The intra-S phase checkpoint targets Dna2 to prevent stalled replication forks from reversing.

When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1(Chk2) effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression-regressed leading or lagging strands-on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress.

Dismissal of RNA Polymerase II Underlies a Large Ligand-Induced Enhancer Decommissioning Program.

Nuclear receptors induce both transcriptional activation and repression programs responsible for development, homeostasis, and disease. Here, we report a previously overlooked enhancer decommissioning strategy underlying a large estrogen receptor alpha (ERα)-dependent transcriptional repression program. The unexpected signature for this E2-induced program resides in indirect recruitment of ERα to a large cohort of pioneer factor basally active FOXA1-bound enhancers that lack cognate ERα DNA-binding elements. Surprisingly, these basally active estrogen-repressed (BAER) enhancers are decommissioned by ERα-dependent recruitment of the histone demethylase KDM2A, functioning independently of its demethylase activity. Rather, KDM2A tethers the E3 ubiquitin-protein ligase NEDD4 to ubiquitylate/dismiss Pol II to abrogate eRNA transcription, with consequent target gene downregulation. Thus, our data reveal that Pol II ubiquitylation/dismissal may serve as a potentially broad strategy utilized by indirectly bound nuclear receptors to abrogate large programs of pioneer factor-mediated, eRNA-producing enhancers.

JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex.

Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC-domain-containing proteins in mediating enhancer activation remain poorly understood. Here, we report that recruitment of the JmjC-domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 is found to interact with MED12 in the mediator complex to regulate its recruitment. Unexpectedly, JMJD6 is necessary for MED12 to interact with CARM1, which methylates MED12 at multiple arginine sites and regulates its chromatin binding. Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERα-induced breast cancer cell growth and tumorigenesis. Our data have uncovered a critical regulator of estrogen/ERα-induced enhancer coding gene activation and breast cancer cell potency, providing a potential therapeutic target of ER-positive breast cancers.

Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ERα-Regulated Transcriptional Program.

The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GRs) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here we report that, in breast cancer cells, liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and it leads to the inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen E2 program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-N-CoR/SMRT-HDAC3 corepressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to hot spot enhancers serves as an effective biological strategy for trans-repression, with clear implications for breast cancer and other diseases.

Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation.

Enhancers instruct spatio-temporally specific gene expression in a manner tightly linked to higher-order chromatin architecture. Critical chromatin architectural regulators condensin I and condensin II play non-redundant roles controlling mitotic chromosomes. But the chromosomal locations of condensins and their functional roles in interphase are poorly understood. Here we report that both condensin complexes exhibit an unexpected, dramatic estrogen-induced recruitment to estrogen receptor α (ER-α)-bound eRNA(+) active enhancers in interphase breast cancer cells, exhibiting non-canonical interaction with ER-α via its DNA-binding domain (DBD). Condensins positively regulate ligand-dependent enhancer activation at least in part by recruiting an E3 ubiquitin ligase, HECTD1, to modulate the binding of enhancer-associated coactivators/corepressors, including p300 and RIP140, permitting full eRNA transcription, formation of enhancer:promoter looping, and the resultant coding gene activation. Collectively, our results reveal an important, unanticipated transcriptional role of interphase condensins in modulating estrogen-regulated enhancer activation and coding gene transcriptional program.

Efficacy and Adverse Reactions of Transcatheter Arterial Chemoembolization Combined with Apatinib in the Treatment of HCC with PVTT: A Meta-Analysis.

