Band 13, Heft 5

Digestive system tumors remain a global health challenge; however, the mechanisms underlying their tumorigenesis remain unclear. Identifying these mechanisms may facilitate early detection and more effective treatment. Members of the plakin family play crucial roles in cytoskeletal integrity and cell adhesion. Moreover, they regulate key cellular processes implicated in tumor development, including tumor cell migration, proliferation, and signaling. Therefore, exploring the potential roles of the plakin family members in digestive system tumors has attracted increasing attention. In this review, we provide a comprehensive examination of the biological characteristics of the plakin family members and an in-depth analysis of their clinicopathological significance and clinical implications in digestive system tumors. In summary, the plakin family is a translationally valuable diagnostic marker and a potential therapeutic target for digestive system tumors.

Background and objectives Colorectal cancer (CRC) is still the leading cause of cancer-related death. With the recognizing the importance of long non-coding RNA (LncRNA) in development and cancer, it is urgently to identify new LncRNA and understand the mechanism to develop novel therapeutic strategies. Methods Nine CRC cell lines, 52,146 and 285 cases of normal colorectal mucosa, adenoma and CRC samples were utilized. Northern blot, rapid amplification of cloned cDNA ends, RNA pulldown, Mass spectrum, RNA immunoprecipitation, CRISPR/Cas9, fluorescence in situ hybridization assays and xenograft mice model were employed. Results Lnc5q21.2 is identified to be a novel long intergenic non-coding RNA and its full length is 668 nt. Lnc5q21.2 is mainly located in cell nucleus and its expression is regulated by N 6 -methyladenine (6mA) modification. Compared to adjacent tissue, the levels of Lnc5q21.2 were increased significantly in CRC samples ( P < 0.001), with a progression tendency from noncancerous colorectal mucosa, adjacent tissue, adenoma to CRC samples ( P < 0.001). Lnc5q21.2 highly expression is associated with alcohol consumption and poor prognosis (both P < 0.05). Lnc5q21.2 promotes cell proliferation, migration, invasion and cell cycle progression. Lnc5q21.2 activates Wnt signaling by interacting with homeobox A10 (HOXA10) and down regulating empty spiracles homeobox 2 expression. Further study demonstrates that Lnc5q21.2 promotes DNA damage repair by enhancing ATR signaling. Lnc5q21.2 sensitizes CRC cells to ATR inhibitor both in vitro and in vivo . Conclusions Lnc5q21.2 is a novel lncRNA. Lnc5q21.2 promotes ATR pathway by activating Wnt signaling via interacting with HOXA10. Lnc5q21.2 sensitizes CRC cells to ATR inhibitor both in vitro and in vivo .

Background Bone marrow mononuclear cells (BMMNCs) therapy should be effective for the improvement of liver function and short-term outcome in patients with liver cirrhosis, but few studies have explored the long-term prognosis of cirrhotic patients treated with BMMNCs. Methods In this retrospective study, eligible patients with liver cirrhosis were selected by using propensity score matching (PSM). Effect of BMMNCs on death was explored by Cox regression analysis, as well as competing risk analysis, where liver transplantation was a competing event. Hazard ratio (HR) and sub-distribution HR (sHR) were calculated. Subgroup analyses were performed based on the age, sex, Child-Pugh class, and model for end-stage liver disease (MELD) score. Results Overall, 260 patients were included, of whom 130 were treated with transhepatic arterial transplantation of BMMNCs. The median follow-up duration was 5.27 (range: 0.37–16.62) years. By adjusting by age, sex, and Child-Pugh score, multivariate Cox regression (HR = 0.707, P = 0.020) and competing risk analyses (sHR = 0.709, P = 0.026) demonstrated that BMMNCs were independently associated with a lower risk of death in cirrhotic patients in the overall analysis. Univariate Cox regression analyses demonstrated that BMMNCs were significantly associated with a decreased risk of death in the subgroup analyses of age ≤50 years (HR= 0.533, P = 0.016), male (HR = 0.626, P = 0.010), Child-Pugh class B (HR = 0.638, P = 0.026), and MELD score > 12 (HR = 0.483, P = 0.002), but not age > 50 years ( P = 0.097), female ( P = 0.170), Child-Pugh class A ( P = 0.309), Child-Pugh class C ( P = 0.369), or MELD score ≤12 ( P = 0.096). Conclusion BMMNCs can provide additional survival benefits in patients with liver cirrhosis. Graphical Abstract

