Research advances in the molecular classification of gastric cancer.

Gastric cancer (GC) is a malignant tumor with one of the lowest five-year survival rates. Traditional first-line treatment regimens, such as platinum drugs, have limited therapeutic efficacy in treating advanced GC and significant side effects, greatly reducing patient quality of life. In contrast, trastuzumab and other immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have demonstrated consistent and reliable efficacy in treating GC. Here, we discuss the intrinsic characteristics of GC from a molecular perspective and provide a comprehensive review of classification and treatment advances in the disease. Finally, we suggest several strategies based on the intrinsic molecular characteristics of GC to aid in overcoming clinical challenges in the development of precision medicine and improve patient prognosis.

The effects of treating GERD on the outcomes of otitis media with effusion: A systematic review and meta-analysis.

OBJECTIVE: Gastroesophageal reflux disease (GERD) may cause otitis media with effusion (OME). However, whether treating GERD can benefit patients with OME has not been well studied. METHODS: We systematically searched PubMed, Embase, Cochrane Library, and Wanfang databases. The search period was from the establishment of the databases until December 31, 2022. Clinical studies related to GERD treatment on the outcomes of OME were included. Two reviewers independently conducted literature screening and data extraction according to the inclusion and exclusion criteria. To evaluate the quality of the included studies, we used the NOS assessment tool and the RevMan 5.4. Subgroup analysis was conducted to reduce the risk of heterogeneity, and Egger and Begg funnel plots were used to evaluate publication bias. Meta-analysis was performed using Stata14.0 and Review Manager 5.4 software. RESULTS: Finally, 21,744 patients from 16 studies were included. The results showed that the rate of GERD in OME patients was 0.56 (95 % confidence interval (CI): 0.33, 0.79), while it was 0.04 (95 % CI: 0.03, 0.05) in the adult GERD population. The combined risk ratio (RR) of OME in patients with versus without GERD was 1.58 (95 % CI: 1.35, 1.85; p < 0.01). The efficacy rate of GERD treatment in OME patients was 0.59 (95 % CI: 0.44, 0.74), especially for those with chronic OME (0.64, 95 % CI: 0.36, 0.92). Compared to the control group, treatment with GERD improved the symptoms and efficacy of OME (OR = 1.65; 95 % CI: 0.95, 2.85; p > 0.05). The hearing loss cure rate was 0.70 (95 % CI: 0.57, 0.82). CONCLUSION: GERD has been suggested to be a high-risk factor for OME. Treatment of GERD can improve the symptoms of OME. However, further studies are required to verify these findings.

High-normal free thyroxine level is related with decreased bone mineral density in nonobese male patients with type 2 diabetes over 50 years old.

Background: The prevalence of 'low bone mineral density (BMD)' in Type 2 diabetes (T2DM), especially stratified by body mass index, is seldom reported. The relation of the euthyroid range and low BMD in T2DM remains to be further elucidated. Objectives: We aim to investigate the thyroid hormones' impact on BMD among euthyroid patients with T2DM. Design and methods: A total of 1452 hospitalized T2DM patients with normal thyroid function (43.6% males aged over 50 and 56.4% postmenopausal females) were enrolled in this cross-sectional study. BMD was measured at lumbar spine by GE lunar dual-energy X-ray absorptiometry system, and 'low BMD' was defined as T-score <-1.0 SD. The prevalence of 'low BMD' was compared between obese and nonobese (body mass index < 25 kg/m2) groups for both sexes, and the relation of low BMD and free T4 quartiles was explored by multiple logistic regression. Results: The general prevalence of 'low BMD' was 12.3% for male patients aged over 50 (15.5% in the nonobese group and 8.0% in the obese group) and 49.8% for postmenopausal females (56.7% in the nonobese group and 48.9% in the obese group). After adjustment in multiple linear regression, free T4 level remained significantly related to decreased BMD in nonobese male subgroup. Multiple logistic regression revealed that BMD of the highest free T4 quartile (1.12-1.48 ng/dL) decreased significantly than other three quartiles after adjusting for confounding factors including age, body mass index, serum calcium and creatinine level, fasting glucose, alkaline phosphatase, glycosylated hemoglobin, total cholesterol, and smoking history (OR = 2.724, 95% CI = 1.085-6.840, p = 0.033). No significant relation was found in obese male or postmenopausal female groups. Conclusion: High-normal free T4 is a potential independent risk factor for 'low BMD' in nonobese male T2DM patients aged over 50. Close attention should be paid to thyroid function profile, even within normal range, in nonobese men with underlying higher fracture risks on diabetes status.

