Association of Fusobacterium nucleatum with immunity andmolecular alterations in colorectal cancer

The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and micro RNA expressions in colorectal cancer.

Role of autophagy in the pathogenesis of inflammatory bowel disease

Inflammatory bowel disease(IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system.Recently, some studies provided strong evidence that the process of autophagy affects several aspects of mucosal immune responses. Autophagy is a cellular stress response that plays key roles in physiological processes, such as innate and adaptive immunity, adaptation to starvation, degradation of aberrant proteins or organelles, antimicrobial defense, and protein secretion. Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including IBD. Autophagy plays multiple roles in IBD pathogenesis by altering processes that include intracellular bacterial killing, antimicrobial peptide secretion by Paneth cells, goblet cell function, proinflammatory cytokine production by macrophages, antigen presentation by dendritic cells, and the endoplasmic reticulum stress response in enterocytes. Recent studies have identified susceptibility genes involved in autophagy, such as NOD2, ATG16L1, and IRGM, and active research is ongoing all over the world. The aim of this review is a systematic appraisal of the current literature to provide a better understanding of the role of autophagy in the pathogenesis of IBD. Understanding these mechanisms will bring about new strategies for the treatment and prevention of IBD.

Prognostic roles of preoperative α-fetoprotein and des-γ-carboxy prothrombin in hepatocellular carcinoma patients

AIM:To clarify the utility of using des-γ-carboxy prothrombin(DCP)andα-fetoprotein(AFP)levels to predict the prognosis of hepatocellular carcinoma(HCC)in patients with hepatitis B virus(HBV)and the hepatitis C virus(HCV)infections.METHODS:A total of 205 patients with HCC(105patients with HBV infection 100 patients with HCV infection)who underwent primary hepatectomy between January 2004 and May 2012 were enrolled retrospectively.Preoperative AFP and DCP levels were used to create interactive dot diagrams to predict recurrence within 2 years after hepatectomy,and cutoff levels were calculated.Patients in the HBV and HCV groups were classified into three groups:a group with low AFP and DCP levels(LL group),a group in which one of the two parameters was high and the other was low(HL group),and a group with high AFP and DCP levels(HH group).Liver function parameters,the postoperative recurrence-free survival rate,and postoperative overall survival were compared between groups.The survival curves were compared by logrank test using the Kaplan-Meier method.Multivariate analysis using a Cox forward stepwise logistic regression model was conducted for a prognosis.RESULTS:The preoperative AFP cutoff levels for recurrence within 2 years after hepatectomy in the HBV and HCV groups were 529.8 ng/m L and 60 m AU/m L,respectively;for preoperative DCP levels,the cutoff levels were 21.0 ng/m L in the HBV group and 67 m AU/m L in the HCV group.The HBV group was significantly different from the other groups in terms of vascular invasion,major hepatectomy,volume of intraoperative blood loss,and surgical duration.Significant differences were found between the LL group,the HL group,and the HH group in terms of both mean disease-free survival time(MDFST)and mean overall survival time(MOST):64.81±7.47 vs 36.63±7.62 vs 18.98±6.17mo(P=0.001)and 85.30±6.55 vs 59.44±7.87 vs46.57±11.20 mo(P=0.018).In contrast,the HCV group exhibited a significant difference in tumor size,vascular invasion,volume of intraoperative blood loss,and surgical duration;however,no significant difference was observed between the three groups in liver function parameters except for albumin levels.In the LL group,the HL group,and the HH group,the MDFST was 50.09±5.90,31.01±7.21,and 14.81±3.08 mo(log-rank test,P<0.001),respectively,and the MOST was 79.45±8.30,58.82±7.56,and 32.87±6.31 mo(log-rank test,P<0.001),respectively.CONCLUSION:In the HBV group,the prognosis was poor when either AFP or DCP levels were high.In the HCV group,the prognosis was good when either or both levels were low;however,the prognosis was poor when both levels were high.High levels of both AFP and DCP were an independent risk factor associated with tumor recurrence in the HBV and HCV groups.The relationship between tumor marker levels and prognosis was characteristic to the type of viral hepatitis.

