Cholangiocarcinoma combined with biliary obstruction: an exosomal circRNA signature for diagnosis and early recurrence monitoring.

Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with currently suboptimal diagnostic and prognostic approaches. We present a novel system to monitor CCA using exosomal circular RNA (circRNA) via serum and biliary liquid biopsies. A pilot cohort consisting of patients with CCA-induced biliary obstruction (CCA-BO, n = 5) and benign biliary obstruction (BBO, n = 5) was used to identify CCA-derived exosomal circRNAs through microarray analysis. This was followed by a discovery cohort (n = 20) to further reveal a CCA-specific circRNA complex (hsa-circ-0000367, hsa-circ-0021647, and hsa-circ-0000288) in both bile and serum exosomes. In vitro and in vivo studies revealed the three circRNAs as promoters of CCA invasiveness. Diagnostic and prognostic models were established and verified by two independent cohorts (training cohort, n = 184; validation cohort, n = 105). An interpreter-free diagnostic model disclosed the diagnostic power of biliary exosomal circRNA signature (Bile-DS, AUROC = 0.947, RR = 6.05) and serum exosomal circRNA signature (Serum-DS, AUROC = 0.861, RR = 4.04) compared with conventional CA19-9 (AUROC = 0.759, RR = 2.08). A prognostic model of CCA undergoing curative-intent surgery was established by calculating early recurrence score, verified with bile samples (Bile-ERS, C-index=0.783) and serum samples (Serum-ERS, C-index = 0.782). These models, combined with other prognostic factors revealed by COX-PH model, enabled the establishment of nomograms for recurrence monitoring of CCA. Our study demonstrates that the exosomal triple-circRNA panel identified in both bile and serum samples serves as a novel diagnostic and prognostic tool for the clinical management of CCA.

Prognostic factors associated with early recurrence following liver resection for colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is the 3rd most common malignancy with the liver being the most common site of metastases. The recurrence rate of colorectal liver metastases (CRLM) after liver resection (LR) is notably high, with an estimated 40% of patients experiencing recurrence within 6 months. In this context, we conducted a meta-analysis to synthesize and evaluate the reliability of evidence pertaining to prognostic factors associated with early recurrence (ER) in CRLM following LR. METHODS: Systematic searches were conducted from the inception of databases to July 14, 2023, to identify studies reporting prognostic factors associated with ER. The Quality in Prognostic Factor Studies (QUIPS) tool was employed to assess risk-of-bias for included studies. Meta-analysis was then performed on these prognostic factors, summarized by forest plots. The grading of evidence was based on sample size, heterogeneity, and Egger's P value. RESULTS: The study included 24 investigations, comprising 12705 individuals, during an accrual period that extended from 2007 to 2023. In the evaluation of risk-of-bias, 22 studies were rated as low/moderate risk, while two studies were excluded because of high risk. Most of the studies used a postoperative interval of 6 months to define ER, with 30.2% (95% confidence interval [CI], 24.1-36.4%) of the patients experiencing ER following LR. 21 studies were pooled for meta-analysis. High-quality evidence showed that poor differentiation of CRC, larger and bilobar-distributed liver metastases, major hepatectomy, positive surgical margins, and postoperative complications were associated with an elevated risk of ER. Additionally, moderate-quality evidence suggested that elevated levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA199), lymph node metastases (LNM) of CRC, and a higher number of liver metastases were risk factors for ER. CONCLUSION: This review has the potential to enhance the efficacy of surveillance strategies, refine prognostic assessments, and guide judicious treatment decisions for CRLM patients with high risk of ER. Additionally, it is essential to undertake well-designed prospective investigations to examine additional prognostic factors and develop salvage therapeutic approaches for ER of CRLM.

Advances in the understanding of circRNAs that influence viral replication in host cells.