The Potential Diagnostic Value of Immune-Related Genes in Interstitial Fibrosis and Tubular Atrophy after Kidney Transplantation.

Background: Inflammation within areas of interstitial fibrosis and tubular atrophy (IF/TA) is associated with kidney allograft failure. The aim of this study was to reveal new diagnostic markers of IF/TA based on bioinformatics analysis. Methods: Raw data of IF/TA samples after kidney transplantation and control samples after kidney transplantation were extracted from the Gene Expression Omnibus (GEO) database (GSE76882 and GSE120495 datasets), and genes that were differentially expressed between the two groups (DEGs) were screened. Gene Set Enrichment Analysis (GSEA), ESTIMATE and single sample GSEA (ssGSEA), least absolute shrinkage and selection operator (LASSO) regression analysis, and competing endogenous RNA (ceRNA) network were used to analyze the data. Results: The results of GSEA revealed that multiple immune-related pathways were enriched in the IF/TA group, and subsequent immune landscape analysis also showed that the IF/TA group had higher immune and stromal scores and up to 15 types of immune cells occupied them, such as B cells, cytotoxic cells, and T cells. LASSO regression analysis selected 6 (including ANGPTL3, APOH, LTF, FCGR2B, HLA-DQA2, and EGF) out of 14 DE-IRGs as diagnostic genes to construct a diagnostic model. Then, receiver operating characteristic (ROC) curve analysis showed the powerful diagnostic value of the model, and the area under the curve (AUC) of a single diagnostic gene was greater than 0.75. The results of ingenuity pathway analysis (IPA) also indicated that DEGs were involved in the immune system and kidney disease-related pathways. Finally, we found multiple miRNAs that could regulate diagnostic genes from the ceRNA network. Conclusion: This study identified 6 IF/TA-related genes, which might be used as a new diagnosis model in the clinical practice.

Efficacy and safety of long-term transcutaneous electroacupuncture versus sham transcutaneous electroacupuncture for delayed gastric emptying after distal gastrectomy: study protocol for a randomized, patient-assessor blinded, controlled trial.

BACKGROUND: Delayed gastric emptying (DGE) after distal gastrectomy impacts patients' nutritional status and quality of life. The current treatments of DGE seem unsatisfactory or need invasive interventions. It is unknown whether transcutaneous electroacupuncture (TEA) is effective in treating DGE. METHODS: A total of 90 eligible participants who underwent distal gastrectomy will be randomly allocated to either the TEA group (n = 60) or the sham transcutaneous electroacupuncture (sham-TEA) group (n = 30). Each participant will receive TEA on the bilateral acupoints of Zusanli (ST36) and Neiguan (PC6) for 4 weeks. The primary outcomes will be the residual rates of radioactivity in the stomach by gastric scintigraphy and total response rates. The secondary outcomes will be endoscopic features, autonomic function, nutritional and psychological status, serum examination, and quality of life (QoL). The adverse events will also be reported. The patients will be followed up 1 year after the treatment. DISCUSSION: The findings of this randomized trial will provide high-quality evidence regarding the efficacy and safety of long-term TEA for treating DGE after distal gastrectomy. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000033965. Registered on 20 June 2020.

Depletion of C12orf48 inhibits gastric cancer growth and metastasis via up-regulating Poly r(C)-Binding Protein (PCBP) 1.

BACKGROUND: Gastric cancer remains a major cause of cancer-related death worldwide. C12orf48, also named PARP1 binding protein, is over-expressed in several cancers. However, the expression profile and potential roles of C12orf48 in gastric cancer are largely unknown. METHODS: We used bioinformatics approaches and tissue microarray immunohistochemistry to analyze the expression profile of C12orf48 in gastric cancer tissues. Plasmid-mediated over-expression or knockdown were performed. CCK-8 assays and flow cytometry were employed to evaluate cellular proliferation and apoptosis respectively. Transwell assays were used to assess migrative and invasive abilities. The roles of C12orf48 were also evaluated in a xenograft tumor model. RESULTS: We found that C12orf48 was over-expressed in gastric cancer tissue, which associated with advanced stage and poor prognosis. In vitro and in vivo experiments showed depletion of C12orf48 attenuated cancer growth, while facilitated apoptosis. Further, the expression of Poly r(C)-Binding Protein (PCBP) 1 was found negatively regulated by C12orf48. Intended up-regulation of PCBP1 prevented C12orf48-mediated proliferation and rescued cells from apoptosis. Besides, C12orf48 promoted cellular migration and invasion, with E-cadherin down-regulated while vimentin and N-cadherin up-regulated, which was reversed by up-regulated PCBP1. CONCLUSIONS: Our findings indicate that depletion of C12orf48 inhibited gastric cancer growth and metastasis via up-regulating PCBP1. Targeting C12orf48-PCBP1 axis may be a potential therapeutic strategy.

