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Abstract Background Surgical penile prosthesis implantation (PPI) procedures have only recently been introduced to mainland China, with the overall number of such procedures having been conducted to date remaining relatively low. Accordingly, relatively little remains known with respect to the annual trends in PPI. Accordingly, this study was developed with the goal of clarifying these trends across different hospitals in mainland China, while also providing a single-center overview of post-PPI patient outcomes. Results To identify males in mainland China who had undergone PPI, a retrospective review of data from January 2019 – October 2023 was conducted. This approach revealed an increase in the total PPI caseload from 120 in 2019 to 413 within the first 10 months of 2023. Over this same interval, the number of surgeons performing PPI rose from 33 to 74. A retrospective review of the 112 patients who had undergone PPI at Shanghai General Hospital from 2019–2023 revealed that these patients had a median age of 39 [27–63] years, and PPI treatment led to a significant increase in median International Index of Erectile Function-5 (IIEF-5) scores from a baseline value of 10.23 ± 1.26 to a post-treatment value of 22.6 ± 2.73. The underlying causes of erectile dysfunction for these patients included vasculogenic factors (58/112; 51.8%), diabetes mellitus (21/112; 18.8%), and injuries to the spinal cord or pelvis (14/112; 12.5%). The overall rates of satisfaction with the PPI reported by patients and their partners were 93.0% and 90.4%, respectively, and the 3-year PPI survival rate for this cohort was 87%. Conclusion These data highlight a rising trend in the number of PPI being performed in China, with these steadily increasing rates since 2019 emphasizing the increasingly high levels of acceptance of this procedure by patients and clinicians as a means of treating erectile dysfunction. However, the expertise is restricted to a small number of surgeons. Even so, it is a safe and efficacious approach to managing severe erectile dysfunction for patients in China, and when performed by experienced surgeons based on standardized protocols, low complication rates can be achieved while providing patients and their sexual partners with high levels of satisfaction.

Abstract Background Dysregulation of zinc homeostasis is widely recognized as a hallmark feature of prostate cancer (PCa) based on the compelling clinical and experimental evidence. Nevertheless, the implications of zinc dyshomeostasis in PCa remains largely unexplored. Methods In this research, the zinc homeostasis pattern subtype (ZHPS) was constructed according to the profile of zinc homeostasis genes. The identified subtypes were assessed for their immune functions, mutational landscapes, biological peculiarities and drug susceptibility. Subsequently, we developed the optimal signature, known as the zinc homeostasis-related risk score (ZHRRS), using the approach won out in multifariously machine learning algorithms. Eventually, clinical specimens, Bayesian network inference and single-cell sequencing were used to excavate the underlying mechanisms of MT1A in PCa. Results The zinc dyshomeostasis subgroup, ZHPS2, possessed a markedly worse prognosis than ZHPS1. Moreover, ZHPS2 demonstrated a more conspicuous genomic instability and better therapeutic responses to docetaxel and olaparib than ZHPS1. Compared with traditional clinicopathological characteristics and 35 published signatures, ZHRRS displayed a significantly improved accuracy in prognosis prediction. The diagnostic value of MT1A in PCa was substantiated through analysis of clinical samples. Additionally, we inferred and established the regulatory network of MT1A to elucidate its biological mechanisms. Conclusions The ZHPS classifier and ZHRRS model hold great potential as clinical applications for improving outcomes of PCa patients.

Abstract Human hematopoiesis starts at early yolk sac and undergoes site- and stage-specific changes over development. The intrinsic mechanism underlying property changes in hematopoiesis ontogeny remains poorly understood. Here, we analyzed single-cell transcriptome of human primary hematopoietic stem/progenitor cells (HSPCs) at different developmental stages, including yolk-sac (YS), AGM, fetal liver (FL), umbilical cord blood (UCB) and adult peripheral blood (PB) mobilized HSPCs. These stage-specific HSPCs display differential intrinsic properties, such as metabolism, self-renewal, differentiating potentialities etc. We then generated highly co-related gene regulatory network (GRNs) modules underlying the differential HSC key properties. Particularly, we identified GRNs and key regulators controlling lymphoid potentiality, self-renewal as well as aerobic respiration in human HSCs. Introducing selected regulators promotes key HSC functions in HSPCs derived from human pluripotent stem cells. Therefore, GRNs underlying key intrinsic properties of human HSCs provide a valuable guide to generate fully functional HSCs in vitro.

Abstract Background Herpes zoster (HZ) is one of the most common skin diseases caused by viruses. Facial HZ develops when the varicella-zoster virus affects the trigeminal nerve, and alveolar osteonecrosis is a rare complication. However, the exact pathogenesis of postherpetic alveolar osteonecrosis remains unclear. Case description We encountered a patient who presented to the dermatology clinic with facial HZ and tooth exfoliation in the upper right jaw, and panoramic radiography revealed decreased bone density and poor alveolar socket healing in his right maxilla. Biopsy of the alveolar process revealed fragments of nonvital lamellar bone, which were devoid of osteoblasts and osteocytes and were surrounded by numerous neutrophils and bacterial aggregates. Thus, the diagnosis of alveolar osteonecrosis following facial HZ was confirmed. He then underwent resection of the osteonecrotic tissue. The pathological findings of postoperative tissue were similar to those of previous biopsies. Varicella-zoster virus and multiple types of bacteria were detected through next-generation sequencing, and the species of bacteria were consistent with the results of bacterial culture. Antibiotics and valaciclovir were administered during the perioperative period. The patient showed good recovery at the 9-month follow-up. Conclusions The coexistence of bacterial and viral infection may play an important role in the pathogenesis of alveolar osteonecrosis following HZ. To our knowledge, we are the first to directly explore microbial pathogens in a case of postherpetic alveolar osteonecrosis through next-generation sequencing and bacterial culture. We recommend that oral examinations be carefully conducted for patients who are diagnosed with facial HZ, even if their facial rashes have faded away. We suggest that a prolonged and full-dose antiviral therapy course may be beneficial for the treatment of facial HZ with intraoral lesions. The implementation of dental preventive measures should be considered for patients with facial HZ. The application of antibiotics and excision of necrotic bone may reduce the abundance of bacteria in lesions and improve wound healing.

Background: Nuclear cap-binding protein 2 (NCBP2), as the component of the cap-binding complex, participates in a number of biological processes, including pre-mRNA splicing, transcript export, translation regulation and other gene expression steps. However, the role of NCBP2 on the tumor cells and immune microenvironment remains unclear. To systematically analyze and validate functions of NCBP2, we performed a pan-cancer analysis using multiple approaches. Methods: The data in this study were derived from sequencing, mutation, and methylation data in the TCGA cohort, normal sample sequencing data in the GTEx project, and cell line expression profile data in the CCLE database. Results: Survival analyses including the Cox proportional-hazards model and log-rank test revealed the poor prognostic role of NCBP2 in multiple tumors. We further validated the oncogenic ability of NCBP2 in prostate cancer cell lines, organoids and tumor-bearing mice. A negative correlation was observed between NCBP2 expression and immune score by the ESTIMATE algorithm. Simultaneously, the NCBP2-induced immunosuppressive microenvironment might be related to the decline in CD8+ T cells and the increase in regulatory T cells and neutrophils, examined by flow cytometry experiments for NCBP2 overexpressed tumor-bearing mice. Conclusion: This research offered strong proof supporting NCBP2 as the prognostic marker and the therapeutic target in the future.

Dermatological conditions in pregnancy pose unique challenges due to concerns for maternal and fetal health. We present a case of a 32-year-old primigravida who, at 36 weeks of gestation, exhibited melanotic papules and neoplasms on her neck, chest, and breasts. Seeking evaluation for potential effects on her unborn child and breastfeeding, she presented to our dermatological outpatient facility. Physical examination revealed varied pigmented papules and verrucous proliferations. Laboratory tests and imaging were unremarkable, with histological analysis confirming fibromas and pityriasis versicolor. The patient declined treatment during pregnancy, and postpartum, spontaneous regression of lesions occurred, with complete resolution within 1 year. The child exhibited normal development, with no recurrence observed at the 2-year follow-up. This case underscores the importance of multidisciplinary care and long-term monitoring in managing dermatological manifestations during pregnancy.

