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Objectives: To determine if circulating mitochondrial deoxyribonucleic acid levels increase after sport activity involving blows to the head, such as boxing, and if it could play a role in inflammatory cascade regulation in response to trauma., Design: Observational, longitudinal., Methods: We measured mitochondrial deoxyribonucleic acid levels and integrity in ten non-professional male boxers before and after three weekly sparring matches. We set up a protocol to separate three different plasma fractions enriched in mitochondria-containing vesicles, mitochondrial deoxyribonucleic acid bound to proteins and naked mitochondrial deoxyribonucleic acid. We quantified the levels of the main cytokines involved in inflammatory response and the levels of neurofilament light, a well-known marker of brain damage., Results: Circulating mitochondrial deoxyribonucleic acid levels increased after each match. In the second fraction, we also observed an increase over the weeks. Mitochondrial deoxyribonucleic acid is less intact after each match if compared with pre-match integrity, especially the naked form which is not protected within vesicles or mitochondria. Circulating levels of interleukin-6, interleukin-1beta and interleukin-10 increased after each match linking traumatic brain injuries to inflammatory state. Neurofilament light chain showed a similar trend to mitochondrial deoxyribonucleic acid., Conclusions: As mitochondrial deoxyribonucleic acid displays an inflammatory effect and neurofilament light chain is more specific for brain injury, we concluded that the simultaneous analysis of these two parameters could be helpful to monitor the effects of traumatic brain injury in contact sports, and that mitochondrial deoxyribonucleic acid is a promising candidate biomarker to study the inflammatory state of patients who suffered repeated traumatic brain injuries., Competing Interests: Declaration of interest statement The authors declare that there are no conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n = 187 patients; validation cohort, n = 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P = .004) with AUROC = 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P ≤ .0001) with AUROC = 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option., (© 2021 by The American Society of Hematology.)

Background: Swimming in pools is a healthy activity that entails exposure to disinfection by-products (DBPs), some of which are irritant and genotoxic., Objectives: We evaluated exposure to DBPs during swimming in a chlorinated pool and the association with short-term changes in genotoxicity and lung epithelium permeability biomarkers., Methods: Non-smoker adults (N = 116) swimming 40 min in an indoor pool were included. We measured a range of biomarkers before and at different times after swimming: trihalomethanes (THMs) in exhaled breath (5 min), trichloroacetic acid (TCAA) in urine (30 min), micronuclei in lymphocytes (1 h), serum club cell protein (CC16) (1 h), urine mutagenicity (2 h) and micronuclei in reticulocytes (4 days in a subset, N = 19). Several DBPs in water and trichloramine in air were measured, and physical activity was extensively assessed. We estimated interactions with polymorphisms in genes related to DBP metabolism., Results: Median level of chloroform, brominated and total THMs in water was 37.3, 9.5 and 48.5, μg/L, respectively, and trichloramine in air was 472.6 μg/m 3 . Median exhaled chloroform, brominated and total THMs increased after swimming by 10.9, 2.6 and 13.4, μg/m 3 , respectively. Creatinine-adjusted urinary TCAA increased by 3.1 μmol/mol. Micronuclei in lymphocytes and reticulocytes, urine mutagenicity and serum CC16 levels remained unchanged after swimming. Spearman correlation coefficients showed no association between DBP exposure and micronuclei in lymphocytes, urine mutagenicity and CC16. Moderate associations were observed for micronuclei in reticulocytes and DBP exposure., Conclusions: The unchanged levels of the short-term effect biomarkers after swimming and null associations with personal estimates of exposure to DBPs suggest no measurable effect on genotoxicity in lymphocytes, urine mutagenicity and lung epithelium permeability at the observed exposure levels. The moderate associations with micronuclei in reticulocytes require cautious interpretation given the reduced sample size., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Despite the scant docetaxel's tolerability, second-line association with nintedanib still represents a standard-of-care for non-squamous non-small cell lung cancer (nsNSCLC), giving to rapidly-progressing patients the greatest survival advantage. The SENECA trial is a phase IIb, open-label, study evaluating whether nintedanib/docetaxel can be equally effective and safe regardless docetaxel schedule., Materials and Methods: Recurrent nsNSCLC patients were stratified into cohort 1 and 2, according to relapse-time (within or over 3 months) from end of first-line chemotherapy. They were treated with docetaxel (T1: 33 mg/mq on days 1 and 8 in a 21-days cycle; T2: 75 mg/mq q3wks) plus nintedanib, allowing maintenance in case of disease-control. Primary endpoint was progression-free survival (PFS) by investigator's assessment; secondary endpoints: overall survival (OS), safety and quality-of-life., Results: Between January 2016-April 2018, 212 patients were evaluated: 30 resulted screening-failures, 12 were excluded for lack of compliance. According to investigator's choice, 85 patients received T1 docetaxel and 85 T2; 138 (81.2%) were stratified in C1, 32 (18.8%) in C2, with a median relapse-time of 0.54 and 9.29 months, respectively. Baseline characteristics were balanced between groups. After 35.5 months follow-up, no survival differences appear between cohorts and treatments; toxicity seems to be slightly higher in T2, especially for chemotherapy-related events. Perception of quality-of-life remains stable and docetaxel schedule doesn't modify patients' load., Conclusion: The SENECA trial confirms efficacy of second-line nintedanib/docetaxel for nsNSCLC, regardless time of recurrence and docetaxel schedule; higher toxicities for q3wks docetaxel, without alterations in quality-of-life, have been described, underling the possibility, adopting the weekly schedule, to maintain efficacy with better tolerability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC., Conclusion: Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000)., (© 2018 by the American Association for the Study of Liver Diseases.)

