Value of Molecular Typing Combined with Integrated Positron Emission Tomography/Magnetic Resonance Imaging in Risk Stratification of Endometrial Cancer.

Objective: In this study, we investigated the value of molecular typing combined with integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) semi-quantitative indices in endometrial cancer risk stratification. Methods: A retrospective study was conducted on 86 patients who were pathologically diagnosed with endometrial cancer and underwent surgical treatment after curettage at the Department of Obstetrics and Gynecology, Xuanwu Hospital, Capital Medical University between January 2017 and March 2023. Prior to surgery, each patient underwent integrated PET/MRI examination. The postoperative samples were subjected to pathological diagnosis, immunohistochemistry, and POLE gene sequencing. The differences in clinicopathological features between the four molecular subtypes and the differences in integrated PET/MRI semi-quantitative indexes (SUV max, ADC min) between the four molecular subtypes were analyzed. The cutoff value of molecular typing combined with integrated PET/MRI semi-quantitative indices for endometrial cancer risk stratification was determined. Results: There were statistically significant differences in pathological types and tumor grades among the four molecular subtypes of endometrial cancer. The values of the four integrated PET/MRI semi-quantitative indices (SUV max and ADC min) of the molecular subtypes were statistically different. The SUV max was greater in the p53abn mutation group than in the POLE mutation group (P < 0.05). The ADC minimum of the POLE mutation group and the MMR-d group was lower than the NSMP group (P < 0.05). Molecular typing combined with the integrated PET/MRI semi-quantitative SUV max index can predict the low/medium risk group of endometrial cancer and the medium-high/high risk group, and the cut-off value of SUV max for predicting the risk of early endometrial cancer was 14.72 (sensitivity 66.7%, specificity 68.7%). Conclusion: Molecular typing combined with integrated PET/MRI semi-quantitative indicators is useful to achieve risk stratification in patients diagnosed with endometrial cancer and guide individualized treatment.

Regulation of Protein Conformation Enables Cell-Selective Targeting of Virus-Mimicking Nanoparticles for siRNA Therapy of Glioblastoma.

Orthotopic glioblastoma (GBM) has an aggressive growth pattern and complex pathogenesis, becoming one of the most common and deadly tumors of the central nervous system (CNS). The emergence of RNA therapies offers promise for the treatment of GBM. However, the efficient and precise delivery of RNA drugs to specific tumor cells in the brain with high cellular heterogeneity remains ongoing. Here, a strategy is proposed to regulate protein conformation through lipid nanoenvironments to custom-design virus-mimicking nanoparticles (VMNs) with excellent selective cell targeting capabilities, leading to efficient and precise delivery of small interfering RNA for effective treatment of GBM. The optimized VMNs not only retain the ability to cross the blood-brain barrier and release the RNA by lysosomal escape like natural viruses but also ensure precise enrichment in the GBM area. This study lays the conceptual foundation for the custom design of VMNs with superior cell-selective targeting capabilities and opens up the possibility of RNA therapies for the efficient treatment of GBM and CNS tumors.

Correlation between serum vitamin D level and uterine volume in girls with idiopathic central precocious puberty.

OBJECTIVES: Investigate serum vitamin D (vit D) levels' relation to uterine volume in idiopathic central precocious puberty (ICPP) girls and compare findings with normal peers. METHODS: Analyzed 278 ICPP cases from January 2017 to September 2022 alongside 239 normally developing girls. Collected clinical data and lab markers and performed subgroup analysis based on vit D levels. Correlation and regression analyses were conducted. RESULTS: The ICPP group exhibited elevated uterine volume and lower serum vit D compared to controls (p<0.05). A weak negative correlation was noted between vit D and uterine volume in ICPP (r=-0.193, p=0.004), and no such correlation in controls (r=-0.073, p=0.319). The ICPP vit D deficiency subgroup displayed higher uterine volume than the insufficiency and sufficiency subgroups (p<0.05). Uterine volume in the insufficiency subgroup exceeded the sufficiency subgroup (p<0.05). After adjusting for confounders, lower vit D is linked to increased ICPP uterine volume (non-standardized regression coefficient ß=-25.55, 95 % CI= -46.23, -4.87, p=0.016). A Limited correlation between vit D and uterine volume was seen in girls with normal pubertal timing. CONCLUSIONS: We demonstrated a correlation between vit D and uterine volume in ICPP girls, absent in normal peers. ICPP girls often exhibit lower vit D levels and increased uterine volume. Further research is vital for understanding vit D's role in ICPP pathogenesis and guiding prevention and treatment strategies.

