Nrf2 and Her3 co-expression in cholangiocarcinoma:Possible biological pathways for potential therapeutic approach

To the Editor:Cholangiocarcinomas(CCAs)are heterogeneous group of malignancies,encompassing intrahepatic CCA(iCCA),and extrahepatic CCA(eCCA);they are also classified into common hepatic duct cholangiocarcinoma(CHDCCA),choledocus extrapancreatic cholangiocarcinoma(EPCCA)and choledocus intrapancreatic cholangiocarcinoma(IPCCA)and,finally,gallbladder carcinoma(GBCCA).CCAs are relatively uncommon but.

Left abdominal mass with carcinosis:Unusual presentation of pancreatic acinar cell carcinoma

Acinar cell carcinoma(ACC)is a rare malignant epithelial neoplasm accounting for 1%-2%of all pancreatic exocrine neoplasm,affecting more frequently man with an age between 50 and 70 years.Most patients present with nonspecific symptoms,which may give rise to difficulties in clinical diagnosis[1].ACC can manifest with diarrhea,weight loss,abdominal pain and,in up to 10%-15%,with lipase hypersecretion syndrome,characterized by elevated lipase production,diffuse subcutaneous fat necrosis and polyarthralgia[1,2].Biliary obstruction and jaundice are infre-quent clinical manifestations,unlike ductal adenocarcinoma,due to pushing rather than infiltrating growth of ACC.

Role of CARD15,DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases

AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predispo- sition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS: Two hundred patients with Crohn’s disease (CD), 186 ulcerative colitis (UC) patients, 434 par- ents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS: Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more com- mon in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an in- creased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was morefrequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION: Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric on- set of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.

Comparison of four proton pump inhibitors for the short-term treatment of esophagitis in elderly patients

AIM: To compare efficacy and tolerability of four proton pump inhibitors (PPIs) commonly used in the short-term therapy of esophagitis in elderly patients.METHODS: A total of 320 patients over 65 years with endoscopically diagnosed esophagitis were randomly assigned to one of the following treatments for 8 wk: (1) omeprazole 20 mg/d; (2) lansoprazole 30 mg/d; (3) pantoprazole 40 mg/d, or (4) rabeprazole 20 mg/d. Major symptoms, compliance, and adverse events were recorded. After 8 wk, endoscopy and clinical evaluation were repeated.RESULTS: Per protocol and intention to treat healing rates of esophagitis were: omeprazole = 81.0% and 75.0%, lansoprazole = 90.7% (P = 0.143 vs omeprazole) and 85.0%, pantoprazole = 93.5% (P = 0.04 vs omeprazole) and 90.0% (P = 0.02 vs omeprazole), rabeprazole = 94.6% (P = 0.02 vs omeprazole) and 88.8% (P = 0.04 vs omeprazole). Dividing patients according to the grades of esophagitis, omeprazole was significantly less effective than the three other PPIs in healing grade 1 esophagitis (healing rates: 81.8% vs 100%, 100% and 100%, respectively, P = 0.012). Pantoprazole and rabeprazole (100%) were more effective vs omeprazole (89.6%, P = 0.0001)and lansoprazole (82.4%, P = 0.0001) in decreasing heartburn. Pantoprazole and rabeprazole (92.2% and 90.1%, respectively) were also more effective vs lansoprazole (75.0%, P < 0.05) in decreasing acid regurgitation. Finally, pantoprazole and rabeprazole (95.2% and 100%) were also more effective vs lansoprazole (82.6%, P < 0.05) in decreasing epigastric pain.CONCLUSION: In elderly patients, pantoprazole and rabeprazole were significantly more effective than omeprazole in healing esophagitis and than omeprazole or lansoprazole in improving symptoms. H pylori infection did not influence the healing rates of esophagitis after a short-term treatment with PPI.