Association of glypican-3 expression with growth signaling molecules in hepatocellular carcinoma

AIM:To clarify the association of glypican-3(GPC3)expression with Wnt and other growth signaling molecules in hepatocellular carcinoma(HCC). METHODS:Expression of GPC3,Wnt,matrix metalloproteinases(MMPs),sulfatase(SULF)1,SULF2,and other growth signaling molecules was analyzed in HCC cell lines and tissue samples by real-time reverse transcriptionpolymerase chain reaction,immunoblotting,and/or immunostaining.Expression of various genes in GPC3 siRNA-transfected HCC cells was analyzed. RESULTS:GPC3 was overexpressed in most HCCs at mRNA and protein levels and its serum levels weresignificantly higher in patients with HCC than in non- HCC subjects(P<0.05).Altered expressions of various MMPs and growth signaling molecules,some of which were correlated with GPC3 expression,were observed in HCCs.Down-regulation of GPC3 expression by siRNA in GPC3-overexpressing HCC cell lines resulted in a significant decrease in expressions of MMP2,MMP14,fibroblast growth factor receptor 1,insulin-like growth factor 1 receptor.GPC3 expression was significantly correlated with nuclear/cytoplasmic localization ofβ-catenin. CONCLUSION:These results suggest that GPC3,in conjunction with MMPs and growth signaling molecules, might play an important role in the progression of HCC.

Genomic characterization of esophageal squamous cellcarcinoma:insights from next-generation sequencing

Two major types of cancer occur in the esophagus: squamous cell carcinoma, which is associated with chronic smoking and alcohol consumption, and adenocarcinoma, which typically arises in gastric reflux-associated Barrett's esophagus. Although there is increasing incidence of esophageal adenocarcinoma in Western counties, esophageal squamous cell carcinoma(ESCC) accounts for most esophageal malignancies in East Asia, including China and Japan. Technological advances allowing for massively parallel, high-throughput next-generation sequencing(NGS) of DNA have enabled comprehensive characterization of somatic mutations in large numbers of tumor samples. Recently, several studies were published in which whole exome or whole genome sequencing was performed in ESCC tumors and compared with matched normal DNA. Mutations were validated in several genes, including in TP53, CDKN2 A, FAT1, NOTCH1, PIK3 CA, KMT2 D and NFE2L2, which had been previously implicated in ESCC. Several new recurrent alterations have also been identified in ESCC. Combining the clinicopathological characteristics of patients with information obtained from NGS studies may lead to the development of effective diagnostic and therapeutic approaches for ESCC. As this research becomes more prominent, it is important that gastroenterologist become familiar with the various NGS technologies and the results generated using these methods. In the present study, we describe recent research approaches using NGS in ESCC.

Potential effects of mesenchymal stem cell derived extracellular vesicles and exosomal miRNAs in neurological disorders

Mesenchymal stem cells are multipotent cells that possess anti-inflammatory,antiapoptotic and immunomodulatory properties.The effects of existing drugs for neurodegenerative disorders such as Alzheimer’s disease are limited,thus mesenchymal stem cell therapy has been anticipated as a means of ameliorating neuronal dysfunction.Since mesenchymal stem cells are known to scarcely differentiate into neuronal cells in damaged brain after transplantation,paracrine factors secreted from mesenchymal stem cells have been suggested to exert therapeutic effects.Extracellular vesicles and exosomes are small vesicles released from mesenchymal stem cells that contain various molecules,including proteins,mRNAs and microRNAs.In recent years,administration of exosomes/extracellular vesicles in models of neurological disorders has been shown to improve neuronal dysfunctions,via exosomal transfer into damaged cells.In addition,various microRNAs derived from mesenchymal stem cells that regulate various genes and reduce neuropathological changes in various neurological disorders have been identified.This review summarizes the effects of exosomes/extracellular vesicles and exosomal microRNAs derived from mesenchymal stem cells on models of stroke,subarachnoid and intracerebral hemorrhage,traumatic brain injury,and cognitive impairments,including Alzheimer’s disease.

