Pathological and physiological functional cross-talks ofα-synuclein and tau in the central nervous system

α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons,respectively.Previous works have revealed that intracellular deposition ofα-synuclein and/or tau causes many neurodegenerative disorders,including Alzheimer’s disease and Parkinson’s disease.Despite intense investigation,the normal physiological functions and roles ofα-synuclein and tau are still unclear,owing to the fact that mice with knockout of either of these proteins do not present apparent phenotypes.Interestingly,the co-occurrence ofα-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies,some of which share similarities in clinical manifestations.Furthermore,the direct interaction ofα-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in vivo.On the other hand,our recent findings have revealed thatα-synuclein and tau are cooperatively involved in brain development in a stage-dependent manner.These findings indicate strong cross-talk between the two proteins in physiology and pathology.In this review,we provide a summary of the recent findings on the functional roles ofα-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases.A deep understanding of the interplay betweenα-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.

Comparing role of ATP between acute pain in neuromyelitis optica spectrum disorder and peripheral neuropathic pain

In this article, we present our previous research, which highlighted adenosine triphosphate(ATP) as the cause of neuropathic pain during the acute phase of neuromyelitis optica spectrum disorder(NMOSD). In NMOSD pathology, damageassociated molecular patterns(DAMPs), including ATP, are released from damaged astrocytes, triggering the activation of innate immune cells. ATP is a central mediator of acute pain in NMOSD.

Novel biomarkers for early detection of gastric cancer

Gastric cancer(GC)remains a leading cause of cancer-related death worldwide.Less than half of GC cases are diagnosed at an advanced stage due to its lack of early symptoms.GC is a heterogeneous disease associated with a number of genetic and somatic mutations.Early detection and effective monitoring of tumor progression are essential for reducing GC disease burden and mortality.The current widespread use of semi-invasive endoscopic methods and radiologic approaches has increased the number of treatable cancers:However,these approaches are invasive,costly,and time-consuming.Thus,novel molecular noninvasive tests that detect GC alterations seem to be more sensitive and specific compared to the current methods.Recent technological advances have enabled the detection of blood-based biomarkers that could be used as diagnostic indicators and for monitoring postsurgical minimal residual disease.These biomarkers include circulating DNA,RNA,extracellular vesicles,and proteins,and their clinical applications are currently being investigated.The identification of ideal diagnostic markers for GC that have high sensitivity and specificity would improve survival rates and contribute to the advancement of precision medicine.This review provides an overview of current topics regarding the novel,recently developed diagnostic markers for GC.

Disease modeling of desmosome-related cardiomyopathy using induced pluripotent stem cell-derived cardiomyocytes

Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation.Although optimized medical therapies have been developed for heart failure during the last few decades,some patients with cardiomyopathy exhibit advanced heart failure and are refractory to medical therapies.Desmosome,which is a dynamic cell-to-cell junctional component,maintains the structural integrity of heart tissues.Genetic mutations in desmo-somal genes cause arrhythmogenic cardiomyopathy(AC),a rare inheritable disease,and predispose patients to sudden cardiac death and heart failure.Recent advances in sequencing technologies have elucidated the genetic basis of cardiomyopathies and revealed that desmosome-related cardiomyopathy is concealed in broad cardiomyopathies.Among desmosomal genes,mutations in PKP2(which encodes PKP2)are most frequently identified in patients with AC.PKP2 deficiency causes various pathological cardiac phenotypes.Human cardiomyocytes differentiated from patient-derived induced pluripotent stem cells(iPSCs)in combination with genome editing,which allows the precise arrangement of the targeted genome,are powerful experimental tools for studying disease.This review summarizes the current issues associated with practical medicine for advanced heart failure and the recent advances in disease modeling using iPSC-derived cardiomyocytes targeting desmosome-related cardiomyopathy caused by PKP2 deficiency.

