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Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4–BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4–BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e−7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2(+/−) and Bola2(−/−) animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.

Background and aims the Barcelona Clinic Liver Cancer intermediate stage (BCLC-B) of hepatocellular carcinoma (HCC) includes extremely heterogeneous patients in terms of tumor burden and liver function. Transarterial-chemoembolization (TACE) is the first-line treatment for these patients although it may be risky/useless for someone, while others could undergo curative treatments. This study assesses the treatment type performed in a large cohort of BCLC-B patients and its outcome. Methods retrospective analysis of 485 consecutive BCLC-B patients from the ITA.LI.CA database diagnosed with naive HCC after 1999. Patients were stratified by treatment. Results 29 patients (6%) were lost to follow-up before receiving treatment. Treatment distribution was: TACE (233, 51.1%), curative treatments (145 patients, 31.8%), sorafenib (18, 3.9%), other (39, 8.5%), best supportive care (BSC) (21, 4.6%). Median survival (95% CI) was 45 months (37.4-52.7) for curative treatments, 30 (24.7-35.3) for TACE, 14 (10.5-17.5) for sorafenib, 14 (5.2-22.7) for other treatments and 10 (6.0-14.2) for BSC (p

none 31 no Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD-related HCC (NAFLD-HCC) and to compare them to those of hepatitis C virus (HCV)-related HCC. A total of 756 patients with either NAFLD (145) or HCV-related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead-time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD-HCC patients, in contrast to the near totality of HCV-HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD-HCC, 25.5 months (95% confidence interval 21.9-29.1), than in those with HCV-HCC, 33.7 months (95% confidence interval 31.9-35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD-HCC and HCV-HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) CONCLUSIONS: NAFLD-HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. Fabio Piscagliaxxx; Gianluca Svegliati-Baroni; Andrea Barchetti; Anna Pecorellixxx; Sara Marinellixxx; Claudio Tiribelli; and; Stefano Bellentani; on behalf of the HCC-NAFLD Italian Study Group [;Mauro Bernardi; Maurizio Biselli; Paolo Caraceni; Marco Domenicali; Francesca Garuti; Annagiulia Gramenzi; Barbara Lenzi; Donatella Magalotti; Matteo Cescon; Matteo Ravaioli; Emanuela Giampalma; Rita Golfieri; Cristina Mosconi; Luigi Bolondi; Marco Zoli; Alessandro Granito; Francesco Tovoli; Franco Trevisani; Laura Venerandi; Giovanni Brandi; Alessandro Cucchetti;] Fabio Piscagliaxxx; Gianluca Svegliati-Baroni; Andrea Barchetti; Anna Pecorellixxx; Sara Marinellixxx; Claudio Tiribelli; and; Stefano Bellentani; on behalf of the HCC-NAFLD Italian Study Group [;Mauro Bernardi; Maurizio Biselli; Paolo Caraceni; Marco Domenicali; Francesca Garuti; Annagiulia Gramenzi; Barbara Lenzi; Donatella Magalotti; Matteo Cescon; Matteo Ravaioli; Emanuela Giampalma; Rita Golfieri; Cristina Mosconi; Luigi Bolondi; Marco Zoli; Alessandro Granito; Francesco Tovoli; Franco Trevisani; Laura Venerandi; Giovanni Brandi; Alessandro Cucchetti;]

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Lead-time is the time by which diagnosis is anticipated by screening/surveillance with respect to the symptomatic detection of a disease. Any screening program, including surveillance for hepatocellular carcinoma (HCC), is subject to lead-time bias. Data regarding lead-time for HCC are lacking. Aims of the present study were to calculate lead-time and to assess its impact on the benefit obtainable from the surveillance of cirrhotic patients. Background & Aims: Lead-time is the time by which diagnosis is anticipated by screening/surveillance with respect to the symptomatic detection of a disease. Any screening program, including surveillance for hepatocellular carcinoma (HCC), is subject to lead-time bias. Data regarding lead-time for HCC are lacking. Aims of the present study were to calculate lead-time and to assess its impact on the benefit obtainable from the surveillance of cirrhotic patients. Methods: One-thousand three-hundred and eighty Child–Pugh class A/B patients from the ITA.LI.CA database, in whom HCC was detected during semiannual surveillance (n = 850), annual surveillance (n = 234) or when patients came when symptomatic (n = 296), were selected. Lead-time was estimated by means of appropriate formulas and Monte Carlo simulation, including 1000 patients for each arm. Results: The 5-year overall survival after HCC diagnosis was 32.7% in semiannually surveilled patients, 25.2% in annually surveilled patients, and 12.2% in symptomatic patients (p

© 2015 The Author(s). The sequencing of the full transcriptome (RNA-seq) has become the preferred choice for the measurement of genome-wide gene expression. Despite its widespread use, challenges remain in RNA-seq data analysis. One often-overlooked aspect is normalization. Despite the fact that a variety of factors or batch effects can contribute unwanted variation to the data, commonly used RNA-seq normalization methods only correct for sequencing depth. The study of gene expression is particularly problematic when it is influenced simultaneously by a variety of biological factors in addition to the one of interest. Using examples from experimental neuroscience, we show that batch effects can dominate the signal of interest; and that the choice of normalization method affects the power and reproducibility of the results. While commonly used global normalization methods are not able to adequately normalize the data, more recently developed RNA-seq normalization can. We focus on one particular method, RUVSeq and show that it is able to increase power and biological insight of the results. Finally, we provide a tutorial outlining the implementation of RUVSeq normalization that is applicable to a broad range of studies as well as meta-analysis of publicly available data.