Abstract Primate‐specific DAZ (deleted in azoospermia) has evolved in the azoospermia factor c (AZFc) locus on the Y chromosome. Loss of DAZ is associated with azoospermia in patients with deletion of the AZFc region (AZFc_del). However, the molecular mechanisms of DAZ in spermatogenesis remain uncertain. In this study, the molecular mechanism of DAZ is identified, which is unknown since it is identified 40 years ago because of the lack of a suitable model. Using clinical samples and cell models, it is shown that DAZ plays an important role in spermatogenesis and that loss of DAZ is associated with defective proliferation of c‐KIT‐positive spermatogonia in patients with AZFc_del. Mechanistically, it is shown that knockdown of DAZ significantly downregulated global translation and subsequently decreased cell proliferation. Furthermore, DAZ interacted with PABPC1 via the DAZ repeat domain to regulate global translation. DAZ targeted mRNAs that are involved in cell proliferation and cell cycle phase transition. These findings indicate that DAZ is a master translational regulator and essential for the maintenance of spermatogonia. Loss of DAZ may result in defective proliferation of c‐KIT‐positive spermatogonia and spermatogenic failure.

Abstract Background Systemic immune‐inflammation index (SII) provides convincing evaluation of systemic immune and inflammatory condition in human body. Its correlation with prostate cancer (PCa) risk remains uncharted. The principal objective of this investigation was to elucidate the association between SII and the risk for PCa in middle‐aged and elderly males. Materials and Methods Analysis entailed multivariate linear and logistic regression, generalized additive model, and smoothing curve fitting using resource from 2007 to 2010 National Health and Nutrition Examination Survey (NHANES). To ascertain robustness and consistency of this association across different demographic strata, we conducted rigorous subgroup analyses and interaction tests. Results Among 3359 participants, those with elevated SII displayed higher total prostate‐specific antigen (tPSA) levels, higher risk for PCa, and lower free/total PSA (f/t PSA) ratio. Specifically, each unit increase of log2 (SII) was associated with a 0.22 ng/mL increase in tPSA (β: 0.22, 95% confidence intervals [CI] 0.05–0.38), a 2.22% decline in f/t PSA ratio (β: −2.22, 95% CI −3.20 to −1.23), and a 52% increased odds of being at high risk for PCa (odds ratio [OR]: 1.52, 95% CI 1.13–2.04). People in the top quartile of log2 (SII) exhibited 0.55 ng/mL increased tPSA (β: 0.55, 95% CI 0.19–0.90), 4.39% reduced f/t PSA ratio (β: −4.39, 95% CI −6.50 to −2.27), and 168% increased odds of being at high risk for PCa (OR: 2.68, 95% CI 1.32–5.46) compared to those in the bottom quartile. Conclusion Systemic immune and inflammatory condition, as represented by SII, is independently and positively associated with tPSA levels and the risk for PCa, as well as independently and negatively associated with f/t PSA ratio among middle‐aged and older US males. These findings may enhance the effectiveness of PCa screening in predicting positive biopsy results.

Prostate cancer (PCa) is commonly occurred with high incidence in men worldwide, and many patients will be eventually suffered from the dilemma of castration-resistance with the time of disease progression. Castration-resistant PCa (CRPC) is an advanced subtype of PCa with heterogeneous carcinogenesis, resulting in poor prognosis and difficulties in therapy. Currently, disorders in androgen receptor (AR)-related signaling are widely acknowledged as the leading cause of CRPC development, and some non-AR-based strategies are also proposed for CRPC clinical analyses. The initiation of CRPC is a consequence of abnormal interaction and regulation among molecules and pathways at multi-biological levels. In this study, CRPC-associated genes, RNAs, proteins, and metabolites were manually collected and integrated by a comprehensive literature review, and they were functionally classified and compared based on the role during CRPC evolution, i.e., drivers, suppressors, and biomarkers, etc. Finally, translational perspectives for data-driven and artificial intelligence-powered CRPC systems biology analysis were discussed to highlight the significance of novel molecule-based approaches for CRPC precision medicine and holistic healthcare.

Abstract Purpose This study aims to establish and validate a new diagnosis model called P.Z.A. score for clinically significant prostate cancer (csPCa). Methods The demographic and clinical characteristics of 956 patients were recorded. Age, prostate-specific antigen (PSA), free/total PSA (f/tPSA), PSA density (PSAD), peripheral zone volume ratio (PZ-ratio), and adjusted PSAD of PZ (aPSADPZ) were calculated and subjected to receiver operating characteristic (ROC) curve analysis. The nomogram was established, and discrimination abilities of the new nomogram were verified with a calibration curve and area under the ROC curve (AUC). The clinical benefits of P.Z.A. score were evaluated by decision curve analysis and clinical impact curves. External validation of the model using the validation set was also performed. Results The AUCs of aPSADPZ, age, PSA, f/tPSA, PSAD and PZ-ratio were 0.824, 0.672, 0.684, 0.715, 0.792 and 0.717, respectively. The optimal threshold of P.Z.A. score was 0.41. The nomogram displayed excellent net benefit and better overall calibration for predicting the occurrence of csPCa. In addition, the number of patients with csPCa predicted by P.Z.A. score was in good agreement with the actual number of patients with csPCa in the high-risk threshold. The validation set provided better validation of the model. Conclusion P.Z.A. score (including PIRADS(P), aPSADPZ(Z) and age(A)) can increase the detection rate of csPCa, which may decrease the risk of misdiagnosis and reduce the number of unnecessary biopsies. P.Z.A. score contains data that is easy to obtain and is worthy of clinical replication.

Abstract Background Prostate cancer (PCa) is currently acknowledged as the second most widespread cancer among men worldwide. Yet, the lack of dependable diagnostic biomarkers and therapeutic targets has presented considerable hurdles to the progression of prostate cancer treatment. Circular RNAs are implicated in the pathogenesis of numerous diseases, positioning them as promising biomarkers for diverse medical conditions. This study aims to uncover a specific circRNA that could serve as a diagnostic and therapeutic target for detecting and treating PCa. Methods The change of circTENM3 expression levels in PCa was detected by qPCR. CCK8 assays, EdU assays, Scratch assay and Transwell migration assay conducted to detect the role of circTENM3 in PCa cells in vitro. RIP assay, RNA-pull down and luciferase reporter assay were performed to explore the mechanism of circTENM3. Gain-of-function analysis was performed to reveal the function of circTENM3 in PCa in vivo. Results The results revealed that the expression level of circTENM3 was significantly down-regulated in PCa. CircTENM3 overexpression alleviated the progression of PCa in vitro. Mechanistically, circTENM3 enhanced RUNX3 levels via miR-558 sponge. Gain-of-function analysis determined that circTENM3 overexpression could inhibit PCa progression in vitro. Conclusions Our research offers profound insights into the protective role played by circTENM3 in PCa. CircTENM3 operates as a sponge for miR-558, thereby triggering the elevation of RUNX3 expression, which subsequently curbs the progression of PCa.

Due to its exceptional mechanical and chemical properties at high temperatures, Inconel 718 is extensively utilized in industries such as aerospace, aviation, and marine. Investigating the flow behavior of Inconel 718 under high strain rates and high temperatures is vital for comprehending the dynamic characteristics of the material in manufacturing processes. This paper introduces a physics-based constitutive model that accounts for dislocation motion and its density evolution, capable of simulating the plastic behavior of Inconel 718 during large strain deformations caused by machining processes. Utilizing a microstructure-based flow stress model, the machinability of Inconel 718 in terms of cutting forces and temperatures is quantitatively predicted and compared with results from orthogonal cutting experiments. The model’s predictive precision, with a margin of error between 5 and 8%, ensures reliable consistency and enhances our comprehension of the high-speed machining dynamics of Inconel 718 components.

The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.

Summary: Kinesin 1 (KIF5) is one major type of motor protein in neurons, but its members’ function in the intact brain remains less studied. Using in vivo two-photon imaging, we find that conditional knockout of Kif5b (KIF5B cKO) in CaMKIIα-Cre-expressing neurons shows heightened turnover and lower stability of dendritic spines in layer 2/3 pyramidal neurons with reduced spine postsynaptic density protein 95 acquisition in the mouse cortex. Furthermore, the RNA-binding protein fragile X mental retardation protein (FMRP) is translocated to the proximity of newly formed spines several hours before the spine formation events in vivo in control mice, but this preceding transport of FMRP is abolished in KIF5B cKO mice. We further find that FMRP is localized closer to newly formed spines after fear extinction, but this learning-dependent localization is disrupted in KIF5B cKO mice. Our findings provide the crucial in vivo evidence that KIF5B is involved in the dendritic targeting of synaptic proteins that underlies dendritic spine plasticity.