Clinicopathological and prognostic significance of Ephrin A3 in bladder urothelial carcinoma.

Ephrin A3 (EFNA3) is a member of the Eph/ephrin tyrosine kinase family, which is associated with multiple signaling pathways involved in cell growth and tumor cell metastasis. Aberrant regulation of EFNA3 is associated with the occurrence and development of various types of cancer. However, despite the high incidence of EFNA3 upregulation in cancer, studies concerning EFNA3 in urothelial carcinoma have not, to the best of our knowledge, been conducted. In the present study, bioinformatics analyses using data from multiple online databases were performed to confirm the upregulation of EFNA3 in bladder cancer. The co-expression gene set of EFNA3 and enriched signaling pathways were also analyzed. In addition, immunohistochemistry was conducted to detect EFNA3 expression in 491 clinically confirmed bladder urothelial carcinoma samples and 80 non-cancerous bladder tissues. Kaplan-Meier survival analysis, binary logistic regression analysis, and Cox regression analysis were conducted to confirm the validity of EFNA3 in predicting patient prognosis and its significance in clinical pathology. Statistical analysis demonstrated a significant association between EFNA3 expression levels with tumor size, lymph node metastasis, distant metastasis, and pathological grade. In conclusion, high EFNA3 expression may be a potential biomarker that indicates bladder tumor occurrence and patient prognosis.

Organoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization.

Intestinal organoid transplantation is a promising therapy for the treatment of mucosal injury. However, how the transplanted organoids regulate the immune microenvironment of recipient mice and their role in treating intestinal ischemia-reperfusion (I/R) injury remains unclear. Here, we establish a method for transplanting intestinal organoids into intestinal I/R mice. We find that transplantation improve mouse survival, promote self-renewal of intestinal stem cells and regulate the immune microenvironment after intestinal I/R, depending on the enhanced ability of macrophages polarized to an anti-inflammatory M2 phenotype. Specifically, we report that L-Malic acid (MA) is highly expressed and enriched in the organoids-derived conditioned medium and cecal contents of transplanted mice, demonstrating that organoids secrete MA during engraftment. Both in vivo and in vitro experiments demonstrate that MA induces M2 macrophage polarization and restores interleukin-10 levels in a SOCS2-dependent manner. This study provides a therapeutic strategy for intestinal I/R injury.

Association of DNA methylation of vitamin D metabolic pathway related genes with colorectal cancer risk.

BACKGROUND: Vitamin D might have anti-tumor effect, which is affected by the genes related to vitamin D metabolic pathway. Epigenetic mechanism may affect the expression level of vitamin D metabolic pathway related genes, then plays an important role in the occurrence and development of colorectal cancer. To date, no study has reported on the association between blood-based DNA methylation level of vitamin D metabolic pathway related genes and colorectal cancer risk. METHODS: A case-control study was conducted including 102 colorectal cancer cases and 102 sex- and age-frequency-matched controls in Guangzhou, China. CpG islands in the VDR, CYP24A1, CYP27B1 and CYP2R1 genes were chosen for DNA methylation analysis by MethylTarget sequencing. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of DNA methylation levels for colorectal cancer. Taking the point with the largest Youden index as the boundary value, the cumulative methylation levels of vitamin D metabolic pathway related genes were divided into hypomethylation and hypermethylation. Unconditional multivariable logistical regression model was used to calculate the adjusted odds ratio (aOR) and 95% confidence intervals (95% CIs) after adjusting for potential confounders. RESULTS: Among 153 CpG sites, 8 CpG sites were significantly different between the cases and the controls. The cumulative methylation level of all CpG sites in CYP2R1 was inversely associated with the risk of colorectal cancer (aOR, 0.49; 95% CI, 0.26-0.91). However, no significant association was found between cumulative methylation levels of all CpG sites in VDR, CYP24A1 and CYP27B1 and colorectal cancer risk. Significant inverse association was observed between cumulative methylation level of significant CpG sites in VDR (aOR, 0.28; 95% CI, 0.16-0.51) and CYP24A1 (aOR, 0.19; 95% CI, 0.09-0.40) and colorectal cancer risk. There were no significant associations between cumulative methylation levels of significant CpG sites in CYP2R1 and CYP27B1 and colorectal cancer risk. CONCLUSIONS: This study indicated that the cumulative methylation levels of significant CpG sites in VDR and CYP24A1 and all CpG sites in CYP2R1 were inversely associated with colorectal cancer risk.

