Meclizine improves endometrial repair and reduces simulated menstrual bleeding in mice with induced adenomyosis.

BACKGROUND: Adenomyosis is one of the structural causes of abnormal uterine bleeding, which often presents as heavy menstrual bleeding. Mostly because of the poor understanding of its pathophysiology, medical management of adenomyosis-induced heavy menstrual bleeding is still a challenge. We have previously reported that glycolysis is crucial to endometrial repair following menstruation and that suppressed glycolysis can cause heavy menstrual bleeding. OBJECTIVE: This study aimed to test the hypothesis that meclizine, a drug with an excellent safety profile, alleviates heavy menstrual bleeding in mice with induced adenomyosis using a simulated menstruation model. STUDY DESIGN: Adenomyosis was induced in 36 female C57BL/6 mice using endometrial-myometrial interface disruption. Three months after induction, the mice were randomly divided into the following 3 groups: low-dose meclizine, high-dose meclizine, and controls. Treatment with meclizine or vehicle started shortly before the simulated menstruation procedure and ended before progesterone withdrawal. The amount of blood loss was quantified and uterine tissue was harvested for histologic evaluation of the grade of endometrial repair. We performed immunohistochemistry analysis of 4 proteins critically involved in glycolysis: Glut1 (glucose transporter 1), Hk2 (hexokinase 2), Pfkfb3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3), and Pkm2 (pyruvate kinase M2). The extent of tissue fibrosis in both ectopic and eutopic endometria was evaluated using Masson trichrome staining. RESULTS: In mice with induced adenomyosis, meclizine accelerated endometrial repair in a dose-dependent manner and reduced the amount of menstrual bleeding. Meclizine administration raised endometrial immunoexpression of Hk2 and Pfkfb3 but not of Glut1 or Pkm2. The extent of endometrial fibrosis was reduced following the meclizine administration. Remarkably, these favorable changes were accompanied by the suppression of lesional progression, as evidenced by the dose-dependent reduction in the extent of fibrosis (a surrogate for lesional progression). CONCLUSION: These encouraging results, taken together, suggest that glycolysis may be a promising therapeutic target and that meclizine may hold therapeutic potential as a nonhormonal treatment for adenomyosis-induced heavy menstrual bleeding without exacerbating the disease.

Single-cell Sequencing Data Reveals Aggressive CD68-type Macrophages and Prognostic Models in Bladder Cancer.

BACKGROUND: The highly heterogeneous, complex pathological histology, and clinical phenotype in bladder cancer (BC) plague the prognostic management of BC to the present day. METHODS: This study was conducted using single-cell sequencing data from the gene expression omnibus (GEO) database (GSE135337). A descending, annotated analysis was performed to identify the cell types contributing to BC aggressiveness. BC cell sequencing data from The Cancer Genome Atlas (TCGA) database were then combined with univariate, least absolute shrinkage and selection operator (LASSO), multivariate COX regression analysis to identify biomarkers of BC prognosis to construct a BC. We identified biomarkers of BC prognosis to construct a prognostic risk guidance system for BC. The feedback of patients in different risk strata to immunotherapy was analyzed. Finally, the regulation of prognostic genes on cancer cell activity was verified in vitro by Western blot and cell counting kit-8 (CCK8) assays. RESULTS: Macrophages specifically expressing CD68 in BC were the cell type with the highest AUCell score, and CD68 was the biomarker of Tumor-associated macrophages (TAMs). CD68 macrophages were potentially the critical cell type in the aggressive BC subtype. Through univariate, LASSO, multivariate COX-based regression analysis. CTSS, GMFG, ANXA5, GSN, SLC2A3, and FTL were authenticated as prognostic biomarkers (p < 0.05) and composed the Risk Score. Patients in the low-risk group showed an excellent survival advantage (p < 0.01) and immunotherapy feedback. Additionally, inhibition of GSN expression decreased EMT activity to inhibit bladder cancer cell viability. CONCLUSION: In conclusion, this study provided feedback on the immune cell types associated with aggressiveness in BC. Importantly, a prognostic management system for BC was created based on the genes involved, providing more insight into the aggressive pathological phenotype as well as the prognosis of BC.

