METTL5 promotes gastric cancer progression via sphingomyelin metabolism.

BACKGROUND: The treatment of gastric cancer (GC) has caused an enormous social burden worldwide. Accumulating studies have reported that N6-methyladenosine (m6A) is closely related to tumor progression. METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells. However, its aberrant regulation in GC has not been fully elucidated. AIM: To excavate the role of METTL5 in the development of GC. METHODS: METTL5 expression and clinicopathological characteristics were analyzed via The Cancer Genome Atlas dataset and further verified via immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples. The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored in vitro by Cell Counting Kit-8 assays, colony formation assays, scratch healing assays, transwell assays and flow cytometry. The tumor-promoting role of METTL5 in vivo was evaluated in a xenograft tumor model. The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification. Next, liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism, which was confirmed by Enzyme-linked immunosorbent assay and rescue tests. In addition, we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin via colony formation and transwell experiments. RESULTS: Our research revealed substantial upregulation of METTL5, which suggested a poor prognosis of GC patients. Increased METTL5 expression indicated distant lymph node metastasis, advanced cancer stage and pathological grade. An increased level of METTL5 correlated with a high degree of m6A methylation. METTL5 markedly promotes the proliferation, migration, and invasion of GC cells in vitro. METTL5 also promotes the growth of GC in animal models. METTL5 knockdown resulted in significant changes in sphingomyelin metabolism, which implies that METTL5 may impact the development of GC via sphingomyelin metabolism. In addition, high METTL5 expression led to cisplatin resistance. CONCLUSION: METTL5 was found to be an oncogenic driver of GC and may be a new target for therapy since it facilitates GC carcinogenesis through sphingomyelin metabolism and cisplatin resistance.

Cross­talk between lymphangiogenesis and malignant melanoma cells: New opinions on tumour drainage and immunization (Review).

Malignant melanoma (MM) is a highly aggressive tumour that can easily metastasize through the lymphatic system at the early stages. Lymph node (LN) involvement and lymphatic vessel (LV) density (LVD) represent a harbinger of an adverse prognosis, indicating a strong link between the state of the lymphatic system and the advancement of MM. Permeable capillary lymphatic vessels are the optimal conduits for melanoma cell (MMC) invasion, and lymphatic endothelial cells (LECs) can also release a variety of chemokines that actively attract MMCs expressing chemokine ligands through a gradient orientation. Moreover, due to the lower oxidative stress environment in the lymph compared with the blood circulation, MMCs are more likely to survive and colonize. The number of LVs surrounding MM is associated with tumour-infiltrating lymphocytes (TILs), which is crucial for the effectiveness of immunotherapy. On the other hand, MMCs can release various endothelial growth factors such as VEGF-C/D-VEGFR3 to mediate LN education and promote lymphangiogenesis. Tumour-derived extracellular vesicles are also used to promote lymphangiogenesis and create a microenvironment that is more conducive to tumour progression. MM is surrounded by a large number of lymphocytes. However, both LECs and MMCs are highly plastic, playing multiple roles in evading immune surveillance. They achieve this by expressing inhibitory ligands or reducing antigen recognition. In recent years, tertiary lymphoid structures have been shown to be associated with response to anti-immune checkpoint therapy, which is often a positive prognostic feature in MM. The present review discusses the interaction between lymphangiogenesis and MM metastasis, and it was concluded that the relationship between LVD and TILs and patient prognosis is analogous to a dynamically tilted scale.

Lactoferrin Prevents Chronic Alcoholic Injury by Regulating Redox Balance and Lipid Metabolism in Female C57BL/6J Mice.

This study aimed to investigate the preventive effects of lactoferrin (Lf) on chronic alcoholic liver injury (ALI) in female mice. Female C57BL/6J mice were randomly divided into four groups: control group (CON), ethanol administration group (EtOH), low-dose Lf treatment group (LLf), and high-dose Lf group (HLf). In the last three groups, chronic ALI was induced by administering 20% ethanol ad libitum for 12 weeks. Mice in the CON and EtOH groups were fed with AIN-93G diet. Meanwhile, 0.4% and 4% casein in the AIN-93G diet were replaced by Lf as the diets of LLf and HLf groups, respectively. HLf significantly reduced hepatic triglyceride content and improved pathological morphology. HLf could inhibit cytochrome P450 2E1 overexpression and promote alcohol dehydrogenase-1 expression. HLf activated protein kinase B and AMP-activated protein kinase (AMPK), as well as upregulating nuclear-factor-erythroid-2-related factor-2 expression to elevate hepatic antioxidative enzyme activities. AMPK activation also benefited hepatic lipid metabolism. Meanwhile, HLf had no obvious beneficial effects on gut microbiota. In summary, Lf could alleviate chronic ALI in female mice, which was associated with redox balance and lipid metabolism regulation.