Reduction in gefitinib resistance mediated by Yi-Fei San-Jie pill in non-small cell lung cancer through regulation of tyrosine metabolism, cell cycle, and the MET/EGFR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal prescription Yi-Fei San-Jie pill (YFSJ) has been used for adjuvant treatment in patients with lung cancer for a long time. AIM OF THE STUDY: Reports have indicated that the combination of gefitinib (Gef) with YFSJ inhibits the proliferation of EGFR-TKI-resistant cell lines by enhancing cellular apoptosis and autophagy in non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying the effect of YFSJ on EGFR-TKI resistance and related metabolic pathways remain to be explored. MATERIALS AND METHODS: In our report, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), metabolomics, network pharmacology, bioinformatics, and biological analysis methods were used to investigate the mechanism. RESULTS: The UPLC-MS/MS data identified 42 active compounds of YFSJ extracts. YFSJ extracts can enhance the antitumor efficacy of Gef without hepatic and renal toxicity in vivo. The analysis of the metabolomics pathway enrichment revealed that YFSJ mainly affected the tyrosine metabolism pathway in rat models. Moreover, YFSJ has been shown to reverse Gef resistance and improve the effects of Gef on the cellular viability, migration capacity, and cell cycle arrest of NSCLC cell lines with EGFR mutations. The results of network pharmacology and molecular docking analyses revealed that tyrosine metabolism-related active compounds of YFSJ affect EGFR-TKIs resistance in NSCLC by targeting cell cycle and the MET/EGFR signaling pathway; these findings were validated by western blotting and immunohistochemistry. CONCLUSIONS: YFSJ inhibits NSCLC by inducing cell cycle arrest in the G1/S phase to suppress tumor growth, cell viability, and cell migration through synergistic effects with Gef via the tyrosine metabolic pathway and the EGFR/MET signaling pathway. To summarize, the findings of the current study indicate that YFSJ is a prospective complementary treatment for Gef-resistant NSCLC.

Expression and clinical significance of DOK3 in renal clear cell carcinoma.

OBJECTIVES: Docking Protein 3 (DOK3) is an adapter protein that has been implicated in various cellular processes relevant to diseases, such as cancer. In this study, we aimed to evaluate the role of DOK3 in kidney renal clear cell carcinoma (KIRC) by examining how its expression levels are correlated with patient characteristics and prognosis. METHODS: We analyzed KIRC-related data from The Cancer Genome Atlas and used several bioinformatics tools, such as LinkedOmics and Oncomine, to evaluate DOK3 mRNA expression in KIRC. DOK3 protein expression was examined in 150 clinical KIRC samples and 100 non-cancerous renal tissues with immunohistochemistry assays. The prognostic value of DOK3 mRNA expression on patient overall survival was analyzed retrospectively using Kaplan-Meier survival and Cox regression analyses. RESULTS: DOK3 mRNA expression was notably higher in KIRC samples compared with normal tissues. Significant correlations were found between DOK3 mRNA expression levels and tumor size, lymph node metastasis, distant metastasis, and pathological grade using the bioinformatics data. This was confirmed at the protein level with immunohistochemistry data. Survival analyses indicated that elevated DOK3 expression is linked to a lower overall survival rate in KIRC patients. CONCLUSIONS: DOK3 is a potential biomarker for determining KIRC patient clinical prognosis.

Microbiota-derived tryptophan metabolites indole-3-lactic acid is associated with intestinal ischemia/reperfusion injury via positive regulation of YAP and Nrf2.

