PRMT6 methylation of STAT3 regulates tumor metastasis in breast cancer.

Overcoming distant metastasis stands as a paramount challenge in enhancing the outcomes of breast cancer treatments. Thus, delving deeper into comprehending the intricate mechanisms underlying breast cancer metastasis becomes imperative, offering potential avenues for pioneering therapeutic approaches. PRMT6, an arginine N-methyltransferase, possesses the ability to methylate both histone and non-histone proteins. It has been reported that methylation of non-histone proteins impacts their cellular localization, stability, and activation, consequently influencing tumor progression. However, the extent to which PRMT6-mediated non-histone protein methylation influences cancer cell metastasis, particularly in the context of breast cancer, remains elusive. In this study, we established that PRMT6 exerted a positive regulatory influence on breast cancer metastasis through both in vivo and in vitro experiments. Mechanistically, we innovatively revealed that PRMT6 asymmetrically di-methylated STAT3 at arginine 729 (STAT3 R729me2a). This modification proved indispensable for STAT3's membrane localization, its interaction with JAK2, STAT3 Y705 phosphorylation, and PRMT6-driven cancer cell metastasis. From a clinical perspective, we unearthed the promising potential of STAT3 R729me2a as a robust prognostic marker for predicting the overall survival time of breast cancer patients. In terms of therapeutic intervention, we demonstrated the significant capability of the PRMT6 inhibitor, EPZ020411, to curtail breast cancer metastasis both in vivo and in vitro. In sum, our study unveils the pivotal biological role of PRMT6-mediated STAT3 R729me2a in breast cancer metastasis and underscores the prospective utility of PRMT6 inhibitors as effective therapeutic strategies against STAT3-driven metastatic breast cancer.

LncRNA LZTS1-AS1 induces proliferation, metastasis and inhibits autophagy of pancreatic cancer cells through the miR-532 /TWIST1 signaling pathway.

The 5 year survival rate after diagnosis of pancreatic cancer (PANC) is less than 5%, and it is one of the malignant tumors with the worst prognosis. Identification of novel oncogenes involved in the occurrence of pancreatic cancer is of great significance to improve the overall survival of PANC patients. Our previous study found that miR-532 is a key factor in PANC occurrence and development, and this study further explored its mechanism. We found that the expression of lncRNA LZTS1-AS1 was elevated in PANC tumor tissues and cells, and correlated with poor prognosis. In vitro experiments confirmed that LZTS1-AS1 could promote proliferation, oncogenicity, migration, and invasion of PANC cells, and inhibit apoptosis and autophagy. However, miR-532 had the completely opposite effect, and inhibition of miR-532 counteracted the effect of LZTS1-AS1 on PANC cells. Dual luciferase gene reporter assay and RNA immunoprecipitation assay confirmed the targeting relationship between LZTS1-AS1 and miR-532, and their expression levels were negatively correlated in PANC tissues. Overexpression of TWIST1 could counteract the effect of miR-532 in PANC cells, and the expression levels of both were negatively changed in PANC tissues and cells. Our results suggest that lncRNA LZTS1-AS1 acts as an oncogene to promote the metastasis of PANC and inhibit autophagy, and its mechanism may be to regulate TWIST1 through sponge miR-532. This study provides novel biomarkers and therapeutic targets for PANC.

Comparison of the effects of endoscopic submucosal dissection and laparoscopic distal radical surgery on the rehabilitation and quality of life of patients with early gastric cancer.

OBJECTIVE: This study was designed to compare the effects of endoscopic submucosal dissection (ESD) and laparoscopic distal radical surgery (LDRS) on patient rehabilitation and quality of life (QoL) in patients with early gastric cancer (GC). METHODS: The clinical data of 52 patients with early GC admitted to Wuhan Union Hospital from January 2018 to December 2020 were retrospectively analyzed. Among them, 32 patients who underwent LDRS were assigned to the laparoscopic group, and the rest of the 20 patients who underwent ESD were assigned to the endoscopic group. The two groups were compared in clinical efficacy, intraoperative blood loss, operation time, postoperative hospitalization time, gastrointestinal ventilation time and postoperative complications, and the postoperative recurrence and postoperative QoL of the two groups were evaluated and recorded. Independent risk factors for recurrence of gastric cancer were analyzed by logistics regression. RESULTS: The laparoscopic group showed a significantly lower complete resection rate than the endoscopic group (P=0.030). The endoscopic group experienced notably less intraoperative blood loss and operation time, significantly earlier time for the first anal exhaust and shorter hospitalization time in contrast to the laparoscopic group (all P<0.05). Six months after operation, the endoscopic group had notably higher MOS 36-Item Short-Form Health Survey (SF-36) scores than the laparoscopic group (P<0.001). In addition, the laparoscopic group had a notably higher total incidence rate of complications than the endoscopic group (P<0.05). Among the 52 patients, 8 patients had recurrence. According to Logistics regression analysis, tumor diameter and invasion depth were independent risk factors for recurrence (both P<0.05). CONCLUSION: With significantly better efficacy than that of LDRS, ESD is beneficial to postoperative rehabilitation and can improve the QoL of patients, and both schemes cause no significant effect on the recurrence of patients.