The Memorial Sloan Kettering Prognostic Score: Correlation with survival in patients with advanced gastric cancer.

BACKGROUND: Notwithstanding that the past decade has witnessed unprecedented medical progress, gastric cancer (GC) remains a leading cause of cancer death, highlighting the need for effective prognostic markers. The Memorial Sloan Kettering Prognostic Score (MPS) has been validated as a valuable prognostic tool for patients with metastatic pancreatic adenocarcinoma (mPDAC). This study aimed to assess the prognostic value of the MPS in advanced GC. METHODS: Data from 367 patients were analyzed in the present study. The MPS for each patient was calculated based on the sum of scores based on the neutrophil-to-lymphocyte ratio and serum albumin levels. Multivariate analyses were performed to identify the independent clinicopathological parameters associated with overall survival (OS). Further subgroup analyses based on clinicopathological features were conducted. RESULTS: Patients with MPS 0 (n = 161), MPS 1 (n = 158), and MPS 2 (n = 48) exhibited significantly different OS, with a median survival duration of 20.7 (95%CI: 12.2-29.2), 14.9 (95%CI: 12.5-17.3), and 12.7 (95%CI: 9.3-16.0) months, respectively (p < 0.001). Significant differences in survival were observed among different groups of patients receiving chemotherapy (18.5 months vs. 14.7 months vs. 11.0 months, p = 0.03) or the subgroup receiving chemotherapy plus immunotherapy as first-line treatment (32.6 months vs. 17.7 months vs. 12.7 months, p = 0.02). The MPS was identified as an independent prognostic factor in multivariate analysis. During subgroup analyses, MPS-low (MPS 0) was consistently associated with a better prognosis than MPS-high (MPS 1 or 2). CONCLUSIONS: MPS is a practical, simple, and useful prognostic tool for patients with advanced GC. Further studies are warranted to validate its prognostic value in advanced GC.

Reduced endometrial expression of histone deacetylase 3 in women with adenomyosis who complained of heavy menstrual bleeding.

RESEARCH QUESTION: What role, if any, does histone deacetylase 3 (HDAC3) play in adenomyosis-associated heavy menstrual bleeding (HMB)? DESIGN: Seventy-two women with adenomyosis-associated HMB were recruited. Of these, 37 women reported moderate/heavy bleeding (MHB) and the remaining 35 women reported excessive bleeding (EXB). The stiffness of adenomyotic lesions and neighbouring endometrial-myometrial interface (EMI) was measured by transvaginal elastosonography, and full-thickness uterine tissue columns were processed for Masson trichrome staining and immunohistochemistry analyses. The protein expression levels of HDAC3 in endometrial cells cultured on substrates of different stiffnesses, and the protein concentrations of nuclear factor-κB (NF-κB) p65 subunit with HDAC3 suppression were evaluated. Mouse experiments were performed to assess the effect of adenomyosis on Hdac3 expression, endometrial repair and bleeding, and to evaluate the effect of HDAC3 inhibition on endometrial repair. RESULTS: Compared with controls, the endometrial staining of HDAC3 was significantly lower in women with adenomyosis-associated HMB, concomitant with a greater extent of fibrosis. The stiffness of lesions and neighbouring EMI was significantly higher in the EXB group compared with the MHB group, as was the extent of fibrosis in lesions, their neighboring EMI and endometrium. Expression of HDAC3 was reduced significantly when endometrial epithelial cells were cultured in stiff substrates. Suppression of HDAC3 abrogated the activation and signalling of NF-κB. Mice with induced adenomyosis exhibited reduced Hdac3 staining and elevated fibrosis in endometrium, concomitant with disrupted endometrial repair and more bleeding. Hdac3 inhibition resulted in botched inflammation and increased bleeding. CONCLUSIONS: Lesional fibrosis results in reduced endometrial HDAC3 expression and subsequent disruption in NF-κB signalling and inflammation, leading to adenomyosis-associated HMB.