Genetically engineered macrophages (GEMs) have emerged as an appealing strategy to treat cancers, but they are largely impeded by the cell availability and technical challenges in gene transfer. Here, we develop an efficient approach to generate large-scale macrophages from human induced pluripotent stem cells (hiPSCs). Starting with 1 T150 dish of 106 hiPSCs, more than 109 mature macrophages (iMacs) could be generated within 1 month. The generated iMacs exhibit typical macrophage properties such as phagocytosis and polarization. We then generate hiPSCs integrated with an IL-12 expression cassette in the AAVS1 locus to produce iMacs secreting IL-12, a strong proimmunity cytokine. hiPSC-derived iMacs_IL-12 prevent cytotoxic T cell exhaustion and activate T cells to kill different cancer cells. Furthermore, iMacs_IL-12 display strong antitumor effects in a T cell-dependent manner in subcutaneously or systemically xenografted mice of human lung cancer. Therefore, we provide an off-the-shelf strategy to produce large-scale GEMs for cancer therapy.

ObjectiveThe purpose of this study was to investigate the clinical significance of serum high sensitive C-reactive protein/albumin ratio in primary prostate biopsy.MethodsRetrospective analysis was done on the clinical data of 1679 patients who had their first transrectal or perineal prostate biopsy at our situation from 2010 to 2018. Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) were the pathologic diagnoses in 819 and 860 cases, respectively. A comparison was made between the HAR differences between PCa and BPH patients as well as the positive prostate biopsy rate differences between groups with increased and normal HAR. The results of the prostate biopsy were examined using logistic regression, and a model for predicting prostate cancer was created. The receiver characteristic curve (ROC) was used to determine the model’s prediction effectiveness. The clinical models integrated into HAR were evaluated for their potential to increase classification efficacy using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). According to the Gleason score (GS) categorization system, prostate cancer patients were separated into low, middle, and high GS groups. The differences in HAR between the various groups were then compared. The prevalence of high GSPCa and metastatic PCa in normal populations and the prevalence of higher HAR in prostate cancer patients were compared using the chi-square test.ResultPatients with PCa had a median HAR (upper quartile to lower quartile) of 0.0379 (10-3), patients with BPH had a median HAR (0.0137 (10-3)), and the difference was statistically significant (p0, IDI>0, and the difference was statistically significant (P>0.05).There was a statistically significant difference in HAR between various GS groups for individuals who had prostate cancer as a consequence of biopsy (p

Background: The association between MTHFR gene polymorphisms (C677T and A1298C) and prostate cancer risk remains controversial.Methods: Two independent researchers searched the PubMed, Embase, Cochrane and Web of Science databases for all papers published up to 12/19/2023 and used various genetic models to evaluate the relationship between MTHFR polymorphisms and prostate cancer risk.Results: The meta-analysis included 26 case‒control studies with a total of 12,455 cases and 13,900 controls with the C677T polymorphism and 6,396 cases and 8,913 controls with the A1298C polymorphism. Overall, no significant association was found between the MTHFR gene polymorphisms and prostate cancer risk. However, the C677T polymorphism was associated with reduced prostate cancer risk in the Asian population (T allele vs. C allele: OR = 0.759, 95% CI 0.669–0.861, p < 0.001; TT + CT vs. CC: OR = 0.720, 95% CI 0.638–0.812, p < 0.001; TT vs. CC + CT: OR = 0.719, 95% CI 0.617–0.838, p < 0.001; TT vs. CC: OR = 0.620, 95% CI 0.522–0.737, p < 0.001); however, the A1298C polymorphism was associated with an increased risk in the mixed race group from the United States (CC + AC vs. AA: OR = 1.464, 95% CI 1.052–2.037, p = 0.024; AC vs. AA: OR = 1.615, 95% CI 1.037–2.514, p = 0.034).Conclusion: The meta-analysis suggested that MTHFR gene polymorphisms (C677T and A1298C) may have different effects on prostate cancer risk in specific populations.

ObjectiveThe development of diffuse large B-cell lymphoma (DLBCL) is closely related to the host infection status. China is a highly endemic area for hepatitis B virus (HBV) infection. It is not clear whether HBV infection has a consistent effect on the prognostic implications of patients with DLBCL in different treatment settings.Materials and methodsWe conducted a cohort study of 692 patients with DLBCL receiving three or more cycles of treatment with a CHOP or R-CHOP regimen from the First Hospital of Jilin University between July 2011 and July 2022. The patients were divided into two groups based on their hepatitis B surface antigen (HBsAg) status: HBsAg-positive (n = 84, 12.1%) and HBsAg-negative (n = 608, 87.9%) groups. Tumor specimens from 180 patients with primary DLBCL were collected for next-generation sequencing (NGS).ResultsThe HBsAg-positive group had more frequent abnormal liver function (P = 0.003), hypoalbuminemia (P < 0.001), incidence of > 2 extranodal organs (P = 0.011), and spleen involvement (P < 0.001) than the HBsAg-negative group. HBsAg-positive patients had lower complete response (CR) and overall response rates (ORR) rates (all the p values < 0.05), in either the CHOP group or R-CHOP group. Among patients receiving R-CHOP, the rates of disease progression within 12 and 24 months were higher in the HBsAg-positive group than in the HBsAg-negative group (P=0.018, P=0.029). However, no significant difference in disease progression was observed between HBsAg-positive and HBsAg-negative patients in the CHOP group(P > 0.05). HBsAg positivity (OS: HR [95% CI] = 2.511 [1.214-5.192], P = 0.013) was only associated with poorer OS in the CHOP group. Whereas in the R-CHOP group, HBsAg positivity was associated with both poorer OS and PFS (OS: HR [95% CI] = 1.672 [1.050-2.665], P = 0.030; PFS: HR [95% CI] = 1.536 [1.013-2.331], P = 0.043). Additionally, HBsAg-positive patients with DLBCL also had a higher prevalence of mutations in MYC, ATM, PTPN6, and epigenetically regulated genes.ConclusionThese findings suggest that HBsAg-positive DLBCL patients may represent a distinct subgroup with a poorer prognosis. The standard therapies may be insufficient and new therapeutic strategies should be developed based on a better understanding of the underlying mechanisms of chemoresistance.

Abstract Background Currently, the clinical strategy for diagnosis of non-muscle invasive bladder cancer (NMIBC) such as cystoscopy and cytology are invasive and/or with limited accuracy. OncoUrine, a urinary assay for mutation and methylation biomarkers, have showed a high accuracy in the detection of upper tract urinary carcinoma (UTUC) patients with hematuria. The aim of this study is to evaluate the performance of OncoUrine in diagnosis of NMIBC patients. Methods In this multicenter prospective study, a total of 203 patients were enrolled, including 60 patients present with hematuria and 143 NMIBC patients under recurrence surveillance. Urine samples were collected before cystoscopy to undergo OncoUrine test. OncoUrine performance was calculated compared to clinical standard methods in hematuria cohort and recurrence surveillance cohort, respectively. Furthermore, NMIBC patients were followed up with a median time of 20.5 months (range 0.03 to 24.03 months) to assess the predictive value of OncoUrine during recurrence monitoring. Results For bladder cancer diagnosis, OncoUrine tested 47 samples and achieved a sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) of 80% (95% CI 44.2–96.5)/91.9% (95% CI 77.0–97.9)/72.7% (95% CI 39.3–92.7)/94.4% (95% CI 80.0–99.0) (kappa value 69.4%, 95% CI 44.4–94.3), indicating 72.3% of unnecessary cystoscopy. For recurrence diagnosis, OncoUrine tested 93 samples, and the sensitivity/specificity/PPV/NPV was 100% (95% CI 59.8–100.0)/68.2% (95% CI 57.1–77.7)/22.9% (95% CI 11.0–40.6)/100% (95% CI 92.3–100.0) (kappa value 27.0%, 95% CI 11.1–42.8), indicating 62.4% of spared cystoscopy. What is more, OncoUrine correctly predicted 80% (20/25) of final recurrence with 12/25 (48%) patients who were OncoUrine positive, but cystoscopy negative was followed with recurrence during follow-up. The test result of OncoUrine was also found significantly correlated with recurrence free survival (RFS) of NMIBC patients (median 34.4-month vs unreached; HR 6.0, 95% CI 2.7–13.5, P

