Objective bayesian variable selection for censored data

In this thesis we study the problem of selecting a set of regressors when the response variable follows a parametric model (such as Weibull or lognormal) and observations are right censored. Under a Bayesian approach, the most widely used tools are the Bayes Factors (BFs) which are, however, undefined when using improper priors. Some commonly used tools in literature, which solve the problem of indeterminacy in model selection, are the Intrinsic Bayes factor (IBF) and the Fractional Bayes factor (FBF). The two proposals are not actual Bayes factors but it can be shown that they asymptotically tend to actual BFs calculated over particular priors called intrinsic and fractional priors, respectively. Each of them depends on the size of a minimal training sample (MTS) and, in particular, the IBF also depends on the MTSs used. When working with censored data, it is not immediate to define a suitable MTS because the sample space of response variables must be fully explored when drawing MTSs, but only uncensored data are actually relevant to train the improper prior into a proper posterior. In fact, an unweighted MTS consisting only of uncensored data may produce a serious bias in model selection. In order to overcome this problem, a sequential MTS (SMTS) is used, leading to an increase in the number of possible MTSs as each one has random size. This prevents the use of the IBF for exploring large model spaces. In order to decrease the computational cost, while maintaining a behavior comparable to that of the IBF, we provide a suitable definition of the FBF that gives results similar to the ones of the IBF calculated over the SMTSs. We first define the conditional FBF on a fraction proportional to the MTS size and, then, we show that the marginal FBF (mFBF), obtained by averaging the conditional FBFs with respect to the probability distribution of the fraction, is consistent and provides also good results. Next, we recall the definition of intrinsic prior for the case of the IBF and the definition of the fractional prior for the FBF and we calculate them in the case of the exponential model for right censored data. In general, when the censoring mechanism is unknown, it is not possible to obtain these priors. Also another approach to the choice of the MTS, which consists in weighting the MTS by a suitable set of weights, is presented. In fact, we define the Kaplan-Meier minimal training sample (KMMTS) which depends on the Kaplan-Meier estimator of the survival function and which contains only suitable weighted uncensored observations. This new proposal could be useful when the censoring percentage is not very high, and it allows faster computations when the predictive distributions, calculated only over uncensored observations, can be obtained in closed-form. The new methodologies are validated by means of simulation studies and applications to real data

Reply to: "YAP in tumorigenesis: Friend or foe?"

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Legal issues in governing genetic biobanks : the Italian framework as a case study for the implications for citizen’s health through public-private initiatives

Deborah Mascalzoni is funded by RD-Connect under grant agreement number 30544.Peer reviewedPublisher PD

Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis

Metabolic changes are associated with cancer, but whether they are just bystander effects of deregulated oncogenic signaling pathways or characterize early phases of tumorigenesis remains unclear. Here we show in a rat model of hepatocarcinogenesis that early preneoplastic foci and nodules that progress towards hepatocellular carcinoma (HCC) are characterized both by inhibition of oxidative phosphorylation (OXPHOS) and by enhanced glucose utilization to fuel the pentose phosphate pathway (PPP). These changes respectively require increased expression of the mitochondrial chaperone TRAP1 and of the transcription factor NRF2 that induces the expression of the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase (G6PD), following miR-1 inhibition. Such metabolic rewiring exclusively identifies a subset of aggressive cytokeratin-19 positive preneoplastic hepatocytes and not slowly growing lesions. No such metabolic changes were observed during non-neoplastic liver regeneration occurring after two/third partial hepatectomy. TRAP1 silencing inhibited the colony forming ability of HCC cells while NRF2 silencing decreased G6PD expression and concomitantly increased miR-1; conversely, transfection with miR-1 mimic abolished G6PD expression. Finally, in human HCC patients increased G6PD expression levels correlates with grading, metastasis and poor prognosis. Our results demonstrate that the metabolic deregulation orchestrated by TRAP1 and NRF2 is an early event restricted to the more aggressive preneoplastic lesions

Diverse MicroRNAs-mRNA networks regulate the priming phase of mouse liver regeneration and of direct hyperplasia

OBJECTIVES: Adult hepatocytes are quiescent cells that can be induced to proliferate in response to a reduction in liver mass (liver regeneration) or by agents endowed with mitogenic potency (primary hyperplasia). The latter condition is characterized by a more rapid entry of hepatocytes into the cell cycle, but the mechanisms responsible for the accelerated entry into the S phase are unknown. MATERIALS AND METHODS: Next generation sequencing and Illumina microarray were used to profile microRNA and mRNA expression in CD‐1 mice livers 1, 3 and 6 h after 2/3 partial hepatectomy (PH) or a single dose of TCPOBOP, a ligand of the constitutive androstane receptor (CAR). Ingenuity pathway and DAVID analyses were performed to identify deregulated pathways. MultiMiR analysis was used to construct microRNA‐mRNA networks. RESULTS: Following PH or TCPOBOP we identified 810 and 527 genes, and 102 and 10 miRNAs, respectively, differentially expressed. Only 20 genes and 8 microRNAs were shared by the two conditions. Many miRNAs targeting negative regulators of cell cycle were downregulated early after PH, concomitantly with increased expression of their target genes. On the contrary, negative regulators were not modified after TCPOBOP, but Ccnd1 targeting miRNAs, such as miR‐106b‐5p, were downregulated. CONCLUSIONS: While miRNAs targeting negative regulators of the cell cycle are downregulated after PH, TCPOBOP caused downregulation of miRNAs targeting genes required for cell cycle entry. The enhanced Ccnd1 expression may explain the more rapid entry into the S phase of mouse hepatocytes following TCPOBOP