Hepatitis delta virus: From infection to new therapeutic strategies

The hepatitis delta virus(HDV)is a small RNA virus that encodes a single protein and which requires the hepatitis B virus(HBV)-encoded hepatitis B surface antigen(HBsAg)for its assembly and transmission.HBV/HDV co-infections exist worldwide and show a higher prevalence among selected groups of HBV-infected populations,specifically intravenous drug users,practitioners of high-risk sexual behaviours,and patients with cirrhosis and hepatocellular carcinoma.The chronic form of HDV-related hepatitis is usually severe and rapidly progressive.Patterns of the viral infection itself,including the status of co-infection or super-infection,virus genotypes(both for HBV and HDV),and persistence of the virus’replication,influence the outcome of the accompanying and manifested liver disease.Unfortunately,disease severity is burdened by the lack of an effective cure for either virus type.For decades,the main treatment option has been interferon,administered as mono-therapy or in combination with nucleos(t)ide analogues.While its efficacy has been reported for different doses,durations and courses,only a minority of patients achieve a sustained response,which is the foundation of eventual improvement in related liver fibrosis.The need for an efficient therapeutic alternative remains.Research efforts towards this end have led to new treatment options that target specific steps in the HDV life cycle;the most promising among these are myrcludex B,which inhibits virus entry into hepatocytes,lonafarnib,which inhibits farnesylation of the viral-encoded LHDAg large hepatitis D antigen,and REP-2139,which interferes with HBsAg release and assembly.

DNA end binding activity and Ku70/80 heterodimer expression in human colorectal tumor

AIM： TO determine the DNA binding activity and protein levels of the Ku70/80 heterodimer, the functional mediator of the NHEJ activity, in human colorectal carcinogenesis. METHODS： The Ku70/80 DNA-binding activity was determined by electrophoretic mobility shift assays in 20 colon adenoma and 15 colorectal cancer samples as well as matched normal colonic tissues. Nuclear and cytoplasmic protein expression was determined by immunohistochemistry and Western blot analysis. RESULTS： A statistical found in both adenomas y significant difference was and carcinomas as compared to matched normal colonic mucosa （P〈0.00）. However, changes in binding activity were not homogenous with approximately 50% of the tumors showing a clear increase in the binding activity, 30% displaying a modest increase and 15% showing a decrease of the activity.Tumors, with increased DNA-binding activity, also showed a statistically significant increase in Ku70 and Ku86 nuclear expression, as determined by Western blot and immunohistochemical analyses （P〈0.001）. Cytoplasmic protein expression was found in pathological samples, but not in normal tissues either from tumor patients or from healthy subjects. CONCLUSION： Overall, our DNA-binding activity and protein level are consistent with a substantial activation of the NHEJ pathway in colorectal tumors. Since the NHEJ is an error prone mechanism, its abnormal activation can result in chromosomal instability and ultimately lead to tumorigenesis.

一种miRNA标记在胶质瘤侵袭性表型的确定与预后评估中的价值(英文)

Gliomas represent a disparate group of tumours for which there are to date no cure. Thus,there is a recognized need for new diagnostic and therapeutic approaches based on increased understanding of their molecular nature. We performed the comparison of the microRNA( miRNA) profile of 8 WHO grade II gliomas and 24 higher grade tumours( 2 WHO grade III and 22 glioblastomas) by using the Affymetrix Gene Chip miRNA Array v. 1. 0. A relative quantification method( RT-q PCR) with standard curve was used to confirm the 22 miRNA signature resulted by array analysis. The prognostic performances of the confirmed miRNAs were estimated on the Tumor Cancer Genome Atlas( TCGA) datasets. We identified 22 miRNAs distinguishing grade II gliomas from higher grade tumours.RT-q PCR confirmed the differential expression in the two patients' groups for 13 out of the 22 miRNAs. The analysis of the Glioblastoma Multiforme( GBM) and Lower Grade Glioma( LGG) datasets from TCGA demonstrated the association with prognosis for 6 of those miRNAs. Moreover,in the GBM dataset miR-21 and miR-210 were predictors of worse prognosis in both univariable and multivariable Cox regression analyses( HR 1. 19,P = 0. 04,and HR 1. 18,P = 0. 029 respectively). Our results support a direct contribution of miRNAs to glioma cancerogenesis and suggest that miR-21 and miR-210 may play a role in the aggressive clinical behaviour of glioblastomas.