BACKGROUND: Lactobacillus has been demonstrated to serve a protective role in intestinal injury. However, the relationship between Lactobacillus murinus (L. murinus)-derived tryptophan metabolites and intestinal ischemia/reperfusion (I/R) injury yet to be investigated. This study aimed to evaluate the role of L. murinus-derived tryptophan metabolites in intestinal I/R injury and the underlying molecular mechanism. METHODS: Liquid chromatograph mass spectrometry analysis was used to measure the fecal content of tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. Immunofluorescence, quantitative RT-PCR, Western blot, and ELISA were performed to explore the inflammation protective mechanism of tryptophan metabolites in WT and Nrf2-deficient mice undergoing intestinal I/R, hypoxia-reoxygenation (H/R) induced intestinal organoids. RESULTS: By comparing the fecal contents of three L. murinus-derived tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. We found that the high abundance of indole-3-lactic acid (ILA) in the preoperative feces was associated with better postoperative intestinal function, as evidenced by the correlation of fecal metabolites with postoperative gastrointestinal function, serum I-FABP and D-Lactate levels. Furthermore, ILA administration improved epithelial cell damage, accelerated the proliferation of intestinal stem cells, and alleviated the oxidative stress of epithelial cells. Mechanistically, ILA improved the expression of Yes Associated Protein (YAP) and Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) after intestinal I/R. The YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of ILA, both in vivo and in vitro. Additionally, we found that ILA failed to protect epithelial cells from oxidative stress in Nrf2 knockout mice under I/R injury. CONCLUSIONS: The content of tryptophan metabolite ILA in the preoperative feces of patients is negatively correlated with intestinal function damage under CPB surgery. Administration of ILA alleviates intestinal I/R injury via the regulation of YAP and Nrf2. This study revealed a novel therapeutic metabolite and promising candidate targets for intestinal I/R injury treatment.

Compounds isolated from the pericarp of Zanthoxylum bungeanum and inhibitory activity against LPS-induced NO production in RAW264.7.

Seventeen compounds were isolated and identified from the ethyl acetate part of Zanthoxylum bungeanum Maxim., including one new compound 18-acetyloxyneocryptotanshinone (1) and 16 known compounds (2-17). Their structures were elucidated by extensive spectroscopy. The absolute configuration of 1 was confirmed by electronic circular dichroism (ECD). All compounds were evaluated for the inhibition of LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, of which 1 and 10 exhibited the most significant inhibitory effect, with IC50 of 17.29 and 10.27 µM, respectively.

5-methoxytryptophan induced apoptosis and PI3K/Akt/FoxO3a phosphorylation in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a highly prevalent malignancy worldwide, and new therapeutic targets urgently need to be found to prolong patient survival. 5-methoxytryptophan (5-MTP) is a tryptophan metabolite found in animals and humans. However, the effects of 5-MTP on proliferation and apoptosis of CRC cells are currently unknown. AIM: To investigate the effects of 5-MTP on the proliferation, migration, invasion, and apoptosis abilities of CRC cells. Additionally, we seek to explore whether 5-MTP has the potential to be utilized as a drug for the treatment of CRC. METHODS: In order to evaluate the effect of 5-MTP on CRC cells, a series of experiments were conducted for evaluation. Colony formation assay and Cell Counting Kit 8 assays were used to investigate the impact of 5-MTP on the proliferation of CRC cell lines. Cell cycle assays were employed to examine the effect of 5-MTP on cellular growth. In addition, we investigated the effects of 5-MTP on apoptosis and reactive oxygen species in HCT-116 cells. To obtain a deeper understanding of how 5-MTP affects CRC, we conducted a study to examine its influence on the PI3K/Akt signaling pathway in CRC cells. RESULTS: This article showed that 5-MTP promoted apoptosis and cell cycle arrest and inhibited cell proliferation in CRC cells. In many articles, it has been reported that PI3K/Akt/FoxO3a signaling pathway is one of the most important signaling pathways involved in internal regulating cell proliferation and differentiation. Nevertheless, 5-MTP combined with PI3K/Akt/FoxO3a signaling pathway inhibitors significantly promoted apoptosis and cell cycle arrest and inhibited cell proliferation in CRC cells compared with 5-MTP alone in our study. CONCLUSION: Therefore, there is strong evidence that 5-MTP can be used as an effective medicine for CRC treatment.

Effect of a disposable endoscope precleaning kit in the cleaning procedure of gastrointestinal endoscope: A multi-center observational study.