Biomarkers of gastric cancer:Current topics and future perspective

Gastric cancer(GC) is one of the most prevalent malignant types in the world and an aggressive disease with a poor 5-year survival. This cancer is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Although the incidence is declining, the outcome of patients with GC remains dismal. Thus, the detection at an early stage utilizing useful screening approaches, selection of an appropriate treatment plan, and effective monitoring is pivotal to reduce GC mortalities. Identification of biomarkers in a basis of clinical information and comprehensive genome analysis could improve diagnosis, prognosis, prediction of recurrence and treatment response. This review summarized the current status and approaches in GC biomarker, which could be potentially used for early diagnosis, accurate prediction of therapeutic approaches and discussed the future perspective based on the molecular classification and profiling.

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma(HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus(HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000 s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBVrelated HCC.

Rho/ROCK signaling in motility and metastasis of gastric cancer

Gastric cancer is one of the most frequent and lethal malignancies worldwide because of high frequency of metastasis. Tumor cell motility and invasion play fundamental roles in cancer metastasis. Recent studies have revealed that the Rho/Rho-associated protein kinases(ROCK) pathway plays a critical role in the regulation of cancer cell motility and invasion. In addition,the Rho/ROCK pathway plays important roles in invasion and metastasis on the basis of its predominant function of cell cytoskeletal regulation in gastric cancer. According to the current understanding of tumor motility,there are two modes of tumor cell movement:mesenchymal and amoeboid. In addition,cancer cell movement can be interchangeable between the mesenchymal and amoeboid movements under certain conditions. Control of cell motility through the actin cytoskeleton creates the potential for regulating tumor cell metastasis. In this review we discuss Rho GTPases and ROCK signaling and describe the mechanisms of Rho/ROCK activity with regard to motility and metastasis in gastric cancer.In addition,we provide an insight of the therapeutic potential of targeting the Rho/ROCK pathway.

Quality of ulcer healing in gastrointestinal tract:Its pathophysiology and clinical relevance

In this paper,we review the concept of quality of ulcer healing(QOUH) in the gastrointestinal tract and its role in the ulcer recurrence.In the past,peptic ulcer disease(PUD) has been a chronic disease with a cycle of repeated healing/remission and recurrence.The main etiological factor of PUD is Helicobacter pylori(H.pylori),which is also the cause of ulcer recurrence.However,H.pylori-negative ulcers are present in 12%-20% of patients;they also recur and are on occasion intractable.QOUH focuses on the fact that mucosal and submucosal structures within ulcer scars are incompletely regenerated.Within the scars of healed ulcers,regenerated tissue is immature and with distorted architecture,suggesting poor QOUH.The abnormalities in mucosal regeneration can be the basis for ulcer recurrence.Our studies have shown that persistence of macrophages in the regenerated area plays a key role in ulcer recurrence.Our studies in a rat model of ulcer recurrence have indicated that proinflammatory cytokines trigger activation of macrophages,which in turn produce increased amounts of cytokines and chemokines,which attract neutrophils to the regenerated area.Neutrophils release proteolytic enzymes that destroy the tissue,resulting in ulcer recurrence.Another important factor in poor QOUH can be deficiency of endogenous prostaglandins and a deficiency and/or an imbalance of endogenous growth factors.Topically active mucosal protective and antiulcer drugs promote high QOUH and reduce inflammatory cell infiltration in the ulcer scar.In addition to PUD,the concept of QOUH is likely applicable to inflammatory bowel diseases including Crohn's disease and ulcerative colitis.