Abstract Background Although the orchiopexy is recommended for cryptorchidism to preserve male fertility, non-obstructive azoospermia (NOA) may occur in adulthood. Fortunately, a great many of azoospermic men may obtain sperm by microdissection testicular sperm extraction (mTESE). Due to the potential injuries caused by testicular diagnostic biopsy and vascular damage at the time of orchidopexy, minimal invasiveness is particularly important during mTESE, aims to reduce the surgical damage and avoids secondary testicular failure. This comparative study aims to investigate the efficacy of stepwise mini-incision mTESE technique by comparison with standard mTESE in the treatment of NOA patients with a history of cryptorchidism. Results A total of 73 mTESE procedures were divided into two groups: Group 1 included 37 cases performed by stepwise mini-incision mTESE, while Group 2 included 36 cases with standard mTESE. The overall sperm retrieval rate (SRR) in the two groups was 68.5% (50/73), with no significant difference in SRR between Group 1 (78.4%, 29/37) and Group 2 (58.3%, 21/36) (P = 0.1). In addition, 46.0% of the patients (17/37) obtained sperm in the first mini-incision step in Group 1, which was also equal to an overall SRR in Group 2 (58.3%, 21/36) (P = 0.3). The operation time in Group 1 (72.6 ± 33.9 min) was significantly shorter than that in Group 2 (90.4 ± 36.4 min) (P = 0.04). Patients with an orchidopexy age no more than 10 years old had a higher SRR (79.5%, 31/39) than others (55.9%, 19/34) (P = 0.03). There were no postoperative complications including wound infection, scrotal hematoma, persistent pain, and testicular atrophy during a follow-up period of at least 6 months. Conclusions In conclusion, our study suggests that the stepwise mini-incision mTESE could be a promising approach for sperm retrieval in NOA men with a history of cryptorchidism. While the technique may potentially reduce operation time and surgical invasiveness, further research is needed to validate these findings on a larger scale. The results also suggest that age at orchidopexy may affect SRR and have important implications for the management of cryptorchidism.

Abstract Background Radical cystectomy and urinary diversion are the standard surgical treatments for patients with muscle-invasive or high-risk, or recurrent non-muscle-invasive bladder cancer. Although this approach significantly prolongs patient survival, it can lead to postoperative complications. This study aims to compare the efficacy and complications of bilateral cutaneous ureterostomy with a single subumbilical stoma to those of cutaneous ureterostomy with two stomas and an ileal conduit as a means of urinary diversion after radical cystectomy. The findings of this study will provide valuable information for healthcare providers in selecting the appropriate urinary diversion method for their patients. Methods The clinical data for 108 patients who received bilateral cutaneous ureterostomy with a single subumbilical stoma (ureterostomy with a single stoma group), cutaneous ureterostomy with two stomas (ureterostomy with two stomas group), or an ileal conduit (ileal conduit group) after radical cystectomy were retrospectively analysed. The operative time, pathological stage, survival status, perioperative complication rate, rate of successful first extubation, rehospitalization rate at 6 months after surgery,ostomy-related medical costs,and postoperative quality of life were compared between the three groups of patients. Results A significant difference in the operative time was found between the three groups (P = 0.001). No significant differences in pathological stage, survival status, perioperative complication rate, rehospitalization rate at 6 months after surgery, or bladder cancer index (BCI) score were identified among the three groups. The difference in the successful first extubation rate between the three groups of patients was significant (P = 0.001). Significant differences in ostomy-related medical costs were observed among the three groups of patients (P = 0.006). Conclusion A single subumbilical stoma for bilateral cutaneous ureterostomy after radical cystectomy may result in shorter surgery time, increased success rates for initial catheter removal, and lower medical expenses. However, to confirm these findings, further prospective randomized clinical trials are necessary.

Backgrounds: Lipid metabolism reprogramming is a hallmark of cancer, however, the associations between fatty acid metabolism (FAM) and kidney renal clear cell carcinoma (KIRC) prognosis are still less investigated. Methods: The gene expression and clinical data of KIRC were obtained from TCGA. Using Cox regression and LASSO regression, a novel prognostic risk score model based on FAM-related genes was constructed, and a nomogram for prediction of overall survival rate of patients with KIRC was proposed. The correlation between risk score and the immune cell infiltration, immune-related function and tumor mutation burden (TMB) were explored. Finally, a hub gene was extracted from the model, and RT-qPCR, Western blot, Immunohistochemical, EdU, Scratch assay and Transwell experiments were conducted to validate and decipher the biomarker role of the hub gene in KIRC theranostics. Results: In this study, a novel risk score model and a nomogram were constructed based on 20 FAM-related genes to predict the prognosis of KIRC patients with AUC>0.7 at 1-, 3-, and 5-years. Patients in different subgroups showed different phenotypes in immune cell infiltration, immune-related function, TMB, and sensitivity to immunotherapy. In particular, the hub gene in the model, i.e., ACADM, was significantly down-expressed in human KIRC samples, and the knockdown of OCLN promoted proliferation, migration and invasion of KIRC cells in vitro. Conclusions: In this study, a novel risk score model and a module biomarker based on FAM-related genes were screened for KIRC prognosis. More clinical carcinogenic validations will be performed for future translational applications of the findings.

Radiotherapy and chemotherapy are effective treatments for patients with locally advanced rectal cancer (LARC) and can significantly improve the likelihood of R0 resection. Radiotherapy can be used as a local treatment to reduce the size of the tumor, improve the success rate of surgery and reduce the residual cancer cells after surgery. Early chemotherapy can also downgrade the tumor and eliminate micrometastases throughout the body, reducing the risk of recurrence and metastasis. The advent of neoadjuvant concurrent radiotherapy (nCRT) and total neoadjuvant treatment (TNT) has brought substantial clinical benefits to patients with LARC. Even so, given increasing demand for organ preservation and quality of life and the disease becoming increasingly younger in its incidence profile, there is a need to further explore new neoadjuvant treatment options to further improve tumor remission rates and provide other opportunities for patients to choose watch-and-wait (W&W) strategies that avoid surgery. Targeted drugs and immunologic agents (ICIs) have shown good efficacy in patients with advanced rectal cancer but have not been commonly used in neoadjuvant therapy for patients with LARC. In this paper, we review several aspects of neoadjuvant therapy, including radiation therapy and chemotherapy drugs, immune drugs and targeted drugs used in combination with neoadjuvant therapy, with the aim of providing direction and thoughtful perspectives for LARC clinical treatment and research trials.

Objective To explore the comparative effectiveness of nutritional supplements in improving glycolipid metabolism and endocrine function in patients with polycystic ovary syndrome (PCOS). Method Randomized controlled clinical trials on the effects of nutritional supplements in PCOS patients were searched in PubMed, Embase, Cochrane Library, and Web of Science from their establishments to March 15, 2023. Then, literature screening, data extraction, and network meta-analysis were performed. This study was registered at PROSPERO (registration number CRD 42023441257). Result Forty-one articles involving 2,362 patients were included in this study. The network meta-analysis showed that carnitine, inositol, and probiotics reduced body weight and body mass index (BMI) compared to placebo, and carnitine outperformed the other supplements (SUCRAs: 96.04%, 97.73%, respectively). Omega-3 lowered fasting blood glucose (FBG) (SUCRAs: 93.53%), and chromium reduced fasting insulin (FINS) (SUCRAs: 72.90%); both were superior to placebo in improving insulin resistance index (HOMA-IR), and chromium was more effective than Omega-3 (SUCRAs: 79.99%). Selenium was potent in raising the quantitative insulin sensitivity index (QUICKI) (SUCRAs: 87.92%). Coenzyme Q10 was the most effective in reducing triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels (SUCRAs: 87.71%, 98.78%, and 98.70%, respectively). Chromium and probiotics decreased TG levels, while chromium and vitamin D decreased TC levels. No significant differences were observed in high-density lipoprotein cholesterol (HDL-C), total testosterone (TT), sex-hormone binding globulin (SHBG), and C-reactive protein (CRP) between nutritional supplements and placebo. Conclusion Carnitine was relatively effective in reducing body mass, while chromium, Omega-3, and selenium were beneficial for improving glucose metabolism. Meanwhile, coenzyme Q10 was more efficacious for improving lipid metabolism. However, publication bias may exist, and more high-quality clinical randomized controlled trials are needed.

We report a case of an exophytic benign prostatic hyperplasia presenting as a polycystic pelvic mass. A 69-year-old man presented with an incidental finding of a pelvic mass of over 18 years. Digital rectal examination revealed a mass on the right anterior rectal wall 8 cm from the anal opening. His current prostate-specific antigen was 3.187 ng/mL. Enhanced computed tomography and magnetic resonance imaging demonstrated an occupancy in the right pelvis. A laparoscopic resection of the pelvic tumor was performed and pathologists identified it as an exophytic benign prostatic hyperplasia nodule. No significant recurrence was found at the 6-month follow-up.