BACKGROUND: Precleaning is a key step in endoscopic reprocessing. AIM: To develop an effective and economic endoscope cleaning method by using a disposable endoscope bedside precleaning kit. METHODS: Altogether, 228 used gastrointestinal endoscopes were selected from five high-volume endoscopy units and precleaned by a traditional precleaning bucket (group T) or a disposable endoscope bedside precleaning kit (group D). Each group was further subdivided based on the replacement frequency of the cleaning solution, which was replaced every time in subgroups T1 and D1 and every several times in subgroups Ts and Ds. The adenosine triphosphate (ATP) level and residual proteins were measured three times: Before and after precleaning and after manual cleaning. RESULTS: After precleaning, the precleaning kit significantly reduced the ATP levels (P = 0.034) and has a more stable ATP clearance rate than the traditional precleaning bucket. The precleaning kit also saved a quarter of the cost of enzymatic detergent used during the precleaning process. After manual cleaning, the ATP levels were also significantly lower in the precleaning kit group than in the traditional precleaning bucket group (P < 0.05). Meanwhile, the number of uses of the cleaning solution (up to four times) has no significant impact on the cleaning effect (P > 0.05). CONCLUSION: Considering its economic cost and cleaning effect, the use of a disposable endoscope bedside precleaning kit can be an optimal option in the precleaning stage with the cleaning solution being replaced several times in the manual cleaning stage.

Roles and crosstalks of macrophages in diabetic nephropathy.

Diabetic nephropathy (DN) is the most common chronic kidney disease. Accumulation of glucose and metabolites activates resident macrophages in kidneys. Resident macrophages play diverse roles on diabetic kidney injuries by releasing cytokines/chemokines, recruiting peripheral monocytes/macrophages, enhancing renal cell injuries (podocytes, mesangial cells, endothelial cells and tubular epithelial cells), and macrophage-myofibroblast transition. The differentiation and cross-talks of macrophages ultimately result renal inflammation and fibrosis in DN. Emerging evidence shows that targeting macrophages by suppressing macrophage activation/transition, and macrophages-cell interactions may be a promising approach to attenuate DN. In the review, we summarized the diverse roles of macrophages and the cross-talks to other cells in DN, and highlighted the therapeutic potentials by targeting macrophages.

Melatonin attenuates radiation-induced cortical bone-derived stem cells injury and enhances bone repair in postradiation femoral defect model.

BACKGROUND: The healing of bone defects can be challenging for clinicians to manage, especially after exposure to ionizing radiation. In this regard, radiation therapy and accidental exposure to gamma (γ)-ray radiation have been shown to inhibit bone formation and increase the risk of fractures. Cortical bone-derived stem cells (CBSCs) are reportedly essential for osteogenic lineages, bone maintenance and repair. This study aimed to investigate the effects of melatonin on postradiation CBSCs and bone defect healing. METHODS: CBSCs were extracted from C57BL/6 mice and were identified by flow cytometry. Then CBSCs were subjected to 6 Gy γ-ray radiation followed by treatment with various concentrations of melatonin. The effects of exogenous melatonin on the self-renewal and osteogenic capacity of postradiation CBSCs in vitro were analyzed. The underlying mechanisms involved in genomic stability, apoptosis and oxidative stress-related signaling were further analyzed by Western blotting, flow cytometry and immunofluorescence assays. Moreover, postradiation femoral defect models were established and treated with Matrigel and melatonin. The effects of melatonin on postradiation bone healing in vivo were evaluated by micro-CT and pathological analysis. RESULTS: The decrease in radiation-induced self-renewal and osteogenic capacity were partially reversed in postradiation CBSCs treated with melatonin (P < 0.05). Melatonin maintained genomic stability, reduced postradiation CBSC apoptosis and intracellular oxidative stress, and enhanced expression of antioxidant-related enzymes (P < 0.05). Western blotting validated the anti-inflammatory effects of melatonin by downregulating interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels via the extracellular regulated kinase (ERK)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway. Melatonin was also found to exhibit antioxidant effects via NRF2 signaling. In vivo experiments demonstrated that the newly formed bone in the melatonin plus Matrigel group had higher trabecular bone volume per tissue volume (BV/TV) and bone mineral density values with lower IL-6 and TNF-α levels than in the irradiation and the Matrigel groups (P < 0.05). CONCLUSION: This study suggested that melatonin could protect CBSCs against γ-ray radiation and assist in the healing of postradiation bone defects.