Danon disease in a Sardinian family: different aspects of the same mutation-a case report

Background Danon disease (DD) is a rare X-linked disorder due to mutations in the lysosome-associated membrane protein 2 gene. It is characterized by a clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and a variable degree of intellectual disability. Case summary In this case series, we describe a mother and her son affected by DD, highlighting consistent clinical severity despite the expected variability related to gender. The mother (Case 1) presented isolated cardiac involvement, with an arrhythmogenic phenotype that evolved into severe heart failure requiring heart transplantation (HT). Danon disease was diagnosed 1 year after this event. Her son (Case 2) showed an earlier age onset of symptoms with complete atrioventricular block and fast progression of cardiac disease. Diagnosis was established 2 years after clinical presentation. He is currently listed for HT. Discussion In both of our patients, diagnostic delay was extremely long and could have been avoided by emphasizing the relevant clinical red flags. Patients affected by DD may present clinical heterogeneity in terms of natural history, age of onset, and cardiac and extracardiac involvement, even in the same family. Early diagnosis that phenotypic sex differences may impact is a crucial factor in managing patients with DD. Considering the rapid progression of cardiac disease and the poor prognosis, early diagnosis is important and close surveillance should be mandatory during follow-up

Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis

Activation of the Nrf2-Keap1 pathway, the main intracellular defense against environmental stress, has been observed in several human cancers, including hepatocellular carcinoma (HCC). Here, we assessed whether distinct mechanisms of activation may be involved at different stages of hepatocarcinogenesis. We adopted an experimental model consisting of treatment with diethylnitrosamine (DENA) followed by a choline-devoid methionine-deficient (CMD) diet for 4 months. The CMD diet was then replaced with a basal diet, and the animals were killed at 6, 10 or 13 months after DENA injection. Nrf2 activation occurred at early steps of hepatocarcinogenesis and persisted throughout the tumorigenic process. WhileNrf2mutations were extremely frequent at early steps (90%), their incidence diminished with the progression to malignancy (25%). Conversely, while p62 was almost undetectable in early nodules, its accumulation occurred in HCCs, suggesting that Nrf2 pathway activation at late stages is mainly due to Keap1 sequestration by p62. We demonstrate that, in a model of hepatocarcinogenesis resembling human non-alcoholic fatty liver disease,Nrf2mutations are the earliest molecular changes responsible for the activation of the Nrf2-Keap1 pathway. The progressive loss of mutations associated with a concomitant p62 accumulation implies that distinct mechanisms are responsible for Nrf2-Keap1 pathway activation at different stages of hepatocarcinogenesis

Quality of Life of Sardinian Immigrants in Buenos Aires and of People Living in Italy and Sardinia: Does the Kind of Care have a Role for People with Depression?

Background / Objectives: The aim of the study was to compare the Quality of Life (QoL) of Sardinian immigrants to Argentina with Sardinians residing in Sardinia. The hypothesis was that a different availability of effective treatments for mood disorders may impact the well being of persons with these disorders. Methods: One out of five families of Sardinian origin was randomly selected. An Italian study (including Sardinia) was adopted as the control. The Mood Disorder Questionnaire was used for screening mania/hypomania; the diagnosis of Current Major Depressive Disorder was conducted by means of the Patient Health Questionnaire in immigrants and by means of a clinical interview in the control study and in an immigrant subsample (to verify comparability); the Short-Form Health Survey-12 was applied to measure QoL. Results: The Sardinian immigrants showed a higher QoL than Italians in Italy (but not with Sardinians residing in Sardinia). On the contrary, the attributable burden worsening QoL due to lifetime manic/hypomanic episodes, as well as to current depressive episodes, was found higher among Sardinian immigrants with respect to both Sardinian residents in Sardinia and the total Italian sample. The use of effective treatment for mood disorder was higher in Italy. Conclusion: The study found that in a sample of Sardinian immigrants in Buenos Aires the impact of a mood disorder affects QoL more incisively than in Sardinians residing in Sardinia. The suggested hypothesis of a possible role of beliefs guiding the search for treatments will be verified in future studies