Background: Hepatocellular carcinoma is a major contributor to cancer-related deaths in China and ranks among the most prevalent malignant tumors. . The study aimed to assess the efficacy and adverse reactions of transcatheter arterial chemoembolization combined with apatinib in treating hepatocellular carcinoma with portal vein tumor thrombus. Methods: When treating hepatocellular carcinoma with a portal vein tumor thrombus, the computer retrieves eight databases to find controlled trials on the effects of transcatheter arterial chemoembolization combined with apatinib. The Cochrane Library, WanFang databases EMbase, PubMed, Web of Science, China Biomedical Literature Database (CBM), & CNKI are all retrieved by the computer. "Transcatheter arterial chemoembolization", "apatinib", & "hepatocellular carcinoma" are the search terms. As this a meta-analysis, Utilizing RevMan 5.3 software, data analysis was carried out following a thorough assessment of the quality of the literature. Results: This meta-analysis finally contained 7 papers. According to a meta-analysis, the disease control rate of the test category was considerably greater than that of the control category (odd Ratio OR: 1.65; 95% Cl: 1.17,2.33; P = .01). The experimental cohort's level of VEGF was substantially lower than that of the control group (standardized mean difference SMD:-25.38; 95% Cl: -28.69,-21.79; P < .01). According to a meta-analysis, caspase-8 levels in the group that underwent the experiment were substantially greater than those in the control category (SMD: 15.12; 95% Cl: 12.09, 18.15; P < .01). The test control experienced considerably less pain than the control sample (OR: 0.86; 95% Cl: 0.75,0.99; P = .033). Conclusion: The findings of this trial indicate that individuals with HCC & PVTT may benefit from TACE & apatinib together, as evidenced by disease control rate, VEGF, Caspase-8, pain, hypertension, nausea and vomiting, and more reputable studies are required to support the aforementioned conclusions.

Patterns, treatments, and prognosis of tumor recurrence after resection for hepatocellular carcinoma with microvascular invasion: a multicenter study from China.

BACKGROUND: Microvascular invasion (MVI) is a risk factor of post-hepatectomy tumor recurrence for hepatocellular carcinoma (HCC). The patterns, treatments, and prognosis have not been documented in HCC patients with MVI. METHODS: A multicenter database of patients with HCC and MVI following resection was analyzed. The clinicopathological and initial operative data, timing and first sites of recurrence, recurrence management, and long-term survival outcomes were analyzed. RESULTS: Of 1517 patients included, the median follow-up was 39.7 months. Tumor recurrence occurred in 928 patients, with 49% within 6 months of hepatectomy and 60% only in the liver. The incidence of intrahepatic only recurrence gradually increased with time after 6 months. Patients who developed recurrence within 6 months of hepatectomy had worse survival outcomes than those who developed recurrence later. Patients who developed intrahepatic only recurrence had better prognosis than those with either extrahepatic only recurrence or those with intra- and extrahepatic recurrence. Repeat resection of recurrence with curative intent resulted in better outcomes than other treatment modalities. CONCLUSION: Post-hepatectomy tumor recurrence in patients with HCC and MVI had unique characteristics and recurrence patterns. Early detection of tumor recurrence and repeat liver resection with curative intent resulted in improved long-term survival outcomes.

The impact of portal vein tumor thrombus on long-term survival after liver resection for primary hepatic malignancy.

BACKGROUND: The aim of this study was to evaluate the effect of portal vein tumor thrombus (PVTT) on the prognosis of patients undergoing liver resection (LR) for primary liver malignancies (PLC). METHODS: The recurrence-free survival (RFS) and overall survival (OS) for patients undergoing LR with and without PVTT for three primary liver malignancies, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and hepato-cholangio carcinoma (CHC) were compared using the Kaplan-Meier method and Cox regression analysis. RESULTS: In total, 3775 patients with PLC who underwent LR were included in this study. The incidence of PVTT in patients undergoing LR with HCC, IHC and CHC were 46%, 20%, and 17%, respectively. The median RFS and OS were significantly better for patients with HCC as compared to ICC or CHC (16 vs 11 vs 13 months; 21 vs 16 vs 18 months, respectively; P < 0.001). However, the presence of PVTT resulted in similarly poor RFS and OS in these 3 subgroups of patients (9 vs 8 vs 8 months, P = 0.062; 14 vs 13 vs 12 months, respectively, P = 0.052). CONCLUSION: Although the prognosis of patients with PLC varied by histological subtype, once PVTT occurred, survival outcomes after LR were similarly poor across all three subgroups.

Association of Preoperative Hypercoagulability with Poor Prognosis in Hepatocellular Carcinoma Patients with Microvascular Invasion After Liver Resection: A Multicenter Study.

BACKGROUND: Microvascular invasion (MVI) predicts poor prognosis in patients with hepatocellular carcinoma (HCC). HCC patients with hypercoagulability are prone to develop thrombosis; however, the relationship between preoperative coagulability state, as reflected by the international normalized ratio (INR) level, and MVI remains unclear. METHODS: From January 2009 to December 2012, HCC patients who underwent R0 liver resection (LR) from four cancer centers entered into this study. The overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of the 2509 HCC patients who were included into this study, 1104 were found to have MVI in the resected specimens. These patients were divided into the low (n = 151), normal (n = 796), and high (n = 157) INR subgroups based on the preoperative INR levels. The low INR subgroup had a significantly higher incidence of MVI than the normal or high INR subgroups (61.6% vs. 41.6% vs. 44.6%; p < 0.001). HCC patients with MVI were significantly more likely to have a low preoperative INR level (p < 0.001); the INR level (p < 0.001) was an independent risk factor of OS and RFS. HCC patients with MVI in the low INR subgroup had significantly worse RFS and OS than the normal or high INR subgroups (median RFS 13.5 vs. 20.2 vs. 21.6 months, p < 0.001; median OS 35.5 vs. 59.5 vs. 57.0 months, p < 0.001). CONCLUSIONS: Preoperative hypercoagulability was associated with poor long-term prognosis in HCC patients with MVI after R0 LR.

Thrombocytopenia: A prognostic factor for hepatocellular carcinoma patients with portal vein tumor thrombus after hepatectomy.

BACKGROUND AND AIM: Portal vein tumor thrombus (PVTT) predicts a poor prognosis in hepatocellular carcinoma (HCC) patients. Platelets (PLTs) play an important role in HCC progression and metastasis. However, the relationship between PLTs and PVTT remains unclear. This study aimed to evaluate the value of PLT counts in the prognosis of HCC patients with PVTT after hepatectomy. METHODS: From January 2002 to December 2012, 694 HCC patients with PVTT after hepatectomy were evaluated. The patients were divided into the thrombocytopenia group (PLT < 100 × 109 /L), the normal group, and the thrombocytosis group (PLT > 300 × 109 /L) based on the preoperative PLT level. A propensity score matching (PSM) analysis was used. RESULTS: Before the PSM, PVTT patients with thrombocytopenia exhibited longer recurrence-free survival (RFS) and overall survival (OS) compared with those with normal PLT counts (both P < 0.001) or thrombocytosis (P = 0.008 and P = 0.046). For the thrombocytopenia group and the normal group, the 1-, 2-, and 3-year RFS values were 30.0%, 17.6%, and 15.7% and were 10.8%, 6.6%, and 5.8% (P < 0.001), respectively; the 1-, 2-, and 3-year OS values were 61.9%, 37.9%, and 31.2% and were 38.3%, 23.3%, and 16.0% (P < 0.001), respectively. After the PSM, the median survival time was 16.6 versus 8.6 months (P < 0.002) in the two groups. A subgroup analysis revealed that thrombocytopenia is associated with improved OS in those with type I PVTT (P = 0.021) or type II PVTT (P = 0.029). CONCLUSION: According to the PSM, preoperative thrombocytopenia predicts an increased RFS and OS in HCC patients with PVTT after hepatectomy.

lncRNA GCAWKR Promotes Gastric Cancer Development by Scaffolding the Chromatin Modification Factors WDR5 and KAT2A.

