[Construction of a Prognostic Prediction Model of Patients with Pathologic N0 
in Resected Invasive Mucinous Adenocarcinoma of the Lung].

BACKGROUND: Invasive mucinous adenocarcinoma (IMA) was a rare and specific type of lung adenocarcinoma, which was often characterized by fewer lymphatic metastases. Therefore, it was difficult to evaluate the prognosis of these tumors based on the existing tumor-node-metastasis (TNM) staging. So, this study aimed to develop Nomograms to predict outcomes of patients with pathologic N0 in resected IMA. METHODS: According to the inclusion criteria and exclusion criteria, IMA patients with pathologic N0 in The Affiliated Lihuili Hospital of Ningbo University (training cohort, n=78) and Ningbo No.2 Hospital (validation cohort, n=66) were reviewed between July 2012 and May 2017. The prognostic value of the clinicopathological features in the training cohort was analyzed and prognostic prediction models were established, and the performances of models were evaluated. Finally, the validation cohort data was put in for external validation. RESULTS: Univariate analysis showed that pneumonic type, larger tumor size, mixed mucinous/non-mucinous component, and higher overall stage were significant influence factors of 5-year progression-free survival (PFS) and overall survival (OS). Multivariate analysis further indicated that type of imaging, tumor size, mucinous component were the independent prognostic factors for poor 5-year PFS and OS. Moreover, the 5-year PFS and OS rates were 62.82% and 75.64%, respectively. In subgroups, the survival analysis also showed that the pneumonic type and mixed mucinous/non-mucinous patients had significantly poorer 5-year PFS and OS compared with solitary type and pure mucinous patients, respectively. The C-index of Nomograms with 5-year PFS and OS were 0.815 (95%CI: 0.741-0.889) and 0.767 (95%CI: 0.669-0.865). The calibration curve and decision curve analysis (DCA) of both models showed good predictive performances in both cohorts. CONCLUSIONS: The Nomograms based on clinicopathological characteristics in a certain extent, can be used as an effective prognostic tool for patients with pathologic N0 after IMA resection.

Cuproptosis-Related lncRNAs Modulate the Prognosis of MIBC by Regulating the Expression Pattern of Immunosuppressive Molecules Within the Tumor Microenvironment.

Background: Cuproptosis-related gene and long non-coding RNA (lncRNA) modulation of cancer regulation is well-established. This investigation aimed to elucidate the prognostic implications of cuproptosis-associated lncRNAs in muscle-invasive bladder cancer (MIBC). Methods: Employing the Cancer Genome Atlas (TCGA) and IMvigor210 cohorts, bioinformatics and statistical analyses probed the prognostic relevance of cuproptosis-related lncRNAs. Results: Co-expression analysis revealed tight associations between lncRNA expression and cuproptosis-linked genes, with 13 cuproptosis-related lncRNAs found to correlate with MIBC prognosis. Lasso regression identified a six-lncRNA prognostic signature, enabling patient stratification into high- and low-risk categories. Tissue validation substantiated differential expression of FAM13A-AS1, GHRLOS, LINC00456, OPA1-AS1, RAP2C-AS1, and UBE2Q1-AS1 between MIBC tumor and normal tissues. Comparative analyses of tumor microenvironments and immune profiles between risk groups disclosed elevated immunosuppressive molecule expression, including programmed cell death-1 (PD-L1) and T-cell immunoglobulin-3 (TIM-3), in high-risk individuals. Conclusion: These findings suggest that cuproptosis-related lncRNAs may modulate the expression of immunosuppressive molecules, thereby influencing MIBC tumorigenesis and progression. Further exploration is warranted to unveil novel therapeutic targets for MIBC based on the expression patterns of cuproptosis-related lncRNAs and their impact on immune responses in the tumor microenvironment.

LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity.