In HCC, tumor microenvironment, heavily influenced by the underlying chronic liver disease, etiology and stage of the tissue damage, affects tumor progression and determines the high heterogeneity of the tumor. Aim of this study was to identify the circulating and tissue components of the microenvironment immune-mediated response affecting the aggressiveness and the ensuing clinical outcome. We analyzed the baseline paired HCC and the surrounding tissue biopsies from a prospective cohort of 132 patients at the first diagnosis of HCC for immunolocalization of PD-1/PD-L1, FoxP3, E-cadherin, CLEC2 and for a panel of 82 microRNA associated with regulation of angiogenesis, cell proliferation, cell signaling, immune control and autophagy. Original microarray data were also explored. Serum samples were analyzed for a panel of 19 cytokines. Data were associated with biochemical data, histopathology and survival. Patients with a more aggressive disease and shorter survival, who we named fast-growing accordingly to the tumor doubling time, at presentation had significantly higher AFP levels, TGF-β1 and Cyphra 21-1 levels. Transcriptomic analysis evidenced a significant downregulation of CLEC2 and upregulation of several metalloproteinases. A marked local upregulation of both PD-1 and PD-L1, a concomitant FoxP3-positive lymphocytic infiltrate, a loss of E-cadherin, gain of epithelial-mesenchymal transition (EMT) phenotype and extreme poor differentiation at histology were also present. Upregulated microRNA in fast-growing HCCs are associated with TGF-β signaling, angiogenesis and inflammation. Our data show that fast HCCs are characterized not only by redundant neo-angiogenesis but also by unique features of distinctively immunosuppressed microenvironment, prominent EMT, and clear-cut activation of TGFβ1 signaling in a general background of long-standing and permanent inflammatory state.

Background: Argininosuccinate synthase (ASS)1 is a urea cycle enzyme that catalyzes the conversion of citrulline and aspartate to argininosuccinate. Mutations in the ASS1 gene cause citrullinemia type I, a rare autosomal recessive disorder characterized by neonatal hyperammonemia, elevated citrulline levels, and early neonatal death. Treatment for this disease is currently restricted to liver transplantation; however, due to limited organ availability, substitute therapies are required. Recently, extracellular vesicles (EVs) have been reported to act as intercellular transporters carrying genetic information responsible for cell reprogramming. In previous studies, we isolated a population of stem cell-like cells known as human liver stem cells (HLSCs) from healthy liver tissue. Moreover, EVs derived from HLSCs were reported to exhibit regenerative effects on the liver parenchyma in models of acute liver injury. The aim of this study was to evaluate whether EVs derived from normal HLSCs restored ASS1 enzymatic activity and urea production in hepatocytes differentiated from HLSCs derived from a patient with type I citrullinemia., Methods: HLSCs were isolated from the liver of a patient with type I citrullinemia (ASS1-HLSCs) and characterized by fluorescence-activated cell sorting (FACS), immunofluorescence, and DNA sequencing analysis. Furthermore, their differentiation capabilities in vitro were also assessed. Hepatocytes differentiated from ASS1-HLSCs were evaluated by the production of urea and ASS enzymatic activity. EVs derived from normal HLSCs were purified by differential ultracentrifugation followed by floating density gradient. The EV content was analyzed to identify the presence of ASS1 protein, mRNA, and ASS1 gene. In order to obtain ASS1-depleted EVs, a knockdown of the ASS1 gene in HLSCs was performed followed by EV isolation from these cells., Results: Treating ASS1-HLSCs with EVs from HLSCs restored both ASS1 activity and urea production mainly through the transfer of ASS1 enzyme and mRNA. In fact, EVs from ASS1-knockdown HLSCs contained low amounts of ASS1 mRNA and protein, and were unable to restore urea production in hepatocytes differentiated from ASS1-HLSCs., Conclusions: Collectively, these results suggest that EVs derived from normal HLSCs may compensate the loss of ASS1 enzyme activity in hepatocytes differentiated from ASS1-HLSCs.