Exploitation of host clock gene machinery by hepatitis viruses B and C

Many aspects of cellular physiology display circadian(approximately 24-h)rhythms.Dysfunction of the circadian clock molecular circuitry is associated with human health derangements,including neurodegeneration,increased risk of cancer,cardiovascular diseases and the metabolic syndrome.Viruses triggering hepatitis depend tightly on the host cell synthesis machinery for their own replication,survival and spreading.Recent evidences support a link between the circadian clock circuitry and viruses’biological cycle within host cells.Currently,in vitro models for chronobiological studies of cells infected with viruses need to be implemented.The establishment of such in vitro models would be helpful to better understand the link between the clock gene machinery and viral replication/viral persistence in order to develop specifically targeted therapeutic regimens.Here we review the recent literature dealing with the interplay between hepatitis B and C viruses and clock genes.

Hepatitis C virus micro-elimination:Where do we stand?

Hepatitis C virus (HCV) elimination by 2030, using direct-acting antiviraltreatments, has been promoted by the World Health Organization. Thisachievement is not attainable, however, particularly after the 2020 pandemic ofthe coronavirus disease 2019. Consequently, the more realistic objective ofeliminating HCV from population segments for which targeted strategies ofprevention and treatment are easily attained has been promoted in Europe, as avalid alternative. The underlying idea is that micro-elimination will ultimatelylead to macro-elimination. The micro-elimination strategy may target differentspecific populations and at-risk groups. Different settings, including prisons andhospitals, have also been identified as micro-elimination scenarios. In addition,dedicated micro-elimination strategies have been designed that are tailored at thegeographical level according to HCV epidemiology and individual country’sincome. The main elements of a valid and successful micro-elimination project arereliable epidemiological data and active involvement of all the stakeholders.Community involvement represents another essential component for a successfulprogram.

Management of cholelithiasis in Italian children:A national multicenter study

AIM:To evaluate the management of Italian children with cholelithiasis observed at Pediatric and Surgical Departments linked to Italian Society of Pediatric Gastroenterology Hepatology and Nutrition. METHODS: One-hundred-eighty children (90 males, median age at diagnosis 7.3 years; range, 0-18 years) with echographic evidence of cholelithiasis were enrolled in the study; the data were collected by an anonymous questionnaire sent to participating centers. RESULTS: One hundred seventeen patients were treated with ursodeoxycholic acid; in 8 children dissolution of gallstones was observed, but the cholelithiasis recurred in 3 of them. Sixty-five percent of symptomatic children treated became asymptomatic. Sixty-four patients were treated with cholecystectomy and in only 2 cases a postoperative complication was reported. Thirty- four children received no treatment and were followed with clinical and echographic controls; in no case thedevelopment of complications was reported. CONCLUSION: The therapeutic strategies were extremely heterogeneous. Ursodeoxycholic acid was ineffective in dissolution of gallstones but it had a positive effect on the symptoms. Laparoscopic cholecystectomy was confirmed to be an efficacy and safe treatment for pediatric gallstones.

Hepatitis E in hemodialysis and kidney transplant patients in south-east Italy

AIM:To investigate the serovirological prevalence and clinical features of hepatitis E virus(HEV) infection in end-stage renal failure patients and in the healthy population.METHODS:HEV infection is a viral disease that can cause sporadic and epidemic hepatitis.Previous studies unexpectedly showed a high prevalence of HEV antibodies in immunosuppressed subjects,including hemodialysis(HD)patients and patients who had undergone kidney transplant.A cohort/case-control study was carried out from January 2012 to August 2013 in two hospitals in southern Italy(Foggia and S.Giovanni Rotondo,Apulia).The seroprevalence of HEV was determined in 801 subjects;231 HD patients,120 renal transplant recipients,and450 health individuals.All HD patients and the recipients of renal transplants were attending the Departments of Nephrology and Dialysis at two hospitals located in Southern Italy,and were included progressively in this study.Serum samples were tested for HEV antibodies(Ig G/Ig M);in the case of positivity they were confirmed by a Western blot assay and were also tested for HEV-RNA,and the HEV genotypes were determined.RESULTS:A total of 30/801(3.7%)patients were positive for anti-HEV Ig(Ig G and/or Ig M)and by Western blot.The healthy population presented with a prevalence of 2.7%,HD patients had a prevalence of 6.0%,and transplant recipients had a prevalence of 3.3%.The overall combined HEV-positive prevalence in the two groups with chronic renal failure was 5.1%.The rates of exposure to HEV(positivity of HEV-Ig G/M in the early samples)were lower in the healthy controls,but the difference among the three groups was not statistically significant(P>0.05).Positivity for anti-HEV/Ig M was detected in 4/30(13.33%)anti-HEV Ig positive individuals,in 2/14 HD patients,in1/4 transplant individuals,and in 1/12 of the healthy population.The relative risk of being HEV-Ig M-positive was significantly higher among transplant recipients compared to the other two groups(OR=65.4,95%CI:7.2-592.7,P<0.001),but the subjects with HEV-Ig M positivity were numerically too few to calculate a significant difference.No patient presented with chronic hepatitis from HEV infection alone.CONCLUSION:This study indicated a higher,but not significant,circulation of HEV in hemodialysis patients vs the healthy population.Chronic hepatitis due to the HEV virus was not observed.