MTA2 is one of 14 Transcription factors predicting recurrence free survival in gastric cancer and promotes cancer progression by targeting MCM5.

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Transcription factors (TFs) are essential gene expression regulators, and play critical roles in cancer development. However, the biological actions and prognostic value of TFs in GC remain unclear. In this study, we identified a risk model based on a 14-TF signature to predict recurrence-free survival in patients with GC. We further analyzed the ability of 14-TF to predict recurrence-free survival time in GC and found that a higher expression level of metastasis-associated protein 2 (MTA2) was associated with shorter overall survival and disease-free survival time in GC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promotes GC growth and metastasis. Furthermore, we identified MTA2 binding to the promoter of minichromosome maintenance deficient 5 (MCM5), thereby promoting GC progression. Overall, these findings strongly support the prognostic potential of the 14-TFs signature and suggest that targeting MTA2 may be a promising strategy to treat GC.

Neoadjuvant tislelizumab and tegafur/gimeracil/octeracil (S-1) plus oxaliplatin in patients with locally advanced gastric or gastroesophageal junction cancer: Early results of a phase 2, single-arm trial.

Background: Recently, the combination of immunotherapy with chemotherapy has been recommended as first-line treatment of metastatic gastric/gastroesophageal junction (G/GEJ) in the clinical guidelines of many countries; the therapeutic potential of this application needs to be further investigated for neoadjuvant therapy of advanced G/GEJ cancer patients. Methods: We performed a prospective, single-arm, open-label, phase 2 trial of the PD-1 inhibitor tislelizumab combined with S-1 plus oxaliplatin (SOX) in patients with advanced LAG/GEJ cancer. All patients underwent the three-cycle (21 days/cycle) treatment except for one patient who underwent two cycles. The primary endpoints were tumor major pathology response (MPR) and other events of tumor response assessed by the RECIST 1.1 and Becker criteria. Moreover, we constructed a few-shot learning model to predict the probability of MPR, which could screen those patients who might benefit from the neoadjuvant immunotherapy-chemotherapy scheme. This study was registered at https://clinicaltrials.gov/ct2/show/NCT0-4890392. Results: Thirty-two patients were enrolled; 17 patients (53.1%) achieved MPR (≤10% viable tumor cells) after treatment, and among them, 8 (25.0%) had a pathological complete response (pCR). The 1-year overall survival (OS) rate was 91.4% and the 1-year recurrence-free survival (RFS) rate was 90.0%. Adverse events occurred in 24 patients (65.6%) and grade III-IV adverse events were observed in 4 patients (12.5%) during the neoadjuvant period. Furthermore, we found commonly used preoperative assessment tools such as CT and EUS, which presented limited accuracy of tumor therapeutic response in this study; thus, we developed a therapeutic response predictive model that consisted of TNFα, IFNγ, IL-10, CD4, and age of patient, and the AUC of this FSL model was 0.856 (95% CI: 0.823-0.884). Discussion: Our study showed that the neoadjuvant PD-1 inhibitor tislelizumab combined with SOX had promising application potential and presented no increasing treatment-related adverse events in patients with advanced G/GEJ cancer. Moreover, the predictive model could help therapists to evaluate the therapeutic response of this scheme accurately. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT0-4890392, identifier [NCT04890392].

Prognostic Utility of Platelet-to-Albumin Ratio among Critically Ill Patients with Colorectal Cancer: A Propensity Score Matching Study.