Circular RNAs (circRNAs) are non-coding RNAs discovered in recent years, which are produced by back-splicing involving the 3' and 5' ends of RNA molecules. There is increasing evidence that circRNAs have important roles in cancer, neurological diseases, cardiovascular and cerebrovascular diseases, and other diseases. In addition, host circRNAs and virus-encoded circRNAs participate in the body's immune response, with antiviral roles. This review summarizes the mechanisms by which host and viral circRNAs interact during the host immune response. Comprehensive investigations have revealed that host circRNAs function as miRNA sponges in a particular manner, primarily by inhibiting viral replication. Viral circRNAs have more diverse functions, which generally involve promoting viral replication. In addition, in contrast to circRNAs from RNA viruses, circRNAs from DNA viruses can influence host cell migration, proliferation, and apoptosis, along with their effects on viral replication. In summary, circRNAs have potential as diagnostic and therapeutic targets, offering a foundation for the diagnosis and treatment of viral diseases.

Development and validation of machine learning-augmented algorithm for insulin sensitivity assessment in the community and primary care settings: a population-based study in China.

Objective: Insulin plays a central role in the regulation of energy and glucose homeostasis, and insulin resistance (IR) is widely considered as the "common soil" of a cluster of cardiometabolic disorders. Assessment of insulin sensitivity is very important in preventing and treating IR-related disease. This study aims to develop and validate machine learning (ML)-augmented algorithms for insulin sensitivity assessment in the community and primary care settings. Methods: We analyzed the data of 9358 participants over 40 years old who participated in the population-based cohort of the Hubei center of the REACTION study (Risk Evaluation of Cancers in Chinese Diabetic Individuals). Three non-ensemble algorithms and four ensemble algorithms were used to develop the models with 70 non-laboratory variables for the community and 87 (70 non-laboratory and 17 laboratory) variables for the primary care settings to screen the classifier of the state-of-the-art. The models with the best performance were further streamlined using top-ranked 5, 8, 10, 13, 15, and 20 features. Performances of these ML models were evaluated using the area under the receiver operating characteristic curve (AUROC), the area under the precision-recall curve (AUPR), and the Brier score. The Shapley additive explanation (SHAP) analysis was employed to evaluate the importance of features and interpret the models. Results: The LightGBM models developed for the community (AUROC 0.794, AUPR 0.575, Brier score 0.145) and primary care settings (AUROC 0.867, AUPR 0.705, Brier score 0.119) achieved higher performance than the models constructed by the other six algorithms. The streamlined LightGBM models for the community (AUROC 0.791, AUPR 0.563, Brier score 0.146) and primary care settings (AUROC 0.863, AUPR 0.692, Brier score 0.124) using the 20 top-ranked variables also showed excellent performance. SHAP analysis indicated that the top-ranked features included fasting plasma glucose (FPG), waist circumference (WC), body mass index (BMI), triglycerides (TG), gender, waist-to-height ratio (WHtR), the number of daughters born, resting pulse rate (RPR), etc. Conclusion: The ML models using the LightGBM algorithm are efficient to predict insulin sensitivity in the community and primary care settings accurately and might potentially become an efficient and practical tool for insulin sensitivity assessment in these settings.

The Expression of Two Distinct Sets of Glycolytic Enzymes Reveals Differential Effects of Glycolytic Reprogramming on Pancreatic Ductal Tumorigenesis in Mice.

Pancreatic ductal adenocarcinoma (PDAC) is associated with enhanced aerobic glycolysis through elevated glucose uptake and the upregulated expression of genes encoding rate-limiting glycolytic enzymes. However, the direct impact of altered glycolytic pathways on pancreatic tumor progression has not been thoroughly investigated. Here, we utilized two strains of BAC transgenic mice with pancreatic expression of two distinct sets of glycolytic genes each arranged in a polycistronic fashion (PFKFB3-HK2-GLUT1 and LDHA-PDK1, respectively) to investigate the role of altered glycolysis on the development of pancreatic ductal tumor development in the Pdx1-Cre; LSL-KrasG12D mice. The overexpression of the two sets of glycolytic genes exhibited no significant effects on tumor development in the 4-5-month-old mice (the PanIN2 lesions stage). In the 9-10-month-old mice, the overexpression of PFKFB3-HK2-GLUT1 significantly accelerated PanIN3 progression, exhibiting elevated levels of ductal cell marker CK19 and tumor fibrosis. Surprisingly, the overexpression of LDHA-PDK1 significantly attenuated the progression of PanIN3 in the 9-10-month-old mice with significantly downregulated levels of CK19 and fibrosis. Therefore, distinct set of glycolytic enzymes that are involved in different glycolytic routes exhibited contrasting effects on pancreatic ductal tumor development depending on the tumor stages, providing novel insights into the complexity of the glycolytic pathway in the perspective of PDAC development and therapy.