TET2 Mutations in Ph-Negative-Myeloproliferative Neoplasms: Identification of Three Novel Mutations and Relationship with Clinical and Laboratory Findings

High-throughput DNA sequence analysis was used to screen for TET2 mutations in peripheral blood derived DNA from 97 patients with BCR-ABL-negative-myeloproliferative neoplasms (MPNs). Overall six mutations in the coding region of the gene were identified in 7 patients with an overall mutational frequency of 7.2%. In polycythemia vera patients (n = 25) were identified 2 mutations (8%);in those with essential thrombocythemia (n = 55) 2 mutations (3.6%);in those with unclassifiable MPN (n = 8) 3 mutations (37.5%). No primary myelofibrosis patiens (n = 6) harboured TET2 mutations. Three unreported mutations were identified (p.P177fs, p.C1298del, p.P411del) the first two in patients with unclassifiable MPN, the last in a patient with essential thrombocythemia. On multivariate analysis the diagnosis of an unclassifiable MPN was significantly related to the presence of TET2 mutations (p = 0.02;OR: 2.81;95% CI 1.11 - 7.06). We conclude that TET2 mutations occur in both JAK2V617F-positive and -negative MPN and are more frequent in MPN-U patients. This could represent the biological link between the different classes of myeloid malignancies.

Emotion recognition and inhibitory control in manifest and pre-manifest Huntington’s disease: evidence from a new Stroop task

Huntington’s disease(HD)is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain.In particular,cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals’mental state may emerge many years before the motor symptoms.This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose:1)the impairment of emotion recognition in HD is moderated by the emotions’valence,and 2)inhibitory control is impaired in HD.Forty manifest and 20 pre-manifest HD patients and their age-and gender-matched controls completed both the traditional“Stroop Color and Word Test”(SCWT)and the newly created“Stroop Emotion Recognition under Word Interference Task”(SERWIT),which consist in 120 photographs of sad,calm,or happy faces with either congruent or incongruent word interference.On the SERWIT,impaired emotion recognition in manifest HD was moderated by emotion type,with deficits being larger in recognizing sadness and calmness than in recognizing happiness,but it was not moderated by stimulus congruency.On the SCWT,six different interference scores yielded as many different patterns of group effects.Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions’valence,but do not provide evidence for the hypothesis that inhibitory control is impaired in HD.Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD,and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD.Looking beyond this study,the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders.The research was approved by the Ethics Committee of the“Istituto Leonarda Vaccari”,Rome on January 24,2018.

Histopathological landscape of rare oesophageal neoplasms

The landscape of neoplastic pathology of the oesophagus is dominated by malignancies of epithelial origin,in particular by oesophageal adenocarcinoma and oesophageal squamous cell carcinoma.However,several other histopathological variants can be distinguished,some associated with peculiar histopathological profiles and prognostic behaviours and frequently underrecognized in clinical practice.The aim of this review is to provide a comprehensive characterization of the main morphological and clinical features of these rare variants of oesophageal neoplastic lesions.