An updated review of gastric cancer in the next-generation sequencing era:Insights from bench to bedside and vice versa

Gastric cancer(GC)is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide.There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs.Recent studies using nextgeneration sequencing(NGS)have revealed a number of potential cancer-driving genes in GC.Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4,a member of the cadherin gene family.Mutations in chromatin remodeling genes(ARID1A,MLL3 and MLL)have been found in 47%of GCs.Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC.Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery,such as DNA methylation,histone modifications,nucleosome positioning,noncoding RNAs and microRNAs.Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings.The antihuman epidermal growth receptor 2(HER2)antibody trastuzumab has led to an era of personalized therapy in GC.In addition,ramucirumab,a monoclonal antibody targeting vascular endothelial growth factor receptor(VEGFR)-2,is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after firstline chemotherapy.Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets,as well as useful biomarkers.In this review,we will summarize the recent advances in the understanding of the molecular pathogenesis of GC,focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.

Assessment of liver fibrosis by a noninvasive method of transient elastography and biochemical markers

瞄准：为了是估计在纤维变性区域(FA ) 之间的关联，并且把 FibroScan 的诊断精确性比作用操作的接收装置的标记弄弯的另外的存在的肝纤维变性(LF ) ，由数字图象分析(DIA ) 计算了分析。方法：我们招募了包括正常的肝，肝炎 B，和丙肝为三不同病原学经历了肝切除术的 30 个病人。肝僵硬被使用 FibroScan 测量。FA 然后被 DIA 计算评估 LF 以便避免任何采样偏爱。结果：FA 否定地与凝血素相关时间(磅) ，血小板计数，卵磷脂胆固醇 acyltransferase (LCAT ) ，和白朊前(白长袍的) 。在另一方面， FibroScan 的调查结果与类似的标记相关。FA 断然与 FibroScan，浆液 hyaluronate 水平，和类型 IV 骨胶原相关水平，和 aspartate 转氨酶到血小板比率索引(APRI ) 。在操作的接收装置下面的区域弯因为 FibroScan 为另外的标记比那高，尽管统计意义是最小的。结论：我们的调查结果建议 FibroScan 能开始被用来作为肝活体检视(磅) 和血清诊断的一种选择估计 LF，因为它是有可比较的诊断精确性考虑的一个安全方法存在 LF 标记。

Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers

AIM: To clarify the expression and role of Ephrin receptor A4 (EphA4) in gastric cancer in relation to clinicopathological characteristics and the expression of fibroblast growth factor receptor 1 (FGFR1) and ephrin ligands. METHODS: Eleven gastric carcinoma cell lines, 24 paired surgical fresh specimens of gastric adenocarcinoma and adjacent nontumor tissue, 74 conventional formalin-fixed, paraffin-embedded tumor specimens, and 55 specimens spotted on tissue microarray (TMA) were analyzed. Reverse transcription-PCR (RT-PCR), real-time RT-PCR, immunohistochemistry, and cell growth assays were performed. RESULTS: Overexpression of EphA4 mRNA expres-sion was observed in 8 (73%) of 11 gastric cancer cell lines and 10 (42%) of 24 gastric cancer tissues. Over-expression of EphA4, analyzed by immunohistochemistry, was observed in 62 (48%) of 129 gastric cancer tissues. EphA4 overexpression, at the protein level, was significantly associated with depth of invasion and recurrence. EphA4 overexpression was also correlated with FGFR1 overexpression. Patients with EphA4-positive cancer had significantly shorter overall survival periods than did those with EphA4-negative cancer (P = 0.0008). The mRNAs for ephrin ligands were coexpressed in various combinations in gastric cancer cell lines and cancer tissues. Downregulation of EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. CONCLUSION: Our results suggest that overexpres-sion of EphA4 plays a role in gastric cancer.