Abstract Prostate cancer (PCa) is a frustrating immunogenic “cold” tumor and generally receives unsatisfied immunotherapy outcomes in the clinic. Pyroptosis is an excellent immunogenic cell death form that can effectively activate the antitumor immune response, promote cytotoxic T‐lymphocyte infiltration, and convert tumors from “cold” to “hot.” However, the in vivo application of pyroptosis drugs is seriously limited, and the upregulation of tumor PD‐L1 caused by photo‐immunotherapy further promotes immune escape. Herein, a new nano‐photosensitizer (YBS‐BMS NPs‐RKC) with pH‐response integrating immunogenic pyroptosis induction and immune checkpoint blockade is developed. The pH‐responsive polymer equipped with the cell membrane anchoring peptide RKC is used as the carrier and further encapsulated with the near‐infrared‐activated semiconductor polymer photosensitizer YBS and a PD‐1/PD‐L1 complex small molecule inhibitor BMS‐202. The pH‐driven membrane‐anchoring and pyroptosis activation of YBS‐BMS NPs‐RKC is clearly demonstrated. In vitro and in vivo studies have shown that this dual‐pronged therapy stimulates a powerful antitumor immune response to suppress primary tumor progression and evokes long‐term immune memory to inhibit tumor relapse and metastasis. This work provides an effective self‐synergistic platform for PCa immunotherapy and a new idea for developing more biocompatible photo‐controlled pyroptosis inducers.

Abstract Background Natural killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with a poor prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit potential novel therapeutic targets for the treatment of NKTL. Histone deacetylase (HDAC) inhibitor chidamide was recently approved for treating relapsed/refractory peripheral T-cell lymphoma (PTCL) patients. However, its therapeutic efficacy in NKTL remains unclear. Methods We performed a phase II clinical trial to evaluate the efficacy of chidamide in 28 relapsed/refractory NKTL patients. Integrative transcriptomic, chromatin profiling analysis and functional studies were performed to identify potential predictive biomarkers and unravel the mechanisms of resistance to chidamide. Immunohistochemistry (IHC) was used to validate the predictive biomarkers in tumors from the clinical trial. Results We demonstrated that chidamide is effective in treating relapsed/refractory NKTL patients, achieving an overall response and complete response rate of 39 and 18%, respectively. In vitro studies showed that hyperactivity of JAK-STAT signaling in NKTL cell lines was associated with the resistance to chidamide. Mechanistically, our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect in vitro and in vivo. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of the JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. Conclusions Our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL. Trial registration: ClinicalTrials.gov, NCT02878278. Registered 25 August 2016, https://clinicaltrials.gov/ct2/show/NCT02878278

The reversed field pinch (RFP) is a toroidal magnetic configuration in which plasmas can spontaneously transform into different self-organized states. Among various states, the ‘quasi-single-helical’ (QSH) state has a dominant component for the magnetic field and significantly improves confinement. Many theoretical and experimental efforts have investigated the transitions among different states. This paper employs the multi-region relaxed magnetohydrodynamic model to study the properties of QSH and other states. The stepped-pressure equilibrium code (SPEC) is used to compute MHD equilibria for the Keda Torus eXperiment (KTX). The toroidal volume of KTX is partitioned into two subvolumes by an internal transport barrier. The geometry of this barrier is adjusted to achieve force balance across the interface, ensuring that the plasma in each subvolume is force-free and that magnetic helicity is conserved. By varying the parameters, we generate distinct self-organized states in KTX. Our findings highlight the crucial role of magnetic helicity in shaping these states. In states with low magnetic helicity in both subvolumes, the plasma exhibits axisymmetric behavior. With increasing core helicity, the plasma gradually transforms from an axisymmetric state to a double-axis helical state and finally to a single-helical-axis state. Elevated core magnetic helicity leads to a more pronounced dominant mode of the boundary magnetic field and a reduced core magnetic shear. This is consistent with previous experimental and numerical results in other RFP devices. We find a linear relationship between the plasma current and helicity in different self-organized states. Our findings suggest that KTX may enter the QSH state when the toroidal current reaches 0.72 MA. This study demonstrates that the stellarator equilibrium code SPEC unveils crucial RFP equilibrium properties, rendering it applicable to a broad range of RFP devices and other toroidal configurations.

The Langmuir probe observed an increase in density and floating potential fluctuations after the sawtooth crash at the edge of HL-2A neutral beam injection heated plasma. This process initiates fluctuating-induced radial inward particle transport once the plasma enters a period with strong sawtooth crash. The inward transport comprises broad-band fluctuations with varying scales, which occur uniquely in the immediate aftermath of the sawtooth crash-driven outflow, signifying a transient phenomenon confined to that specific interval. These results demonstrate that the sawtooth crash can significantly impact edge turbulence by modifying electrostatic fluctuations. This modification changes the direction of electric fluctuation-induced particle transport, thereby reducing the influence of the intense sawtooth crash-driven outflow. Furthermore, the observations support the existence of a damping mechanism for the outflow during the formation of inward flux after the sawtooth crash, which may be associated with the recovery process of sawtooth cycle.

BackgroundOccludin (OCLN) is an important tight junction protein and has been reported to be abnormally expressed in the development of malignant tumors. However, its biomarker and carcinogenic roles in kidney renal clear cell carcinoma (KIRC) are less investigated.MethodsThe Cancer Genome Atlas database and Human Protein Atlas database were used to analyze the expression of OCLN in KIRC. UALCAN database and methylation-specific PCR assay were used to evaluate the methylation level of OCLN in KIRC. Univariate and multivariate Cox regression analyses were performed to model the prognostic significance of OCLN in KIRC patient cohorts. The correlation between OCLN expression and the immune cell infiltration, immune-related function and immune checkpoints were explored. Finally, EdU, scratch assay and transwell experiments were conducted to validate the role of OCLN in KIRC development.ResultsThe expression of OCLN was significantly downregulated in KIRC, compared with normal renal tissues (p

IntroductionShort bowel syndrome (SBS) is featured by impaired nutrients and fluids absorption due to massive small intestine resection. Gut dysbiosis has been implicated in SBS, this study aimed to characterize the metagenomic and metabolomic profiles of SBS and identify potential therapeutic targets.MethodsFecal samples from SBS and Sham rats (n = 8 per group) were collected for high-throughput metagenomic sequencing. Fecal metabolomics was measured by untargeted liquid chromatography-mass spectrometry.ResultsWe found that the species-level α-diversity significantly decreased in SBS rats, accompanied by altered microbiome compositions. The beneficial anaerobes from Firmicutes and Bacteroidetes were depleted while microorganisms from Lactobacillus, Escherichia, Enterococcus, and Streptococcus were enriched in faces from SBS rats. LEfSe analysis identified 17 microbial species and 38 KEGG modules that were remarkably distinct between SBS and Sham rats. In total, 1,577 metabolites with known chemical identity were detected from all samples, among them, 276 metabolites were down-regulated and 224 metabolites were up-regulated in SBS group. The typical signatures of SBS fecal metabolome comprised reduced short-chain fatty acids and products of amino acid metabolism (indole derivatives and p-cresol), as well as altered bile acid spectrum. We revealed 215 robust associations between representative differentially abundant microbial species and metabolites, the species with the same changing trend tended to have a similar correlation with some certain metabolites.ConclusionThe fecal microbiome and metabolome significantly altered in SBS. Our findings may lay the foundation for developing new strategies to facilitate intestinal adaptation in SBS patients.

Background Prostate cancer (PCa) is among the most prevalent cancers in males with high biochemical recurrence risk. LINC00106 contributes to the carcinogenesis of Hepatocellular carcinoma (HCC). However, it is unclear how it affects PCa advancement. Here, we studied LINC00106’s effects on PCa cells’ ability to proliferate, invade, and metastasize. Methods The data of LINC00106 from The Cancer Genome Atlas (TCGA) in human PCa tissues were analyzed using TANRIC and survival analysis. In order to determine the expression levels of genes and proteins, we also performed reverse transcription-quantitative PCR and western blot analysis. The migration, invasion, colony formation, and proliferation (CCK-8) of PCa cells with LINC00106 knockdown were investigated. The impact of LINC00106 on cell proliferation and invasion was also analyzed in mice. LncRNA prediction software catRAPID omics v2.1 (catRAPID omics v2.0 (tartaglialab.com)) was used to predict proteins that might interact with LINC00106. The interactions were verified via RNA immunoprecipitation and RNA pull-down assays and finally, the interaction between LINC00106 and its target protein and the p53 signaling pathway was studied using a dual-luciferase reporter assay. Results In PCa, LINC00106 was over-expressed in comparison to normal tissues, and it was linked to an unfavorableprognosis. In vitro and in vivo analyses showed that downregulating LINC00106 decreased PCa cells’ability to proliferate and migrate. A common regulatory axis generated by LINC00106 and RPS19BP1 prevents p53 activity. Conclusion Our experimental data indicate that LINC00106 functions as an oncogene in the onset of PCa, and the LINC00106/RPS19BP1/P53 axis canserve as a novel therapeutic target for PCa treatment.