Losartan alleviates renal fibrosis by inhibiting the biomechanical stress-induced epithelial-mesenchymal transition of renal epithelial cells.

Angiotensin receptor blockers (ARBs) have been reported to be beneficial of renal fibrosis, but the molecular and cellular mechanisms are still unclear. In this study, we investigated the effectiveness and relevant mechanism of ARBs in alleviating renal fibrosis, especially by focusing on biomechanical stress-induced epithelial to mesenchymal transition (EMT) of renal epithelial cells. Unilateral ureteral obstruction (UUO) renal fibrosis model was established in mice by ligating the left ureter, and then randomly received losartan at a low dose (1 mg/kg) or a regular dose (3 mg/kg) for 2 weeks. Compared to the control, histological analysis showed that losartan treatment at either a low dose or a regular dose effectively attenuated renal fibrosis in the UUO model. To further understand the mechanism, we ex vivo loaded primary human renal epithelial cells to 50 mmHg hydrostatic pressure. Western blot and immunostaining analyses indicated that the loading to 50 mmHg hydrostatic pressure for 24 h significantly upregulated vimentin, ß-catenin and α-SMA, but downregulated E-cadherin in renal epithelial cells, suggesting the EMT. The addition of 10 or 100 nM losartan in medium effectively attenuated the EMT of renal epithelial cells induced by 50 mmHg hydrostatic pressure loading. Our in vivo and ex vivo experimental data suggest that losartan treatment, even at a low dose can effectively alleviate renal fibrosis in mouse UUO model, at least partly by inhibiting the biomechanical stress-induced EMT of renal epithelial cells. A low dose of ARBs may repurpose for renal fibrosis treatment.

Metabolomics profiling reveals differences in proliferation between tumorigenic and non-tumorigenic Madin-Darby canine kidney (MDCK) cells.

Background: Madin-Darby canine kidney (MDCK) cells are a cellular matrix in the production of influenza vaccines. The proliferation rate of MDCK cells is one of the critical factors that determine the vaccine production cycle. It is yet to be determined if there is a correlation between cell proliferation and alterations in metabolic levels. This study aimed to explore the metabolic differences between MDCK cells with varying proliferative capabilities through the use of both untargeted and targeted metabolomics. Methods: To investigate the metabolic discrepancies between adherent cell groups (MDCK-M60 and MDCK-CL23) and suspension cell groups (MDCK-XF04 and MDCK-XF06), untargeted and targeted metabolomics were used. Utilizing RT-qPCR analysis, the mRNA expressions of key metabolites enzymes were identified. Results: An untargeted metabolomics study demonstrated the presence of 81 metabolites between MDCK-M60 and MDCK-CL23 cells, which were mainly affected by six pathways. An analysis of MDCK-XF04 and MDCK-XF06 cells revealed a total of 113 potential metabolites, the majority of which were impacted by ten pathways. Targeted metabolomics revealed a decrease in the levels of choline, tryptophan, and tyrosine in MDCK-CL23 cells, which was in accordance with the results of untargeted metabolomics. Additionally, MDCK-XF06 cells experienced a decrease in 5'-methylthioadenosine and tryptophan, while S-adenosylhomocysteine, kynurenine, 11Z-eicosenoic acid, 3-phosphoglycerate, glucose 6-phosphate, and phosphoenolpyruvic acid concentrations were increased. The mRNA levels of MAT1A, MAT2B, IDO1, and IDO2 in the two cell groups were all increased, suggesting that S-adenosylmethionine and tryptophan may have a significant role in cell metabolism. Conclusions: This research examines the effect of metabolite fluctuations on cell proliferation, thus offering a potential way to improve the rate of MDCK cell growth.