Dickkopf-related protein 3 alters aerobic glycolysis in pancreatic cancer BxPC-3 cells, promoting CD4+ T-cell activation and function.

BACKGROUND: To investigate the value of Dickkopf-related protein 3 (DKK3) on aerobic glycolysis in pancreatic cancer cells, where DKK3-overexpression is used to determine its effects on CD4+ T cells. METHODS: The BxPC-3-DKK3 cell line was constructed, and peripheral blood mononuclear cell (PBMC) was prepared. After isolated the CD4+ T cells, the lactic acid, glucose uptake ability, cellular viability, proliferation, apoptosis, and markers were detected by PCR and western blot, and the concentrations of multiple cytokines were determined using the ELISA method. RESULTS: After co-culture with pancreatic cancer cells overexpressing DKK3, the glucose uptake markedly, proliferation enhanced and apoptosis inhibited in CD4+ T cells. The co-culture model also revealed that DKK3-overexpression promotes the activation and regulates the metabolism and function of CD4+ T cells. CONCLUSIONS: DKK3 alters the metabolic microenvironment of pancreatic cancer cells and further facilitates the function of CD4+ T cells which suggesting that DKK3 may have a therapeutic potential in pancreatic cancer.

De-Ubiquitinating Enzymes USP21 Regulate MAPK1 Expression by Binding to Transcription Factor GATA3 to Regulate Tumor Growth and Cell Stemness of Gastric Cancer.

USP21 is a kind of deubiquitinating enzymes involved in the malignant progression of various cancers, while its role in gastric cancer (GC) and the specific molecular mechanism are still unclear. This study probed into the function of USP21 in vitro and in vivo, and discussed the regulatory mechanism of USP21 in GC in vitro. We reported that USP21 promoted GC cell proliferation, migration, invasion, and stemness in vitro, and regulated GC tumor growth and cell stemness in mice in vivo. USP21 stabilized the expression of GATA3 by binding to GATA3. Besides, GATA3 also regulated the expression of MAPK1 at the transcriptional level. A series of in vitro experiments testified that USP21 regulated the expression of MAPK1 by binding to transcription factor GATA3, thereby regulating the tumor growth and cell stemness of GC. Overall, this study identified a new USP21/GATA3/MAPK1 axis, which plays a pivotal role in promoting the malignant progression of GC and might provide a potential target for treatment.

Resection of GIST in the duodenum and proximal jejunum: A retrospective analysis of outcomes.

INTRODUCTION: Gastrointestinal stromal tumors (GISTs), with a primary occurrence in the duodenum and proximal jejunum, are rare and treatment is poorly understood. This study aimed to evaluate the main factors influencing the prognosis of GIST resection in this complex anatomical structure. MATERIALS AND METHODS: This retrospective study included 47 patients who underwent surgery for primary GIST of the duodenum (20) and proximal jejunum (27) between 2012 and 2017. Perioperative clinical data as well as relapse and survival information were collected. RESULTS: All patients underwent negative margin resection (R0) of duodenal and proximal jejunum GISTs. Complications occurred more frequently in treatment of duodenal GISTs than proximal jejunum GISTs (p = 0.003). GISTs in D3 (the 3rd portion of duodenum) were related to larger tumor size (p = 0.001), higher probability of severe complication rate (p = 0.042), longer hospital stays (p = 0.023) and fasting time (p = 0.020). More complications were found for patients with digestive reconstruction than limited resection (p = 0.010). Additionally, patients with a tumor mass larger than 5 cm or a mitotic index greater than 5 mitoses/50 HPFs showed poorer therapeutic outcomes. The 1- and 3-year overall survival was 97.9% and 86.1%, respectively and were not influenced by operation type (p = 0.061) or GIST position (p = 0.447). CONCLUSION: With negative operational margins, limited resection is a safe and feasible procedure for duodenal and proximal jejunum GIST patients and unnecessary digestive reconstruction should be avoided. Considering the severe complication rate, resection for GISTs in D3 should be performed with care.

