Reliable predictors of outcomes after treatment discontinuation in HBeAg-negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon-inducible protein-10 (IP10) and hepatitis B core-related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg-negative CHB patients who discontinued long-term antiviral therapy. All HBsAg-positive (n = 57) patients of the prospective DARING-B study were included and followed monthly for 3 months, every 2/3 months until month-12 and every 3/6 months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE-B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18-month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month-1 IP10 levels. Of 10 patients with baseline HBsAg ≤100 IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000 IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100-1000 IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month-1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150 pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE-B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg-negative CHB. | 119PAPATHEODORIDI ET Al.

Aims: The definition of original acute severe autoimmune hepatitis (AS-AIH) is unclear. However, its rapid recognition and early treatment is potentially life-saving. Therefore, we present herein an open, real-world observational study for the assessment of the efficacy and safety of early high-dose i.v. corticosteroids in original AS-AIH patients.Methods: Prospectively collected data from 184 AIH patients were analyzed retrospectively. Original AS-AIH defined as an acute symptomatic presentation of newly diagnosed AIH (transaminases >10× upper limit of normal, bilirubin >4 mg/dL, and international normalized ratio [INR] ≥1.5) without histological lesions of chronic disease.Results: Thirty-four of 184 (18.5%) patients had original AS-AIH.These patients were promptly treated with i.v. corticosteroids (either 1 g methylprednisolone for 3 consecutive days followed by i.v. 1 mg/kg/day prednisolone or i.v. 1.5 mg/kg/day prednisolone from the beginning). Only 1/34 (2.9%) died due to sepsis; none required liver transplantation during follow-up (65 [1-175] months). No significant differences were detected in baseline characteristics between original AS-AIH patients and those with insidious presentation (not-AS-AIH; n = 117) apart from antinuclear antibodies negativity (P = 0.038), and higher immunoglobulin G, transaminases, INR, and bilirubin in original AS-AIH patients (P = 0.001 for all). Complete response and corticosteroids withdrawal (for patients treated >12 months) were significantly more frequent in original AS-AIH (n = 28) than in not-AS-AIH (n = 79; P = 0.026 and P = 0.016, respectively). Presence of original AS-AIH was the only independent predictor for achieving complete response.Conclusions: Prompt initiation of high-dose i.v. corticosteroids in original AS-AIH seems safe and efficient as it prevents disease deterioration and the need for liver transplantation. The long-term overall survival of these patients was high (97% for 5.3 years), and the long-term treatment response and corticosteroids withdrawal rates were higher compared to not-AS-AIH patients.

Scaffold attachment factor B1 (SAFB1) is an integral component of the nuclear matrix of vertebrate cells. It binds to DNA on scaffold/matrix attachment region elements, as well as to RNA and a multitude of different proteins, affecting basic cellular activities such as transcription, splicing and DNA damage repair. In the present study, we show that enhancer of rudimentary homologue (ERH) is a new molecular partner of SAFB1 and its 70% homologous paralogue, scaffold attachment factor B2 (SAFB2). ERH interacts directly in the nucleus with the C-terminal Arg-Gly-rich region of SAFB1/2 and co-localizes with it in the insoluble nuclear fraction. ERH, a small ubiquitous protein with striking homology among species and a unique structure, has also been implicated in fundamental cellular mechanisms. Our functional analyses suggest that the SAFB/ERH interaction does not affect SAFB1/2 function in transcription (e.g. as oestrogen receptor α co-repressors), although it reverses the inhibition exerted by SAFB1/2 on the splicing kinase SR protein kinase 1 (SRPK1), which also binds on the C-terminus of SAFB1/2. Accordingly, ERH silencing decreases lamin B receptor and SR protein phosphorylation, which are major SRPK1 substrates, further substantiating the role of SAFB1 and SAFB2 in the co-ordination of nuclear function.

HIF-1α is the inducible subunit of the dimeric transcription factor HIF-1 (Hypoxia Inducible Factor 1). It is induced by hypoxia and hypoxia-mimetics in most cell types, as well as non-hypoxic signals such as growth factors, cytokines and oncogenes, often in a cell specific manner. HIF-1 is present in virtually all cells of higher eukaryotes and its function is of great biomedical relevance since it is highly involved in development, tumor progression and tissue ischemia. Intracellular signaling to HIF-1α, as well as its further action, involves its participation in numerous protein complexes. Using the yeast two-hybrid system we have identified MgcRacGAP (male germ cell Rac GTPase Activating Protein) as a HIF-1α interacting protein. The MgcRacGAP protein is a regulator of Rho proteins, which are principally involved in cytoskeletal organization. We have verified specific binding of HIF-1α and MgcRacGAP in vitro and in vivo in mammalian cells. We have additionally shown that MgcRacGAP overexpression inhibits HIF-1α transcriptional activity, without lowering HIF-1α protein levels, or altering its subcellular localization. Moreover, this inhibition is dependent on the MgcRacGAP domain that interacts with HIF-1α. In conclusion, our findings demonstrate that HIF-1α function is negatively affected by its interaction with MgcRacGAP.

BackgroundWe investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era.ResultsTP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0.001) and p53 protein positivity (p = 0.001) were more frequent in HER2-positive and triple negative (TNBC) tumors, while PIK3CA mutations were more frequent in Luminal A/B tumors (p < 0.001). TP53 mutation status and p53 protein expression but not PIK3CA mutation status interacted with trastuzumab treatment for disease-free survival; patients with tumors bearing TP53 mutations or immunopositive for p53 protein fared better when treated with trastuzumab, while among patients treated with trastuzumab those with the above characteristics fared best (interaction p = 0.017 for mutations; p = 0.015 for IHC). Upon multivariate analysis the above interactions remained significant in HER2-positive patients; in the entire cohort, TP53 mutations were unfavorable in patients with Luminal A/B (p = 0.003) and TNBC (p = 0.025); p53 immunopositivity was strongly favorable in patients treated with trastuzumab (p = 0.009).Materials and MethodsTP53 and PIK3CA mutation status was examined in 1766 paraffin tumor DNA samples with informative semiconductor sequencing results. Among these, 1585 cases were also informative for p53 protein status assessed by immunohistochemistry (IHC; 10% positivity cut-off).ConclusionsTP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting.