy and surgery + chemotherapy groups (8 mo vs 9 mo vs 13 mo, P > 0.05). Race was an independent factor affecting the prognosis of CSS. CONCLUSION: Distant metastatic penile cancer is a rare malignancy with poor prognosis, for which there have been no existing ideal treatment options.

[Difference between prostate cancer patients' Gleason scores from preoperative biopsy and those from postoperative pathology].

OBJECTIVE: To evaluate the consistency of the Gleason scores of PCa patients based on preoperative biopsy with those from postoperative pathology, identify the possible factors influencing results of scoring, and construct a risk scoring model. METHODS: We collected the demographic and clinical data on the patients with PCa confirmed by preoperative prostate biopsy or postoperative pathology and treated by radical prostatectomy within 6 months after diagnosis. Using paired sample t-test, we identified the difference between the Gleason scores based on preoperative biopsy and those from postoperative pathology, analyzed the demographic and clinical data on the patients for relevant factors affecting the consistency of the Gleason scores, and calculated and visualized the relative risk values of the factors through Poisson regression. From the continuous variables with statistical significance, we screened independent risk factors for the difference in the Gleason scores by Lasso regression analysis, established a risk scoring model, generated risk coefficients, and evaluated the predictive ability of the model using the ROC curve. Based on the results of imaging examination with statistically significant differences, we constructed a column chart by logistic regression and evaluated the predictive validity of the chart using calibration curves, decision curves and ROC curves. RESULTS: The results of paired sample t-test for 210 PCa patients showed statistically significant differences between the Gleason scores from preoperative biopsy and those from postoperative pathology (P < 0.001). There were significant differences in the body weight, BMI and PSA level as well as in all other factors but prostate calcification between the patients with consistent and those with inconsistent Gleason scores (all P < 0.05). An 8-factor prediction model was successfully constructed, which could predict the consistency of Gleason scores, with a better predicting performance than the single indicator within the model. The nomogram exhibited a C-index value of 0.85, with the calibration curve similar to the standard one, the threshold of the decision curve 0.10－0.92, and the area under the ROC curve higher than other predictive indicators. CONCLUSION: Based on the demographic and clinical data on PCa patients, a risk prediction model and a column chart were successfully constructed, which could effectively predict the difference between the Gleason scores from preoperative prostate biopsy and those from postoperative pathology.

[Clinical study of artificial intelligence-guided image fusion assisted transperineal prostate biopsy].

OBJECTIVE: To compare the diagnostic efficacy of AI-guided mpMRI-TRUS fusion assisted transperineal systematic biopsy, targeted biopsy and combined biopsy in the diagnosis of PCa, and to evaluate the clinical application value of combined biopsy. METHODS: From April 2022, the general personal information and clinical data of patients with suspicious prostate lesions (PI-RADS≥3) detected by 3.0T mpMRI were collected, then underwent AI-guided mpMRI-TRUS fusion-assisted transperineal prostate biopsy. The data included age, PSA level, PV, PSAD, PI-RADS score, Gleason score of biopsy tissue, etc. The mpMRI image data were imported into the real-time fusion imaging system before biopsy. After image fusion, the suspected PCa lesion was taken as the target, 2 to 3 cores of targeted biopsy were first performed, then 12 cores of systematic biopsy were continued. The results of targeted biopsy + systematic biopsy were defined as the results of combined biopsy. The detection rate of PCa, CsPCa and pathological Gleason score were compared among different biopsy methods, and the diagnostic efficacy in different PI-RADS score groups was further evaluated. RESULTS: A total of 118 PCa cases were detected in 220 patients enrolled in this study. The PCa detection rates of systematic biopsy and targeted biopsy were 40.45% and 43.64%, the result reveals no statistical significance (P=0.562). The PCa detection rate of combined biopsy was 53.64%, higher than single biopsy method and the differences were statistically significant (P<0.05). The detection rates of CsPCa in systematic biopsy and targeted biopsy were 28.18% and 37.27% which reveals significant statistical difference (P=0.042). The CsPCa detection rate of combined biopsy was 41.82%, higher than single biopsy method, the difference was statistically significant compared with systematic biopsy (P=0.003), but was not compared with targeted biopsy (P=0.330). In PI-RADS score 3 group, the PCa detection rate of systematic biopsy and targeted biopsy was 39.29% and 21.43%, which reveals no statistical significance (P=0.146). The PCa detection rate of combined biopsy was 50%, higher than single biopsy method, the difference was statistically significant compared with targeted biopsy (P=0.026), but was not compared with systematic biopsy (P=0.420). In PI-RADS 4 ~5 group, the PCa detection rate of systematic biopsy and targeted biopsy was 40.10%, and 46.88% which reveals no statistical significance (P=0.181). The PCa detection rate of combined biopsy was 54.17%, higher than single biopsy method, the difference was statistically significant compared with systematic biopsy (P=0.006), but was not compared with targeted biopsy (P=0.153). Among PCa patients detected by both systematic and targeted biopsy, 39 had concordant pathologic Gleason scores, 13 had escalating pathologic Gleason scores for systematic biopsy, and 18 had escalating pathologic Gleason scores for targeted biopsy. CONCLUSION: Compared with systematic biopsy, AI-guided mpMRI-TRUS image fusion assisted transperineal targeted prostate biopsy has a higher detection rate of CsPCa and is probably closer to the true pathological Gleason score. Compared with single biopsy, combined biopsy has higher diagnostic efficiency for PCa, which can be used as one of the options of prostate biopsy in clinical practice.

[Influence factors of erectile dysfunction in patients with localized prostate cancer after radical surgery].