Dulaglutide, a long-acting GLP-1 receptor agonist, can improve hyperandrogenemia and ovarian function in DHEA-induced PCOS rats.

OBJECTIVE: The purpose of this study was to explore the effect of dulaglutide on DHEA induced PCOS rats and its mechanism, to provide new drugs and research directions for clinical treatment of PCOS. METHODS: In this study, the PCOS model was established by giving female SD rats subcutaneous injection of DHEA for 21 consecutive days. After modeling, the treatment group was injected subcutaneously with three doses of dulaglutide for 3 weeks. The model group was injected with sterile ultrapure water, and the normal group did not get any intervention. The body weight changes of rats in each group were recorded from the first day when rats received the administration of dulaglutide. Three weeks later, the rats were fasted the night after the last treatment, determined fasting insulin and fasting glucose the next day. After the rats were anesthetized by chloral hydrate, more blood was collected from the heart of the rat. The serum insulin, testosterone and sex hormone binding globulin (SHBG) levels were detected by the enzyme-linked immunoassay method. After removing the adipose tissue, the obtained rat ovary tissue was used for subsequent experimental detection, using HE staining for morphology and follicular development analysis; qRT-PCR for the detection of 3ßHSD, CYP17α1, CYP19α1, and StAR gene expression in ovarian tissue; and western blotting analysis of CYP17α1, CYP19α1, StAR protein expression and insulin level to verify whether dulaglutide has a therapeutic effect on PCOS in rats. RESULTS: After treated with different concentrations of dulaglutide, we found that the body weight of rats in the treatment groups were reduced. Compared with the rats in PCOS group, the serum androgen level of rats in the treatment groups was significantly decreased, and the serum sex hormone binding protein content was significantly increased, and there was statistically significant difference between these groups and PCOS group. In terms of protein expression and gene regulation, the expression of 3ßHSD, CYP19α1 and StAR in the ovarian tissue of rats in treatment groups were decreased significantly after received the treatment of dulaglutide, and there was statistically significant difference between these groups and PCOS group. In addition, dulaglutide reduced the insulin content in the ovarian tissue of PCOS rats. CONCLUSION: Dulaglutide may reduce the hyperandrogenemia of PCOS rats by regulating the content of serum SHBG and the expression of 3ßHSD, CYP19α1, and StAR related genes and proteins, thereby inhibiting the excessive development of small follicles and the formation of cystic follicles in the ovaries of PCOS rats, thereby improving polycystic ovary in PCOS rats. In addition, dulaglutide may reduce the weight of PCOS rats, further reducing the level of high androgen in PCOS rats, and improving the morphology of their polycystic ovaries.

Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2.

Rationale: Tanshinone, a type of diterpenes derived from salvia miltiorrhiza, is a particularly promising herbal medicine compound for the treatment of cancers including acute myeloid leukemia (AML). However, the therapeutic function and the underlying mechanism of Tanshinone in AML are not clear, and the toxic effect of Tanshinone limits its clinical application. Methods: Our work utilizes human leukemia cell lines, zebrafish transgenics and xenograft models to study the cellular and molecular mechanisms of how Tanshinone affects normal and abnormal hematopoiesis. WISH, Sudan Black and O-Dianisidine Staining were used to determine the expression of hematopoietic genes on zebrafish embryos. RNA-seq analysis showed that differential expression genes and enrichment gene signature with Tan I treatment. The surface plasmon resonance (SPR) method was used with a BIAcore T200 (GE Healthcare) to measure the binding affinities of Tan I. In vitro methyltransferase assay was performed to verify Tan I inhibits the histone enzymatic activity of the PRC2 complex. ChIP-qPCR assay was used to determine the H3K27me3 level of EZH2 target genes. Results: We found that Tanshinone I (Tan I), one of the Tanshinones, can inhibit the proliferation of human leukemia cells in vitro and in the xenograft zebrafish model, as well as the normal and malignant definitive hematopoiesis in zebrafish. Mechanistic studies illustrate that Tan I regulates normal and malignant hematopoiesis through direct binding to EZH2, a well-known histone H3K27 methyltransferase, and inhibiting PRC2 enzymatic activity. Furthermore, we identified MMP9 and ABCG2 as two possible downstream genes of Tan I's effects on EZH2. Conclusions: Together, this study confirmed that Tan I is a novel EZH2 inhibitor and suggested MMP9 and ABCG2 as two potential therapeutic targets for myeloid malignant diseases.