Mitochondrial dysfunction is one of the key features of acute kidney injury (AKI) and associated fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in kidneys and regulates mitochondrial homeostasis. How it functions in AKI is unclear. Herein we reported that LRRK2 was dramatically downregulated in AKI kidneys. Lrrk2-/- mice exhibited less severity of AKI when compared to wild-type counterparts with less mitochondrial fragmentation and decreased reactive oxygen species (ROS) production in proximal renal tubular cells (PTCs) due to mitofusin 2 (MFN2) accumulation. Overexpression of LRRK2 in human PTC cell lines promoted LRRK2-MKK4/JNK-dependent phosphorylation of MFN2Ser27 and subsequently ubiquitination-mediated MFN2 degradation, which in turn exaggerated mitochondrial damage upon ischemia/reperfusion (I/R) mimicry treatment. Lrrk2 deficiency also alleviated AKI-to-chronic kidney disease (CKD) transition with less fibrosis. In vivo pretreatment of LRRK2 inhibitors attenuated the severity of AKI as well as CKD, potentiating LRRK2 as a novel target to alleviate AKI and fibrosis.

Applications and prospects of functional oligosaccharides in pig nutrition: A review.

Oligosaccharides are low molecular weight carbohydrates between monosaccharides and polysaccharides, which consist of 2 to 20 monosaccharides linked by glycosidic bonds. They have the effects of promoting growth, regulating immunity, improving the structure of intestinal flora, and are anti-inflammatory and antioxidant. With the comprehensive implementation of the antibiotic prohibition policy in China, oligosaccharides as new green feed additive have been paid more attention. Oligosaccharides can be divided into the following 2 categories according to their digestive characteristics: one is easy to be absorbed by the intestine, called common oligosaccharides, such as sucrose and maltose oligosaccharide; the other is difficult to be absorbed by the intestine and has special physiological functions, called functional oligosaccharides. The common functional oligosaccharides include mannan oligosaccharides (MOS), fructo-oligosaccharides (FOS), chitosan oligosaccharides (COS), xylo-oligosaccharides (XOS) and so on. In this paper, we review the types and sources of functional oligosaccharides, their application in pig nutrition, and the factors limiting their efficacy in recent years. This review provides the theoretical basis for further research of functional oligosaccharides, and the future application of alternative antibiotics in pig industry.

Analysis of the Regulatory Effect of ACTG2 on Biological Behavior of Bladder Cancer Cells Based on Database Screening.

To identify genes aberrantly expressed in bladder cancer (BC) in the GEO dataset GSE 52519, and analyze the impact of abnormal Actin Gamma 2, Smooth Muscle (ACTG2) expression on BC cells. GSE 52519, a public dataset in the Gene expression omnibus (GEO) database, was selected for differential expression analysis. Differentially expressed ACTG2 vectors were selected to construct the aberrant expression vectors and transfected into BC T24 and J82 cells. The influences of ACTG2 on BC cell biological behavior were determined by cell cloning, Transwell and flow cytometry, and alterations in cell cycle status were observed. A total of 166 DEGs were found in the GSE 52519 dataset, among which ACTG2 was abnormally low in expression. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses identified that the keywords involved mainly included "extracellular region", "cytoskeleton", "Vascular smooth muscle contraction", "IL-17 signaling pathway", etc. Further, through online data analysis, ACTG2 was also found to be under-expressed in neoplastic diseases such as bladder urothelial carcinoma (BLCA) and prostate adenocarcinoma (PRAD). In vitro, ACTG2 presented lower expression in T24 and J82 than in SV-HUC-1 (P<0.05). Enhanced capacities to proliferate and invade and reduced apoptosis of T24 and J82 were found after silencing ACTG2 expression, with shortened G0-G1 phase and prolonged S phase (P<0.05). However, overexpressing ACTG2 came with decreased BC cell activity, enhanced apoptosis, as well as prolonged G0-G1 phase and shortened S phase (P<0.05). In conclusion, low expression of ACTG2 in BC can shorten the G0-G1 phase of BC cells, prolong the S-phase.

Anlotinib Enhances the Therapeutic Effect of Bladder Cancer with GSDMB Expression: Analyzed from TCGA Bladder Cancer Database & Mouse Bladder Cancer Cell Line.