Protective effect of vitamin B6 against doxorubicin-induced cardiotoxicity by modulating NHE1 expression.

Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na+ /H+ exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB6 ) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB6 supplement on the DOX-induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB6 supplement could alleviate DOX-induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl-2-associated X protein/B-cell lymphoma-2 ratio, respectively. Collectively, VitB6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX-induced cardiotoxicity.

CDC20 is a potential target gene to inhibit the tumorigenesis of MDCK cells.

MDCK is currently the main cell line used for influenza vaccine production in culture. Previous studies have reported that MDCK cells possess tumorigenic ability in nude mice. Although complete cell lysis can be ensured during vaccine production, host cell DNA released after cell lysis may still pose a risk for tumorigenesis. Greater caution is needed in the production of human vaccines; therefore, the use of gene editing to establish cells incapable of forming tumors may significantly improve the safety of influenza vaccines. Knowledge regarding the genes and molecular mechanisms that affect the tumorigenic ability of MDCK cells is crucial; however, our understanding remains superficial. Through monoclonal cell screening, we previously obtained a cell line, CL23, that possesses significantly reduced cell proliferation, migration, and invasion abilities, and tumor-bearing experiments in nude mice showed the absence of tumorigenic cells. With a view to exploring tumorigenesis-related genes in MDCK cells, DIA proteomics was used to compare the differences in protein expression between wild-type (M60) and non-tumorigenic (CL23) cells. Differentially expressed proteins were verified at the mRNA level by RT-qPCR, and a number of genes involved in cell tumorigenesis were preliminarily screened. Immunoblotting further confirmed that related protein expression was significantly reduced in non-tumorigenic cells. Inhibition of CDC20 expression by RNAi significantly reduced the proliferation and migration of MDCK cells and increased the proliferation of the influenza virus; therefore, CDC20 was preliminarily determined to be an effective target gene for the inhibition of cell tumorigenicity. These results contribute to a more comprehensive understanding of the mechanism underlying cell tumorigenesis and provide a basis for the establishment of target gene screening in genetically engineered non-tumorigenic MDCK cell lines.

Safety and efficacy of microwave ablation for the treatment of low-risk papillary thyroid microcarcinoma: a prospective multicenter study.

OBJECTIVES: To assess the safety and efficacy of ultrasound-guided thermal ablation for low-risk papillary thyroid microcarcinoma (PTMC) via a prospective multicenter study. METHODS: From January 2017 through June 2021, low-risk PTMC patients were screened. The management details of active surveillance (AS), surgery, and thermal ablation were discussed. Among patients who accepted thermal ablation, microwave ablation (MWA) was performed. The main outcome was disease-free survival (DFS). The secondary outcomes were tumor size and volume changes, local tumor progression (LTP), lymph node metastasis (LNM), and complication rate. RESULTS: A total of 1278 patients were included in the study. The operation time of ablation was 30.21 ± 5.14 min with local anesthesia. The mean follow-up time was 34.57 ± 28.98 months. Six patients exhibited LTP at 36 months, of whom 5 patients underwent a second ablation, and 1 patient received surgery. The central LNM rate was 0.39% at 6 months, 0.63% at 12 months, and 0.78% at 36 months. Of the 10 patients with central LNM at 36 months, 5 patients chose ablation, 3 patients chose surgery and the other 2 patients chose AS. The overall complication rate was 1.41%, and 1.10% of patients developed hoarseness of the voice. All of the patients recovered within 6 months. CONCLUSIONS: Thermal ablation of low-risk PTMC was observed to be safe and efficacious with few minor complications. This technique may help to bridge the gap between surgery and AS as treatment options for patients wishing to have their PTMC managed in a minimally invasive manner. CLINICAL RELEVANCE STATEMENT: This study proved that microwave ablation is a safe and effective treatment method for papillary thyroid microcarcinoma. KEY POINTS: Percutaneous US-guided microwave ablation of papillary thyroid microcarcinoma is a very minimally invasive treatment under local anesthesia during a short time period. The local tumor progression and complication rate of microwave ablation in the treatment of papillary thyroid microcarcinoma are very low.