Current status of function-preserving surgery for gastric cancer

Recent advances in diagnostic techniques have allowed the diagnosis of gastric cancer(GC)at an early stage.Due to the low incidence of lymph node metastasis and favorable prognosis in early GC,function-preserving surgery which improves postoperative quality of life may be possible.Pylorus-preserving gastrectomy(PPG)is one such function-preserving procedure,which is expected to offer advantages with regards to dumping syndrome,bile reflux gastritis,and the frequency of flatus,although PPG may induce delayed gastric emptying.Proximal gastrectomy(PG)is another functionpreserving procedure,which is thought to be advantageous in terms of decreased duodenogastric reflux and good food reservoir function in the remnant stomach,although the incidence of heartburn or gastric fullness associated with this procedure is high.However,these disadvantages may be overcome by the reconstruction method used.The other important problem after PG is remnant GC,which was reported to occur in approximately 5%of patients.Therefore,the reconstruction technique used with PG should facilitate postoperativeendoscopic examinations for early detection and treatment of remnant gastric carcinoma.Oncologic safety seems to be assured in both procedures,if the preoperative diagnosis is accurate.Patient selection should be carefully considered.Although many retrospective studies have demonstrated the utility of function-preserving surgery,no consensus on whether to adopt functionpreserving surgery as the standard of care has been reached.Further prospective randomized controlled trials are necessary to evaluate survival and postoperative quality of life associated with function-preserving surgery.

Role of hepatitis B virus DNA integration in human hepatocarcinogenesis

Liver cancer ranks sixth in cancer incidence,and is the third leading cause of cancer-related deaths worldwide.Hepatocellular carcinoma(HCC)is the most common type of liver cancer,which arises from hepatocytes and accounts for approximately 70%-85%of cases.Hepatitis B virus(HBV)frequently causes liver inflammation,hepatic damage and subsequent cirrhosis.Integrated viral DNA is found in 85%-90%of HBV-related HCCs.Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis.Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection.Integration has two potential consequences:(1)the host genome becomes altered("cis"effect);and(2)the HBV genome becomes altered("trans"effect).The cis effect includes insertional mutagenesis,which can potentially disrupt host gene function or alter host gene regulation.Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences.However,the role of integrated HBV DNA in hepatocarcinogenesis remains controversial.Modern technology has provided a new paradigm to further our understanding ofdisease mechanisms.This review summarizes the role of HBV DNA integration in human carcinogenesis.

Prognostic significance of the lymphocyte-to-monocyte ratio in patients with metastatic colorectal cancer

AIM:To evaluate the prognostic significance of the lymphocyte to monocyte ratio(LMR) in patients with unresectable metastatic colorectal cancer who received palliative chemotherapy.METHODS:A total of 104 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy were enrolled. The LMR was calculated from blood samples by dividing the absolute lymphocyte count by the absolute monocyte count. Pretreatment LMR values were measured within one week before the initiation of chemotherapy,while posttreatment LMR values were measured eight weeks after the initiation of chemotherapy.RESULTS:The median pre-treatment LMR was 4.16(range:0.58-14.06). We set 3.38 as the cut-off level based on the receiver operating characteristic curve. Based on the cut-off level of 3.38,66 patients were classified into the high pre-treatment LMR group and 38 patients were classified into the low pretreatment LMR group. The low pre-treatment LMR group had a significantly worse overall survival rate(P = 0.0011). Moreover,patients who demonstrated low pre-treatment LMR and normalization after treatmentexhibited a better overall survival rate than the patients with low pre-treatment and post-treatment LMR values.CONCLUSION:The lymphocyte to monocyte ratio is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy.

Noninvasive assessment of liver fibrosis in patients with chronic hepatitis B

Infection with hepatitis B virus is an important healthproblem worldwide:it affects more than 350 millionpeople and is a leading cause of liver-related morbidity,accounting for 1 million deaths annually.Hepatic fibrosis is a consequence of the accumulation of extracellular matrix components in the liver.An accurate diagnosis of liver fibrosis is essential for the management of chronic liver disease.Liver biopsy has been considered the gold standard for diagnosing disease,grading necroinflammatory activity,and staging fibrosis.However,liver biopsy is unsuitable for repeated evaluations because it is invasive and can cause major complications,including death.Several noninvasive evaluations have been introduced for the assessment of liver fibrosis:serum biomarkers,combined indices or scores,and imaging techniques including transient elastography,acoustic radiation force impulse,real-time tissue elastography,and magnetic resonance elastography.Here,we review the recent progress of noninvasive assessment of liver fibrosis in patients with chronic hepatitis B.Most noninvasive evaluations for liver fibrosis have been validated first in patients with chronic hepatitis C,and later in those with chronic hepatitis B.The establishment of a noninvasive assessment of liver fibrosis is urgently needed to aid in the management of this leading cause of chronic liver disease.