Inhibition of USP10 induces myeloma cell apoptosis by promoting cyclin D3 degradation.

The cell cycle regulator cyclin D3 (CCND3) is highly expressed in multiple myeloma (MM) and it promotes MM cell proliferation. After a certain phase of cell cycle, CCND3 is rapidly degraded, which is essential for the strict control of MM cell cycle progress and proliferation. In the present study, we investigated the molecular mechanisms regulating CCND3 degradation in MM cells. By utilizing affinity purification-coupled tandem mass spectrometry, we identified the deubiquitinase USP10 interacting with CCND3 in human MM OPM2 and KMS11 cell lines. Furthermore, USP10 specifically prevented CCND3 from K48-linked polyubiquitination and proteasomal degradation, therefore enhancing its activity. We demonstrated that the N-terminal domain (aa. 1-205) of USP10 was dispensable for binding to and deubiquitinating CCND3. Although Thr283 was important for CCND3 activity, it was dispensable for CCND3 ubiquitination and stability modulated by USP10. By stabilizing CCND3, USP10 activated the CCND3/CDK4/6 signaling pathway, phosphorylated Rb, and upregulated CDK4, CDK6 and E2F-1 in OPM2 and KMS11 cells. Consistent with these findings, inhibition of USP10 by Spautin-1 resulted in accumulation of CCND3 with K48-linked polyubiquitination and degradation that synergized with Palbociclib, a CDK4/6 inhibitor, to induce MM cell apoptosis. In nude mice bearing myeloma xenografts with OPM2 and KMS11 cells, combined administration of Spautin-l and Palbociclib almost suppressed tumor growth within 30 days. This study thus identifies USP10 as the first deubiquitinase of CCND3 and also finds that targeting the USP10/CCND3/CDK4/6 axis may be a novel modality for the treatment of myeloma.

Decreased Glycolysis at Menstruation is Associated with Increased Menstrual Blood Loss.

Heavy menstrual bleeding (HMB) is common and severely affects the quality of life of the afflicted women. While HMB is known to be caused by impaired endometrial repair after menstruation, its more proximate cause remains unknown. To investigate whether glycolysis plays any role in endometrial repair and thus HMB, we conducted two mouse experiments using a mouse model of simulated menstruation. We performed immunohistochemistry analyses of proteins involved in glycolysis as well as pro- and anti-inflammatory cytokines in endometrium from decidualized and non-decidualized uterine horns. We also assessed the extent of endometrial repair by staging endometrial morphology from decidualization to full repair using histological scoring of uterine sections and quantitated the amount of menstrual blood loss (MBL). In addition, we employed the scratch assay and the CCK-8 assay to evaluate the effect of glycolysis suppression on cellular migration and proliferation, respectively. Finally, we performed an immunohistochemistry analysis of HK2 in endometrium from women with adenomyosis who experienced either moderate/heavy or excessive MBL. We found that endometrial repair coincided with increased glycolysis in endometrium and glycolysis suppression delayed endometrial repair, resulting in increased MBL. Additionally, glycolysis suppression significantly inhibited the proliferative and migratory capability of endometrial cells, and disrupted normal endometrial repair even when hypoxia was maintained. Women with adenomyosis who experienced excessive MBL had significantly lower HK2 staining than those who experienced moderate/heavy MBL. Thus, our study highlights the importance of glycolysis as well as inflammation in optimal endometrial repair, and provides clues for the cause of HMB in women with adenomyosis.

Nomogram Based on Monocyte-to-Lymphocyte Ratio to Predict Survival of Unresectable Esophageal Squamous Cell Carcinoma Who Receive First-Line PD-1/PD-L1 Inhibitors Combined with Chemotherapy.