OBJECTIVE: To analyze the influential factors of erectile dysfunction (ED) in patients with localized prostate cancer (LPC) after radical surgery. METHODS: The clinical data of 150 male patients diagnosed with LPC and normal erectile function (EF) before surgery admitted to the Department of Urology of the Eastern Theatre General Hospital from January 2021 to January 2023 were retrospectively analyzed. The EF status of the patients 6 months after surgery was assessed using the International Erectile Function Index -5(IIEF-5). Age, Gleason score, PSA level, TNM stage, preoperative International prostatic symptom score (IPSS), preoperative prostate volume, smoking index, alcohol consumption index, educational level, comorbidities, operation mode, and psychosexual state were used as influencing factors to analyze their effects on postoperative ED. RESULTS: Of the 150 patients, 88 had ED and 62 had normal EF. Univariate analysis showed that age, preoperative IPSS, preoperative prostate volume, comorbidities and sexual and psychological status were significantly correlated with postoperative ED. Further multivariate logistic regression analysis showed that age, preoperative prostate volume, comorbidities and sexual and psychological status were independent factors influencing the occurrence of ED after RP in LPC patients. CONCLUSION: The recovery of sexual function of patients with localized prostate cancer after radical surgery is generally poor, and the incidence of ED is high. Its independent influencing factors include age, preoperative prostate volume, comorbidities and sexual psychological state, etc. Correct intervention of different influencing factors is required in clinical work. In order to provide a better diagnosis and treatment scheme for LPC patients undergoing radical treatment, reduce the incidence of postoperative ED and improve the quality of life of patients after surgery.

Prenatal Genetic Diagnosis of Fetal Cystic Hygroma: A Retrospective Single-Center Study from China.

Fetal cystic hygroma (CH) is associated with poor prognosis and chromosomal anomalies. Recent studies have suggested that the genetic background of affected fetuses is essential for predicting pregnancy outcomes. However, the detection performance of different genetic approaches for the etiological diagnosis of fetal CH remains unclear. In this study, we aimed to compare the diagnostic efficiency of karyotyping and chromosomal microarray analysis (CMA) in a local fetal CH cohort, and tried to propose an optimized testing strategy that may help improve the cost-effectiveness of disease management. We reviewed all pregnancies that underwent invasive prenatal diagnosis between January 2017 and September 2021 at one of the largest prenatal diagnostic centers in Southeast China. We collected cases identified by the presence of fetal CH. Prenatal phenotypes and laboratory records of these patients were audited, collated, and analyzed. The detection rates of karyotyping and CMA were compared, and the concordance rate of these two methods was calculated. A total of 157 fetal CH cases were screened from 6,059 patients who underwent prenatal diagnosis. Diagnostic genetic variants were identified in 44.6% (70/157) of the cases. Karyotyping, CMA, and whole-exome sequencing (WES) identified pathogenic genetic variants in 63, 68, and 1 case, respectively. The Cohen's κ coefficient between karyotyping and CMA was 0.96, with a concordance of 98.0%. Of the 18 cases in which cryptic copy number variants <5 Mb were detected by CMA, 17 were interpreted as variants of uncertain significance, and the remaining cases were interpreted as pathogenic. Trio exome sequencing revealed a pathogenic homozygous splice site mutation in the PIGN gene in a case undiagnosed by CMA and karyotyping. Our study demonstrated that chromosomal aneuploidy abnormalities are the main genetic cause of fetal CH. Based on this, we recommend karyotyping combined with rapid aneuploidy detection as a first-tier approach for the genetic diagnosis of fetal CH. WES and CMA could improve the diagnostic yield when routine genetic tests fail to determine the cause of fetal CH.

Exosomal AP000439.2 from clear cell renal cell carcinoma induces M2 macrophage polarization to promote tumor progression through activation of STAT3.

BACKGROUND: Tumorigenic phenotype of M2 tumor-associated macrophages promote tumor progression in response to exosomes cues imposed by tumor cells. However, the effect and underlying mechanisms of clear cell renal cell carcinoma (ccRCC)-derived exosomes (ccRCC-exo) on instructing macrophages phenotype remains unclear. METHODS: Macrophages were cocultured with ccRCC-exo and then evaluate the polarization of macrophages and migration of ccRCC cells. The effect and mechanism of lncRNA AP000439.2 overexpressed or deleted exosomes on macrophages M2 polarization were examined. Xenograft tumor mice model was used for in vivo validation. RESULTS: The ccRCC-exo significantly activated macrophages to M2 phenotype presented by increased expression of transforming growth factor-beta (TGF-ß) and interleukin 10 (IL-10) at mRNA and protein levels, and these M2 macrophages in turn facilitating the migration of ccRCC cells. LncRNA AP000439.2 was highly enriched in the ccRCC-exo. Overexpression of exosomal AP000439.2 promoted M2 macrophage polarization whereas AP000439.2-deficient exosome had the opposite effects. Nuclear-localized AP000439.2 directly interacted with signal transducer and activator of transcription 3 (STAT3) proteins and phosphorylated STAT3 in macrophages. RNA-Seq results showed overexpression of AP000439.2 activated NF-κB signaling pathway. Silencing of STAT3 suppressed overexpression of AP000439.2-induced up-regulation of TGF-ß and IL-10 expression, and p65 phosphorylation. AP000439.2-deleted exosome inhibited tumor growth in vivo. CONCLUSION: Exosomes from ccRCC deliver AP000439.2 to promote M2 macrophage polarization via STAT3, thus enhancing ccRCC progression, indicating exosomal AP000439.2 might be a novel therapeutic target in ccRCC. Video Abstract.