Is positivity for hepatitis C virus antibody predictive of lower risk of death in COVID-19 patients with cirrhosis?

Liver injury has been reported in coronavirus disease 2019(COVID-19)cases but the impact of pre-existing liver damage and related etiology have not been completely elucidated.Our research interests include the potential reciprocal influence of COVID-19 and pre-existing liver damage related to hepatitis C virus(HCV)infection,in particular.To this end,we have evaluated three cohorts of patients admitted at three Italian hospitals during the coronavirus pandemic;these included 332 patients with COVID-19 and 1527 patients with HCV who were from established real-world antiviral treatment study cohorts(sofosbuvir/velpatasvir),with either liver disease(various severities;n=1319)or cirrhosis(n=208).Among the COVID-19 patients,10 had cirrhosis(3%),including 7 of metabolic origin and 3 of viral origin.Mortality among the COVID-19 patients was 27.1%,with 70%of those with cirrhosis of metabolic etiology having died.Cirrhosis,older age,low white blood cell count and lymphocyte count being identified as risk predictors of death[odds ratio(OR)=13.7,95%confidence interval(CI):2.59-83.01,P=0.006;OR=1.05,95%CI:1.03-1.08,P=0.0001;OR=1.09,95%CI:1.36-1.16,P=0.001;OR=0.61,95%CI:0.39-0.93,P=0.023,respectively].In the two cohorts of HCV patients,COVID-19 diagnosis was made in 0.07%of those with liver disease and 1%of those with cirrhosis.Thus,the prevalence of HCV antibodies among COVID-19-infected patients was comparable to that currently reported for the general population in Italy.Amongst the COVID-19 patients,pre-existing metabolic cirrhosis appears to be associated with higher mortality,while HCV antibodies may be suggestive of“protection”against COVID-19.

Successful robot-assisted surgery for treating endometrial cancer affecting bicornuate-bicollis or didelphic uterus

Uterine anomalies are mainly associated with improper development of Mullerian ducts. To our knowledge, reports describing the use of a da Vinci Robot System for treating an endometrial cancer in a woman with an abnormal uterus are lacking. Here, we reported the description of two extremely obese women, affected by endometrial cancer and presenting bicornuate-bicollis and didelphic uterus have been treated by Robot System-assisted surgery. No operative and postoperative complications were recorded. Both women are disease-free to follow-up. A robot-assisted surgery could represent an effective treatment option for complex hysterectomies and in complicated patients, as those showing an extreme obesity.

Cross-linked self-assembling peptide scaffolds

Self-assembling peptides （SAPs） are synthetic bioinspired biomaterials that can be feasibly multi-functionalized for cell transplantation and/or drug delivery therapies. Despite their superior biocompatibility and ease of scaling-up for production, they are unfortunately hampered by weak mechanical properties due to transient non-covalent interactions among and within the self-assembled peptide chains, thus limiting their potential applications as fillers, hemostat solutions, and fragile scaffolds for soft tissues. Here, we have developed and characterized a cross-linking strategy that increases both the stiffness and the tailorability of SAP hydrogels, enabling the preparation of transparent flexible threads, discs, channels, and hemispherical constructs. Empirical and computational results, in close agreement with each other, confirmed that the cross-linking reaction does not affect the previously self-assembled secondary structures. In vitro tests also provided a first hint of satisfactory biocompatibility by favoring viability and differentiation of human neural stem cells. This work could bring self-assembling peptide technology to many applications that have been precluded so far, especially in regenerative medicine.

Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility

Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)maturation.Through fine-mapping in a large Italian dataset(4,198 patients with MS and3,903 controls),we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region.Expression quantitative trait locus(e QTL)analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells,which is consistent with the allelic imbalance in RNA-Seq reads(P<0.0001).The MS risk allele is associated with reduced levels of TNFSF14 gene expression(P<0.01)in blood cells from 84 Italian patients with MS and 80 healthy controls(HCs).Interestingly,patients with MS are lower expressors of TNFSF14 compared to HC(P<0.007).Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs(CD11 c+,P=0.035)in 37 HCs,as well as in in vitro monocyte-derived DCs from 22 HCs(P=0.04).Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells,which may play a role in MS pathogenesis.