BACKGROUND: Chemoimmunotherapy has become the first-line treatment for unresectable esophageal squamous cell carcinoma (ESCC). Still, reliable biomarkers to identify patients who could benefit from this combined therapy remain uncertain. This study focused on elucidating the predictive significance of the monocyte-to-lymphocyte ratio (MLR) and establishing the prognostic nomogram for unresectable ESCC treated with chemoimmunotherapy. METHODS: Data of clinical features, peripheral blood parameters, and treatment records were collected in unresectable ESCC patients who received PD-1/PD-L1 inhibitors plus chemotherapy as the first-line treatment from September 2017 to August 2021. The nomogram based on MLR and clinical parameters for predicting the overall survival (OS) was developed and validated. RESULTS: Out of 81 patients enrolled, patients with a lower MLR had significantly longer progression-free survival (PFS) and OS than patients with a higher pretreatment MLR (p = 0.0067; p = 0.00069). The OS nomogram integrating MLR, performance status (PS) score, and body mass index (BMI) achieved a C-index of 0.770 (95%CI 0.645-0.896). The area under the ROC curve (AUC) value of the nomogram predicting 12-, 18-, and 24-month OS rates were 0.855, 0.792, and 0.744, respectively, which were higher than the clinical TNM staging system or the MLR. Stratified by the nomogram-generated scores, three risk groups (low, moderate, and high) in survival curves manifested a distinct difference (p < 0.0001). CONCLUSION: MLR emerged as an independent predictive factor for PFS and OS in treatment-naive unresectable ESCC patients treated with chemoimmunotherapy. The constructed nomogram of MLR and clinical parameters was a reliable model for prognostic estimation.

Association of inflammatory markers with survival in patients with advanced gastric cancer treated with immune checkpoint inhibitors combined with chemotherapy as first line treatment.

Background: The emergence of immune checkpoint inhibitors has changed the landscape of first-line treatment of patients with advanced gastric cancer. Currently, the prognostic significance of inflammatory markers in first-line immunotherapy combined with chemotherapy for gastric cancer is currently unclear. This study aimed to identify inflammatory markers with potential to predict treatment outcome in advanced gastric cancer patients receiving immunotherapy combined with chemotherapy. Methods: This retrospective study enrolled untreated advanced or metastatic gastric or gastro-esophageal junction cancer patients from 5 clinical trials (the clinical trial cohort) and the real world (the real-word cohort). Inflammatory markers included in the analysis included neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and derived neutrophil-to-lymphocyte ratio (dNLR). Receiver operating characteristic (ROC) curves were constructed to identify optimal cut-off values. The prognostic potential of the markers was determined using Kaplan-Meier analysis, univariate and multivariate Cox-regression analyses in the clinical trial cohort and the findings were validated in the real-world cohort. Results: In the clinical trial cohort (n=45), MLR, PLR and SII were associated with PFS but not OS (All P<0.05), while dNLR was not correlated with PFS or OS. Only NLR was associated with PFS and OS and identified as an independent prognostic predictor in the univariate and multivariate analyses. The prognostic value of NLR was validated in the real-world cohort (n=55). Conclusions: NLR was a strong predictor of PFS and OS in patients with advanced gastric cancer receiving immune checkpoint inhibitors combined with chemotherapy. Further prospective studies are required to validate our results.

Influence of Cold Environments on Growth, Antioxidant Status, Immunity and Expression of Related Genes in Lambs.

