Prognostic Significance of Preoperative and Postoperative Evaluation of Combined Tumor Markers for Patients With Colon Cancer.

BACKGROUND: The combined value of the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in patients with colon cancer (CC) is unclear. This study aimed to investigate the role of composite tumor markers in the prognosis of CC. METHODS: Patients who underwent curative resection of colon adenocarcinoma were enrolled. The tumor marker status before and after the operation was used to divide the patients into groups according to the number of tumor markers with abnormal expression, and recurrence-free survival (RFS) and overall survival (OS) of different groups were compared. The impact of changes in composite tumor markers in the perioperative period on outcomes was further explored. RESULTS: Ultimately, 531 patients were enrolled in the study. As the number of preoperative and postoperative elevated tumor markers increased, both RFS and OS rates became lower (both P <0.05). Further analysis revealed that the number of elevated tumor markers after resection can significantly affect the outcomes (both P <0.05). In patients with abnormal preoperative tumor markers, normalization of markers after surgery was a protective factor for prognosis (both P <0.05), and patients with postoperative elevated levels of both tumor markers had a 5.5-fold and 6-fold increase in the risk of recurrence and death. In addition, patients with elevated markers after surgery had a high risk of recurrence within 5 years after colectomy. CONCLUSIONS: Postoperative tumor markers had a better ability to differentiate postoperative outcomes in patients with CC than preoperative tumor markers. Patients whose tumor markers normalized after surgery had a better prognosis.

Research Advances in Fusion Protein-Based Drugs for Diabetes Treatment.

Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood glucose levels, resulting in multi-organ dysfunction and various complications. Fusion proteins can form multifunctional complexes by combining the target proteins with partner proteins. It has significant advantages in improving the performance of the target proteins, extending their biological half-life, and enhancing patient drug compliance. Fusion protein-based drugs have emerged as promising new drugs in diabetes therapeutics. However, there has not been a systematic review of fusion protein-based drugs for diabetes therapeutics. Hence, we conducted a comprehensive review of published literature on diabetic fusion protein-based drugs for diabetes, with a primary focus on immunoglobulin G (IgG) fragment crystallizable (Fc) region, albumin, and transferrin (TF). This review aims to provide a reference for the subsequent development and clinical application of fusion protein-based drugs in diabetes therapeutics.

Survival outcomes of 2018 FIGO stage IIIC versus stages IIIA and IIIB in cervical cancer: A systematic review with meta-analysis.

OBJECTIVE: To assess the difference in survival outcomes between stage IIIC and stages IIIA and IIIB in the 2018 FIGO cervical cancer staging system. METHODS: The PubMed, EMBASE, MEDLINE and Web of Science were searched for articles published from November 1, 2018 to January 31, 2023. Articles published in English were considered. The included studies compared the survival outcomes of patients with cervical cancer in FIGO 2018 stage IIIC with those in stages IIIA and IIIB. Studies focused on rare histopathological types were excluded. The statistical analyses were performed using Stata 17 software. The endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: Ten retrospective cohort studies were eligible, involving 2113 (6.2%), 9812 (28.6%), 44 (0.1%), 10 171 (29.7%), 11 677 (34.1%) and 445 (1.3%) patients in stage IIIA, IIIB, IIIA&B, IIIC, IIIC1, and IIIC2, respectively. In the OS group, stage IIIC/C1 was significantly associated with superior survival compared with stage IIIA (hazard risk [HR] 0.62, 95% confidence interval [CI] 0.41-0.93, P = 0.022; I2 = 92.9%) and stage IIIB(A&B) (HR 0.56, 95% CI 0.44-0.71, P < 0.001; I2 = 94.0%). The FIGO 2018 stage IIIC2 was not associated with an increased mortality risk compared with stage IIIA and stage IIIB(A&B). In the PFS group, the outcome of FIGO 2018 stage IIIC/C1 was similar to stage IIIA (HR 0.66, 95% CI 0.27-1.64, P = 0.371; I2 = 65.6%), but better than stage IIIB(A&B) (HR 0.75, 95% CI 0.68-0.83, P < 0.001; I2 = 0.0%). The FIGO 2018 stage IIIC2 has similar PFS outcomes to stage IIIA and stage IIIB(A&B). CONCLUSION: Our findings demonstrate that survival outcomes of stage IIIC are no worse than those of stage IIIA and stage IIIB in the 2018 FIGO cervical cancer staging system. In cervical cancer, FIGO 2018 stage IIIC1 has significantly better OS outcomes than stage IIIA and stage IIIB.