Introduction and Objective: The mitogen-activated protein kinase (MAPK) pathway is inhibited by the pan-target inhibitor Anlotinib, which induces tumor cell death. In addition to the common apoptosis and necrosis, there is also a pyroptosis mode of cancer cell death in recent years, which is mainly manifested by the cleavage of gasdermin proteins (GSDMs). Gasdermin B (GSDMB) participates in the progression and outcome of bladder cancer. The efficacy and mechanism of Anlotinib in the treatment of GSDMB-positive bladder tumors have not been studied to date. Methods: The relationship between GSDMB expression and tumor stage, overall survival rate, immunotherapy response, tumor recurrence and progression rate was analyzed from the TCGA bladder cancer database. Anlotinib was used to treat GSDMB-positive bladder cancer in mice followed by flow analysis of the secretion of inflammatory factors related to pyroptosis and the level of anti-tumor factors. Western blot analysis detected which MAPK and MEK signal transduction pathways. Results: TCGA data analysis showed that the overall survival rate of bladder cancer patients with high GSDMB expression was better than that of patients with low GSDMB expression. In vivo experiments showed that Anlotinib was more effective in the treatment of GSDMB-positive bladder cancer than GSDMB-negative bladder cancer. Anlotinib can increase the secretion of antitumor-related factors in GSDMB-positive bladder cancer such as TNF-a and CD107a. In addition, Anlotinib also induced an increase in GSDMB protein expression. Anlotinib treatment of GSDMB-positive bladder cancer decreased AKT and MEK protein expression, which were involved in Anlotinib signal transduction pathway. Conclusion: Anlotinib has a strong antitumor effect on GSDMB-positive bladder tumors. This effect is mainly achieved by anlotinib stimulating the secretion of relevant antitumor factors by lymphocytes. The PI3K/AKT and MEK signal transduction pathways were inhibited by Anlotinib in bladder cancer expressing GSDMB protein.

Peripheral tuberculin purified protein derivative specific T cell immunoreactivity dynamics in non-muscle invasive bladder cancer patients receiving bacillus Calmette-Guerin instillation treatment.

Intravesical bacillus Calmette-Guerin (BCG) instillation is recommended as an adjuvant therapy for intermediate-risk and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBt) with nearly 70% reoccurrence. In the present study, we investigated the dynamics of peripheral purified protein derivative (PPD)-specific immune responses along the treatment. Intravesical BCG instillation caused a significant increase in peripheral PPD-specific IFN-γ release of NMIBC patients, when compared to those receiving chemo-drug instillation. Through a follow-up study, we detected rapid increase in PPD-specific IFN-γ, IL-2, and IL-17A producing CD4+ and CD8+ T cells in the induction phase. Interestingly, the frequencies of PPD-specific IFN-γ and IL-2 producing CD4+ and CD8+ T cells decreased dramatically after induction treatment and were restored after BCG re-instillation, whereas IL-17A-producing T cells remained at the maintenance phase. However, we only observed that the percentages of peripheral CD8+ T cells were significantly higher in BCG responder patients than those in BCG refractory patients at the baseline with the potential of predicting the recurrence. A more dramatic increase in PPD-specific IFN-γ and IL-2 producing CD4+ and CD8+ T cells after one and two dose BCG instillations was observed in refractory NMIBC patients. Therefore, regional BCG instillation induced transient peripheral PPD-specific T cell responses, which could be restored through repetitive BCG instillation. Higher proportions of peripheral CD8+ T cells at baseline were associated with better responses to BCG instillation for the prevention of recurrence of bladder cancer.

Revealing prognostic and tumor microenvironment characteristics of cuproptosis in bladder cancer by genomic analysis.