Cold climates may be a risk to the health and welfare of lambs during winter because cold environments alter the physiological processes of lambs, and we used cold environments with three different temperature gradients-an indoor heating control group (IHC) using electric heating; an indoor temperature group (IT) with intermittent and slight degrees of stimulation of coldness; an outdoor temperature group (OT) exposed to cold environments in an external natural environment. The results showed that the lambs in the OT group had a greater decrease in the average daily gain (ADG) and increase in the average daily feed intake (ADFI) and the feed-to-gain ratio (F:G) compared to the other two groups. The decrease in immunoglobulin A (IgA) and interleukin 2 (IL-2) contents and IL-2 gene expression, and the increase in tumor necrosis factor α (TNF-α) content and TNF-α and nuclear factor kappa-B p65 (NF-κB p65) gene expressions in the OT group suggested that the lambs had a compromised immune status in cold environments. Moreover, the decrease in catalase (CAT), glutathione peroxidase (GPx), total superoxide dismutase (T-SOD), and total antioxidant capacity (T-AOC) levels, and CAT, GPx, SOD1, SOD2, and nuclear factor-erythroid 2-related factor 2 (Nrf2) gene expressions, and the increase in malondialdehyde (MDA) in the OT group suggested that the lambs had a lower antioxidant defense capacity in cold environments. Thus, in extreme cold, lambs kept outdoors could reduce growth, immune function and antioxidant status. However, shelter feeding in winter could relieve the stress of cold environments on lambs, and housing with heating equipment was more conducive to the improve growth, immune, and antioxidant function of the lambs.

Gene editing monkeys: Retrospect and outlook.

Animal models play a key role in life science research, especially in the study of human disease pathogenesis and drug screening. Because of the closer proximity to humans in terms of genetic evolution, physiology, immunology, biochemistry, and pathology, nonhuman primates (NHPs) have outstanding advantages in model construction for disease mechanism study and drug development. In terms of animal model construction, gene editing technology has been widely applied to this area in recent years. This review summarizes the current progress in the establishment of NHPs using gene editing technology, which mainly focuses on rhesus and cynomolgus monkeys. In addition, we discuss the limiting factors in the applications of genetically modified NHP models as well as the possible solutions and improvements. Furthermore, we highlight the prospects and challenges of the gene-edited NHP models.

Long-term survival of gastric mixed neuroendocrine-non-neuroendocrine neoplasm: Two case reports.

BACKGROUND: Gastric mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), which consists of neuroendocrine and non-neuroendocrine components, is quite rare. Until now, most data on gastric MiNEN come from clinical cases, without large-scale retrospective studies or controlled clinical trials. Consequently, no consensus regarding the origin, molecular characteristics, or appropriate treatment of MiNEN has been reached so far. We conducted chemotherapy of irinotecan plus cisplatin (IP regimen) and surgery in two patients with gastric MiNEN, which had never been used in treating this kind of tumor, leading to their long-term survival for more than 3 and 7 years, respectively. CASE SUMMARY: We present two patients (one male and one female) with gastric MiNEN, with the primary manifestation of recurrent upper abdominal pain. After they were referred to our hospital, a diagnosis of gastric MiNEN was defined with the help of CT scan, and histopathological and immunohistochemical examinations on the samples of gastrointestinal endoscopy or radical surgery. The male patient (case 1) were found to have metastases in the reginal lymph nodes and the left liver. He received four cycles of IP regimens first, then the gastrectomy and partial left liver resection, followed by additional two cycles of IP chemotherapy. The female patient (case 2) underwent a laparoscopic gastrectomy, and received six cycles of IP regimen. She was found to have metastatic lesions in the right lung 2 years after that, and underwent video-assisted thoracoscopic surgery (VATS) of the lower lobe of the right lung. The two patients have now survived for more than 3 years and 7 years, respectively, without any evidence of recurrence or metastases. CONCLUSION: IP regimen, combined with curative-intent surgery if feasible, could be considered as the priority in the choice of front-line chemotherapy for gastric MiNEN.

Induction of zinc finger protein RNF6 auto-ubiquitination for the treatment of myeloma and chronic myeloid leukemia.