The platelet-to-albumin ratio (PAR) was developed to evaluate inflammatory and nutritional status among patients. The primary goal of the current study was to gain insight into the prognostic role of PAR in critically ill patients with colorectal cancer (CRC). The secondary aim was to develop and verify a clinical model including PAR for the prediction of 28-day mortality. This observational, multicenter study used data from the Medical Information Mart for Intensive Care (MIMIC) IV, e-ICU databases, and Union cohort. Data from 776 critically ill patients with CRC were from the e-ICU database, 219 from the MIMC-IV database, and 135 from the Wuhan Union Hospital. Propensity score matching (PSM) analysis, along with inverse probability treatment weighting, was used to control the influence of confounding factors. Support vector machine (SVM) and LASSO Cox models were then applied to identify significant metrics associated with 28-day mortality in the test cohort. Receiver operating curve (ROC) analysis, along with sensitivity and specificity, was measured to assess the predictive performances of PAR and the survival nomogram. The threshold value for PAR was 8.6, and patients with high PAR (≥8.6) experienced higher 28-day mortality compared to those with low PAR (<8.6). ROC curve analyses revealed that the discriminative ability of PAR was better than platelet count and albumin alone. LASSO Cox regression along with SVM identified six significant metrics associated with 28-day mortality in critically ill patients with CRC, including PAR. The C-index of the critically ill CRC nomogram was 0.802 (0.744-0.859) in the e-ICU training cohort, 0.839 (0.779-0.899) in the e-ICU validation cohort, 0.787 (0.695-0.879) in the MIMIC-IV cohort, and 0.767 (0.703-0.831) in the Union cohort. PAR is a simple score that combines inflammatory and nutritional status. PAR was a reliable index to predict short-term survival outcome of critically ill patients with CRC. Moreover, a clinical nomogram incorporating PAR exhibited satisfactory performance for predicting 28-day mortality of critically ill patients with CRC.

circRNA_101277 Influences Cisplatin Resistance of Colorectal Cancer Cells by Modulating the miR-370/IL-6 Axis.

Background: Colorectal cancer (CRC) is among the most prevalent malignancies globally. Early detection of precancerous lesions through routine colonoscopy has led to a dramatic reduction in CRC-related incidence and mortality among those between the ages of 50 and 70. However, in those where the disease progresses to an advanced stage, chemotherapy remains the primary available treatment option, and the associated 5-year survival rate remains low. The identification of genes associated with CRC chemoresistance would thus be a beneficial approach to identifying novel treatments for this deadly disease. Methods: The expression of circRNA_101277, miR-370, and IL-6 was assessed via qRT-PCR. IL-6 levels were measured with a human IL-6 ELISA kit based on the provided protocols. CRC cellular proliferation and cisplatin IC50 values were quantified via MTT assays. Luciferase assays were used to detect circRNA_101277 and miR-370 binding sites or miR-370 and IL-6 binding sites. Results: circRNA_101277 was increased in CRC tissues compared with control samples. circRNA_101277 overexpression was evident in CRC cells, and knockdown of this circRNA suppressed cellular proliferation and cisplatin resistance in these cancer cells. At a mechanistic level, circRNA_101277 was found to function by sequestering miR-370, thereby upregulating the miR-370 target gene IL-6 and promoting cisplatin resistance via this miR-370/IL-6 axis. Conclusion: In summary, our data highlight circRNA_101277 as a novel driver of CRC cell cisplatin resistance that functions by sequestering miR-370 and thereby enhancing IL-6 expression. These findings suggest that this circRNA_101277/miR-370/IL-6 axis may represent a critical axis of chemoresistance in CRC that can be targeted to diagnose and/or treat this cancer.

Transmission of COVID-19 from community to healthcare agencies and back to community: a retrospective study of data from Wuhan, China.

BACKGROUND: The early spatiotemporal transmission of COVID-19 remains unclear. The community to healthcare agencies and back to community (CHC) model was tested in our study to simulate the early phase of COVID-19 transmission in Wuhan, China. METHODS: We conducted a retrospective study. COVID-19 case series reported to the Municipal Notifiable Disease Report System of Wuhan from December 2019 to March 2020 from 17 communities were collected. Cases from healthcare workers (HW) and from community members (CM) were distinguished by documented occupations. Overall spatial and temporal relationships between HW and CM COVID-19 cases were visualised. The CHC model was then simulated. The turning point separating phase 1 and phase 2 was determined using a quadratic model. For phases 1 and 2, linear regression was used to quantify the relationship between HW and CM COVID-19 cases. RESULTS: The spatial and temporal distributions of COVID-19 cases between HWs and CMs were closely correlated. The turning point was 36.85±18.37 (range 15-70). The linear model fitted well for phase 1 (mean R2=0.98) and phase 2 (mean R2=0.93). In phase 1, the estimated [Formula: see text]s were positive (from 18.03 to 94.99), with smaller [Formula: see text]s (from 2.98 to 15.14); in phase 2, the estimated [Formula: see text]s were negative (from -4.22 to -81.87), with larger [Formula: see text]s (from 5.37 to 78.12). CONCLUSION: Transmission of COVID-19 from the community to healthcare agencies and back to the community was confirmed in Wuhan. Prevention and control measures for COVID-19 in hospitals and among HWs are crucial and warrant further attention.