Background: Bladder cancer (BC) is among the most common malignancies worldwide. The identification of new biomarkers for early BC detection, recurrence/progression is urgently needed. The cytokinesis-block micronucleus assay (CBMN) evaluates chromosome damage in cultured human lymphocytes and micronuclei (MN) provide a convenient and reliable index of both chromosome breakage and loss., Methods: Chromosomal damage (expressed as frequencies of MN, nucleoplasmic bridges and nuclear buds (NBUD)) was evaluated by CBMN assay in cryopreserved lymphocytes from 158 age/smoking-matched pairs of cases and controls in relation to BC risk, recurrence or progression. Moreover, non-muscle invasive BC (NMIBC) patients were characterised for 783 DNA repair gene polymorphisms for their possible association with the investigated cytogenetic end points., Results: MN and NBUD frequencies were significantly higher in cases than in controls (P=0.001 and P=0.006, respectively), with the associations being stronger in NMIBC. In a logistic regression model, for each increase of one unit in the MN frequency, a 1.12 increased risk of developing NMIBC was observed. In NMIBC cases, 10 polymorphisms were associated with different MN frequencies after genotype stratification., Conclusions: A model including traditional BC risk factors, MN frequency and the selected polymorphisms differentially distributed in cases and controls improved BC patient identification. Understanding the meaning of systemic chromosomal damage in BC patients with respect to the general population may help to adopt specific prevention strategies and therapeutic intervention.

Granulocyte monocyte apheresis (GMA) is a non-pharmacological treatment for inflammatory bowel disease. In our study, we tested a novel GMA adsorber device in terms of clinical efficacy and safety in patients' non-response to pharmacological therapy. Secondary outcomes were the evaluation of adsorber's technical performance, the reduction of inflammatory markers and the improvement of patients' life quality. The prospective study included 18 patients enrolled from 2011 to 2012 with a monitoring of 48 weeks. All patients with Crohn's disease achieved a clinical remission after GMA treatments, sustained until the end of follow up, while 80% of ulcerative colitis patients obtained a clinical benefit, maintained after 48 weeks of monitoring. Leukocytes, neutrophils, monocytes and platelets, compared to erythrocytes and lymphocytes, were effectively removed from peripheral blood. There was no statistically significant result about serological markers of inflammation. A consistent improvement of the patients' quality of life was observed up to the end of follow up. No significant side-effects were recorded. Our study underlines the efficacy and the safety of this novel GMA adsorber device; a prospective randomized clinical trial with adequate sample size should be performed., (© 2016 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Most bladder cancer (BC) patients need life-long, invasive and expensive monitoring and treatment, making it a serious burden on the health system. Thus, there is a pressing need for an accurate test to assist diagnosis and surveillance of BC as an alternative to cystoscopy. Mutations in human TERT, FGFR3, PIK3CA, and RAS genes have been proposed as potential molecular markers in bladder tumor. Their concomitant presence in urine samples has not been fully explored.We investigated a panel of mutations in DNA from exfoliated urinary cells of 255 BC patients at diagnosis. Forty-one mutations in TERT, FGFR3, PIK3CA, and RAS were analyzed by SNaPshot assay in relation to clinical outcome. In 81 of these patients under surveillance, the same set of mutations was screened in additional 324 samples prospectively collected.The most common mutations detected in urine at diagnosis were in the TERT promoter. In non-invasive BC, these mutations were related to high risk and grade (p<0.0001) as well as progression to muscle-invasive disease (p=0.01), whereas FGFR3 mutations were observed in low-grade BC (p=0.02) and patients with recurrences (p=0.05). Stronger associations were observed for combined TERT and FGFR3 mutations and number of recurrences (OR: 4.54 95% CI: 1.23-16.79, p=0.02). Analyses of the area under the curve for combinations of mutations detected at diagnosis and follow-up showed an accuracy of prediction of recurrence of 0.80 (95% CI: 0.71-0.89).Mutations in urine of BC patients may represent reliable biomarkers. In particular, TERT and FGFR3 mutations have a good accuracy of recurrence prediction.