Transverse Coloplasty Pouch versus Straight Coloanal Anastomosis Following Intersphincteric Resection for Low Rectal Cancer: the Functional Benefits May Emerge After Two Years.

PURPOSE: This study aimed to compare the oncological and functional outcomes following intersphincteric resection (ISR) with transverse coloplasty pouch (TCP) or straight coloanal anastomosis (SCAA) for low rectal cancer. METHODS: A single-center retrospective analysis was performed on patients with low rectal cancer who received ISR between January 2016 and June 2021. The primary endpoint was to compare the outcomes of bowel function within 1 year, 1 to 2 years, and 2 years after ileostomy closure in patients undergoing two different bowel reconstruction procedures (TCP or SCAA). The postoperative complications and oncological results were also compared between the two groups. RESULTS: A total of 235 patients were enrolled in this study (SCAA group: 166; TCP group: 69). There was no significant difference in complications, including grades A-C anastomotic leakage (9.6% vs 15.9%), 3-year local recurrence rates (6.1% vs 3.9%), disease-free survival (82.4%vs 83.8%), or overall survival (94.1% vs 94.7%) between the two groups. Two years after ileostomy closure, 52.7% of patients in the SCAA group were assessed as having major low anterior resection syndrome (LARS), which was significantly higher than the 25.9% of patients in the TCP group (P = 0.014), but no difference was found prior to 2 years. Similar differences were seen in Wexner scores 2 years after surgery (P = 0.032). Additionally, TCP was an independent protective factor for postoperative bowel function as measured by both the LARS (OR, 0.28; 95% CI, 0.10-0.82; p = 0.020) and Wexner scoring (OR, 0.28; 95% CI, 0.09-0.84; p = 0.023). CONCLUSION: This study suggests that TCP is a safe technique that may decrease bowel dysfunction after ISR for low rectal cancer compared with SCAA 2 years after ileostomy closure.

Circumstellar material ejected violently by a massive star immediately before its death.

Type II supernovae represent the most common stellar explosions in the Universe, for which the final stage evolution of their hydrogen-rich massive progenitors towards core-collapse explosion are elusive. The recent explosion of SN 2023ixf in a very nearby galaxy, Messier 101, provides a rare opportunity to explore this longstanding issue. With the timely high-cadence flash spectra taken within 1-5 days after the explosion, we can put stringent constraints on the properties of the surrounding circumstellar material around this supernova. Based on the rapid fading of the narrow emission lines and luminosity/profile of Hα emission at very early times, we estimate that the progenitor of SN 2023ixf lost material at a mass-loss rate M≈6×10-4M⊙a-1 over the last 2-3 years before explosion. This close-by material, moving at a velocity vw≈55kms-1, accumulates a compact CSM shell at the radius smaller than 7×1014 cm from the progenitor. Given the high mass-loss rate and relatively large wind velocity presented here, together with the pre-explosion observations made about two decades ago, the progenitor of SN 2023ixf could be a short-lived yellow hypergiant that evolved from a red supergiant shortly before the explosion.

Comparison of survival outcomes and survival prediction in patients with primary colorectal MANEC and primary colorectal SRCC: a population-based propensity-score matching study.