Gut Microbiome Dysbiosis in Patients with Endometrial Cancer vs. Healthy Controls Based on 16S rRNA Gene Sequencing.

Metabolic diseases like obesity, diabetes, and hypertension are considered major risk factors associated with endometrial cancer. Considering that an imbalance in the gut microbiome may lead to metabolic alterations, we hypothesized that alteration in the gut microbioma might be an indirect factor in the development of endometrial cancer. Our aim was to profile the gut microbiota of patients with endometrial cancer compared with healthy controls in this study. Thus, we used 16S rRNA high-throughput gene sequencing on the Illumina NovaSeq platform to profile microbial communities. Fecal samples were collected from 33 endometrial cancer patients (EC group) and 32 healthy controls (N group) between February 2021 and July 2021. The total numbers of operational taxonomic units (OTUs) in the N and EC groups were 28,537 and 18,465, respectively, while the number of OTUs shared by the two groups was 4771. This study was the first to report that the alpha diversity of the gut microbiota was significantly reduced in endometrial cancer patients vs. healthy controls. Also, there was a significant difference in the distribution of microbiome between the two groups: the abundance of Firmicutes, Clostridia, Clostridiales, Ruminococcaceae, Faecalibacterium, and Gemmiger_formicis decreased, while that of Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae and Shigella increased significantly in the EC group vs. healthy controls (all p < 0.05). The predominant intestinal microbiota of the endometrial cancer patients was Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, and Shigella. These results imply that adjusting the composition of the gut microbiota and maintaining microbiota homeostasis may be an effective strategy for preventing and treating endometrial cancer.

A pilot study of lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell therapy in patients with advanced solid tumors.

Currently, the optimal lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell (Neo-T) therapy has yet to be determined. We report a single-arm, open-label and non-randomized phase 1 study (NCT02959905) of Neo-T therapy with lymphodepletion at various dose intensity in patients with locally advanced or metastatic solid tumors that are refractory to standard therapies. The primary end point is safety and the secondary end points are disease control rate (DCR), progression-free survival (PFS), overall survival (OS). Results show that the treatment is well tolerated with lymphopenia being the most common adverse event in the highest-intensity lymphodepletion groups. Neo-T infusion-related adverse events are only grade 1-2 in the no lymphodepletion group. The median PFS is 7.1 months (95% CI:3.7-9.8), the median OS is 16.8 months (95% CI: 11.9-31.7), and the DCR is 66.7% (6/9) among all groups. Three patients achieve partial response, two of them are in the no lymphodepletion group. In the group without lymphodepletion pretreatment, one patient refractory to prior anti-PD1 therapy shows partial response to Neo-T therapy. Neoantigen specific TCRs are examined in two patients and show delayed expansion after lymphodepletion treatment. In summary, Neo-T therapy without lymphodepletion could be a safe and promising regimen for advanced solid tumors.

Mechanism of annexin A1/N-formylpeptide receptor regulation of macrophage function to inhibit hepatic stellate cell activation through Wnt/ß-catenin pathway.