Objectives: Bladder cancer (BLCA) is the most common malignant tumor in the urinary system, while the prognosis of muscle-invasive bladder cancer (MIBC) is poor. Cuproptosis might be a promising therapeutic approach to trigger tumor cell death. This study aimed to figure out the role of cuproptosis in BLCA and constructed a new cuproptosis scoring system to guide clinical diagnosis and individualize treatments. Methods: Consensus clustering was used to classify 490 patients with BLCA from TCGA and GEO cohorts. Survival outcomes and functional enrichment analyses were performed between the different subtypes. The cuproptosis scoring system was constructed by LASSO-Cox analysis. ESTIMATE, CIBERSORT, and ssGSEA were used to investigate the tumor microenvironment (TME). Drug sensitivity was evaluated with pRRophetic. An immunotherapy cohort was used to investigate the treatment response. The cuproptosis scoring system was verified in our own cohort with quantitative real-time PCR. Results: An overview of 12 cuproptosis genes (CuGs) in the TCGA database was depicted. Based on the mRNA expression profiles of CuGs, patients were classified into two cuproptosis molecular patterns. Based on the differential genes between the two cuproptosis patterns, the patients were classified into two cuproptosis gene clusters. There were distinct survival outcomes, signaling pathways, and TME between the two subtypes. A 7-gene cuproptosis scoring system was constructed. Patients with high cuproptosis scores showed worse OS and more immunosuppressing TME than those with low cuproptosis scores. The two cuproptosis score groups had distinct mutation profiles. Patients with high cuproptosis scores tended to be sensitive to chemotherapy drugs, but insensitive to immune checkpoint inhibitors (ICIs) treatment. Conclusion: This study depicted the landscape of cuproptosis in BLCA. We constructed a cuproptosis scoring system to predict the prognosis of BLCA patients. There were significant differences in survival outcomes, TME, mutation profiles, and drug sensitivities in high and low cuproptosis score patients. The cuproptosis scoring system could help oncologists comprehensively understand the tumor characteristic of BLCA and make individualized treatment strategies.

Tumor-associated macrophages promote migration and invasion via modulating IL-6/STAT3 signaling in renal cell carcinoma.

Tumor-associated macrophages (TAMs) promote tumor cell growth and metastasis in various human cancers. However, the role of TAMs in renal cell carcinoma (RCC) is rarely investigated. Herein, we observed that the infiltration of TAMs was obviously elevated in RCC tumor tissues, high infiltration of TAMs was closely associated with tumor progression and poor prognosis in RCC patients. In vitro assays further indicated that the conditioned medium of TAMs (TAMs CM) facilitated migration, invasion, and epithelial-mesenchymal transition (EMT) in RCC cells. Moreover, we found that IL-6 was involved in the functions of TAMs in RCC; IL-6 neutralizing antibody (IL-6NA) partly abolished the effect of TAMs on RCC cells. In addition, we demonstrated that TAMs might exert their roles by activating STAT3 signaling in RCC, and IL-6 was responsible for TAMs-induced STAT3 signaling activation. In conclusion, our results revealed that high infiltration of TAMs may promote RCC cells migration, invasion, and EMT via modulating IL-6/STAT3 signaling, further suggesting a potential of novel treatment strategies targeting TAMs or IL-6 for metastatic RCC.

Ischemic Preconditioning Alleviates Mouse Renal Ischemia/Reperfusion Injury by Enhancing Autophagy Activity of Proximal Tubular Cells.

Objectives: Ischemia/reperfusion injury (IRI) is one of the most vital pathogenesis leading to kidney injury but lacks effective prevention and treatment strategies. This study was conducted to investigate the influences of ischemic preconditioning (IPC) on the pathological process of mouse renal IRI (RIRI) and to figure out the role of autophagy of proximal tubular cells (PTCs) in this process. Methods: C57BL/6J mice were randomized to three groups, i.e., sham-operated group, ischemia/reperfusion (I/R) group, and IPC + I/R group. Meanwhile, 3-methyladenine, an autophagy inhibitor, was administered when further verification was needed. Histological and functional severity of kidney injury, the autophagy and apoptosis activity of PTCs, as well as the characterization of the immune cell infiltration landscape in kidney tissues were investigated. Furthermore, HK-2 cells and primary cultured PTC were cultured to set up the hypoxic preconditioning and hypoxia/reoxygenation model for in vitro simulation and verification, and a microarray dataset derived from the Gene Expression Omnibus database was analyzed to explore the transcriptome profiles after IPC. Results: IPC could significantly attenuate I/R-induced kidney injury functionally and histologically both in the acute and recovery phase of RIRI by enhancing the autophagy activity of PTCs. Cell autophagy could regulate the release of monocyte chemoattractant protein-1, and sequentially decrease macrophages infiltration in kidney tissues in the acute phase of RIRI, thus mediating the reno-protective effect. Conclusions: IPC could attenuate mouse RIRI-induced kidney injury. IPC-mediated activation of autophagy of PTCs plays a vital role in affording protection in RIRI-induced kidney injury.

Whole blood transcriptome profiling identifies candidate genes associated with alopecia in male giant pandas (Ailuropoda melanoleuca).