In this study, we present an innovative approach that harnesses deep neural networks to simulate respiratory lung motion and extract local functional information from single-phase chest X-rays, thus providing valuable auxiliary data for early diagnosis of lung cancer. A novel radiograph motion simulation (RMS) network was developed by combining a U-Net and a long short-term memory (LSTM) network for image generation and sequential prediction. By utilizing a spatial transformer network to deform input images, our proposed network ensures accurate image generation. We conducted both qualitative and quantitative assessments to evaluate the effectiveness and accuracy of our proposed network. The simulated respiratory motion closely aligns with pulmonary biomechanics and reveals enhanced details of pulmonary diseases. The proposed network demonstrates precise prediction of respiratory motion in the test cases, achieving remarkable average Dice scores exceeding 0.96 across all phases. The maximum variation in lung length prediction was observed during the end-exhale phase, with average deviation of 4.76 mm (±6.64) for the left lung and 4.77 mm (±7.00) for the right lung. This research validates the feasibility of generating patient-specific respiratory motion profiles from single-phase chest radiographs.

Background Massive or repeated intestinal resections for Crohn’s disease (CD) could lead to disabling consequences. The present study aimed to assess the effect of preoperative anti-TNF therapy on the length of resected bowel and identify risk factors for postoperative morbidity following ileocolic resection for CD. Methods Patients undergoing elective ileocolic resection for CD were included prospectively. Medical variables including demographics, Montréal classification, preoperative treatment, surgical details and 30-day postoperative morbidity were collected. Potential impact of preoperative anti-TNF treatment on length of ileocolic specimen and risk factors for postoperative morbidity were investigated. Results One hundred and eight-four patients were included in this study, and 66 (35.9%) of them received anti-TNF agents within 8 weeks prior to surgery. Primary anastomosis was performed in 145 patients (78.8%). The mean length of resected intestine was 10 cm shorter in subjects receiving preoperative anti-TNF treatment than those without preoperative anti-TNF therapy (P

Abstract Background Non-obstructive azoospermia (NOA) is the most severe disease in male infertility, but the genetic causes for majority of NOA remain unknown. Methods Two Chinese NOA-affected patients were recruited to identify the genetic causal factor of infertility. Whole-exome sequencing (WES) was conducted in the two patients with NOA. Sanger sequencing and CNV array were used to ascertain the WES results. Hematoxylin and eosin (H&E) staining and immunofluorescence (IF) were carried out to evaluate the stage of spermatogenesis arrested in the affected cases. Results Novel heterozygous deletion (LOH) within SYCE1 (seq[GRCh37] del(10)(10q26.3)chr10:g.135111754_135427143del) and heterozygous loss of function (LoF) variant in SYCE1 (NM_001143763: c.689_690 del:p.F230fs) were identified in one NOA-affected patient. While homozygous deletion within SYCE1 (seq[GRCh37] del(10)(10q26.3)chr10:g.135340247_135379115del) was detected in the other patient with meiotic arrest. H&E and IF staining demonstrated that the spermatogenesis was arrested at pachytene stage in the two patients with NOA, suggesting these two novel CNVs within SYCE1 could lead to meiotic defect and NOA. Conclusions We identified that two novel CNVs within SYCE1 are associated with meiotic arrest and male infertility. Thus, our study expands the knowledge of variants in SYCE1 and provides a new insight to understand the genetic etiologies of NOA.

Abstract Radiomic model reliability is a central premise for its clinical translation. Presently, it is assessed using test–retest or external data, which, unfortunately, is often scarce in reality. Therefore, we aimed to develop a novel image perturbation-based method (IPBM) for the first of its kind toward building a reliable radiomic model. We first developed a radiomic prognostic model for head-and-neck cancer patients on a training (70%) and evaluated on a testing (30%) cohort using C-index. Subsequently, we applied the IPBM to CT images of both cohorts (Perturbed-Train and Perturbed-Test cohort) to generate 60 additional samples for both cohorts. Model reliability was assessed using intra-class correlation coefficient (ICC) to quantify consistency of the C-index among the 60 samples in the Perturbed-Train and Perturbed-Test cohorts. Besides, we re-trained the radiomic model using reliable RFs exclusively (ICC > 0.75) to validate the IPBM. Results showed moderate model reliability in Perturbed-Train (ICC: 0.565, 95%CI 0.518–0.615) and Perturbed-Test (ICC: 0.596, 95%CI 0.527–0.670) cohorts. An enhanced reliability of the re-trained model was observed in Perturbed-Train (ICC: 0.782, 95%CI 0.759–0.815) and Perturbed-Test (ICC: 0.825, 95%CI 0.782–0.867) cohorts, indicating validity of the IPBM. To conclude, we demonstrated capability of the IPBM toward building reliable radiomic models, providing community with a novel model reliability assessment strategy prior to prospective evaluation.

Bioresorbable scaffolds have emerged as a new generation of vascular implants for the treatment of atherosclerosis, and designed to provide a temporary scaffold that is subsequently absorbed by blood vessels over time. Presently, there is insufficient data on the biological and mechanical responses of blood vessels accompanied by bioresorbable scaffolds (BRS) degradation. Therefore, it is necessary to investigate the inflexion point of degradation, the response of blood vessels, and the pathophysiological process of vascular, as results of such studies will be of great value for the design of next generation of BRS. In this study, abdominal aortas of SD rats were received 3-D printed poly-l-actide vascular scaffolds (PLS) for various durations up to 12 months. The response of PLS implanted aorta went through two distinct processes: (1) the neointima with desirable barrier function was obtained in 1 month, accompanied with slow degradation, inflammation, and intimal hyperplasia; (2) significant degradation occurred from 6 months, accompanied with decreasing inflammation and intimal hyperplasia, while the extracellular matrix recovered to normal vessels which indicate the positive remodeling. These in vivo results indicate that 6 months is a key turning point. This “two-stage degradation and vascular characteristics” is proposed to elucidate the long-term effects of PLS on vascular repair and demonstrated the potential of PLS in promoting endothelium function and positive remodeling, which highlights the benefits of PLS and shed some light in the future researches, such as drug combination coatings design.

BackgroundThe rapid growth of publications on the gut microbiome and colorectal cancer (CRC) makes it feasible for text mining and bibliometric analysis.MethodsPublications were retrieved from the Web of Science. Bioinformatics analysis was performed, and a machine learning-based Latent Dirichlet Allocation (LDA) model was used to identify the subfield research topics.ResultsA total of 5,696 publications related to the gut microbiome and CRC were retrieved from the Web of Science Core Collection from 2000 to 2022. China and the USA were the most productive countries. The top 25 references, institutions, and authors with the strongest citation bursts were identified. Abstracts from all 5,696 publications were extracted for a text mining analysis that identified the top 50 topics in this field with increasing interest. The colitis animal model, expression of cytokines, microbiome sequencing and 16s, microbiome composition and dysbiosis, and cell growth inhibition were increasingly noticed during the last two years. The 50 most intensively investigated topics were identified and further categorized into four clusters, including “microbiome sequencing and tumor,” “microbiome compositions, interactions, and treatment,” “microbiome molecular features and mechanisms,” and “microbiome and metabolism.”ConclusionThis bibliometric analysis explores the historical research tendencies in the gut microbiome and CRC and identifies specific topics of increasing interest. The developmental trajectory, along with the noticeable research topics characterized by this analysis, will contribute to the future direction of research in CRC and its clinical translation.