BACKGROUND: Hepatic fibrosis is a common pathological process of chronic liver diseases with various causes, which can progress to cirrhosis. AIM: To evaluate the effect and mechanism of action annexin (Anx)A1 in liver fibrosis and how this could be targeted therapeutically. METHODS: CCl4 (20%) and active N-terminal peptide of AnxA1 (Ac2-26) and N-formylpeptide receptor antagonist N-Boc-Phe-Leu-Phe-Leu-Phe (Boc2) were injected intraperitoneally to induce liver fibrosis in eight wild-type mice/Anxa1 knockout mice, and to detect expression of inflammatory factors, collagen deposition, and the role of the Wnt/ß-catenin pathway in hepatic fibrosis. RESULTS: Compared with the control group, AnxA1, transforming growth factor (TGF)-ß1, interleukin (IL)-1ß and IL-6 expression in the liver of mice with hepatic fibrosis induced by CCl4 was significantly increased, which promoted collagen deposition and expression of α-smooth muscle actin (α-SMA), collagen type I and connective tissue growth factor (CTGF), and increased progressively with time. CCl4 induced an increase in TGF-ß1, IL-1ß and IL-6 in liver tissue of AnxA1 knockout mice, and the degree of liver inflammation and fibrosis and expression of α-SMA, collagen I and CTGF were significantly increased compared with in wild-type mice. After treatment with Ac2-26, expression of liver inflammatory factors, degree of collagen deposition and expression of a-SMA, collagen I and CTGF were decreased compared with before treatment. Boc2 inhibited the anti-inflammatory and antifibrotic effects of Ac2-26. AnxA1 downregulated expression of the Wnt/ß-catenin pathway in CCl4-induced hepatic fibrosis. In vitro, lipopolysaccharide (LPS) induced hepatocyte and hepatic stellate cell (HSC) expression of AnxA1. Ac2-26 inhibited LPS-induced RAW264.7 cell activation and HSC proliferation, decreased expression of α-SMA, collagen I and CTGF in HSCs, and inhibited expression of the Wnt/ß-catenin pathway after HSC activation. These therapeutic effects were inhibited by Boc2. CONCLUSION: AnxA1 inhibited liver fibrosis in mice, and its mechanism may be related to inhibition of HSC Wnt/ß-catenin pathway activation by targeting formylpeptide receptors to regulate macrophage function.

Enhanced nuclear translation is associated with proliferation and progression across multiple cancers.

Recent technological advances have re-invigorated the interest in nuclear translation (NT), but the underlying mechanisms and functional implications of NT remain unknown. Here we show that NT is enhanced in malignant cancer cells and is associated with rapid cell growth. Nuclear ribopuromycylation analyses in a panel of diverse cell lines revealed that NT is scarce in normal immortalized cells, but is ubiquitous and robust in malignant cancer cells. Moreover, NT occurs in the nucleolus and requires normal nucleolar function. Intriguingly, NT is reduced by cellular stresses and anti-tumor agents and positively correlates with cancer cell proliferation and growth. By using a modified puromycin-associated nascent chain proteomics, we further identified numerous oncoproteins that are preferentially translated in the nucleus, such as transforming growth factor-beta 2 (TGFB2) and nucleophosmin 1 (NMP1). Specific overexpression of TGFB2 and NMP1 messenger RNAs in the nucleus can increase their protein levels and promote tumorigenesis. These findings establish a previously unknown link between NT and malignancy and suggest that cancer cells might have adapted a mechanism of NT to support their need for rapid growth, which highlight the potential of NT in tumorigenesis and might also open up new possibilities for therapeutic targeting of cancer-specific cellular functions.

TGM2 inhibits the proliferation, migration and tumorigenesis of MDCK cells.

Madin-Darby canine kidney (MDCK) cells are one of the main cell lines used for influenza vaccine production due to their high virus yield and low mutation resistance. Due to their high tumorigenicity, the safety of vaccines produced from these cells is controversial. TGM2 is a multifunctional protein that plays an important role in the adhesion and migration of cells and is associated with tumor formation. We found that the expression level of TGM2 was significantly up-regulated in low tumorigenic MDCK cells. We first analyzed TGM2-overexpressed and knockout MDCK cells in vitro. Scratch-wound assay and Transwell chamber experiments showed that TGM2 overexpression significantly inhibited the migration and invasion of MDCK cells and significantly reduced their proliferation. TGM2 knockout significantly enhanced cell migration, invasion, and proliferation. The tumorigenesis results in nude mice were consistent with those in vitro. TGM2 knockout significantly enhanced the tumorigenesis rate of MDCK cells in nude mice. We also investigated the effects of TGM2 gene expression on the replication of the H1N1 influenza A virus in MDCK cells. The results showed that TGM2 induced the negative regulation of H1N1 replication. These findings contribute to a comprehensive understanding of the tumor regulation mechanism and biological functions of TGM2.