Decreased Incidence of Intraventricular Hemorrhage in Extremely Low Birth Weight Infants Using Customized Circulatory Management to Evaluate the Hemodynamic Change of Patent Ductus Arteriosus.

Background: In extremely low birth weight (ELBW) infants, the patent ductus arteriosus (PDA) with left-to-right shunt and an increase in systemic artery resistance may cause increasing preload and afterload of the left ventricle. The immature myocardium in ELBW infants has a limited ability to respond to the change, which leads to hemorrhagic complications. In this study, we detected the hemodynamic change of cardiac performance and applied a clinical strategy to prevent PDA-associated hemorrhagic complications in ELBW infants. Methods: We enrolled ELBW infants at a single medical center in Taiwan. The customized circulatory management was performed by echocardiography after birth until the PDA closed. Inotropic agents were administrated according to the requirements of hemodynamic parameters or clinical conditions. The primary outcomes were hemorrhagic complications including pulmonary hemorrhage and intraventricular hemorrhage (IVH) greater than grade II. The secondary outcomes were the rate of surgical ligation of PDA, mortality, necrotizing enterocolitis, and bronchopulmonary dysplasia. Results: A total of 20 ELBW infants were evaluated by customized circulatory management from 2019 to 2020. We reviewed 35 ELBW infants born between 2017 and 2018 in our hospital, who served as the non-management group. The management group had a significantly lower incidence rate of IVH greater than grade 2 (p = 0.02). Other outcomes showed no significant differences. Dobutamine was prescribed in 8 cases in the management group, and end-systolic wall stress (ESWS) was significantly decreased after Dobutamine administration (p = 0.017). Conclusion: The incidence rate of IVH greater than grade II in ELBW infants decreased after use of customized circulatory management in our study. The strategy of customized circulatory management might be an effective "early target therapy" for hemodynamically significant PDA in high-risk ELBW infants. Inotropic therapy with Dobutamine could be a useful medical choice for improving cardiac function to prevent hemorrhagic complications.

Serum iron and risk of nonalcoholic fatty liver disease and advanced hepatic fibrosis in US adults.

Epidemiological evidence on the relationship between serum iron and liver diseases is limited. This study aims to investigate whether serum iron is associated with nonalcoholic fatty liver disease (NAFLD) and advanced hepatic fibrosis (AHF). Cross-sectional data for adults aged ≥ 18 years who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were analyzed. Odds ratio (ORs) and 95% confidence intervals (CIs) of NAFLD and AHF associated with serum iron were estimated using multivariable logistic regression models. A total of 18,031 males and 18,989 females were included in the analysis. After multivariable adjustment for potential confounders, serum iron was significantly and inversely associated with NAFLD in both genders (P-trend < 0.001) and AHF in females (P-trend = 0.018). Compared to the bottom quartile, those in higher quartiles of serum iron had no significant ORs for AHF in males, but the trend across the quartiles was significant (P-trend = 0.046). In conclusion, higher serum iron level was associated with lower risk of NAFLD in males and females, and with lower risk of AHF in females but not in males. No significant racial/ethnical differences in these associations were observed.

Gastrointestinal involvement by mantle cell lymphoma observed by endoscopy: A case report.

INTRODUCTION: Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin B-cell lymphoma, accounting for 6% of all non-Hodgkin lymphoma. The typical appearance of intestinal MCL is multiple lymphomatous polyposis, whereas presentation as protruding lesions is uncommon. We herein report the case of a 64-year-old male patient who was admitted to our hospital with epigastric pains. On endoscopy, submucosal neoplasma were identified in the gastric antrum, the duodenal bulb, and the rectum. On endoscopic ultrasonography (EUS) (OLYMPUS EUS EU-ME2, Miniprobe sonography), the lesions were homogeneously hypoechoic and originated from the submucous layer or muscularis mucosa. Pathological examination of biopsied specimens from the lesions of the rectum revealed diffuse lymphomatous proliferation and dense infiltration by monomorphic and small cleaved cells with irregularly shaped nuclei. On immunohistochemistry, the cells were positive for cyclin D1, CD20, CD21, SOX-11, and Bcl-2, but negative for CD3 and CD10; these findings were compatible with a diagnosis of MCL. CONCLUSION: The EUS characteristics initially led to the suspicion of digestive neuroendocrine tumors, since MCL presenting as submucosal tumors on EUS is rarely reported. We herein present this case to suggest clinician to include MCL in the differential diagnosis of submucosal intestinal lesions, as early diagnosis and timely treatment may improve patient prognosis.