BACKGROUND: The giant panda (Ailuropoda melanoleuca) is a threatened species endemic to China. Alopecia, characterized by thinning and broken hair, mostly occurs in breeding males. Alopecia significantly affects the health and public image of the giant panda and the cause of alopecia is unclear. RESULTS: Here, we researched gene expression profiles of four alopecia giant pandas and seven healthy giant pandas. All pandas were approximately ten years old and their blood samples collected during the breeding season. A total of 458 up-regulated DEGs and 211 down-regulated DEGs were identified. KEGG pathway enrichment identified that upregulated genes were enriched in the Notch signaling pathway and downregulated genes were enriched in ribosome, oxidative phosphorylation, and thermogenesis pathways. We obtained 28 hair growth-related DEGs, and identified three hub genes NOTCH1, SMAD3, and TGFB1 in PPI analysis. Five hair growth-related signaling pathways were identified with abnormal expression, these were Notch, Wnt, TGF-ß, Mapk, and PI3K-Akt. The overexpression of NOTCH1 delays inner root sheath differentiation and results in hair shaft abnormalities. The delayed hair regression was associated with a significant decrease in the expression levels of TGFB1. CONCLUSIONS: Our data confirmed the abnormal expression of several hair-related genes and pathways and identified alopecia candidate genes in the giant panda. Results of this study provide theoretical basis for the establishment of prevention and treatment strategies for giant pandas with alopecia.

Allicin Improves Intestinal Epithelial Barrier Function and Prevents LPS-Induced Barrier Damages of Intestinal Epithelial Cell Monolayers.

Gut barrier disruption is the initial pathogenesis of various diseases. We previously reported that dietary allicin improves tight junction proteins in the endoplasmic reticulum stressed jejunum. However, whether the allicin benefits the gut barrier within mycotoxin or endotoxin exposure is unknown. In the present study, IPEC-J2 cell monolayers within or without deoxynivalenol (DON) or lipopolysaccharide (LPS) challenges were employed to investigate the effects of allicin on intestinal barrier function and explore the potential mechanisms. Results clarified that allicin at 2 µg/mL increased the viability, whereas the allicin higher than 10 µg/mL lowered the viability of IPEC-J2 cells via inhibiting cell proliferation. Besides, allicin increased trans-epithelial electric resistance (TEER), decreased paracellular permeability, and enhanced ZO-1 integrity of the IPEC-J2 cell monolayers. Finally, allicin supplementation prevented the LPS-induced barrier damages via activating Nrf2/HO-1 pathway-dependent antioxidant system. In conclusion, the present study strongly confirmed allicin as an effective nutrient to improve intestinal barrier function and prevent bacterial endotoxin-induced barrier damages.

Blood transcriptome analysis revealed the immune changes and immunological adaptation of wildness training giant pandas.

The giant panda (Ailuropoda melanoleuca) is a global flagship species for biodiversity conservation. As the time for captive giant pandas to be released into the wild matures, wildness training is provided to allow adaptation to their natural environment. It is assumed that changes in the immune system would be integral in this adaptation from captive to wild, where many more pathogens would be encountered in their natural habitats. Therefore, this study aims to determine the expression changes of immune-related genes and their potential as immunoassay markers for adaptation monitoring in wildness training giant pandas, and then to understand the adaptation strategy of wildness training giant pandas to the wild environment, thereby improving the success rate of panda reintroduction. We obtained 300 differentially expressed genes (DEGs) by RNA-seq, with 239 up-regulated and 61 down-regulated DEGs in wildness training giant pandas compared to captive pandas. Functional enrichment analysis indicated that up-regulated DEGs were enriched in several immune-related terms and pathways. There were 21 immune-related DEGs, in which most of them were up-regulated in wildness training giant pandas, including several critical innate and cellular immune genes. IL1R2 was the most significantly up-regulated gene and is a signature of homeostasis within the immune system. In the protein-protein interaction (PPI) analysis, CXCL8, CXCL10, and CCL5 were identified as the hub immune genes. Our results suggested that wildness training giant pandas have stronger innate and cellular immunity than captive giant pandas, and we proposed that a gene set of CXCL8, CXCL10, CCL5, CD3D, NFKBIA, TBX21, IL12RB2, and IL1R2 may serve as potential immunoassay markers to monitor and assess the immune status of wildness training giant pandas. Our study offers the first insight into immune alterations of wildness training giant pandas, paving the way for monitoring and evaluating the immune status of giant pandas when reintroducing them into the wild.