Different effects of ghrelin, des-acyl ghrelin and obestatin on gastroduodenal motility in conscious rats

Three peptides, ghrelin, des-acyl ghrelin and obestatin are derived from a common prohormone, preproghrelin by posttranslational processing, originating from endocrine cells in the stomach. To examine the effects of these peptides, we applied the manometric measurement of gastrointestinal motility in freely moving conscious rat models. Ghrelin exerts stimulatory effects on the motility of antrum and duodenum in both fed and fasted state of animals. Des-acyl ghrelin exerts inhibitory effects on the motility of antrum, but not on the motility of duodenum in the fasted state of animals. Obestatin exerts inhibitory effects on the motility of antrum and duodenum in the fed state, but not in the fasted state of animals. NPY Y2 or Y4 receptors in the brain may mediate the action of ghrelin, CRF type 2 receptors in the brain mediate the action of des-acy ghrelin, whereas CRF type 1 and type 2 receptors in the brain mediate the action of obestatin. Vagal afferent pathways might be involved in the action of ghrelin, but not involved in the action of des-acyl ghrelin, whereas vagal afferent pathways might be partially involved in the action of obestatin.

Comprehensive review of post-liver resection surgical complications and a new universal classification and grading system

Liver resection is the gold standard treatment for certain liver tumors such as hepatocellular carcinoma and metastatic liver tumors. Some patients with such tumors already have reduced liver function due to chronic hepatitis, liver cirrhosis, or chemotherapy-associated steatohepatitis before surgery. Therefore, complications due to poor liver function are inevitable after liver resection. Although the mortality rate of liver resection has been reduced to a few percent in recent case series, its overall morbidity rate is reported to range from 4.1% to 47.7%. The large degree of variation in the post-liver resection morbidity rates reported in previous studies might be due to the lack of consen-sus regarding the definitions and classification of postliver resection complications. The Clavien-Dindo(CD) classification of post-operative complications is widely accepted internationally. However, it is hard to apply to some major post-liver resection complications because the consensus definitions and grading systems for posthepatectomy liver failure and bile leakage established by the International Study Group of Liver Surgery are incompatible with the CD classification. Therefore, a unified classification of post-liver resection complications has to be established to allow comparisons between academic reports.

Overexpression of β3/γ2 chains of laminin-5 and MMP7 in biliary cancer

AIM:To clarify the clinicopathological significance of laminin-5 γ2 (LNγ2) and β3 (LNβ3) chains and MMP7 expression in biliary tract cancer.METHODS: We analyzed the association between immunohistochemically detected LNγ2, LNβ3, and MMP7 expression in biliary tract cancer and clinicopathological characteristics. Activity of MMP7 was analyzed by casein zymography. An in vitro invasion assay after treatment with MMP7-specific siRNA was performed.RESULTS: LNγ2 expression was predominantly observed in carcinoma cells at the invasive front. LNγ2 expression was seen in 57% of patients with biliary tract cancer, and was associated with depth of invasion, histologic type, and advanced stage. The expression pattern of LNβ3 was classified into two types: invasive front dominant type (38%) and diffuse type (28%).The invasive front dominant type was associated with histologic type and advanced stage. MMP7 positivity was correlated with LNγ2 or LNβ3 expression but not with clinicopathological characteristics. Active MMP7 detected by casein zymography was correlated with depth of invasion and advanced stage. Downregulation of MMP7 expression by siRNA resulted in a significant decrease in biliary tract cancer cell invasion in vitro.CONCLUSION: Our results suggest that LNγ2 and LNβ3, in conjunction with MMP7, play a key role in the progression of biliary tract cancer.