Log odds of positive lymph nodes: a novel prognostic indicator superior to the number-based and the ratio-based N category for gastric cancer patients with R0 resection.

BACKGROUND: Log odds of positive lymph nodes (LODDS) is defined as the log of the ratio between the probability of being a positive lymph nodes and the probability of being a negative lymph nodes when one lymph node is retrieved. The value of LODDS staging system on prognostic assessment for gastric cancer patients with R0 resection is still unclear. METHODS: Clinicopathologic and prognostic data of 2547 gastric cancer patients underwent D2 or D3 lymphadenectomy with R0 surgery were retrospectively studied. RESULTS: Multivariate analysis indentified LODDS stage was an independent prognostic factor, but not pN classification or rN classification. The scatter plots of the relationship between LODDS and the number, the ratio of nodes metastasis, suggested that the LODDS stage had power to divide patients with the same number or ratio of nodes metastasis into different groups. For patients in each of the pN or rN classifications, significant differences in survival could always be observed among patients in different LODDS stages. However, for patients in each LODDS stage, prognosis was highly homologous between those in different pN or rN classifications. A minimum number of 10, 15, 20, 25, and 10 nodes retrieved should be met for patients in the pN0, pN1, pN2, pN3, and rN0-3 classifications, respectively, unless the hazard risks of death would be underestimated or overestimated. However, LODDS stage could discriminate among 5 groups of patients with highly homologous prognosis, regardless how many nodes retrieved. CONCLUSIONS: The LODDS system is more reliable than the Union Internationale Contre le Cancer and American Joint Committee on cancer pN system and the rN system for prognostic assessment.

Advanced gastric cancer with early cancer macroscopic appearance: is it worthy of D2 lymphadenectomy?

BACKGROUND: Previous studies report that 5.9-22.2% of patients with preoperatively diagnosed early gastric cancers were eventually proven to have advanced gastric cancers by postoperative pathological examination. Such misdiagnosed cases commonly had cancers with macroscopic appearance like early gastric cancer and consequently can be recognized as a subgroup of cancer, namely advanced gastric cancer with early cancer macroscopic appearance (eAGC). Theoretically eAGCs might require D2 lymphadenectomy, but frequently undergo limited lymphadenectomy. However, the validity of the limited surgery is still unclear. METHODS: Clinicopathologic features of 134 patients with eAGC were retrospectively reviewed and compared with those of patients with early gastric cancers and advanced gastric cancers, respectively. RESULTS: Clinicopathologic features of eAGCs were similar to those of submucosa cancers, but significantly different from those of mucosa cancers and other muscularis propria cancers. Tumor size, lymphatic and/or blood vessels invasion (LBVI), and depth of invasion were identified as independent factors predicting lymph node metastasis; however, postoperative stage was not. All patients with eAGCs were proven to have lymph node metastasis restricted to the perigastric lymph nodes and lymph nodes at stations 7, 8a, and 9. Age, LBVI, and depth of invasion were independent prognostic factors for patients with preoperatively diagnosed early gastric cancers; however, the misdiagnosis of early cancer and the option of lymphadenectomy (D2 or not D2) had no impact on patient survival. The incidence of recurrence of eAGCs was similar to that of submucosa cancers, but significantly different from that of mucosa cancers and other muscularis propria cancers. CONCLUSIONS: Modified gastrectomy B (dissection of perigastric lymph nodes and nodes at stations 7, 8a, and 9) might be recommended for patients with eAGCs.

Prognostic significance of microscopic positive margins for gastric cancer patients with potentially curative resection.

BACKGROUND: Most previous studies concerning the impact of positive margins on patient outcomes were based on patients with D1 lymphadenectomy. The prognostic significance of positive margins for patients with D2/D3 lymphadenectomy has not been investigated. METHODS: Clinicopathologic and prognostic data were compared between 110 patients with positive margins and 2,159 patients with negative margins who underwent R0 surgery (D2/D3 lymphadenectomy). Multivariate analysis was performed to identify independent factors correlated with positive margins. Cox's proportional hazard model was applied to investigate whether a positive margin was an independent factor predicting poor outcome. Overall survival rates and the incidence of recurrence were compared between patients with positive and negative margins, stratifying by pT, pN, and TNM stage. RESULTS: Tumor size, pT stage, and pN stage were independent factors associated with positive margins. Although the overall survival rate of patients with positive margins was significantly poorer than that of patients with negative margins, margin status was not an independent prognostic factor on multivariate analysis. Significant differences in survival between patients with negative and positive margins could be observed for those in pT1-2, pN0-1, and I-II stage, but not for those in pT3-4, pN2-3, and III-VI stage. Although locoregional recurrence was more frequently observed for patients with positive margins, the incidence of any recurrence was significantly higher only for patients in pT1-2, pN0-1, and I-II stage, but not for those in pT3-4, pN2-3, and III-VI stage. CONCLUSION: A positive margin results in a significantly worse outcome for pT1-2, pN0-1, and I-II stage gastric cancer patients who undergo D2/D3 lymphadenectomy, but not for those in pT3-4, pN2-3, and III-IV stage.