Long noncoding RNAs (lncRNAs) have been demonstrated to play a role in carcinogenesis, but their mechanisms of function remain elusive. We explored the mechanisms of the oncogenic role of GCAWKR in gastric cancer (GC) using human tissues and cell lines. The in situ hybridization analysis was utilized to determine GCAWKR levels in samples from 42 GC patients and real-time qPCR in tissues from 123 patients. The GCAWKR levels were modulated in GC cell lines, and relevant biological and molecular analyses were performed. Levels of the GCAWKR were upregulated in GC tissues compared with normal tissues and associated with tumor size, lymph node metastasis, TNM stage, and patient outcomes. GCAWKR affected cell proliferation and cell invasion in multiple GC models. Mechanistically, GCAWKR bound WDR5 and KAT2A and acted as a molecular scaffold of WDR5/KAT2A complexes, modulating the affinity for WDR5/KAT2A complexes in the target gene's promoter region. Thus, our data defined a mechanism of lncRNA-mediated carcinogenesis in GC, suggesting new therapeutic targets in GC.

Prognostic Value of Inflammatory Biomarkers in Gastric Cancer Patients and the Construction of a Predictive Model.

BACKGROUND: It is known that inflammation promotes cancer development. However, a few studies have evaluated the prognostic significance of inflammatory biomarkers in gastric cancer (GC). METHODS: In this study, 2,334 patients who underwent gastrectomy for GC at Fudan University Shanghai Cancer Center between 2003 and 2007 were retrospectively analyzed, and 1,227 patients were found to be eligible. The preoperative serum neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), and albumin/globulin ratio (AGR) levels were analyzed. A nomogram was constructed with the Cox proportional hazards regression model in the training set (n = 818) to predict the probability of overall survival (OS) and disease-free survival (DFS). The predictive accuracy and discriminative ability were determined using the concordance index (C-index) and calibration curve. RESULTS: We found that lower AGR and LMR values were correlated with decreased OS, lower LMR values, and higher NLR values with a decreased DFS. Other significant factors were included to construct the nomogram. The discriminative ability of the nomogram was higher than that of the eighth American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system (0.746 for TNM v.s. 0.654 for the nomogram, p < 0.001). CONCLUSIONS: The nomogram yielded a more accurate prognostic prediction in GC patients after gastrectomy, suggesting great clinical value.

Long non-coding RNA linc00261 suppresses gastric cancer progression via promoting Slug degradation.

Gastric cancer (GC) remains a threat to public health with high incidence and mortality worldwide. Increasing evidence demonstrates that long non-coding RNAs (lncRNAs) play critical regulatory roles in cancer biology, including GC. Previous profiling study showed that lncRNA linc00261 was aberrantly expressed in GC. However, the role of linc00261 in GC progression and the precise molecular mechanism remain unknown. In this study, we report that linc00261 was significantly down-regulated in GC tissues and the expression level of linc00261 negatively correlated with advanced tumour status and clinical stage as well as poor prognostic outcome. In vitro functional assays indicate that ectopic expression of linc00261 suppressed cell invasion by inhibiting the epithelial-mesenchymal transition (EMT). By RNA pull-down and mass spectrum experiments, we identified Slug as an RNA-binding protein that binds to linc00261. We confirmed that linc00261 down-regulated Slug by decreasing the stability of Slug proteins and that the tumour-suppressive function of linc00261 can be neutralized by Slug. linc00261 may promote the degradation of Slug via enhancing the interaction between GSK3ß and Slug. Moreover, linc00216 overexpression repressed lung metastasis in vivo. Together, our findings suggest that linc00261 acts a tumour suppressor in GC by decreasing the stability of Slug proteins and suppressing EMT. By clarifying the mechanisms underlying GC progression, these findings may facilitate the development of novel therapeutic strategies for GC.

Efficacy and safety of B-mode ultrasound-guided percutaneous transhepatic gallbladder drainage combined with laparoscopic cholecystectomy for acute cholecystitis in elderly and high-risk patients.