[Comparative analysis of binding multi-fold rib graft, iliac bone graft and titanium mesh graft during surgery of tuberculosis of thoracic vertebra].

OBJECTIVE: To compare the clinical effects of three different methods of binding multi-fold rib graft, iliac bone graft and titanium mesh graft in tuberculosis of thoracic vertebra by approach of transverse rib process. METHODS: A hundred and seven patients with tuberculosis of thoracic vertebra received surgical treatment from January 2010 to December 2016 were retrospectively analyzed. The patients were divided into three groups according different methods of bone graft. The surgical approach of the transverse rib process was used in all 107 patients, after thoroughly remove the necrotic tissue of tuberculosis, three different bone grafts were used respectively including iliac bone graft (36 cases, group A), binding multi-fold rib graft (35 cases, group B), titanium mesh bone graft (36 cases, group C). Perioperative indexes, the time required for bone graft during operation, intraoperation blood loss, the loss rate of the anterior edge of the lesion, Cobb angle, postoperative bone graft fusion time, spinal nerve recovery and Oswestry Disability Index were compared among three groups. RESULTS: All the patients were followed up for 13 to 24 months, and the operation time required for bone graft was (23.2±4.1) min in group A, (23.8± 4.4)min in group B, and (25.5±4.2) min in group C, with no statistically significant difference among three groups (P>0.05). Intraoperative blood loss was (541.6±35.3) ml in group A, (546.8±27.8) ml in group B, and (540.1±34.5) ml in group C, withno statistically significant difference among three groups(P>0.05). Preoperative anterior vertebral height loss rate was (46.0± 3.1)% in group A, (46.4±3.3)% in group B, and (45.3±3.6)% in group B;at the final follow up, the loss rate of anterior vertebral height among three groups was (8.6±5.0)%, (8.1±4.2)%, (9.4±4.3)%, respectively. There were no statistically significant differences before operation and final follow-up among three groups (P>0.05). Preoperative Cobb angle was (35.1±4.8)° in group A, (35.2±4.5)° in group B and (35.2±4.5)° in group C, with no statistically significant difference among three groups (P>0.05);postoperative at 3 days, Cobb angle in three groups was (15.1±3.6)°, (15.3±3.1)° and (15.2±3.4)°, respectively, there was no statistically significant difference among three groups (P>0.05);at the final follow-up, the Cobb angle among three groups was (17.7±3.3)°, (17.9±3.9)°, (18.6±3.6)°, respectively, with no statistically significant difference among three groups (P>0.05). The time of bone graft fusion was (5.6±0.5) months in group A, (5.6±0.6) months in group B and (5.8±0.6)months in group C, with no statistically significant difference among three groups (P>0.05). Frankel classification at the final follow up, 4 cases were grade B, 7 cases were grade C, 10 cases were grade D, and 86 cases were grade E. Spinal nerve function in all three groups recovered to a certain extent after treatment, with no statistically significant difference among three groups (P> 0.05). Oswestry Disability Index at the final follow-up showed no statistically significant difference among three groups (P> 0.05). CONCLUSION: The approach of transverse rib process for debridement of lesions can effectively treat tuberculosis of thoracic vertebra by binding multi-fold rib graft, iliac bone graft and titanium mesh graft, but binding multi-fold rib graft can effectively avoid iliac bone donor complications, and is an effective alternative to iliac bone graft, which is worth popularizing.

Clinical significance of signet ring cells in surgical esophageal and esophagogastric junction adenocarcinoma: A systematic review and meta-analysis.