The impact of N-ratio in minimizing stage migration phenomenon in gastric cancer patients with insufficient number or level of lymph node retrieved: results from a Chinese mono-institutional study in 2159 patients.

BACKGROUND: Previous studies indicate that N-ratio has significant superiority in minimizing 'stage migration' for patients with >15 lymph nodes retrieved. Whether the result is applicable to patients with < or =15 lymph nodes retrieved is still in question. PATIENTS AND METHODS: Overall survival rates of 2159 gastric cancer patients who underwent radical resection were compared between patients with different number and level of lymph nodes retrieved according to pN [International Union Against Cancer (Union Internationale Contre le Cancer)/AJCC N stage], n (JGCA N stage) and rN (N-ratio) staging system. RESULTS: Patient number was significantly different between insufficient and sufficient number or level retrieved group in pN and n system, respectively, but not in rN system, while overall survival rates were not significantly different between those groups. The 5-year survival rates of patients with insufficient nodes retrieved were significantly lower than those with sufficient nodes retrieved in pN and n system, but not in rN system. The hazard risk for patients with insufficient nodes retrieved was significantly higher than that for patients with sufficient nodes retrieved in pN and n system, but not in rN system. CONCLUSION: The rN stage has more potential advantages in minimizing stage migration phenomenon for patients with insufficient number or level of lymph nodes retrieved.

Endoscopic diagnosis and treatment of biliary leak in patients following liver transplantation: a prospective clinical study.

BACKGROUND: Orthotopic liver transplantation has been widely used in patients with end-stage liver disease within the last two decades. However, the prevalence of biliary complications after liver transplantation remains high. The most common short-term biliary complication may be biliary leak. So, we examined 13 patients with biliary leak after liver transplantation, attempting to evaluate the role of endoscopic diagnosis and treatment of biliary leak and the incidence of bile duct stricture after healing of the leak. METHODS: Six cases of T-tube leak and seven cases of anastomosis leak complicating liver transplantation were enrolled in this prospective study. Six patients were treated by endoscopic plastic stent placement, two by nasobiliary catheter drainage, two by papillosphincterotomy, and three by nasobiliary catheter drainage combined with plastic stent placement. Some patients received growth hormone treatment. RESULTS: The bile leak resolution time was 10-35 days in 10 patients with complete documentation. The median time of leak resolution was 15.3 days. Four cases of anastomosis stricture, three cases of common hepatic duct and one case of multiple bile duct stenosis were detected by follow-up nasobiliary catheter cholangiography or endoscopic retrograde cholangiopancreatography. CONCLUSIONS: Endoscopic nasobiliary catheter or plastic stent placement is a safe and effective treatment for bile duct stricture occurring after bile leak resolution in most liver transplantation patients. Nasobiliary catheter combined with plastic stent placement may be the best choice for treating bile leak, because, theoretically, it may prevent the serious condition resulting from accidental nasobiliary catheter dislocation, and it may have prophylactic effects on upcoming bile duct stricture, although this should be further confirmed.

[Virological response of chronic hepatitis C management with peg-interferon alpha-2b and ribavirin].

OBJECTIVE: To evaluate the virological response of managing chronic hepatitis C (CHC) with peg-interferon alpha-2b (PEG-IFN alpha-2b) and ribavirin. METHODS: We retrospectively analyzed the virological response of 40 patients with different genotypes of hepatitis C virus (HCV) infection after anti-HCV management. Patients were given different dosages of PEG-IFN alpha-2b and ribavirin based on their weights. The duration of treatment was 48 weeks for patients infected by HCV genotype 1, and was 24 weeks for the others. HCV RNA was tested before treatment, 12 weeks post management, end of treatment, and 24 weeks after treatment stopped. RESULTS: Data from 40 patients were collected. Among them, 24 cases experienced HCV genotype 1 infection, and 16 cases were infected with other genotypes. Between these two groups, the early virological responses were 75.0% (18/24) and 87.5% (14/16), the end-of-treatment virological responses were 80.0% (16/20) and 85.7% (12/14), and the sustained virological responses were 56.2% (9/16) and 78.5% (11/14), respectively. CONCLUSION: Body weight-based customized PEG-IFN alpha-2b in combination with ribavirin can effectively treat patients with different genotypes of CHC.