BACKGROUND: Standards in treatment of acute cholecystitis (AC) in the elderly and high-risk patients has not been established. Our study evaluated the efficacy and safety of B-mode ultrasound-guided percutaneous transhepatic gallbladder drainage (PTGD) in combination with laparoscopic cholecystectomy (LC) for acute cholecystitis (AC) in elderly and high-risk patients. METHODS: Our study enrolled 35 elderly and high-risk AC patients, hospitalized between January 2010 and April 2014 at the Wenzhou People's Hospital. The patients underwent B-mode ultrasound-guided PTGD and LC (PTGD + LC group). As controls, a separate group of 35 elderly and high-risk AC patients who underwent LC alone (LC group) during the same period at the same hospital were randomly selected from a pool of 186 such cases. The volume of bleeding, surgery time, postoperative length of stay, conversion rate to laparotomy and complication rates (bile leakage, bleeding, incisional hernia, incision infection, pulmonary infarction and respiratory failure) were recorded for each patient in the two groups. RESULTS: All patients in the PTGD + LC group successfully underwent PTGD. In the PTGD + LC group, abdominal pain in patients was relieved and leukocyte count, alkaline phosphatase level, total bilirubin and carbohydrate antigen 19-9 (CA19-9) decreased to normal range, and alanine aminotransferase and aspartate aminotransferase levels improved significantly within 72 h after treatment. All patients in the PTGD + LC group underwent LC within 6-10 weeks after PTGD. Our study revealed that PTGD + LC showed a significantly higher efficacy and safety compared to LC alone in AC treatment, as measured by the following parameters: duration of operation, postoperative length of hospital stay, volume of bleeding, conversion rate to laparotomy and complication rate (operation time of LC: 55.6 ± 23.3 min vs. 91.35 ± 25.1 min; hospitalized period after LC: 3.0 ± 1.3 d vs. 7.0 ± 1.7 d; intraoperative bleeding: 28.7 ± 15.2 ml vs. 60.38 ± 16.4 ml; conversion to laparotomy: 3 cases vs. 10 cases; complication: 3 cases vs. 8 cases; all P < 0.05 ). CONCLUSION: Our results suggest that B-mode ultrasound-guided PTGD in combination with LC is superior to LC alone for treatment of AC in elderly and high-risk patients, showing multiple advantages of minimal wounding, accelerated recovery, higher safety and efficacy, and fewer complications.

Effectiveness and Safety of Radiofrequency Ablation versus Liver Resection in the Treatment of Early-stage Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically evaluate the efficacy and safety of radiofrequency ablation and liver resection in the therapeutic management of early-stage hepatocellular carcinoma. METHOD: We conducted a comprehensive search of domestic and foreign databases including PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang to retrieve literature on radiofrequency ablation and liver resection for the treatment of early hepatocellular carcinoma. The retrieved literature underwent thorough screening, and relevant data were extracted. Following the evaluation of the literature's quality, Meta-analysis was performed using RevMan 5.4 software. RESULTS: In this study, a total of 11 documents were selected, comprising 1334 patients with hepatocellular carcinoma. Meta-analysis results indicated that there was no statistically significant difference in the 1-year overall survival rate [Relative risk (RR) = 1.01, 95% confidence intervals (CI) (0.98; 1.04)] and the 3-year overall survival rate [RR = 0.95, 95% CI (0.90; 1.01)] between the radiofrequency ablation and liver resection groups (p > 0.05). Similarly, there was no statistically significant difference in the 1-year disease-free survival rate [RR = 0.94, 95% CI (0.87; 1.01)] between the two groups. However, the 3-year disease-free survival rate [RR = 0.84, 95% CI (0.74; 0.96)] of patients in the radiofrequency ablation group was significantly lower than that in the hepatectomy group (p < 0.05). Notably, the incidence of complications [RR = 0.42, 95% CI (0.33; 0.55)] was significantly lower in the radiofrequency ablation group compared to the hepatectomy group. Conversely, the local recurrence rate [RR = 1.45, 95% CI (1.22; 1.73)] was significantly higher in the radiofrequency ablation group compared to the hepatectomy group (p < 0.05). CONCLUSION: During the treatment of hepatocellular carcinoma, hepatectomy demonstrates superior clinical efficacy compared to radiofrequency ablation, particularly in its ability to control tumor recurrence. However, radiofrequency ablation presents with fewer complications and a higher level of safety. These findings can serve as a valuable foundation for clinicians when selecting the most suitable treatment approaches for liver cancer.