The zinc finger ubiquitin ligase RNF6 has been proposed as a potential therapeutic target in several cancers, but understanding its molecular mechanism of degradation has been elusive. In the present study, we find that RNF6 is degraded via auto-ubiquitination in a manner dependent on its Really Interesting New Gene (RING) domain. We determine that when the RING domain is deleted (ΔRING) or the core cysteine residues in the zinc finger are mutated (C632S/C635S), the WT protein, but not the ΔRING or mutant RNF6 protein, undergoes polyubiquitination. We also identify USP7 as a deubiquitinase of RNF6 by tandem mass spectrometry. We show that USP7 interacts with RNF6 and abolishes its K48-linked polyubiquitination, thereby preventing its degradation. In contrast, we found a USP7-specific inhibitor promotes RNF6 polyubiquitination, degradation, and cell death. Furthermore, we demonstrate the anti-leukemic drug Nilotinib and anti-myeloma drug Panobinostat (LBH589) induce RNF6 K48-linked polyubiquitination and degradation in both multiple myeloma (MM) and leukemia cells. In agreement with our hypothesis on the mode of RNF6 degradation, we show these drugs promote RNF6 auto-ubiquitination in an in vitro ubiquitination system without other E3 ligases. Consistently, reexpression of RNF6 ablates drug-induced MM and leukemia cell apoptosis. Therefore, our results reveal that RNF6 is a RING E3 ligase that undergoes auto-ubiquitination, which could be abolished by USP7 and induced by anti-cancer drugs. We propose that chemical induction of RNF6 auto-ubiquitination and degradation could be a novel strategy for the treatment of hematological malignancies including MM and leukemia.

The Roles of Adipose Tissue Macrophages in Human Disease.

Macrophages are a population of immune cells functioning in antigen presentation and inflammatory response. Research has demonstrated that macrophages belong to a cell lineage with strong plasticity and heterogeneity and can be polarized into different phenotypes under different microenvironments or stimuli. Many macrophages can be recruited by various cytokines secreted by adipose tissue. The recruited macrophages further secrete various inflammatory factors to act on adipocytes, and the interaction between the two leads to chronic inflammation. Previous studies have indicated that adipose tissue macrophages (ATMs) are closely related to metabolic diseases like obesity and diabetes. Here, we will not only conclude the current progress of factors affecting the polarization of adipose tissue macrophages but also elucidate the relationship between ATMs and human diseases. Furthermore, we will highlight its potential in preventing and treating metabolic diseases as immunotherapy targets.

Research Progress of RNA Methylation Modification in Colorectal Cancer.

Accumulating evidence indicates that RNA methylation, as the most common modification of mRNA, is of great significance in tumor progression and metastasis. Colorectal cancer is a common malignant tumor of the digestive system that seriously affects the health of middle-aged and elderly people. Although there have been many studies on the biological mechanism of the occurrence and development of colorectal cancer, there are still major deficiencies in the diagnosis and prognosis of colorectal cancer. With the deep study of RNA methylation, it was found that RNA modification is highly related to colorectal cancer tumorigenesis, development and prognosis. Here, we will highlight various RNA chemical modifications including N6-methyladenosine, 5-methylcytosine, N1-methyladenosine, 7-methylguanine, pseudouridine and their modification enzymes followed by summarizing their functions in colorectal cancer.

Identification of glycolysis-associated long non-coding RNA regulatory subtypes and construction of prognostic signatures by transcriptomics for bladder cancer.