The poor prognosis of the primary gastric epithelioid angiosarcoma: A case report.

RATIONALE: Primary gastric epithelioid angiosarcoma is a highly aggressive endothelial cell malignancy and may pose a great diagnostic challenge. PATIENT CONCERNS: Here we describe the case of a 56-year-old man presented with melena and epigastric dull pain for 2 weeks. DIAGNOSIS: Primary gastric epithelioid angiosarcomas: the definitive diagnosis was provided by immunohistochemical analysis with endothelial markers such as cluster of differentiation 31 (CD31), ether-a-go-go-related gene (ERG), and Freund leukemia integration (FLI-1). INTERVENTIONS: After gastroscopic biopsy was performed at the bleeding fundus and the results suggested malignant tumor, radical gastrectomy was performed. OUTCOMES: Unfortunately, regional lymph node enlargement and distant metastases occurred about 1 month later. The patient did not have the opportunity to undergo chemotherapy or other treatment and died from multiple organ dysfunction syndrome. LESSONS: Primary gastric epithelioid angiosarcomas are rare tumors with a high rate of lymph nodes and peripheral organs metastasis. The strong cytokeratin expression in epithelioid angiosarcomas represents a diagnostic pitfall for pathologists. Their clinical behaviors are unpredictable and results with surgical excision alone have been disappointing. Thus, the prognosis is generally considered poor and patients seldom can survive over 1 year after diagnosis.

Transcutaneous electroacupuncture alleviates postoperative ileus after gastrectomy: A randomized clinical trial.

AIM: To investigate the efficacy and safety of transcutaneous electroacupuncture (TEA) to alleviate postoperative ileus (POI) after gastrectomy. METHODS: From April 2014 to February 2017, 63 gastric cancer patients were recruited from the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. After gastrectomy, the patients were randomly allocated to the TEA (n = 33) or control (n = 30) group. The patients in the TEA group received 1 h TEA on Neiguan (ST36) and Zusanli (PC6) twice daily in the morning and afternoon until they passed flatus. The main outcomes were hours to the first flatus or bowel movement, time to nasogastric tube removal, time to liquid and semi-liquid diet, and hospital stay. The secondary outcomes included postoperative symptom assessment and complications. RESULTS: Time to first flatus in the TEA group was significantly shorter than in the control group (73.19 ± 15.61 vs 82.82 ± 20.25 h, P = 0.038), especially for open gastrectomy (76.53 ± 14.29 vs 87.23 ± 20.75 h, P = 0.048). Bowel sounds on day 2 in the TEA group were significantly greater than in the control group (2.30 ± 2.61/min vs 1.05 ± 1.26/min, P = 0.017). Time to nasogastric tube removal in the TEA group was earlier than in the control group (4.22 ± 1.01 vs 4.97 ± 1.67 d, P = 0.049), as well as the time to liquid diet (5.0 ± 1.34 vs 5.83 ± 2.10 d, P = 0.039). Hospital stay in the TEA group was significantly shorter than in the control group (8.06 ± 1.75 vs 9.40 ± 3.09 d, P = 0.041). No significant differences in postoperative symptom assessment and complications were found between the groups. There was no severe adverse event related to TEA. CONCLUSION: TEA accelerated bowel movements and alleviated POI after open gastrectomy and shortened hospital stay.

Successive Release of Tissue Inhibitors of Metalloproteinase-1 Through Graphene Oxide-Based Delivery System Can Promote Skin Regeneration.

The purpose of this study was to testify the hypothesis that graphene oxide (GO) could act as an appropriate vehicle for the release of tissue inhibitors of metalloproteinase-1 (TIMP-1) protein in the context of skin repair. GO characteristics were observed by scanning electron microscopy, atomic force microscopy, and thermal gravimetric analysis. After TIMP-1 absorbing GO, the release profiles of various concentrations of TIMP-1 from GO were compared. GO biocompatibility with fibroblast viability was assessed by measuring cell cycle and apoptosis. In vivo wound healing assays were used to determine the effect of TIMP-1-GO on skin regeneration. The greatest intensity of GO was 1140 nm, and the most intensity volume was 10,674.1 nm (nanometer). TIMP-1 was shown to be continuously released for at least 40 days from GO. The proliferation and viability of rat fibroblasts cultured with TIMP-1-GO were not significantly different as compared with the cells grown in GO or TIMP-1 alone (p > 0.05). Skin defect of rats treated with TIMP-1 and TIMP-1-GO showed significant differences in histological and immunohistochemical scores (p < 0.05). GO can be controlled to release carrier materials. The combination of TIMP-1 and GO promoted the progression of skin tissue regeneration in skin defect.