Background: Trihalomethanes (THMs) in exhaled breath and trichloroacetic acid (TCAA) in urine are internal dose biomarkers of exposure to disinfection by-products (DBPs) in swimming pools., Objective: We assessed how these biomarkers reflect the levels of a battery of DBPs in pool water and trichloramine in air, and evaluated personal determinants., Methods: A total of 116 adults swam during 40min in a chlorinated indoor pool. We measured chloroform, bromodichloromethane, dibromochloromethane and bromoform in exhaled breath and TCAA in urine before and after swimming, trichloramine in air and several DBPs in water. Personal determinants included sex, age, body mass index (BMI), distance swum, energy expenditure, heart rate and 12 polymorphisms in GSTT1, GSTZ1 and CYP2E1 genes., Results: Median level of exhaled total THMs and creatinine adjusted urine TCAA increased from 0.5 to 14.4µg/m(3) and from 2.5 to 5.8µmol/mol after swimming, respectively. The increase in exhaled brominated THMs was correlated with brominated THMs, haloacetic acids, haloacetonitriles, haloketones, chloramines, total organic carbon and total organic halogen in water and trichloramine in air. Such correlations were not detected for exhaled chloroform, total THMs or urine TCAA. Exhaled THM increased more in men, urine TCAA increased more in women, and both were affected by exercise intensity. Genetic variants were associated with differential increases in exposure biomarkers., Conclusion: Our findings suggest that, although affected by sex, physical activity and polymorphisms in key metabolizing enzymes, brominated THMs in exhaled breath could be used as a non-invasive DBP exposure biomarker in swimming pools with bromide-containing source waters. This warrants confirmation with new studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported); liver biopsy was scored according to 'The Pathology Committee of the NASH Clinical Research Network'. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI), histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR): 1.408, 95% confidence interval (95% CI): 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06). In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04) was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl) and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males), whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis., (© 2015. Published by The Company of Biologists Ltd.)

The Coiled-Coil Domain Containing 80 (CCDC80) gene has been identified as strongly induced in rat thyroid PC CL3 cells immortalized by the adenoviral E1A gene. In human, CCDC80 is a potential oncosoppressor due to its down-regulation in several tumor cell lines and tissues and it is expressed in almost all tissues. CCDC80 has homologous in mouse, chicken, and zebrafish. We cloned the zebrafish ccdc80 and analyzed its expression and function during embryonic development. The in-silico translated zebrafish protein shares high similarity with its mammalian homologous, with nuclear localization signals and a signal peptide. Gene expression analysis demonstrates that zebrafish ccdc80 is maternally and zygotically expressed throughout the development. In particular, ccdc80 is strongly expressed in the notochord and it is under the regulation of the Hedgehog pathway. In this work we investigated the functional effects of ccdc80-loss-of-function during embryonic development and verified its interaction with gadd45β2 in somitogenesis., (© 2014 Wiley Periodicals, Inc.)