Glycolysis-targeted cancer therapy based on long non-coding RNAs (lncRNAs), owing to its high specificity and less toxicity, is at the preclinical stages. Our study aimed to examine the roles of the core glycolysis-associated lncRNAs in bladder cancer (BC). Glycolysis scores of BC were computed by single-sample gene set enrichment analysis (ssGSEA). Glycolysis-associated lncRNAs were screened by Pearson's correlation analysis. Unsupervised consensus clustering using ConsensusClusterPlus assessed the glycolysis-associated lncRNAs for the identification of molecular subtypes of BC. The Kaplan-Meier survival analysis, genomic mutations, and tumor microenvironment (TME) analysis were used to compare the characteristics of different subtypes. Key glycolysis-associated lncRNAs were screened by first-order partial correlation and univariate Cox proportional-hazards model analyses; finally, the lncRNA signature was constructed. Four glycolysis-associated lncRNA-regulated subtypes having differential overall survival (OS), clinical features, genomic mutation profiles, and TME profiles along with nuclear immunotherapeutic responses were identified. Nine lncRNAs localized in the nucleus were identified and transcription factors (TFs) significantly negatively associated with these were found to be enriched in multiple oncogenic signaling pathways. Among them, three lncRNAs (AC093673.5, AC034220.3, and RP11-250B2.3) exerted the most profound effects on glycolysis and constituted the lncRNA signature, which could substantially distinguish the risk levels among different BC patients. Four glycolysis-associated lncRNA-regulated subtypes were identified in this study, reflective of the biological characteristics and heterogeneity of BC. Three key glycolysis-associated lncRNA constituting a signature could predict the risk levels in BC, provide a reference for stratification, and be used as prognostic markers for BC diagnosis and treatment.

Analysis of the gut microbiota composition of myostatin mutant cattle prepared using CRISPR/Cas9.

Myostatin (MSTN) negatively regulates muscle development and positively regulates metabolism through various pathways. Although MSTN function in cattle has been widely studied, the changes in the gut microbiota due to MSTN mutation, which contribute to host health by regulating its metabolism, remain unclear. Here, high-throughput sequencing of the 16S rRNA gene was conducted to analyze the gut microbiota of wild-type (WT) and MSTN mutant (MT) cattle. A total of 925 operational taxonomic units (OTUs) were obtained, which were classified into 11 phyla and 168 genera. Alpha diversity results showed no significant differences between MT and WT cattle. Beta diversity analyses suggested that the microbial composition of WT and MT cattle was different. Three dominant phyla and 21 dominant genera were identified. The most abundant bacterial genus had a significant relationship with the host metabolism. Moreover, various bacteria beneficial for health were found in the intestines of MT cattle. Analysis of the correlation between dominant gut bacteria and serum metabolic factors affected by MSTN mutation indicated that MSTN mutation affected the metabolism mainly by three metabolism-related bacteria, Ruminococcaceae_UCG-013, Clostridium_sensu_stricto_1, and Ruminococcaceae_UCG-010. This study provides further insight into MSTN mutation regulating the host metabolism by gut microbes and provides evidence for the safety of gene-edited animals.

Semen as a rich source of diagnostic biomarkers for prostate cancer: latest evidence and implications.

Prostate cancer (PCa) is one of the most common cancers in men and the cause of numerous cancer deaths in the world. Nowadays, based on diagnostic criteria, prostate-specific antigen (PSA) evaluation and rectal examination are used to diagnose prostate-related malignancies. However, due to the different types of PCa, there are several doubts about the diagnostic value of PSA. On the other hand, semen is considered an appropriate source and contains various biomarkers in non-invasive diagnosing several autoimmune disorders and malignancies. Evidence suggests that analysis of semen biomarkers could be helpful in PCa diagnosis. Therefore, due to the invasiveness of most diagnostic methods in PCa, the use of semen as a biologic sample containing various biomarkers can lead to the emergence of novel and non-invasive diagnostic approaches. This review summarized recent studies on the use of various seminal biomarkers for diagnosis, prognosis and prediction of PCa.

A Double-Edged Sword Role of Cytokines in Prostate Cancer Immunotherapy.