BACKGROUND: The clinical significance of signet ring cells (SRCs) in surgical esophageal and esophagogastric junction adenocarcinoma (EEGJA) remains unclear now. AIM: To explore the association between the presence of SRCs and the clinicopathological and prognostic characteristics in surgical EEGJA patients by combining and analyzing relevant studies. METHODS: The PubMed, Web of Science, and EMBASE electronic databases were searched for the relevant literature up to March 28, 2021. The relative risk (RR) with 95% confidence interval (CI) was calculated to assess the relationship between SRCs and clinicopathological parameters of surgical EEGJA patients, and the hazard ratio (HR) with 95%CI was calculated to explore the impact of SRC on the prognosis. All statistical analyses were conducted with STATA 12.0 software. RESULTS: A total of ten articles were included, involving 30322 EEGJA patients. The pooled results indicated that the presence of SRCs was significantly associated with tumor location (RR: 0.76, 95%CI: 0.61-0.96, P = 0.022; I 2 = 49.4%, P = 0.160) and tumor-node-metastasis stage (RR: 1.30, 95%CI: 1.02-1.65, P = 0.031; I 2 = 73.1%, P = 0.002). Meanwhile, the presence of SRCs in surgical EEGJA patients predicted a poor overall survival (HR: 1.36, 95%CI: 1.12-1.65, P = 0.002; I 2 = 85.7%, P < 0.001) and disease-specific survival (HR: 1.86, 95%CI: 1.55-2.25, P < 0.001; I 2 = 63.1%, P = 0.043). CONCLUSION: The presence of SRCs is related with advanced tumor stage and poor prognosis and could serve as a reliable and effective parameter for the prediction of postoperative survival and formulation of therapy strategy in EEGJA patients. However, more high-quality studies are still needed to verify the above findings.

Endoscopic Versus Surgical Therapy for Early Esophagogastric Junction Adenocarcinoma Based on Lymph Node Metastasis Risk: A Population-Based Analysis.

BACKGROUND: In this study, we aimed to compare the prognosis and lymph node metastasis (LNM) risk in patients with early-stage esophagogastric junction (EGJ) adenocarcinoma after endoscopic treatment (ET) or radical surgery. METHODS: We collected data from eligible patients based on the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. Logistic regression analysis was used to determine independent predictors of LNM (examination of at least 16 lymph nodes). Cox regression analysis and propensity score-matched (PSM) analysis were subsequently utilized to compare the overall survival (OS) and cancer-specific survival (CSS) of patients treated with ET or radical surgery. RESULTS: In total, 3708 patients were identified. Among them, 856 patients had greater than or equal to 16 examined lymph nodes (LNs) (LNE≥16). The LNM rates were 18.8% in all patients 8.3% in T1a patients and 24.6% in T1b patients. Independent predictors of LNM were submucosal invasion, tumor size ≥3cm and decreasing differentiation (P<0.05). The LNM rate decreased to approximately 5.3% in T1b tumors with well differentiation and tumor size <3cm. However, the LNM incidence increased to 17.9% or 33.3% in T1a tumors with poor differentiation or with both tumor size≥3cm and poor differentiation. Cox regression analysis demonstrated CSS was not significantly different in early-stage EGJ adenocarcinoma patients undergoing ET and those treated with radical surgery (HR= 1.004, P=0.974), which were robustly validated after PSM analysis. Moreover, subgroup analysis stratified by T1a and T1b showed similar results. CONCLUSIONS: The findings of this study indicated ET as an alternative to radical surgery in early EGJ adenocarcinoma.

Recent advances in visual detection for cancer biomarkers and infectious pathogens.

It is an urgency to detect infectious pathogens or cancer biomarkers using rapid, simple, convenient and cost-effective methods in complex biological samples. Many existing approaches (traditional virus culture, ELISA or PCR) for the pathogen and biomarker assays face several challenges in the clinical applications that require lengthy time, sophisticated sample pre-treatment and expensive instruments. Due to the simple and rapid detection manner as well as no requirement of expensive equipment, many visual detection methods have been considered to resolve the aforementioned problems. Meanwhile, various new materials and colorimetric/fluorescent methods have been tried to construct new biosensors for infectious pathogens and biomarkers. However, the recent progress of these aspects is rarely reviewed, especially in terms of integration of new materials, microdevice and detection mechanism into the visual detection systems. Herein, we provide a broad field of view to discuss the recent progress in the visual detection of infectious pathogens and cancer biomarkers along with the detection mechanism, new materials, novel detection methods, special targets as well as multi-functional microdevices and systems. The novel visual approaches for the infectious pathogens and biomarkers, such as bioluminescence resonance energy transfer (BRET), metal-induced metallization and clustered regularly interspaced short palindromic repeats (CRISPR)-based biosensors, are discussed. Additionally, recent advancements in visual assays utilizing various new materials for proteins, nucleic acids, viruses, exosomes and small molecules are comprehensively reviewed. Future perspectives on the visual sensing systems for infectious pathogens and cancers are also proposed.