The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma.

This study was performed to investigate the role of interleukin-1 receptor accessory protein (IL1RAP) in stomach carcinoma in vitro and in vivo, determine whether IL1RAP knockdown could regulate the development of stomach carcinoma, and elucidate the relationship between IL1RAP knockdown and inflammation by tumor microenvironment-related inflammatory factors in stomach carcinoma. We first used TCGA and GEPIA systems to predict the potential function of IL1RAP. Second, western blot and RT-PCR were used to analyze the expression, or mRNA level, of IL1RAP at different tissue or cell lines. Third, the occurrence and development of stomach carcinoma in vitro and in vivo were observed by using IL1RAP knockdown lentivirus. Finally, the inflammation of stomach carcinoma in vitro and in vivo was observed. Results show that in GEPIA and TCGA systems, IL1RAP expression in STAD tumor tissue was higher than normal, and high expression of IL1RAP in STAD patients had a worse prognostic outcome. Besides, GSEA shown IL1RAP was negative correlation of apopopsis, TLR4 and NF-κB signaling pathway. We also predicted that IL1RAP may related to IL-1 s, IL-33, and IL-36 s in STAD. The IL1RAP expression and mRNA level in tumor, or MGC803, cells were increased. Furthermore, IL1RAP knockdown by lentivirus could inhibit stomach carcinoma development in vitro and in vivo through weakening tumor cell proliferation, migration, invasion, therefore reducing tumor volume, weight, and biomarker levels, and increasing apoptotic level. Finally, we found IL1RAP knockdown could increase inflammation of tumor microenvironment-related inflammatory factors of stomach carcinoma, in vitro and in vivo. Our study demonstrates that IL1RAP is possibly able to regulate inflammation and apoptosis in stomach carcinoma. Furthermore, TLR4, NF-κB, IL-1 s, IL-33, and IL-36 s maybe the downstream target factor of IL1RAP in inflammation. These results may provide a new strategy for stomach carcinoma development by regulating inflammation.

Influence of bariatric surgery on the expression of nesfatin-1 in rats with type 2 diabetes mellitus.

OBJECTIVE: Bariatric surgery has been reported to be very effective in the remission of type 2 diabetes mellitus (T2DM). However, the mechanism is still under debate. Nesfatin-1, a recently discovered anorexigenic neuropeptide, was reported to be very important in glucose metabolism and regulating food intake. In this study, the effects of bariatric surgery on the expression and regulation of nesfatin-1 were discussed. METHODS: T2DM was induced in SD rats by a diet high in sugar and fat plus a low dose of streptozotocin (STZ) (25 mg/kg) injection. Bariatric surgeries, including Roux-En-Y Gastric Bypass (RYGB) and sleeve gastrectomy (SG), were performed on these rats. Two months after the surgery, the plasma nesfatin-1 level and the expression of nesfatin-1 in different organs of the rats were tested. Next, in vivo administration of nesfatin-1 after surgery was performed to investigate the role of nesfatin-1 in bariatric surgery. RESULTS: Both RYGB and SG could reduce the weight of the rats. However, only RYGB had significant effects on the blood glucose level. Neither surgeries seemed to affect the blood concentration of insulin. However, RYGB significantly improved insulin sensitivity. Expression of nesfatin-1 in the plasma and relative organs decreased in T2DM rats and rose again after RYGB; however, this pattern did not occur in SG. Injection of nesfatin-1 after SG significantly improved insulin resistance and reduced blood glucose levels. CONCLUSIONS: Nesfatin-1 may improve insulin sensitivity in T2DM rats and thus plays a very important role in the remission of T2DM after RYGB. This neuropeptide could be a new target for directing future improvements in the bariatric surgical process.