CD97 promotion of gastric carcinoma lymphatic metastasis is exosome dependent.

BACKGROUND: CD97 knockdown impairs the metastatic capacity of SGC-7901 gastric cancer cells. However, the role of CD97 in the distant lymphatic premetastatic niche formation of gastric cancer remains unknown. METHODS: Exosomes and the soluble fraction were isolated from SGC-L (an SGC-7901-cell-derived highly lymphatic metastatic cell line) and CD97-knockdown (SGC-L/CD97-kd) cells, and were co-cultured with gastric cancer cells. The metastatic capacity of the two cell lines was evaluated in vitro and in a footpad lymph node metastasis mouse model. Premetastatic-niche-formation-related proteins were examined immunohistochemically. RESULTS: CD97 expression was ninefold higher in SGC-L cells than in SGC-7901 cells. In vitro, exosomes or conditioned medium from the SGC-L cells enhanced cell proliferation (20 % increase) and invasion (30 % increase) as compared with that from SGC-L/CD97-kd cells (p < 0.01). Intrafootpad injections of SGC-L, but not SGC-L/CD97-kd exosomes or conditioned medium, strongly promoted SGC-L and SGC-L/CD97-kd cell accumulation in the draining lymph nodes (p < 0.01) and increased CD55, CD44v6, α5ß1, CD31, epithelial cell adhesion molecule, and CD151 expression. Although the SGC-L/CD97-kd exosomes alone were insufficient for promotion of metastasis, they were partly aided by the SGC-L-cell-derived soluble fraction. CONCLUSIONS: The CD97 small isoform promotes SGC-L cell lymphatic metastasis exosome dependently, and aided by the soluble fraction, the exosome-dependent CD97 plays a pivotal role in premetastatic niche formation.

Management of perivascular epithelioid cell tumor of the liver: A case report and review of the literature.

Perivascular epithelioid cell tumor (PEComa) is a rare tumor that originates from mesenchymal tissues. Cases of PEComa in the liver are extremely rare. The present study aimed to analyze the clinical features of PEComa in the liver and discuss its management. Here we report a 25-year-old female with multiple lesions of low density with poorly defined borders in the liver, as shown by a computed tomography (CT) scan. A partial hepatectomy was proceeded and PEComa was diagnosed by immunohistochemistry. No evidence of recurrence was observed during the one year follow-up. A total of 20 patients with hepatic PEComa, including one case from the present study and 19 cases that were reported in literature between June 2001 and December 2012, were reviewed and analyzed. The mean patient age was 43.4 years (range, 25-67 years) and the cases consisted of 18 female and two male patients. The tumor size ranged between 2.0×1.6 and 15.0×12.0 cm. Of the 20 patients, nine were asymptomatic and 11 had mild to significant complaints. Immunohistochemistry plays a key role in the diagnosis of PEComa. All the cases in this study were strongly positive for human melanoma black-45. A surgical resection is the gold standard for curative intent. All the patients underwent a surgical resection and none were administered perioperative chemotherapy or radiotherapy. In total, 13 of the 14 patients with follow-up information survived during the 8-36-month follow-up period and one patient succumbed due to recurrence two years after the surgery.

RNA secondary structure in mutually exclusive splicing.

Mutually exclusive splicing is a regulated means to generate protein diversity, but the underlying mechanisms are poorly understood. Here comparative genome analysis revealed the built-in intronic elements for controlling mutually exclusive splicing of the 14-3-3ξ pre-mRNA. These elements are clade specific but are evolutionarily conserved at the secondary structure level. Combined evidence revealed the triple functions of these inter-intronic RNA pairings in synergistically ensuring the selection of only one of multiple exons, through activation of the proximal variable exon outside the loop by the approximation of cis elements, and simultaneous repression of the exon within the loop, in combination with the physical competition of RNA pairing. Additionally, under this model, we also deciphered a similar structural code in exon clusters 4 and 9 of Dscam (38,016 isoforms) and Mhc (480 isoforms). Our findings suggest a broadly applicable mechanism to ensure mutually exclusive splicing.