Insulin-like growth factor-1, IGF binding protein-3, and the risk of esophageal cancer in a nested case-control study

AIM To assess the relationship between serum levels of insulin-like growth factor-1(IGF1)/IGF-binding protein-3(IGFBP3)and the risk of esophageal carcinoma.METHODS We assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective,nested case-control study of participants from the Japan Collaborative Cohort Study.A baseline survey was conducted from 1988 to 1990.Of the 110585 enrolled participants,35%donated blood samples.Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies.A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 levels.RESULTS Thirty-one cases and 86 controls were eligible for the present assessment.The molar ratio of IGF1/IGFBP3,which represents the free and active form of IGF1,was not correlated with the risk of esophageal carcinoma.A higher molar difference between IGFBP3and IGF1,which estimates the free form of IGFBP3,was associated with a decreased risk of esophageal carcinoma(P=0.0146),and people in the highest tertile had the lowest risk(OR=0.107,95%CI:0.017-0.669).After adjustment for body mass index,tobacco use,and alcohol intake,the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma(P=0.0150).CONCLUSION The free form of IGFBP3,which is estimated by this molar difference,may be inversely associated with esophageal cancer incidence.

Prevention of hepatocellular carcinoma: Focusing on antioxidant therapy

Oxidative stress has been investigated in the context of alcoholic liver injury for many years and shown to be a causal factor of chronic hepatitis C(CHC), nonalcoholic steatohepatitis(NASH), drug-induced liver injury, Wilson's disease, and hemochromatosis. In CHC, it has been demonstrated that oxidative stress plays an important role in hepatocarcinogenesis. In cases with persistent hepatitis due to failure of hepatitis C virus eradication,or chronic liver disease, such as NASH, the treatment of which remains unestablished, it is important to reduce serum alanine aminotransferase levels and prevent liver fibrosis and development of hepatocellular carcinoma. This also suggests the importance of antioxidant therapy. Among treatment options where it would be expected that anti-inflammatory activity plays a role in their confirmed efficacy for chronic hepatitis, iron depletion therapy, glycyrrhizin, ursodeoxycholic acid, Sho-Saiko-To, and vitamin E can all be considered antioxidant therapies. To date, however, the ability of these treatments to prevent cancer has been confirmed only in CHC. Nevertheless, anti-inflammatory and antifibrotic effects have been demonstrated in other liver diseases and these therapies may potentially be effective for cancer prevention.

Atherogenic lipids profile relates to postprandial hyperglycemia and hyperinsulinemia due to whole body insulin resistance in prediabetic subjects

Backgrounds: Differences in serum lipids profiles in different type of glucose intolerance are unclear. Aims: To characterize lipid profiles in different type of glucose intolerance, and to assess relationships between serum lipids profile and disturbance of glucose metabolism in prediabetic subjects. Methods: Using the measurements in medical check-up with 75 goral glucose tolerance test (OGTT), total of 620 male subjects, who are not on medications for metabolic diseases or hypertension, were divided into normal fasting glucose and glucose tolerance (NFG/ NGT), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined IFG and IGT (IFG/IGT) based on results of the OGTT. Results: Age and body mass index (BMI) were similar in the four groups. Matsuda index (an index of whole body insulin sensitivity) was lower in iIFG, iIGT and IFG/IGT as compared with NFG/NGT. Plasma insulin excursion during the OGTT was significantly higher in IFG/IGT versus NFG/NGT. Serum triglyceride level (TG) and TG to HDL ratio (TG/HDL) were higher in IFG/IGT versus NFG/NGT. Matsuda index was positively correlated with HDL and was inversely correlated with TG, LDL, non-HDL, TG/ HDL and LDL to HDL ratio (LDL/HDL). Backward stepwise multiple regression analysis indicated that increases in BMI, plasma insulin level at 60 min (PI60) and plasma glucose level at 120 min in the OGTT were independently associated with increases in TG and TG/HDL. Increases in BMI and PI60 were related to an increase in non-HDL and LDL/HDL and a decrease in HDL. Conclusions: These results indicate that postprandial hyperglycemia and hyperinsulinemia based on advanced insulin resistance are closely related to lipid risk factors of atherosclerotic macrovascular disease in prediabetic subjects.