The combination therapy of Everolimus and anti-PD-1 improves the antitumor effect by regulating CD8+ T cells in bladder cancer.

This study aimed to investigate the efficacy of Everolimus (EVE) in combination with immune checkpoint inhibitors (ICIs) in bladder cancer treatment and the underlying mechanisms. In vitro, MB49 cells were exposed to gradient concentrations (0 nM-100 nM) of EVE for 48 h, to investigate the cell viability and cell proliferative potential. In vivo, we applied a subcutaneous tumor mouse model of bladder cancer and the mice were treated with EVE monotherapy (different doses) or in combination with anti-programmed cell death protein 1 (PD-1) agents to study the impacts on tumor growth and explore the immune mechanism. The influences of treatments on peripheral immune profiles and tumor immune microenvironment were also discussed. EVE could inhibit the growth of MB49 cells in vitro. Though high-dose EVE monotherapy could induce tumor regression in vivo, it also contributed to immunosuppression. High-dose EVE inhibited the expression of PD-L1 by inhibiting Th1 cytokine secretion, while combined therapy with PD-1 inhibitors showed no extra profit. Low-dose EVE in combination with PD-1 inhibitors could effectively suppress tumor growth by increasing periphery CD8+ T cell frequency and GZMB+ CD8+ T cell frequency in the tumor microenvironment. High-dose EVE monotherapy induced tumor regression, but with immunosuppression to some content. Combination therapy with low-dose EVE and PD-1 inhibitor could effectively inhibit the growth of bladder tumors by enhancing the antitumor immunity of CD8+ T cells in both periphery and tumor microenvironment.

Novel Ferroptosis-Related Multigene Prognostic Models for Patients with Bladder Cancer.

OBJECTIVE: Bladder cancer contributes to a serious disease burden in clinical settings. The characteristics and prognosis of patients with muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC) are distinctly different. The study aims to figure out the respective role of ferroptosis in MIBC and NMIBC and to construct ferroptosis-related gene signatures that could predict patients' prognoses. METHODS: A total of 608 MIBC and 414 NMIBC RNA-seq transcriptome data with intact clinical and follow-up information were downloaded from The Cancer Genome Atlas (TCGA), ArrayExpress, and Gene expression omnibus (GEO) database. Ferroptosis-related multigene prognostic models were constructed and externally validated, respectively, in MIBC and NMIBC. Further functional enrichment analyses were also performed to explicate the underlying mechanisms and the differences between the two bladder cancer subtypes. RESULTS: In MIBC, a 7-gene signature for prognostic prediction was constructed. Patients were then divided into high-risk and low-risk groups according to the risk scores calculated by the 7-gene prognostic model. Patients in the high-risk group presented an impaired OS when compared with patients in the low-risk group both in the training cohort and validation cohort. Further functional analyses revealed distinctly different immune statuses between the two risk-stratification groups, speculating that exhausted immune cell function was a cause of the worst OS in the high-risk group. In NMIBC, 6 ferroptosis-related genes were identified that were significantly correlated with recurrence-free survival (RFS). Similarly, a 6-gene prognostic model was constructed and verified as an independent prognostic predictor for RFS. Functional analyses revealed significant differences in the expressions of nuclear division genes between the high-risk group and low-risk group. CONCLUSION: Two novel ferroptosis-related multigene prognostic models for, respectively, predicting OS in MIBC and RFS in NMIBC were identified in this study, which indicated ferroptosis played vital roles in the oncogenesis and development of MIBC and NMIBC.

Partial inhibition of activin receptor-like kinase 4 alleviates bladder fibrosis caused by bladder outlet obstruction.