Background and objectives Sex steroid hormones have been hypothesized to be associated with the risk of gastric cancer (GC); however, it has not been widely validated in prospective studies. We aimed to investigate the associations between sex steroid hormone metabolites and the risk of gastric cancer and precancerous lesions in a prospective cohort of Chinese men. Methods Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and electrochemical luminescence immunoassay, we examined 20 sex steroid hormone metabolites and sex hormone-binding globulin (SHBG) in serum from 470 eligible men, including high-grade lesions or GC ( n = 32), intestinal metaplasia (IM, n = 146), and 1:2 matched normal participants ( n = 292) from 2007 to 2012. IM and normal participants were further followed up until December 2021, during which 32 new GC cases were identified with a median follow-up of 11.8 years. Associations between baseline sex steroid hormone metabolites and IM, high-grade lesions and gastric cancer were assessed using logistic regression, and associations between sex steroid hormone metabolites and incident GC risk were assessed using Cox proportional hazards regression in the prospective analysis. Results In the cross-sectional analysis, androstenedione levels were potentially associated with IM risk and significantly associated with high-grade lesions or GC risk (OR continuous = 2.45, 95% CI: 1.01–5.95). Higher concentrations of 17α-hydroxypregnenolone (OR continuous = 2.35, 95% CI: 1.13–4.88), progesterone (OR continuous = 2.68, 95% CI: 1.09–6.61), and estrone (OR continuous = 5.36, 95% CI: 1.28–22.52) were also associated with an increased risk of high-grade lesions or GC. Furthermore, significant positive associations between GC risk and serum levels of SHBG (HR continuous = 2.57, 95% CI: 1.04–6.36), epitestosterone (HR continuous = 2.10, 95% CI: 1.07–4.15) and pregnenolone (HR continuous = 1.30, 95% CI: 1.03–1.63) were identified in the follow-up study focusing on participants diagnosed as normal or IM. Notably, the subgroup analyses stratified by H. pylori status revealed similar associations between androstenedione, 17α-hydroxypregnenolone, progesterone, estrone, SHBG, pregnenolone, and GC risk. Conclusions Several sex hormone metabolites were significantly associated with gastric cancer and its precancerous lesions, indicating a role for sex hormones in gastric carcinogenesis and potentially providing novel biomarkers for the identification of high-risk populations and risk prediction for GC.

Background and Objectives Despite the discovery of cuproptosis as a new type of cell death, less is known about the role cuproptosis-related genes (CRGs) may play in B-cell Non-Hodgkin Lymphoma (NHL). There remained a lack of knowledge regarding the clinical and biological roles of CRG signatures and the therapeutic value of the potent copper ionophore (elesclomol) in B-cell NHL. In this study, the purpose is to investigate the prognostic value of CRGs and their relationship to the tumor immune microenvironment, as well as the mechanism of cuproptosis in B-cell NHL. Methods B-cell NHL patients’ clinical and gene expression data were retrieved from Gene Expression Omnibus (GEO). Our prognostic model was developed using least absolute shrinkage and selection operator (LASSO) regression analysis and univariate Cox analysis. Prediction accuracy of the model was estimated by receiver operating characteristic (ROC) curves. Functional pathway enrichments and immune features were also analyzed. Vitro experiments were conducted to investigate the combination therapy of elesclomol and doxorubicin, and to explore the application value in B-cell NHL. Results Seven CRGs were strongly associated with patient survival and 4 genes were identified to construct the prognostic model. ROC curves indicated great predictive sensitivity and specificity of the model in all cohorts. Patients were divided into low-and high-risk groups by median risk score in each cohort and the survival of the low-risk group was significantly superior than that of the high-risk group. Correlations with clinical features showed that higher Risk-Score was significantly associated with advanced Ann Arbor stages, which were further confirmed in two validation cohorts. We also observed a close relationship between functional pathways and immune features with risk scores. Moreover, we combined elesclomol and doxorubicin in our in vitro experiments and found synergetic antitumor effects of the two agents, and the underlying mechanism is the overgeneration of intracellular Reactive Oxygen Species (ROS). Conclusions We demonstrated the important value of CRG signatures in prognosis of B-cell NHL patients, and that may be a potential antitumor target for B-cell NHL.

Background and Objectives Recombinant human tenecteplase (TNK) tissue-type plasminogen activator (rhTNK-tPA, also named tenecteplase) is non-inferior to alteplase when given up to 4.5 hours after acute ischemic stroke (AIS) within 4.5 hours. Whether intravenous tenecteplase compared with supportive care improves the outcome of patients with AIS due to non-large vessel occlusion (non-LVO) between 4.5-24 hours is uncertain. The Tenecteplase for Acute Non-large vessel occlusion in the Extended Time Window (OPTION) trial aims to test the efficacy and safety of intravenous tenecteplase in patients presenting between 4.5-24 hours after symptom onset who have a non-LVO and evidence of salvageable tissue on perfusion imaging. Methods OPTION is a multicenter, prospective, randomized, open-label, blinded endpoint (PROBE) study. Patients with AIS due to non-LVO and evidence of salvageable brain tissue within 4.5-24 hour time window meeting eligibility criteria will be allocated in a 1∶1 ratio to tenecteplase or standard medical treatment. A target mismatch profile is defined as ischemic core volume <50 mL, a mismatch ratio ≥1.2, and a mismatch volume ≥10 mL. A total of 568 patients will provide >80% power to detect a 12% absolute difference in the proportion of patients achieving an excellent functional outcome (modified Rankin scale [mRS] 0-1 at 90 days) at the two-sided 0.05 significance level. The primary efficacy outcome is excellent functional outcome (mRS 0-1) at 90 days. Secondary efficacy outcomes include disability level (ordinal distribution of mRS) at 90 days, functional independence (mRS 0-2) at 90 days, reperfusion at 24 hours, infarct volume at 24 hours, early clinical response at 24 hours, the National Institutes of Health Stroke Scale (NIHSS) change from baseline at 7 days/discharge, health status and quality of life at 90 days. Safety outcomes include symptomatic intracranial hemorrhage within 36 hours, systemic bleeding within 90 days, and mortality within 90 days. Discussion The OPTION trial (NCT05752916) will provide evidence regarding the efficacy and safety of tenecteplase 4.5 to 24 hours in patients with AIS due to non-LVO.