Abstract Background Non-obstructive azoospermia (NOA) is one of the most severe type in male infertility, and the genetic causes of NOA with meiotic arrest remain elusive. Methods Four Chinese families with NOA participated in the study. We performed whole-exome sequencing (WES) for the four NOA-affected patients in four pedigrees. The candidate causative gene was further verified by Sanger sequencing. Hematoxylin and eosin staining (H&E) and immunohistochemistry (IHC) were carried out to evaluate the stage of spermatogenesis arrested in the patients with NOA. Results We identified two novel homozygous frameshift mutations of MSH4 and two novel compound heterozygous variants in MSH4 in four pedigrees with NOA. Homozygous loss of function (LoF) variants in MSH4 was identified in the NOA-affected patient (P9359) in a consanguineous Chinese family (NM_002440.4: c.805_812del: p.V269Qfs*15) and one patient with NOA (P21504) in another Chinese family (NM_002440.4: c.2220_2223del:p.K741Rfs*2). Also, compound heterozygous variants in MSH4 were identified in two NOA-affected siblings (P9517 and P9517B) (NM_002440.4: c.G1950A: p.W650X and c.2179delG: p.D727Mfs*11), and the patient with NOA (P9540) (NM_002440.4: c.G244A: p.G82S and c.670delT: p.L224Cfs*3). Histological analysis demonstrated lack of spermatozoa in seminiferous tubules of all patients and IHC showed the spermatogenesis arrested at the meiotic prophase I stage. Consistent with the autosomal recessive mode of inheritance, all of these mutations were inherited from heterozygous parental carriers. Conclusions We identified that six novel mutations in MSH4 responsible for meiotic arrest and NOA. And these results provide researchers with a new insight to understand the genetic etiology of NOA and to identify new loci for genetic counselling of NOA.

BackgroundTo clarify the prognostic effect of preoperative sarcopenia and systemic inflammation, and to develop a nomogram for predicting overall survival (OS) of patients with renal cell carcinoma (RCC) following partial or radical nephrectomy.MethodsPatients with RCC following nephrectomy from the First Affiliated Hospital of Soochow University during January 2018 to September 2020 were included in this study. The relationship between sarcopenia and inflammatory markers was identified by logistic regression analysis. Then univariable Cox regression analysis, LASSO regression analysis and multivariable Cox regression analysis were analyzed sequentially to select the independent prognostic factors. Kaplan-Meier survival curves were applied to ascertain the prognostic value. Finally, the identified independent predictors were incorporated in a nomogram, which was internally validated and compared with other methods.ResultsA total of 276 patients were enrolled, and 96 (34.8%) were diagnosed with sarcopenia, which was significantly associated with neutrophil-to-lymphocyte ratio (NLR). Sarcopenia and elevated inflammation markers, i.e., NLR, platelet-to-lymphocyte ratio (PLR) and the modified Glasgow Prognostic Score (mGPS), were independent factors for determining the OS. The model had good discrimination with Concordance index of 0.907 (95% CI: 0.882–0.931), and the calibration plots performed well. Both net reclassification index (NRI) and integrated discriminant improvement (IDI) exhibited better performance of the nomogram compared with clinical stage-based, sarcopenia-based and integrated “NLR+PLR+mGPS” methods. Moreover, decision curve analysis showed a net benefit of the nomogram at a threshold probability greater than 20%.ConclusionsPreoperative sarcopenia was significantly associated with NLR. A novel nomogram with well validation was developed for risk stratification, prognosis tracking and personalized therapeutics of RCC patients.

Prostate cancer (PCa) is a common malignancy that poses a major threat to the health of men. Prostate-specific antigen (PSA) and its derivatives, as FDA-approved detection assays, are insufficient to serve as optimal markers for patient prognosis and clinical decision-making. It is widely acknowledged that aberrant glycolytic metabolism in PCa is related to tumor progression and acidifies the tumor microenvironment (TME). Considering the non-negligible impacts of glycolysis and immune functions on PCa, we developed a combined classifier in prostate cancer. The Glycolysis Score containing 19 genes and TME Score including three immune cells were created, using the univariate and multivariate Cox proportional hazards model, log-rank test, least absolute shrinkage and selection operator (LASSO) regression analysis and the bootstrap approach. Combining the glycolysis and immunological landscape, the Glycolysis-TME Classifier was then constructed. It was observed that the classifier was more accurate in predicting the prognosis of patients than the current biomarkers. Notably, there were significant differences in metabolic activity, signaling pathways, mutational landscape, immunotherapeutic response, and drug sensitivity among the Glycolysishigh/TMElow, Mixed group and Glycolysislow/TMEhigh identified by this classifier. Overall, due to the significant prognostic value and potential therapeutic guidance of the Glycolysis-TME Classifier, we anticipate that this classifier will be clinically beneficial in the management of patients with PCa.

Abstract Background Kidney transplantation is an optimal method for treatment of end-stage kidney failure. However, kidney transplant rejection (KTR) is commonly observed to have negative effects on allograft function. MicroRNAs (miRNAs) are small non-coding RNAs with regulatory role in KTR genesis, the identification of miRNA biomarkers for accurate diagnosis and subtyping of KTR is therefore of clinical significance for active intervention and personalized therapy. Methods In this study, an integrative bioinformatics model was developed based on multi-omics network characterization for miRNA biomarker discovery in KTR. Compared with existed methods, the topological importance of miRNA targets was prioritized based on cross-level miRNA-mRNA and protein–protein interaction network analyses. The biomarker potential of identified miRNAs was computationally validated and explored by receiver-operating characteristic (ROC) evaluation and integrated “miRNA-gene-pathway” pathogenic survey. Results Three miRNAs, i.e., miR-145-5p, miR-155-5p, and miR-23b-3p, were screened as putative biomarkers for KTR monitoring. Among them, miR-155-5p was a previously reported signature in KTR, whereas the remaining two were novel candidates both for KTR diagnosis and subtyping. The ROC analysis convinced the power of identified miRNAs as single and combined biomarkers for KTR prediction in kidney tissue and blood samples. Functional analyses, including the latent crosstalk among HLA-related genes, immune signaling pathways and identified miRNAs, provided new insights of these miRNAs in KTR pathogenesis. Conclusions A network-based bioinformatics approach was proposed and applied to identify candidate miRNA biomarkers for KTR study. Biological and clinical validations are further needed for translational applications of the findings.

Abstract Purpose To investigate the performance of magnetic resonance imaging (MRI)-based radiomics models for benign and malignant prostate lesion discrimination and extracapsular extension (ECE) and positive surgical margins (PSM) prediction. Methods and materials In total, 459 patients who underwent multiparametric MRI (mpMRI) before prostate biopsy were included. Radiomic features were extracted from both T2-weighted imaging (T2WI) and the apparent diffusion coefficient (ADC). Patients were divided into different training sets and testing sets for different targets according to a ratio of 7:3. Radiomics signatures were built using radiomic features on the training set, and integrated models were built by adding clinical characteristics. The areas under the receiver operating characteristic curves (AUCs) were calculated to assess the classification performance on the testing sets. Results The radiomics signatures for benign and malignant lesion discrimination achieved AUCs of 0.775 (T2WI), 0.863 (ADC) and 0.855 (ADC + T2WI). The corresponding integrated models improved the AUC to 0.851/0.912/0.905, respectively. The radiomics signatures for ECE achieved the highest AUC of 0.625 (ADC), and the corresponding integrated model achieved the highest AUC (0.728). The radiomics signatures for PSM prediction achieved AUCs of 0.614 (T2WI) and 0.733 (ADC). The corresponding integrated models reached AUCs of 0.680 and 0.766, respectively. Conclusions The MRI-based radiomics models, which took advantage of radiomic features on ADC and T2WI scans, showed good performance in discriminating benign and malignant prostate lesions and predicting ECE and PSM. Combining radiomics signatures and clinical factors enhanced the performance of the models, which may contribute to clinical diagnosis and treatment.

PurposeThe aim of this study was to explore a new model of clinical decision-making to predict the occurrence of clinically significant prostate cancer (csPCa).Patients and MethodsThe demographic and clinical characteristics of 152 patients were recorded. Prostate-specific antigen (PSA), PSA density (PSAD), adjusted PSAD of peripheral zone (aPSADPZ), and peripheral zone volume ratio (PZ ratio) were calculated and subjected to receiver operating characteristic (ROC) curve analysis. The calibration and discrimination abilities of new nomograms were verified with calibration curve and area under the ROC curve (AUC). The clinical benefits of these models were evaluated by decision curve analysis and clinical impact curves.ResultsThe AUCs of PSA, PSAD, aPSADPZ, and PZ ratio were 0.521, 0.645, 0.745, and 0.717 for prostate cancer (PCa) diagnosis, while the corresponding values were 0.590, 0.678, 0.780, and 0.731 for csPCa diagnosis, respectively. All nomograms displayed higher net benefit and better overall calibration than the scenarios for predicting the occurrence of csPCa. The new model significantly improved the diagnostic accuracy of csPCa (0.865 vs. 0.741, p = 0.0284) compared with the base model. In addition, the new model was better than the base model for predicting csPCa in the low or medium probability while the number of patients with csPCa predicted by the new model was in good agreement with the actual number of patients with csPCa in the high-risk threshold.ConclusionsThis study demonstrates that aPSADPZ has a higher predictive accuracy for csPCa diagnosis than the conventional indicators. Including aPSADPZ, PZ ratio, and age can improve csPCa diagnosis and avoid unnecessary biopsies.