Prostate cancer (PC) is one of the most common malignancies among men and is the second leading cause of cancer death. PC immunotherapy has taken relatively successful steps in recent years, and these treatments are still being developed and tested. Evidence suggests that immunotherapy using cytokines as essential mediators in the immune system may help treat cancer. It has been shown that cytokines play an important role in anti-tumor defense. On the other hand, other cytokines can also favor the tumor and suppress anti-tumor responses. Moreover, the dose of cytokine in cancer cytokine-based immunotherapy, as well as the side effects of high doses, can also affect the outcomes of treatment. Cytokines can also be determinative in the outcome of other immunotherapy methods used in PC. In this review, the role of cytokines in the pathogenesis of cancer and their impacts on the main types of immunotherapies in the treatment of PC are discussed.

Assessment of TMB, PD-L1, and lymphocyte to monocyte ratio as predictive potential in a phase Ib study of sintilimab in patients with advanced solid tumors.

BACKGROUND: Sintilimab is a humanized monoclonal antibody against the programmed cell death 1 (PD-L1). We aimed to assess the safety and activity of sintilimab monotherapy or in combination with chemotherapy in advanced solid tumors. METHODS: This phase Ib study included six cohorts. Cohort A-C were sintilimab monotherapy settings, and enrolled pretreated patients (2/3 L cohorts). Cohort D-F were treatment-naïve patients (1 L cohorts), and received sintilimab plus different chemotherapies. The primary endpoints were safety and objective response rate (ORR). Exploratory endpoints were potential biomarkers for the prognosis after treatment, such as tumor mutation burden scores (TMB), PD-L1 and lymphocyte-to-monocyte ratio (LMR). RESULTS: The ORR was 14.6% in the 2/3 L cohorts (n=146), and 73.2% in the 1 L cohorts (n=61). The incidence of grade 3-4 adverse events occurred in 55 patients (37.7%) in 2/3 L cohorts, and in 38 (62.3%) in 1 L cohorts. 157 patients had available TMB scores, and in 2/3 L cohorts, patients in the high TMB groups (TMB≥10) showed a longer progression-free survival (PFS) and overall survival (OS) than those in the low TMB groups (TMB<10). No significant differences in PFS and OS were observed across different PD-L1 groups in both 1 L and 2/3 L cohorts. A high LMR was significantly associated with an improved PFS in 1 L cohorts (P=0.022). CONCLUSION: Sintilimab alone or combined with chemotherapy had a tolerable safety profile in solid tumors. The combination therapy showed a favorable activity with advanced non-small cell lung cancer and gastric or esophagogastric junction adenocarcinoma. LMR might be a prognostic factor for the combination regimen in these patients. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02937116. Registered 18 October 2016.

Optimization of BCG Therapy Targeting Neutrophil Extracellular Traps, Autophagy, and miRNAs in Bladder Cancer: Implications for Personalized Medicine.

Bladder cancer (BC) is the ninth most common cancer and the thirteenth most common cause of mortality worldwide. Bacillus Calmette Guerin (BCG) instillation is a common treatment option for BC. BCG therapy is associated with the less adversary effects, compared to chemotherapy, radiotherapy, and other conventional treatments. BCG could inhibit the progression and recurrence of BC by triggering apoptosis pathways, arrest cell cycle, autophagy, and neutrophil extracellular traps (NETs) formation. However, BCG therapy is not efficient for metastatic cancer. NETs and autophagy were induced by BCG and help to suppress the growth of tumor cells especially in the primary stages of BC. Activated neutrophils can stimulate autophagy pathway and release NETs in the presence of microbial pathogenesis, inflammatory agents, and tumor cells. Autophagy can also regulate NETs formation and induce production of reactive oxygen species (ROS) and NETs. Moreover, miRNAs are important regulator of gene expression. These small non-coding RNAs are also considered as an essential factor to control the levels of tumor development. However, the interaction between BCG and miRNAs has not been well-understood yet. Therefore, the present study discusses the roles of miRNAs in regulations of autophagy and NETs formation in BCG therapy in the treatment of BC. The roles of autophagy and NETs formation in BC treatment and efficiency of BCG are also discussed.