A novel single-port robot for total gastrectomy to treat gastric cancer: A case report (with video).

Multiport robots are now widely used for total gastrectomy for gastric cancer, while there is almost a void of research on whether single-port (SP) robots can be used for total gastrectomy. Here, we report a case of a 75-year-old female patient who was diagnosed with gastric cardia adenocarcinoma by gastroscopy and underwent total gastrectomy assisted by the SHURUI SP robot. We successfully accomplished total gastrectomy and D2 lymph node dissection using the novel SP robotic platform. The patient was discharged from the hospital successfully with no complications during or after the surgery. Pathologic diagnosis showed adenocarcinoma of the gastric mucosa with partial signet-ring cell carcinoma, and no metastasis was found in the 29 cleared lymph nodes. The use of the SHURUI SP robot for total gastrectomy in treating gastric cancer is both technically feasible and safe.

Construction of a Nomogram Model for Predicting Peritoneal Dissemination in Gastric Cancer Based on Clinicopathologic Features and Preoperative Serum Tumor Markers.

Background: Peritoneal dissemination (PD) is the most common mode of metastasis for advanced gastric cancer (GC) with poor prognosis. It is of great significance to accurately predict preoperative PD and develop optimal treatment strategies for GC patients. Our study assessed the diagnostic potential of serum tumor markers and clinicopathologic features, to improve the accuracy of predicting the presence of PD in GC patients. Methods: In our study, 1264 patients with GC at Fudan University Shanghai Cancer Center and Wenzhou people's hospital from 2018 to 2020 were retrospectively analyzed, including 316 cases of PD and 948 cases without PD. All patients underwent enhanced CT scan or magnetic resonance imaging (MRI) before surgery and treatment. Clinicopathological features, including tumor diameter and tumor stage (depth of tumor invasion, nearby lymph node metastasis and distant metastasis), were obtained by imaging examination. The independent risk factors for PD were screened through univariate and multivariate logistic regression analyses, and the results were expressed with 95% confidence intervals (CIs). A model of PD diagnosis and prediction was established by using Cox proportional hazards regression model of training set. Furthermore, the accuracy of the prediction model was verified by ROC curve and calibration plots. Results: Univariate analysis showed that PD in GC was significantly related to tumor diameter (odds ratio (OR)=12.06, p<0.0006), depth of invasion (OR=14.55, p<0.0001), lymph node metastases (OR=5.89, p<0.0001), carcinoembryonic antigen (CEA) (OR=2.50, p<0.0001), CA125 (OR=11.46, p<0.0001), CA72-4 (OR=4.09, p<0.0001), CA19-9 (OR=2.74, p<0.0001), CA50 (OR=5.20, p<0.0001) and CA242 (OR=3.83, p<0.0001). Multivariate analysis revealed that clinical invasion depth and serum marker of CA125 and CA72-4 were independent risk factors for PD. The prediction model was established based on the risk factors using the R program. The area under the curve (AUC) of the receiver operating characteristics (ROC) was 0.931 (95% CI: 0.900-0.960), with the accuracy, sensitivity and specificity values of 90.5%, 86.2% and 82.2%, respectively. Conclusion: The nomogram model constructed using CA125, CA72-4 and depth of invasion increases the accuracy and sensitivity in predicting the incidence of PD in GC patients and can be used as an important tool for preoperative diagnosis.

Perioperative and short-term outcomes of laparoscopic liver resection for recurrent hepatocellular carcinoma: A retrospective study comparing open hepatectomy.