Background: Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear., Methods: We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome., Results: IFN-λ3 was determined in 264 patients (52% males, mean age 57±8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression., Conclusion: IFN-λ3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background. The growing social emergency represented by Alzheimer's disease (AD) and the lack of medical treatments able to modify the disease course have kindled the interest in nonpharmacological therapies. Objective. We introduced a novel nonpharmacological approach for people with AD (PWA) named Multidimensional Stimulation group Therapy (MST) to improve PWA condition in different disease domains: cognition, behavior, and motor functioning. Methods. Enrolling 60 PWA in a mild to moderate stage of the disease, we evaluated the efficacy of MST with a randomized-controlled study. Neuropsychological and neurobehavioral measures and functional magnetic resonance imaging (fMRI) data were considered as outcome measures. Results. The following significant intervention-related changes were observed: reduction in Neuropsychiatric Inventory scale score, improvement in language and memory subscales of Alzheimer's Disease Assessment Scale-Cognitive subscale, and increased fMRI activations in temporal brain areas, right insular cortex, and thalamus. Conclusions. Cognitive-behavioral and fMRI results support the notion that MST has significant effects in improving PWA cognitive-behavioral status by restoring neural functioning., (© The Author(s) 2014.)

HBV vaccine contains the 'a' determinant region, the major immune-target of antibodies (anti-HBs). Failure of immunization may be caused by vaccine-induced or spontaneous 'a' determinant surface gene mutants. Here, we evaluate the possible lack of protection by HBV vaccine, describing the case of an acute hepatitis B diagnosed in a 55-year-old Caucasian male unpaid blood donor, vaccinated against HBV. Sequencing data for preS-S region revealed multiple point mutations. Of all the substitutions found, Q129H, located in the "a" determinant region of HBsAg, can alter antigenicity, leading to mutants. This mutant may cause vaccine failure especially when associated with high viremia of infecting source., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aim: To investigate the safety/efficacy of Boceprevir-based triple therapy in hepatitis C virus (HCV)-G1 menopausal women who were historic relapsers, partial-responders and null-responders., Methods: In this single-assignment, unblinded study, we treated fifty-six menopausal women with HCV-G1, 46% F3-F4, and previous PEG-α/RBV failure (7% null, 41% non-responder, and 52% relapser) with 4 wk lead-in with PEG-IFNα2b/RBV followed by PEG-IFNα2b/RBV+Boceprevir for 32 wk, with an additional 12 wk of PEG-IFN-α-2b/RBV if patients were HCV-RNA-positive by week 8. In previous null-responders, 44 wk of triple therapy was used. The primary objective of retreatment was to verify whether a sustained virological response (SVR) (HCV RNA undetectable at 24 wk of follow-up) rate of at least 20% could be obtained. The secondary objective was the evaluation of the percent of patients with negative HCV RNA at week 4 (RVR), 8 (RVR BOC), 12 (EVR), or at the end-of-treatment (ETR) that reached SVR. To assess the relationship between SVR and clinical and biochemical parameters, multiple logistic regression analysis was used., Results: After lead-in, only two patients had RVR; HCV-RNA was unchanged in all but 62% who had ≤ 1 log10 decrease. After Boceprevir, HCV RNA became undetectable at week 8 in 32/56 (57.1%) and at week 12 in 41/56 (73.2%). Of these, 53.8% and 52.0%, respectively, achieved SVR. Overall, SVR was obtained in 25/56 (44.6%). SVR was achieved in 55% previous relapsers vs. 41% non-responders (P = 0.250), in 44% F0-F2 vs 54% F3-F4 (P = 0.488), and in 11/19 (57.9%) of patients with cirrhosis. At univariate analysis for baseline predictors of SVR, only previous response to antiviral therapy (OR = 2.662, 95%CI: 0.957-6.881, P = 0.043), was related with SVR. When considering "on treatment" factors, 1 log10 HCV RNA decline at week 4 (3.733, 95%CI: 1.676-12.658, P = 0.034) and achievement of RVR BOC (7.347, 95%CI: 2.156-25.035, P = 0.001) were significantly related with the SVR, although RVR BOC only (6.794, 95%CI: 1.596-21.644, P = 0.010) maintained significance at multivariate logistic regression analysis. Anemia and neutropenia were managed with Erythropoietin and Filgrastim supplementation, respectively. Only six patients discontinued therapy., Conclusion: Boceprevir obtained high SVR response independent of previous response, RVR or baseline fibrosis or cirrhosis. RVR BOC was the only independent predictor of SVR.

Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival., Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years., Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non-muscle-invasive tumor/high-grade and with non-muscle-invasive tumor/non-high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10(-2) and 0.8 ± 0.2, P = 3.6 × 10(-2)). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10(-4)). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7-9.1; P = 1.2 × 10(-3))., Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade., Impact: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer., (©2014 American Association for Cancer Research.)