Abstract Background Previous studies showed that type 2 short bowel syndrome (SBS) rats were accompanied by severe intestinal bacterial dysbiosis. Limited data are available for intestinal fungal dysbiosis. Moreover, no effective therapeutic drugs are available for these microbiota dysbiosis. The aims of our study were to investigate the therapeutic potential of glucagon-like peptide 2 (GLP-2) for these microbiota dysbiosis in type 2 SBS rats. Methods 8-week-old male SD rats which underwent 80% small bowel resection, ileocecum resection, partial colon resection and jejunocolostomy, were treated with saline (SBS group, n = 5) or GLP-2 (GLP2.SBS group, n = 5). The Sham group rats which underwent transection and re-anastomosis were given a saline placebo (Sham group, n = 5). 16S rRNA and ITS sequencing were applied to evaluate the colonic bacterial and fungal composition at 22 days after surgery, respectively. Results The relative abundance of Actinobacteria, Firmicutes and proinflammatory Proteobacteria increased significantly in SBS group rats, while the relative abundance of Bacteroidetes, Verrucomicrobia and Tenericutes decreased remarkably. GLP-2 treatment significantly decreased Proteus and increased Clostridium relative to the saline treated SBS rats. The diversity of intestinal fungi was significantly increased in SBS rats, accompanied with some fungi abnormally increased and some resident fungi (e.g., Penicillium) significantly decreased. GLP-2 treatment significantly decreased Debaryomyces and Meyerozyma, and increased Penicillium. Moreover, GLP-2 partially restored the bacteria-fungi interkingdom interaction network of SBS rats. Conclusion Our study confirms the bacterial and fungal dysbiosis in type 2 SBS rats, and GLP-2 partially ameliorated these microbiota dysbiosis.

Objective: Several reports have proposed that lncRNAs, as potential biomarkers, participate in the progression and growth of malignant tumors. HIF1A-AS2 is a novel lncRNA and potential biomarker, involved in the genesis and development of carcinomas. However, the molecular mechanism of HIF1A-AS2 in renal carcinoma is unclear. Methods: The relative expression levels of HIF1A-AS2 and miR-30a-5p were detected using RT-qPCR in renal carcinoma tissues and cell lines. Using loss-of-function and overexpression, the biological effects of HIF1A-AS2 and miR-30a-5p in kidney carcinoma progression were characterized. Dual luciferase reporter gene analysis and Western blot were used to detect the potential mechanism of HIF1A-AS2 in renal carcinomas. Results: HIF1A-AS2 was upregulated in kidney carcinoma tissues when compared with para-carcinoma tissues (P < 0.05). In addition, tumor size, tumor node mestastasis stage and differentiation were identified as being closely associated with HIF1A-AS2 expression (P < 0.05). Knockdown or overexpression of HIF1A-AS2 either restrained or promoted the malignant phenotype and WNT/β-catenin signaling in renal carcinoma cells (P < 0.05). MiR-30a-5p was downregulated in renal cancers and partially reversed HIF1A-AS2 functions in malignant renal tumor cells. HIF1A-AS2 acted as a microRNA sponge that actively regulated the relative expression of SOX4 in sponging miR-30a-5p and subsequently increased the malignant phenotypes of renal carcinomas. HIF1A-AS2 showed a carcinogenic effect and miR-30a-5p acted as an antagonist of the anti-oncogene effects in the pathogenesis of renal carcinomas. Conclusions: The HIF1A-AS2-miR-30a-5p-SOX4 axis was associated with the malignant progression and development of renal carcinoma. The relative expression of HIF1A-AS2 was negatively correlated with the expression of miR-30a-5p, and was closely correlated with SOX4 mRNA levels in renal cancers.

Abstract Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.

Primary diffuse large B cell lymphoma of the central nervous system (CNS DLBCL) is a rare malignancy with a distinct genetic profile. The clinicopathological significance of the mutation patterns remains unknown. Forty cases of primary CNS DLBCL were subjected to targeted exome sequencing covering 413 genes, including MYD88, CD79B and PIM1. Mutational analysis recognized two groups. The CDP (including CD79B and/or PIM1mutations) group was identified in 27 cases (67.5%), and the non-CDP (without CD79B and PIM1 mutations) group was identified in 13 cases 32.5%). The CDP group tended to occur in older patients (median age 57.0 vs. 48.4 years, p=0.015). Patients in the CDP group had a significantly longer 2-year overall survival (OS) (76% and 40%, p=0.0372) than those in the non-CDP group. Multivariate analysis revealed that age less than 60 years, no MYC and BCL2 double expression, and CDP group were three independent risk factors indicating favorable OS. PyClone analysis revealed the subcloning heterogeneity between the groups. In addition, transcriptional sequencing was successfully performed in 8 cases. A total of 131 genes were significantly differentially expressed between these two groups. The major categories of biological processes that were significantly altered between these two groups related to intracellular metabolism mechanisms. We developed a new molecular classification to divide CNS DLBCL into CDP and non-CDP groups based on CD79B and PIM1 mutational status. Patients with PIM1 and/or CD79B mutations had favorable long-term survival after high-dose methotrexate-based polychemotherapy.

Abstract Background Metaplastic breast carcinoma (MBC) is a rare histological type of breast cancer, which commonly shows resistance to standard therapies and is associated with poor prognosis. The immune microenvironment in MBC and its significance has not been well established due to its low incurrence rate and complex components. We aimed to investigate the diversity of immune parameters including subsets of TILs and PDL1/PD1 expression in MBC, as well as its correlation with prognosis. Methods A total of 60 patients diagnosed with MBC from January 2006 to December 2017 were included in our study. The percentage (%) and quantification (per mm2) of TILs and presence of tertiary lymphoid structures (TLS) were evaluated by hematoxylin and eosin staining (HE). The quantification of CD4+, CD8+ TILs (per mm2), and PD-1/PDL1 expression were evaluated through immunohistochemistry and analyzed in relation to clinicopathological characteristics. A ≥ 1% membranous or cytoplasmatic expression of PD1 and PDL1 was considered a positive expression. Results We found squamous cell carcinoma MBC (33/60, 55%) exhibiting most TILs of all the MBC subtypes (p = 0.043). Thirty-three of 60 (50%) of the patients had coexisting invasive ductal carcinoma of no special type (IDC-NST), and the average percentage of TILs in MBC components was lower compared with NST components (p 300/mm2, 20%), CD4+ TILs (> 250/mm2), and CD8+ TILs (> 70/mm2) in MBC were found associated with longer disease-free survival. Positive expression of PDL1 in tumor cells (≥ 1%) and PD1 in stromal cells (≥ 1%) were also associated with longer survival. Conclusions The immune characteristics differ in various subtypes as well as components of MBC. Immune parameters are key predictive factors of MBC and provide the clinical significance of applying immune checkpoint therapies in patients with MBC.

Abstract Background To evaluate the clinical outcomes and the duration required for the sperm to return to the ejaculate after a modified single-armed 2-suture longitudinal intussusception vasoepididymostomy (SA-LIVE). Methods From March 2015 to December 2018, 134 patients with epididymal obstruction azoospermia underwent the modified single-armed vasoepididymostomy at Shanghai General Hospital. The outcomes and clinical findings were documented and evaluated. The mean follow-up period was 17 (range: 3–36) months. Results Patency was assessed by the return of sperm in the ejaculate. The overall patency rate was 55.2%, and the patency rates were 58.9, 40.7, 36.4, and 58.9% for bilateral surgery, unilateral surgery, proximal anastomosis, and distal anastomosis, respectively. The average time to achieve patency was 4.11 ± 2.74 months. In the first 6 months, 87.8% (65/74) patency patients reported sperm in the ejaculate. The overall pregnancy rate was 40.9% (29/66) at the follow-up of 3–36 months, and the natural pregnancy rate was 30.3% (20/66). The natural pregnancy rate was 32.1% post-bilateral surgery and 33.3% for the site of distal anastomosis; surprisingly, it was 0% for the site of proximal anastomosis. Conclusion Modified SA-LIVE is safe and may achieve favorable patency and pregnancy rates. When double-armed sutures are not accessible, single-armed may be preferable. The expected patency time was within 1 year. Moreover, because of the low natural pregnancy rate for proximal anastomosis, sperm banking is preferred to SA-LIVE.