The bladder undergoes profound structural alterations after bladder outlet obstruction (BOO), characterized by hypertrophy of the bladder wall and accumulation of extracellular matrix (ECM). Transforming growth factor-ß (TGF-ß) has been found to promote fibrosis of the bladder induced by partial bladder outlet obstruction (pBOO). Activin receptor-like kinase 4 (ALK4) is a downstream receptor of the TGF-ß superfamily. However, the role of the ALK4-Smad2/3 pathway in the pathogenesis of bladder fibrosis caused by pBOO remains unknown. This study focused on learning the role of ALK4 in the process of bladder fibrosis caused by pBOO. The pBOO mice models showed that ALK4 expression was found to upregulate in the wild-type bladder 6 weeks after pBOO compared to control group. Then, mice with heterozygous knockout of the ALK4 gene (ALK4+/-) were generated. Histological analysis and Western blot (WB) results showed significant suppression of collagen expression in the bladders of ALK4+/- mice after pBOO compared with WT mice. WB also showed that ALK4+/- mice demonstrated significant suppression of phosphorylated Smad2/3 (p-Smad2/3) expression in the bladder 6 weeks after pBOO but not of phosphorylated extracellular signal-regulated kinase, c-Jun N-terminal kinase or protein 38 (p-ERK, p-JNK, p-P38) expression. This effect might have occurred through partial inactivation of the Smad2/3 signaling pathway. In vitro, ALK4 overexpression promoted collagen production in cultured BSMCs and activated the Smad2/3 signaling pathway. Taken together, our results demonstrated that ALK4 insufficiency alleviated bladder fibrosis in a mouse model of pBOO partly by suppressing Smad2/3 activity.

Correlation of prostatic morphological parameters and clinical progression in aging Chinese men with benign prostatic hyperplasia: Results from a cross-sectional study.

OBJECTIVES: Our study aimed to investigate the correlation of prostatic morphological parameters and benign prostatic hyperplasia (BPH) clinical progression in aging Chinese men. METHODS: In this retrospective study, a total of 1038 patients were reviewed. Prostatic morphology was measured by transrectal ultrasound (TRUS). Detailed medical history of all candidates was recorded and analyzed after being classified by specific prostatic measurements. Univariate and multivariate logistic regression analyses were used to estimate the correlation between variables. RESULTS: The cumulative incidence of BPH clinical progression was 63.68% (661/1038) in the study population. Prostate volume (PV), transitional zone volume (TZV), transitional zone index (TZI), and intravesical prostatic protrusion (IPP) were all positively associated with BPH progression (all p < .001). Patients with a PV > 60 ml, TZV > 15 ml, TZI > 0.5, or IPP > 5 mm had a significantly higher possibility of overall BPH clinical progression (adjusted odds ratio (OR): 2.485, 1.678, 1.886, and 1.924, respectively; 95% confidence interval (CI): 1.559-3.960, 1.131-2.489, 1.379-2.579, and 1.357-2.728, correspondingly). CONCLUSION: Prostatic morphological parameters are significantly associated with BPH clinical progression. Patients with larger prostatic morphological parameters are more easily prone to clinical progress. As a result, reasonable managements should be timely considered for those patients before clinical progression occurs.

Immune profiles of male giant panda (Ailuropoda melanoleuca) during the breeding season.

BACKGROUND: The giant panda (Ailuropoda melanoleuca) is a threatened endemic Chinese species and a flagship species of national and global conservation concern. Life history theory proposes that reproduction and immunity can be mutually constraining and interrelated. Knowledge of immunity changes of male giant pandas during the breeding season is limited. RESULTS: Here, we researched peripheral blood gene expression profiles associated with immunity. Thirteen captive giant pandas, ranging from 9 to 11 years old, were divided into two groups based on their reproductive status. We identified 318 up-regulated DEGs and 43 down-regulated DEGs, which were enriched in 87 GO terms and 6 KEGG pathways. Additionally, we obtained 45 immune-related genes with altered expression, mostly up-regulated, and identified four hub genes HSPA4, SUGT1, SOD1, and IL1B in PPI analysis. These 45 genes were related to pattern recognition receptors, autophagy, peroxisome, proteasome, natural killer cell, antigen processing and presentation. SUGT1 and IL1B were related to pattern recognition receptors. HSP90AA1 was the most up-regulated gene and is a member of heat shock protein 90 family. HSP90 contributes to the translocation of extracellular antigen. KLRD1 encodes CD94, whose complex is an inhibitor of the cytotoxic activity of NK cells, was down-regulated. IGIP, which has the capability of inducing IgA production by B cells, was down-regulated, suggesting low concentration of IgA in male giant pandas. Our results suggest that most immune-related genes were up-regulated and more related to innate immune than adaptive immune. CONCLUSIONS: Our results indicated that breeding male giant pandas presented an immunoenhancement in innate immunity, enhanced antigen presentation and processing in cellular immunity compared to non-breeding males. The humoral immunity of male giant pandas may show a tendency to decrease during the breeding season. This study will provide a foundation for further studies of immunity and reproduction in male giant pandas.