PURPOSE: Primary mixed adeno-neuroendocrine carcinoma (MANEC) and primary signet-ring cell cancer (SRCC) are two rare but highly malignant tumors in colorectal cancer. Therefore, we attempted to compare the tumors' survival outcomes, identify risk factors, and ultimately evaluate the prognosis by developing a nomogram. METHODS: We identified 755 MANEC and 5836 SRCC patients of colorectal cancer. PSM was used to balance the influence of baseline clinical and pathological differences. Kaplan-Meier method was used to compare the prognosis of different pathological grades and AJCC stages. Cox proportional hazards model was used to identify potential prognostic factors for the two groups. Finally, we developed a nomogram and evaluated the feasibility of the model. RESULTS: After PSM, the median OS and CSS of MANEC patients were significantly better than those of SRCC patients in stage III-IV (P < 0.001) but similar in stage I-II. The median OS and CSS of MANEC patients in each pathological grade were also greater than those of SRCC patients. Patients with MANEC and SRCC who underwent lymph node dissection in more than four areas had longer survival time. MANEC patients benefited from postoperative chemotherapy and radiotherapy; among SRCC patients, those who received preoperative and postoperative comprehensive chemotherapy and radiotherapy had benefits in OS and CSS. CONCLUSION: Both MANEC and SRCC are often diagnosed in advanced stages, highlighting the importance of early screening. Despite the better prognosis of MANEC compared to SRCC, both types of patients require the formulation of personalized treatment strategies based on different risk factors combined with column charts.

Expression patterns and prognostic value of key regulators associated with m7G RNA modification based on all gene expression in colon adenocarcinoma.

BACKGROUND: N7-methylguanosine (m7G) is present in a wide variety of organisms and has important roles. m7G has been reported to be involved in multiple biological processes, and recent studies have reported that changes in RNA modifications result in tumor cellular transformation and cancer, such as colon adenocarcinoma, lung cancer, and intrahepatic cholangiocarcinoma. However, little is known about the function of the m7G in colon adenocarcinoma. METHODS: We established two clusters based on the expression of all genes associated with m7G to explore the expression pattern of 31 key regulatory factors of m7G RNA and assess the prognostic value of regulatory factors. Wilcoxon test and differential box line plots were applied for bioinformatics analysis. Receiver Operating and Kaplan‒Meier curves were utilized to evaluate the prognostic value. Finally, four genes' expression in the colon cancer cell line was confirmed by qRT-PCR. RESULTS: From The Cancer Genome Atlas database, we found that the expression levels of 25 out of the 31 key N7-methylguanosine RNA modification regulators were significantly different in colon adenocarcinoma. According to 25 methylation regulators' expression, we identified two subgroups by consensus clustering, in which the prognosis was worse in Group 2 than in Group 1 and was significantly correlated with age. Cluster 2 was significantly enriched in tumor-associated pathways, and immune cells were highly infiltrated in Cluster 1 but weakly infiltrated in Cluster 2. Further results indicated that this risk profile may serve as a standalone predictive factor for colon adenocarcinoma, and the four genetic risk profiles' prognostic relatedness was successfully verified through Gene Expression Omnibus dataset. At last, A nomogram for prognosis was created according to age, sex, histological grading, clinicopathological staging, and hazard score to accurately predict patient prognosis in colon adenocarcinoma. We successfully validated the differential expression of four genes using qRT-PCR. CONCLUSIONS: In the present study, we revealed the important contribution of key regulators associated with m7G RNA modifications based on all gene expression in colon adenocarcinoma and developed a signature of risk that serves as a promising prognostic marker for patients with colon adenocarcinoma.

Impact of cystectomy versus ablation for endometrioma on ovarian reserve: a systematic review and meta-analysis.

OBJECTIVE: To investigate whether cystectomy or ablation for endometrioma has less impact on ovarian reserve as evaluated by antral follicle count (AFC) and antimüllerian hormone (AMH) levels. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Patients with endometriomas undergoing cystectomy or ablation. INTERVENTION(S): All prospective studies comparing cystectomy with ablation for endometrioma in the PubMed, EMBASE, MEDLINE and Web of Science until April 3, 2022 were retrieved and reviewed. Medical treatment used as adjuvant therapy for the surgery was excluded. Two authors assessed eligibility and risk of bias independently. The statistical data were pooled using the Review Manager software. MAIN OUTCOME MEASURE(S): The changes of AMH levels and AFC values in cystectomy group and ablation group, including intergroup comparisons and intragroup comparisons. RESULT(S): Four randomized clinical trials and 2 prospective cohort studies were eligible for the meta-analysis, with a total of 294 patients. In the intergroup comparisons, preoperative AFC values were similar with low heterogeneity, but postoperative AFC values were significantly lower in cystectomy than ablation (mean differences [MD], -1.33; 95% credible interval, -2.15 to -0.51; I2 = 57%). In the intragroup comparisons of AFC values, sensitivity analyses showed a significant decrease in cystectomy (MD, -1.93; 95% credible interval, -2.40 to -1.45; I2 = 0%) at 6-month follow-up, compared with no reduction in ablation. The intragroup comparisons of AMH levels supported negative effects on ovarian reserve of both cystectomy (MD, -1.26; 95% credible interval, -1.64 to -0.88; I2 = 45%) and ablation (MD, -0.70; 95% credible interval, -1.07 to -0.32; I2 = 0%). CONCLUSION(S): Both ablation and cystectomy have significantly detrimental effects on ovarian reserve as evaluated by AMH, but the ablation causes relatively less damage to ovarian reserve as appraised by AFC. CLINICAL TRIAL REGISTRATION NUMBER: CRD42020152823;PROSPERO (york.ac.uk).