Down-regulation of pancreatic transcription factors and incretin receptors in type 2 diabetes

Type 2 diabetes is one of the most prevalent and serious metabolic diseases.Under diabetic conditions,chronic hyperglycemia and subsequent induction of oxidative stress deteriorate pancreaticβ-cell function,which leads to the aggravation of type 2 diabetes.Although such phenomena are well known as glucose toxicity,its molecular mechanism remains unclear.In this review article,we describe the possible molecular mechanism forβ-cell dysfunction found in type 2 diabetes,focusing on(1)oxidative stress,(2)pancreatic transcription factors(PDX-1 and MafA)and(3)incretin receptors(GLP-1 and GIP receptors).Under such conditions,nuclear expression levels of PDX-1 and MafA are decreased,which leads to suppression of insulin biosynthesis and secretion.In addition,expression levels of GLP-1 and GIP receptors are decreased,which likely contributes to the impaired incretin effects found in diabetes.Taken together,it is likely that downregulation of pancreatic transcription factors(PDX-1and MafA)and down-regulation of incretin receptors(GLP-1 and GIP receptors)explain,at least in part,the molecular mechanism forβ-cell dysfunction found in type 2 diabetes.

Recent advances in the HER2 targeted therapy of gastric cancer

Recent advances in molecular targeted therapies, including targeting human epidermal growth factor receptor 2(HER2), had a major forward step in the therapy for gastric cancer patients. Application of HER2-targeted therapies, in particular trastuzumab in combination with chemotherapy in metastatic HER2-positive gastric cancers, resulted in improvements in response rates, time to progression and overall survival. Nevertheless, as with breast cancer, many patients with gastric cancer develop resistance to trastuzumab. Several promising therapies are currently being developed in combination with chemotherapy to increase the efficacy and overcome the cancerresistance. Here we review the current overview of clinical application of agents targeting HER2 in gastric cancer. We also discuss the ongoing trials supporting the use of HER2-targeted agents combined with cytotoxic agents or other monoclonal antibodies.

HLA class Ⅱ associated with outcomes of hepatitis B and C infections

Several factors influence the clinical course of hepatitis B virus(HBV)and hepatitis C virus(HCV)infection.The human leukocyte antigen(HLA)system,the major histocompatibility complex(MHC)in humans,has been considered one of the most important host factors with respect to outcomes.To date,conventional genotyping studies have shown that HLA classⅡloci are mainly associated with spontaneous clearance of HBV and HCV.However,the specific HLA locus associated with the outcomes of hepatitis virus infection remains unclear.A recent genome-wide association study(GWAS)using a comprehensive approach for human genotyping demonstrated single nucleotide polymorphisms(SNPs)associated with the outcomes of hepatitis virus infection.Examination of large numbers of cohorts revealed that several SNPs in both HLA-DPA1 and HLADPB1 loci are associated with persistent HBV infection in Asian populations.To date,however,few studies have focused on HLA-DP because polymorphisms of HLA-DP haplotype do not vary greatly as compared with other loci of HLA.There are not enough studies to reveal the function of HLA-DP.GWAS additionally detected candidate SNPs within HLA loci associated with chronic HBV or HCV hepatitis,hepatic fibrosis,and the development of hepatocellular carcinoma.The results of one cohort were not always consistent with those of other cohorts.To solve several controversial issues,it is necessary to validate reported SNPs on HLA loci in global populations and to elucidate the HLA-allele-regulated molecular response to hepatitis virus infection.