Identification of antioxidant peptides after digestion and absorption of isinglass by serum peptidomics and cellular antioxidant activity analysis.

Isinglass, a dried product of the swim bladder, has been widely used in traditional Chinese medicine. This study attempts to identify natural antioxidant peptides after digestion and absorption of isinglass in vivo. The antioxidant effects of dietary isinglass were demonstrated by evaluating the activities of SOD, CAT and MDA contents in the mouse liver. Four novel antioxidant-related peptides (RLLWENGNLL, GSKAENPTNPGP, SPVPDLVPGSF and VPDLVPGSF) were screened based on serum peptidomics and amino acid composition. Furthermore, pretreating with four peptides significantly increased the cell viability, and SOD and CAT activities of AML12 cells with H2O2-mediated oxidative damage, meanwhile, significantly reduced the ROS level, MDA content and apoptosis rate and attenuated DNA damage. Therefore, it was concluded that pretreatment of the identified peptides had a protective effect on oxidatively damaged cells. This result can aid in the recognition of active peptides from isinglass consumption for potential application in nutraceuticals or functional ingredients in food.

Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response.

Protein arginine methyltransferase (PRMT) 5 is over-expressed in a variety of cancers and the master transcription regulator E2F1 is an important methylation target. We have explored the role of PRMT5 and E2F1 in regulating the non-coding genome and report here a striking effect on long non-coding (lnc) RNA gene expression. Moreover, many MHC class I protein-associated peptides were derived from small open reading frames in the lncRNA genes. Pharmacological inhibition of PRMT5 or adjusting E2F1 levels qualitatively altered the repertoire of lncRNA-derived peptide antigens displayed by tumour cells. When presented to the immune system as either ex vivo-loaded dendritic cells or expressed from a viral vector, lncRNA-derived peptides drove a potent antigen-specific CD8 T lymphocyte response, which translated into a significant delay in tumour growth. Thus, lncRNA genes encode immunogenic peptides that can be deployed as a cancer vaccine.

The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity.

Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be deployed in other therapeutic contexts. We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response. Zabadinostat treatment increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue. Remarkably, zabadinostat enhanced the activity of DCs, and CD4 and CD8 T lymphocytes. Using an antigenic peptide presented to the immune system by MHC class I, zabadinostat caused an increase in antigen-specific CD8 T lymphocytes. Further, mice immunised with covid19 spike protein and treated with zabadinostat exhibit enhanced covid19 neutralising antibodies and an increased level of T lymphocytes. The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system.

Efficacy and pregnancy outcomes of hysteroscopic surgery combined with progestin as fertility-sparing therapy in patients with early stage endometrial cancer and atypical hyperplasia.

PURPOSE: This study aims to evaluate the efficacy of hysteroscopic curettage combined with progestin therapy in young patients with early-stage endometrial cancer (EC) and endometrial atypical hyperplasia (EAH) who wished to preserve their fertility. METHODS: This prospective cohort study included 16 patients with early-stage EC and 25 patients with EAH in Dalian Maternal and Child Health Hospital from August 2014 to October 2018. All patients received fertility-sparing therapy with hysteroscopic evaluation every 3 months until achieving complete response (CR). Demographic, clinical, and pathological data follow-up information as well as fertility outcomes was analyzed. RESULTS: There were 92.6% (37/41) patients who achieved CR. The mean treatment duration to CR was 7.47 ± 2.91 months. BMI ≤ 30 kg/m2 was associated with shorter treatment duration to achieve CR (P = 0.003). Among the patients who attempted to conceive, 30.3% (10/33) had successful pregnancy, and 18.2% (6/33) delivered live births. The implementation of assisted reproductive technology (ART) is closely associated with pregnancy (P = 0.001). CONCLUSION: The fertility-sparing therapy, hysteroscopic curettage combined with progestin therapy, of early young EC and EAH patients is safe and effective. BMI is the main factor affecting the duration of CR. After achieving CR, ART can significantly improve the pregnancy rate of these patients.