A New Pharmacokinetic Model of Propofol for Japanese Patients

Target-controlled infusion (TCI) of propofol is used for general anesthesia. However, the only pharmacokinetic parameter commercially used for Japanese patients is weight, and pharmacokinetic models are based on European physical attributes. Drug metabolism also differs in races. This study aimed to identify optimal continuous doses of propofol for Japanese patients and to create a simulated pharmacokinetic (PK) model. Thirty Japanese patients were enrolled. Patients received a constant infusion of 9 mg/kg/h of propofol. Arterial blood samples were collected and the time course of plasma propofol concentrations was modeled using the nonlinear mixed effects model (NONMEM) three-compartmental PK model. We validated the model by intravenously injecting 10 patients with a TCI driver system programmed with the NONMEM model. Our model’s performance was evaluated using the median prediction error (MDPE), median absolute prediction error (MDAPE), and Wobble. We analyzed 320 blood samples for model building and 160 samples for validating our new model. The calculated parameters for the three-compartmental PK model were volume [V1, 3.58;V2, 13.0 + 0.49 × (Age—64);and V3, 186] and elimination clearance [CL1, 0.77 + (WT—54) × 0.04 + (HT—158) × 0.03;CL2, 0.89 + 0.12 × (Age—64);and CL3, 0.98 × exp ((Age—64)/10)]. The new model improved MDPE, MDAPE, and Wobble values (11.5% ± 43.8%, 14.3% ± 33.0%, and 25.0% ± 21.3%, respectively). We created a new pharmacokinetic model for Japanese patients, which is more accurate than the three existing models applied to Japanese populations. Electronic document is a “live” template. The various components of your paper [title, text, heads, etc.] are already defined on the style sheet, as illustrated by the portions given in this document.

Case series of three patients with hereditary diffuse gastric cancer in a single family:Three case reports and review of literature

BACKGROUND Hereditary diffuse gastric cancer(HDGC)is a familial cancer syndrome often associated with germline mutations in the CDH1 gene.However,the frequency of CDH1 mutations is low in patients with HDGC in East Asian countries.Herein,we report three cases of HDGC harboring a missense CDH1 variant,c.1679C>G,from a single Japanese family.CASE SUMMARY A 26-year-old female(Case 1)and a 51-year-old male(father of Case 1),who had a strong family history of gastric cancer,were diagnosed with advanced diffuse gastric cancer.After genetic counselling,a 25-year-old younger brother of Case 1 underwent surveillance esophagogastroduodenoscopy that detected small signet ring cell carcinoma foci as multiple pale lesions in the gastric mucosa.Genetic analysis revealed a CDH1 c.1679C>G variant in all three patients.CONCLUSION It is important for individuals suspected of having HDGC to be actively offered genetics evaluation.This report will contribute to an increased awareness of HDGC.

Low-dose steroid pretreatment ameliorates the transient impairment of liver regeneration