INTRODUCTION: Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but the selection criteria and priority are still debated. AIMS: To ascertain the number and features of patients with HCC who undergo transplantation in a Western country, the number of patients eligible for LT according to the American Association for the Study of Liver Diseases (AASLD) guidelines, the number of patients who actually undergo transplantation and whether adherence affects survival. METHODS: This is a retrospective analysis from a multicentre Italian database of 2042 cases of HCC, recruited prospectively and consecutively. Kaplan-Meier (log rank) and Cox multivariate analysis estimated survival. RESULTS: Patients who had undergone transplantation (50, 2.5%, with no change over time) had a median survival of 133 months, significantly influenced by the number of lesions and alpha-fetoprotein levels, which were found to be independent predictors of survival on multivariate analysis. Milan criteria were fulfilled in 68%, impacting on survival, whereas 48% fulfilled AASLD guidelines, without such an impact. Two hundred and twenty-eight (11%) patients were eligible for LT according to AASLD; in this group, alpha-fetoprotein levels and Child-Pugh class were independent predictors of survival. CONCLUSION: Among patients with HCC, those undergoing LT represent a small minority; even fewer (1%) are those who undergo transplantation according to AASLD guidelines, adherence to which only marginally affects survival. Overall, LT impact on HCC patients' treatment is very limited

Motivation: Microarray normalization is a fundamental step in removing systematic bias and noise variability caused by technical and experimental artefacts. Several approaches, suitable for large- scale genome arrays, have been proposed and shown to be effective in the reduction of systematic errors. Most of these methodologies are based on specific assumptions that are reasonable for whole- genome arrays, but possibly unsuitable for small microRNA (miRNA) platforms. In this work, we propose a novel normalization (loessM), and we investigate, through simulated and real datasets, the influence that normalizations for two-colour miRNA arrays have on the identification of differentially expressed genes. Results: We show that normalizations usually applied to large-scale arrays, in several cases, modify the actual structure of miRNA data, leading to large portions of false positives and false negatives. Nevertheless, loessM is able to outperform other techniques in most experimental scenarios. Moreover, when usual assumptions on differential expression distribution are missed, channel effect has a strikingly negative influence on small arrays, bias that cannot be removed by normalizations but rather by an appropriate experimental design. We find that the combination of loessM with eCADS, an experimental design based on biological replicates dye-swap recently proposed for channel-effect reduction, gives better results in most of the experimental conditions in terms of specificity/sensitivity both on simulated and real data.

In order to identify any predictive factors of relapse after the discontinuation of anticonvulsive therapy, a catamnestic study was made of 86 epileptic children and adolescents who had started or completed the withdrawal of AEDs. Their clinical records were examined retrospectively, and univariate analysis showed that the factors which correlated significantly with a higher relapse rate were the age at the time of reducing treatment, the presence of more than 30 generalised or partial tonic-clonic seizures, the presence of febrile seizures, the duration of the active phase of the disease, the duration of therapy, and the coexistence of more than one type of seizure. At multivariate analysis, only the presence of 30 generalised or partial tonic-clonic seizures and febrile seizures were significant. Given the small size of the diagnostic subgroups, no significant correlation could be demonstrated between epileptological diagnosis and the risk of recurrence.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is one of the most frequent aetiological factors associated with the development of hepatocellular carcinoma (HCC). AIM: This study evaluated the temporal trend in the aetiological role played by HBV infection alone in patients diagnosed with HCC during the last 20 years in Italy. METHODS: Among the 2042 HCC patients included in the Italian Liver Cancer (ITA.LI.CA.) database, 346 had chronic HBV infection alone. We assessed the proportion of HCC patients with HBV infection in four quinquennia (1987-1991, 1992-1996, 1997-2001, 2002-2006) and evaluated their main clinical, virological and oncological characteristics across these periods. RESULTS: Although the absolute number increased, the proportion of HBV-related HCC relatively decreased over time from 26.7% (47/176 patients) in 1987-1991 to 14.7% (127/862 patients) in 2002-2006 (P=0.0005). Patients' demographical, clinical and virological characteristics were similar across the four quinquennia. A greater proportion of patients was diagnosed with non-advanced HCC in more recent years (from 26% in 1987-1991 to 48% in 2002-2006, P=0.025), likely owing to a growing use of semiannual surveillance (from 63% in 1987-1991 to 80% in 2002-2006). CONCLUSIONS: We observed a significant, relative decrease in the role played by chronic HBV infection alone in the determinism of HCC during the last 20 years. In recent years, more patients are diagnosed with non-advanced HCC probably owing to improvements in HCC detection.