Background: To compare the perioperative and short-term outcomes of laparoscopic liver resection (LLR) and open liver resection (OLR) in recurrent hepatocellular carcinoma (rHCC) based on propensity score matching (PSM) to investigate therapeutic safety, efficacy, and value for clinical application. Methods: Forty-nine patients with rHCC who underwent surgery at Wenzhou People's Hospital between January 2017 and March 2022 were retrospectively analyzed and classified into LLR (n=30) and OLR (n=22) cases based on the surgical method. Thirty-eight patients were screened using PSM for data analysis to compare basic clinical characteristics, perioperative outcomes, and postoperative recurrence in both groups. Results: Before PSM, the tumour diameter was larger, tumor staging (BCLC staging system), intraoperative blood loss, units of blood transfused, constituent ratio of liver cirrhosis, incidence of MVI and intravascular tumour thrombus and postoperative complication were higher, and duration of hospital stay was significantly longer in the OLR group compared to those in the LLR group (p < 0.05). After PSM, there were no significant differences regarding tumour diameter, MVI incidence, blood transfusion amount or postoperative complication rate in the LLR and OLR groups. The tumor staging, incidence of vascular cancer thrombus, intraoperative blood loss and postoperative duration of hospitalisation were significantly higher in the OLR group than in the LLR group (p<0.05). The difference in recurrence-free survival (RFS) between the two groups was not statistically significant (p = 0.383). Conclusion: LLR for recurrent hepatocellular carcinoma can reduce intraoperative blood loss and postoperative complication rate, shorten the duration of hospitalisation, and is superior to OLR regarding perioperative and short-term efficacy, demonstrating good safety and feasibility.

Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer.

Introduction: Tumors are usually refractory to anti-cancer therapeutics under hypoxic conditions. However, the underlying molecular mechanism remains to be elucidated. Objectives: Our study intended to identify hypoxia inducible lncRNAs and their biological function in gastric cancer (GC). Methods: Differentially expressed lncRNAs were determined by microarray analysis between GC cells exposed to hypoxia (1% O2) and normoxia (21% O2) for 24 h. The expression level of CBSLR was manipulated in several GC cell lines to perform molecular and biological analyses both in vitro and in vivo. Results: We identified a hypoxia-induced lncRNA-CBSLR that protected GC cells from ferroptosis, leading to chem-resistance. Mechanically, CBSLR interacted with YTHDF2 to form a CBSLR/YTHDF2/CBS signaling axis that decreased the stability of CBS mRNA by enhancing the binding of YTHDF2 with the m6A-modified coding sequence (CDS) of CBS mRNA. Furthermore, under decreased CBS levels, the methylation of the ACSL4 protein was reduced, leading to protein polyubiquitination and degradation of ACSL4. This, in turn, decreased the pro-ferroptosis phosphatidylethanolamine (PE) (18:0/20:4) and PE (18:0/22:4) content and contributed to ferroptosis resistance. Notably, CBSLR is upregulated, whereas CBS is downregulated in GC tissues compared to matched normal tissues; and GC patients with high CBSLR/low CBS levels have a worse clinical outcome and a poorer response to chemotherapy. Conclusion: Our study reveals a novel mechanism in how HIF1α/CBSLR modulates ferroptosis/chemoresistance in GC, illuminating potential therapeutic targets for refractory hypoxic tumors.

Activation of MAT2A-ACSL3 pathway protects cells from ferroptosis in gastric cancer.

BACKGROUND: Ferroptosis, a unique form of nonapoptotic-regulated cell death caused by overwhelming lipid peroxidation, represents an emerging tumor suppression mechanism. Growing evidence has demonstrated that cell metabolism plays an important role in the regulation of ferroptosis. Specifically, the association between methionine metabolism and ferroptosis remains undefined. METHODS: We performed in vitro and in vivo experiments to evaluate the influence of methionine metabolism on ferroptosis sensitivity. Pharmacological and genetic blockade of the methionine cycle was utilized and relevant molecular analyses were performed. RESULTS: We identified MAT2A as a driver of ferroptosis resistance. Mechanistically, MAT2A mediates the production of S-adenosylmethionine (SAM), which upregulates ACSL3 by increasing the trimethylation of lysine-4 on histone H3 (H3K4me3) at the promoter area, resulting in ferroptosis resistance. CONCLUSIONS: Collectively, these results established a link between methionine cycle activity and ferroptosis vulnerability in gastric cancer.