The global, regional, and national early-onset colorectal cancer burden and trends from 1990 to 2019: results from the Global Burden of Disease Study 2019.

PURPOSE: The incidence of early-onset colorectal cancer (EO-CRC), which occurs in people under age 50, has been increasing annually. The aim of this study was to provide an up-to-date estimate of the global EO-CRC burden. METHODS: We used Global Burden of Disease Study data and methodologies to describe changes in the EO-CRC burden from 1990 to 2019, including incidence, prevalence, mortality, and disability-adjusted life years (DALYs). The driving factors for cancer burden variation were further analyzed using decomposition analysis. Frontier analysis was used to visually demonstrate the potential for burden reduction in each country or region based on their development levels. RESULTS: The global EO-CRC incidence more than doubled, increasing from 95,737 (95% uncertainty interval (UI): 90,838-101.042) /100,000 in 1990 to 226,782 (95% UI: 207,495-248,604) /100,000 in 2019. Additionally, related deaths increased from 50,997 (95% UI: 47,692-54,410) /100,000 to 87,014 (95% UI: 80,259-94,339) /100,000, and DALYs increased from 256,1842 (95% UI: 239,4962-2,735,823) /100,000 to 4,297,573 (95% UI: 3,965,485-4,650,790) /100,000. Regarding age-standardized rates, incidence and prevalence increased significantly, while mortality and DALYs rate were basically unchanged. Decomposition analysis showed a significant increase in DALYs in the middle sociodemographic index (SDI) quintile region, in which aging and population growth played a major driving role. Frontier analysis showed that countries or regions with a higher SDI quintile tend to have greater improvement potential. CONCLUSION: The current EO-CRC burden was found to be the greatest in the high-middle SDI quintile region and East Asia, which may need to adjust screening guidelines accordingly and introduce more effective interventions.

Development and validation of artificial intelligence models for preoperative prediction of inferior mesenteric artery lymph nodes metastasis in left colon and rectal cancer.

BACKGROUND: Dissection of lymph nodes at the roots of the inferior mesenteric artery (IMAN) should be offered only to selected patients at a major risk of developing IMAN involvement. The aim of this study is to present the first artificial intelligence (AI) models to predict IMAN metastasis risk in the left colon and rectal cancer patients. METHODS: A total of 2891 patients with descending colon including splenic flexure, sigmoid colon and rectal cancer undergoing major primary surgery and IMAN dissection were included as a study cohort, which was then split into a training set (67%) and a testing set (33%). Feature selection was conducted using the least absolute shrinkage and selection operator (LASSO) regression model. Seven AI algorithms, namely Support Vector Machine (SVM), Logistic Regression (LR), Extreme Gradient Boosting (XGB), Light Gradient Boosting (LGB), Decision Tree Classifier (DTC), Random Forest (RF) classifier, and Multilayer Perceptron (MLP), as well as traditional multivariate LR model were employed to construct predictive models. The optimal hyperparameters were determined with 5 fold cross-validation. The predictive performance of models and the expert surgeon was assessed and compared in the testing set independently. RESULTS: The IMAN involvement incidence was 4.6%. The optimal set of features selected by LASSO included 10 characteristics: neoadjuvant treatment, age, synchronous liver metastasis, synchronous lung metastasis, signet ring adenocarcinoma, neural invasion, lymphovascular invasion, CA199, endoscopic obstruction, T stage evaluated by MRI. The most accurate model derived from MLP showed excellent prediction power with area under the receiver operating characteristic curve (AUROC) of 0.873 and produced 81.0% recognition sensitivity and 82.5% specificity in the testing set independently. In contrast, the judgment of IMAN metastasis by expert surgeon yield rather imprecise and unreliable results with a significantly lower AUROC of 0.509. Additionally, the proposed MLP had the highest net benefits and the largest reduction of unnecessary IMAN dissection without the cost of additional involved IMAN missed. CONCLUSION: MLP model was able to maintain its prediction accuracy in the testing set better than other models and expert surgeons. Our MLP model could be used to help identify IMA nodal metastasis and to select candidates for individual IMAN dissection.