AIM:To determine if liver regeneration (LR) could be disturbed following radiofrequency (RF) ablation and whether modification of LR by steroid administration occurs.METHODS:Sham operation,partial hepatectomy (PH),and partial hepatectomy with radiofrequency ablation (PHA) were performed on adult Fisher 344 rats.We investigated the recovery of liver volume,DNA synthetic activities,serum cytokine/chemokine levels and signal transducers and activators of transcription 3 DNA-binding activities in the nucleus after the operations.Additionally,the effects of steroid (dexamethasone) pretreatment in the PH group (S-PH) and the PHA group (S-PHA) were compared.RESULTS:The LR after PHA was impaired,with high serum cytokine/chemokine induction compared to PH,although the ratio of the residual liver weight to body weight was not significantly different.Steroid pretreatment disturbed LR in the S-PH group.On the other hand,low-dose steroid pretreatment improved LR and suppressed tumor necrosis factor (TNF)-α elevation in the S-PHA group,with recovery of STAT3 DNA-binding activity.On the other hand,low-dose steroid pretreatment improved LR and suppressed TNF-α elevation in the S-PHA group,with recovery of STAT3 DNA-binding activity.CONCLUSION:LR is disturbed after RF ablation,with high serum cytokine/chemokine induction.Low-dose steroid administration can improve LR after RF ablation with TNF-α suppression.

IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions

AIM:To investigate insulin-like growth factor 2(IGF2)differentially methylated region(DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.METHODS:To accurately analyze the association between the histological types and molecular features of each type of serrated lesion,we consecutively collected1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types[hyperplastic polyps(HPs,n=121),sessile serrated adenomas(SSAs,n=132),traditional serrated adenomas(TSAs,n=111),non-serrated adenomas(n=195),and colorectal cancers(n=827)].We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1(LINE-1)in HPs(n=115),SSAs(n=120),SSAs with cytological dysplasia(n=10),TSAs(n=91),TSAs with high-grade dysplasia(HGD)(n=15),non-serrated adenomas(n=80),non-serrated adenomas with HGD(n=105),and CRCs(n=794).For the accurate quantification of the relative methylation levels(scale 0%-100%)of IGF2 DMR0 and LINE-1,we used bisulfite pyrosequencing method.Tumor specimens were analyzed for microsatellite instability,KRAS(codons 12 and 13),BRAF(V600E),and PIK3CA(exons 9and 20)mutations;MLH1 and MGMT methylation;and IGF2 expression by immunohistochemistry.RESULTS:The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas(with or without HGD)was as follows:mean61.7,median 62.5,SD 18.0,range 5.0-99.0,interquartile range 49.5-74.4.The IGF2 DMR0 methylation level was divided into quartiles(Q1≥74.5,Q2 62.6-74.4,Q3 49.6-62.5,Q4≤49.5)for further analysis.With regard to the histological type,the IGF2 DMR0 methylation levels of SSAs(mean±SD,73.1±12.3)were significantly higher than those of HPs(61.9±20.5),TSAs(61.6±19.6),and non-serrated adenomas(59.0±15.8)(P<0.0001).The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level(r=-0.21,P=0.0051).IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs,TSAs,and non-serrated adenomas(P<0.0001).Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs(P<0.0001).The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD(50.2±18.7and 55.7±5.4,respectively)were significantly lower than those in TSAs(61.6±19.6 and 58.8±4.7,respectively)(IGF2 DMR0,P=0.038;LINE-1,P=0.024).CONCLUSION:IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathway.Hypomethylation of IGF2 DMR0 and LINE-1 may play a role in TSA pathway progression.

Longitudinal observation of ten family members with idiopathic basal ganglia calcification: A case report

BACKGROUND Familial idiopathic basal ganglia calcification (FIBGC) is a rare autosomal dominant disorder that causes bilateral calcification of the basal ganglia and/or cerebellar dentate nucleus, among other locations. CASE SUMMARY The aim of this study is to report 10 cases of FIBGC observed in a single family. Seven patients showed calcification on their computed tomography scan, and all of these patients carried the SLC20A2 mutation. However, individuals without the mutation did not show calcification. Three patients among the 7 with calcification were symptomatic, while the remaining 4 patients were asymptomatic. Additionally, we longitudinally observed 10 subjects for ten years. In this paper, we mainly focus on the clinical course and neuroradiological findings in the proband and her son.CONCLUSION The accumulation of more case reports and further studies related to the manifestation of FIBGC are needed.