Preoperative hydronephrosis predicts adverse pathological features and postoperative survival in patients with high-grade upper tract urothelial carcinoma

ABSTRACT Purpose: Epidemiological studies reported conflicting results about preoperative hydronephrosis in upper tract urothelial carcinoma (UTUC). This study aimed to investigate the association between preoperative hydronephrosis and pathologic features and oncologic outcomes in patients with UTUC treated by radical nephroureterectomy (RNU). Materials and Methods: This was a retrospective, single-center cohort study of 377 patients treated by RNU without perioperative chemotherapy between January 2001 and December 2014. Logistic regression, Cox regression, and survival analyses were performed. Results: Among the 226 patients with high-grade UTUC, 132 (58%) had preoperative hydronephrosis. Multivariable logistic regression revealed that hydronephrosis was independently associated with advanced pT stage (P=0.017) and lymph node or lymphovascular invasion (P=0.002). Median follow-up was 36 months (interquartile range: 20-48 months). The 3- and 5-year overall survival (OS) rates in patients with hydronephrosis were significantly lower than in those without hydronephrosis (both P <0.001). The 3- and 5-year cancer-specific survival (CSS) rates in patients with hydronephrosis were significantly lower than in those without hydronephrosis (both P=0.001). Hydronephrosis was independently associated with OS and CSS (P=0.001 and P=0.004, respectively). Among the 151 patients with low-grade UTUC, hydronephrosis was not associated with pathologic features and postoperative survival. Conclusions: Preoperative hydronephrosis was significantly associated with adverse pathologic features and postoperative survival in patients with high-grade UTUC.

Efficacy of multi-groove silicone drains in single-port video-assisted thoracoscopic lung cancer surgery and their effect on C-reactive protein: a single-center experience.

BACKGROUND: The purpose of this study was to systematically evaluate the effectiveness and safety of a multi-groove silicone drain in single-port video-assisted thoracoscopic lung cancer surgery and its effect on postoperative serum C-reactive protein (CRP) levels. METHODS: We retrospectively analyzed 122 surgical cases who underwent standard lobectomy and lymph node dissection for primary lung cancer between May 2020 and December 2020. A total of 62 patients received 19-F multi-groove silicone drains (experimental group) and 60 patients received 24-F conventional chest drains (control group). According to the different thoracic drainage approaches, the clinical efficacy in the perioperative period, postoperative complications, and postoperative serum CRP levels were compared between the 2 groups. RESULTS: In this study, thoracic drainage volume, the average visual analog scale (VAS) pain scores in incisions, the rate of primary healing at the site of incisions, and the pulmonary infection rate in the multi-groove silicone drain group were significantly lower than those in the conventional chest drain group (P<0.05), but there was no significant difference in the average hospital stay time, arrhythmia rates, and chest tube removal time between the 2 groups. At postoperative day 1, the levels of serum CRP in the 2 groups were further increased (P>0.05), and the comparison between the 2 groups showed that the levels of serum CRP in the multi-groove silicone drain group at 72 h after the operation were significantly lower than those in the conventional drain group (P<0.05). CONCLUSIONS: Our results showed that a multi-groove silicone drain is feasible and relatively safe in single-port video-assisted thoracoscopic lung cancer surgery for most patients. However we should take cautious in those patients with higher susceptibility of postoperative active bleeding. In patients undergoing lung cancer surgery in the clinical treatment process, the use of a multi-groove silicone drain can improve the quality of life of patients. Due to a small number of included studies and unclear bias, the above results should be verified by high-quality, large-sample randomized controlled studies. KEYWORDS: Video-assisted thoracoscopic lung cancer surgery; multi-groove silicone drains; conventional chest drains.