N6-methyladenosine-dependent pri-miR-17-92 maturation suppresses PTEN/TMEM127 and promotes sensitivity to everolimus in gastric cancer.

N6-methyladenosine (m6A) is the most common epigenetic RNA modification with essential roles in cancer progression. However, roles of m6A and its regulator METTL3 on non-coding RNA in gastric cancer are unknown. In this study, we found elevated levels of m6A and METTL3 in gastric cancer. Increased METTL3 expression indicated poor outcomes of patients and high malignancy in vitro and in vivo. Mechanically, m6A facilitated processing of pri-miR-17-92 into the miR-17-92 cluster through an m6A/DGCR8-dependent mechanism. The m6A modification that mediated this process occurred on the A879 locus of pri-miR-17-92. The miR-17-92 cluster activated the AKT/mTOR pathway by targeting PTEN or TMEM127. Compared with those with low levels of METTL3, METTL3-high tumors showed preferred sensitivity to an mTOR inhibitor, everolimus. These results reveal a perspective on epigenetic regulations of non-coding RNA in gastric cancer progression and provide a theoretical rationale for use of everolimus in the treatment of m6A/METTL3-high gastric cancer.

CD148 Serves as a Prognostic Marker of Gastric Cancer and Hinders Tumor Progression by Dephosphorylating EGFR.

CD148 is a member of the receptor-type protein tyrosine phosphatase family encoded by the PTPRJ gene and has controversial impacts on cancers. In this study, we investigated the clinical significance of CD148 in gastric cancer and the possible mechanisms. Suppressed CD148 expression indicated adverse pathological features and poor outcomes in gastric cancer patients. CD148 overexpression impeded tumor proliferation, motility, and invasiveness, while CD148 knock-down or knockout promoted the ability of gastric cancer cells to grow and metastasize in vitro and in vivo. Mechanistically, CD148 negatively regulated EGFR phosphorylation of multiple tyrosine residues, including Y1173, Y1068, and Y1092, and remarkably inhibited downstream PI3K/AKT and MEK/ERK pathways. In silico analysis revealed that gene deletions or missense/truncated mutations of PTPRJ gene rarely occurred in gastric cancers. Instead, a 3' UTR-specific methylation might regulate CD148 expression, and the potential regulators were TET2 and TET3. Collectively, our results suggest that CD148 is a convincing prognostic marker as well as a potential therapeutic target for gastric cancer.

CDC25A Facilitates Chemo-resistance in Ovarian Cancer Multicellular Spheroids by Promoting E-cadherin Expression and Arresting Cell Cycles.

Peritoneal metastasis is the most common pathway for the spread of ovarian cancer and one of the major causes of cancer death. Ovarian cancer cells in ascites prefer to aggregate into the multicellular spheroids (MCS) with an inadequate response to chemotherapy. In this study, gene expression analysis implicated that ovarian cancer MCS had its unique expression pattern and the cell cycle-related pathways were prominently altered in MCS cells compared to the monolayer adherent cells. Flow cytometry and western blots confirmed the cell cycle stagnancy in MCS. Among the cell cycle-related proteins, we found that expression of CDC25A was upregulated in MCS and displayed a time-dependent decrease during the transition from MCS to monolayer adherent cells. Loss-of-function studies showed that CDC25A promoted cisplatin-resistance and paclitaxel-resistance and inhibited the drug-induced apoptosis in ovarian cancer MCS. Mechanically, CDC25A impeded cell cycle progression in MCS cells, enhanced their structure integrity, and maintained upregulation of E-cadherin in MCS cells. Accordingly, addition of NSC95397, a small molecular inhibitor of CDC25A, sensitized the ovarian cancer MCS to chemotherapeutic agents. This provides us a novel strategy for the treatment of ovarian cancer peritoneal metastasis and may help improve the overall survival of ovarian cancer patients.

Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2.

PURPOSE: Peritoneal metastasis is the most common pathway for the spread of ovarian cancer. Ovarian cancer cells in ascites prefer to aggregate into the more chemoresistant multicellular spheroids (MCSs), leading to treatment failure and disease recurrence. We previously established a suspension MCS model of ovarian cancer cells in vitro and found that the MCS cells acquired drug resistance to cisplatin. In the present study, we aimed to uncover the underlying mechanism of the platinum resistance of MCS and the potential targets to reverse the drug resistance. MATERIALS AND METHODS: MCS models were established for the phenotypic studies, including proliferation, invasion, migration, drug resistance, apoptosis assays, and signaling pathway analysis. The key molecule, Bcl-2, was screened by profile analysis and validated by Western blotting. siRNA was used to verify the anti-cisplatin-induced apoptosis effect of Bcl-2. The Bcl-2 inhibitor, ABT-737, was used for improving the sensitivity of MCS to cisplatin. The 50% inhibitory concentrations (IC50) were measured by viability assays treated with different concentrations of cisplatin. Flow cytometry and Western blotting were used for quantification of drug-induced apoptosis. RESULTS: The ovarian cancer MCS showed a proliferation-stagnant but invasive phenotype when resuspended. When treated with cisplatin, MCS cells showed much higher viability, with significantly fewer apoptotic cells than the adherent cells. Levels of Bcl-2 were upregulated in ovarian cancer ascitic cells and MCS cells. Bcl-2 knockdown by siRNA or blockage by ABT-737 enhanced the cisplatin-induced apoptosis and reduced the 50% inhibitory concentrations of cisplatin for MCS by 58.5% and 88.2%, respectively. CONCLUSION: The upregulated Bcl-2 contributes to cisplatin resistance in our MCS model and targeting it sensitizes the MCS to cisplatin treatment. This provides us a preliminary treatment method for ovarian cancer peritoneal metastasis.

LIMD1 is a survival prognostic marker of gastric cancer and hinders tumor progression by suppressing activation of YAP1.

PURPOSE: The purpose of this study was to investigate the clinical significance of LIMD1 and its biological roles in gastric cancer (GC). MATERIALS AND METHODS: The prognostic value of LIMD1 in GC patients was determined by the online tool Kaplan-Meier Plotter. The biological functions of LIMD1 in GC were examined by in vitro assays, including proliferation, anchorage-independent growth, migration, invasion, and epithelial to mesenchymal transition (EMT) assays. The levels of downstream YAP1 regulated by LIMD1 were measured by Western blot analysis, and the sub-localization of YAP1 in GC cells was visualized by immunofluorescence staining. Differential expression levels and copy number levels of LIMD1 between GC and normal tissues were compared using the Oncomine database. A correlation of LIMD1 mRNA level and the copy number level was depicted by cBioPortal. We also evaluated the methylation status around the LIMD1 genes by Wanderer. RESULTS: The expression level of LIMD1 positively correlated with the prognosis of GC patients regardless of tumor stage, size, lymph node, metastasis, Lauren's classification, differentiation, gender, treatment, and ERBB2 amplification status. Overexpression of LIMD1 impeded the tumor growth, cell motility, invasiveness, and metastasis, and knockdown of LIMD1 promoted these phenotypes in GC cells. Mechanistically, YAP1 was one of the downstream effectors of LIMD1; LIMD1 suppressed the expression of YAP1 as well as its intracellular translocation. Furthermore, we found that LIMD1 expression was reduced in some of the GC profiling datasets. Gene deletion, instead of DNA methylation, contributed to the reduced expression of LIMD1 in GC. CONCLUSION: Our results identified LIMD1 as a convincing prognostic marker as well as a potentially therapeutic target for GC.