Molecular targets for the treatment of pancreatic cancer:Clinical and experimental studies

Pancreatic cancer is the fourth most common cause of cancer deaths worldwide. Although recent therapeutic developments for patients with pancreatic cancer have provided survival benefits, the outcomes for patients with pancreatic cancer remain unsatisfactory. Molecularly targeted cancer therapy has advanced in the past decade with the use of a number of pathways as candidates of therapeutic targets. This review summarizes the molecular features of this refractory disease while focusing on the recent clinical and experimental findings on pancreatic cancer. It also discusses the data supporting current standard clinical outcomes, and offers conclusions that may improve the management of pancreatic cancer in the future.

Fulminant phlegmonitis of the esophagus, stomach,and duodenum due to Bacillus thuringiensis

We report a case of phlegmonitis of the esophagus, stomach, and duodenum in patient in an immunocompromised state. Culture of gastric juice and blood yielded Bacillus thuringiensis. This case showed that even low-virulence bacilli can cause lethal gastrointestinalphlegmonous gastritis in conditions of immunodeficiency.

Precision medicine for gastrointestinal cancer:Recent progress and future perspective

Gastrointestinal(GI)cancer has a high tumor incidence and mortality rate worldwide.Despite significant improvements in radiotherapy,chemotherapy,and targeted therapy for GI cancer over the last decade,GI cancer is characterized by high recurrence rates and a dismal prognosis.There is an urgent need for new diagnostic and therapeutic approaches.Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer.Here we review the application and status of precision medicine in GI cancer.Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy.With the introduction of gene panels including next-generation sequencing,it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer.Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors,novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs.These progressions will make it feasible to incorporate clinical,genome-based,and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.

Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis

AIM:To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis(UC)patients.METHODS:This was a prospective,multicenter,observational study.Between May 2010 and August 2012,49 steroid-refractory UC patients(55 flare-ups)were consecutively enrolled.All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1mg/kg per day.The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/m L for the first 2 wk.Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger’s clinical activity index(CAI).RESULTS:The mean CAI was 12.6±3.6 at onset.Within the first 7 d,93.5%of patients maintained high trough levels(10-15 ng/m L).The CAI significantly decreased beginning 2 d after treatment initiation.At 2wk,73.1%of patients experienced clinical responses.After tacrolimus initiation,31.4%and 75.6%of patients achieved clinical remission at 2 and 4 wk,respectively.Treatment was well tolerated.CONCLUSION:Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation.Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.

A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

Transforming growth factor-β(TGF-β)and bone morphogenetic protein(BMP)play important roles in bone metabolism.Smad ubiquitination regulatory factors(Smurfs)regulate TGF-β/BMP signaling via ubiquitination,resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP signaling.Though Smurf2 has been shown to negatively regulate TGF-β/Smad signaling,its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly investigated.In the present study,we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone metabolism.Absorbable collagen sponges containing 3μg of recombinant human BMP2(rhBMP2)were implanted in the dorsal muscle pouches of wild type(WT)and Smurf2−/−mice.The rhBMP2-induced ectopic bone in Smurf2−/−mice showed greater bone mass,higher mineral apposition and bone formation rates,and greater osteoblast numbers than the ectopic bone in WT mice.In WT mice,the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular bone.In contrast,in Smurf2−/−mice,the induced bone consisted of a thick,continuous outer cortical shell and abundant inner trabecular bone.Additionally,rhBMP2-stimulated bone marrow stromal cells(BMSCs)from Smurf2−/−mice showed increased osteogenic differentiation.Smurf2 induced the ubiquitination of Smad1/5.BMP/Smad signaling was enhanced in Smurf2−/−BMSCs stimulated with rhBMP2,and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these BMSCs.These findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling,thereby identifying a new regulatory mechanism in bone metabolism.