Glucocorticoids and Antivirals for HBV Reactivation in Onco-Hematologic Patients.

Patients with inactive or occult hepatitis B virus infection and onco-hematological malignancies are at risk of hepatitis flare, hepatic failure and death due to chemotherapy-mediated reactivation. Nucleot(s)ide analogues can reduce reactivation risks and/or hepatitis. However, immuno-mediated phenomena combine to determine liver damage and clinical outcome. We describe in this report two patients with onco-hematological malignancies and hepatitis B reactivation after chemotherapy in whom glucocorticoids were added to nucleot(s)ide. Antiviral therapy was effective on replication, while glucocorticoids managed hyperergic response. One patient without underlying liver disease survived, while the second died and the autopsy demonstrated cirrhosis undetected before death. This clinical trial suggests that in patients with onco-hematological malignancies and altered liver function tests in spite of effective antiviral response, glucocorticoids could control the effects of immune response. However prognosis and survival are related to the underlying liver status

The GBAP1 pseudogene acts as a ceRNA for the glucocerebrosidase gene GBA by sponging miR-22-3p.

Mutations in the GBA gene, encoding lysosomal glucocerebrosidase, represent the major predisposing factor for Parkinson's disease (PD), and modulation of the glucocerebrosidase activity is an emerging PD therapy. However, little is known about mechanisms regulating GBA expression. We explored the existence of a regulatory network involving GBA, its expressed pseudogene GBAP1, and microRNAs. The high level of sequence identity between GBA and GBAP1 makes the pseudogene a promising competing-endogenous RNA (ceRNA), functioning as a microRNA sponge. After selecting microRNAs potentially targeting both transcripts, we demonstrated that miR-22-3p binds to and down-regulates GBA and GBAP1, and decreases their endogenous mRNA levels up to 70%. Moreover, over-expression of GBAP1 3'-untranslated region was able to sequester miR-22-3p, thus increasing GBA mRNA and glucocerebrosidase levels. The characterization of GBAP1 splicing identified multiple out-of-frame isoforms down-regulated by the nonsense-mediated mRNA decay, suggesting that GBAP1 levels and, accordingly, its ceRNA effect, are significantly modulated by this degradation process. Using skin-derived induced pluripotent stem cells of PD patients with GBA mutations and controls, we observed a significant GBA up-regulation during dopaminergic differentiation, paralleled by down-regulation of miR-22-3p. Our results describe the first microRNA controlling GBA and suggest that the GBAP1 non-coding RNA functions as a GBA ceRNA

Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.A combination of Drosophila dGBA1b loss-of-function models and Gaucher Disease (GD) patient-derived iPSCs reveals an impairment in GD neuronal cell growth and that Hippo pathway hyperactivation contributes to the impairment

Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization

Since gastro-entero-pancreatic endocrine tumors are rare and heterogeneous diseases, their prognosis and long-term survival are not well known. This study aimed at identifying prognostic factors and assessing long-term survival in gastro-entero-pancreatic endocrine tumors. A total of 156 patients enrolled. Prognostic factors were determined by univariate/multivariate analysis; survival rates were assessed by the Kaplan–Meier method. The tumors were non-functioning in 59.6% of patients, and originated from the pancreas in 42.9%. At diagnosis, 64.3% of patients had metastases. The tumors were well differentiated in 89.6% of patients. Ki67 was >2% in 39.6% of patients. Primary tumor size was >3 cm in 49.6% of cases studied. For the univariate analysis, the negative prognostic factors were: pancreatic origin (rate ratio 4.64, P = 0.0002), poorly differentiated tumor (rate ratio 7.70, P = 0.0001), primary tumor size >3 cm (rate ratio 4.26, P = 0.0009), presence of distant metastases (liver: rate ratio 5.88, P = 0.01; distant extra-hepatic: rate ratio 13.41, P = 0.0008). The pancreatic site, the poor degree of differentiation and the distant metastases were confirmed as negative prognostic factors at multivariate analysis. Overall 5-year survival rate was 77.5%. Survival rates differed according to: primary tumor site (62% for pancreatic vs 89.9% for gastrointestinal tract, P = 0.0001) and size (65.7% for >3 cm vs 88.8% for ≤ 3 cm, P = 0.0003), degree of differentiation (22% for poor vs 86.8% for good, P 2% vs 90.1% for ≤ 2%, P = 0.003), metastases (96.1, 77, 73.3 and 50.1% for absent, local, liver and distant extra-hepatic metastases respectively), age at diagnosis (85.3% for ≤ 50 years vs 70.3% for > 50 years, P = 0.03). Although 64.3% of gastro-entero-pancreatic endocrine tumors present metastases at diagnosis, the 5-year survival rate is 77.5%. Pancreatic site, a poor degree of tumor cell differentiation and distant extra-hepatic metastases are the major negative prognostic factors

Adherence to AASLD guidelines in the “real world”

Valutazione dell’applicabilità del BCLC al di fuori di studi controllati (real world) con analisi della concordanza tra sua proposta gestionale e reale soluzione terapeutica adottat

Effect of Sulphur Fertilization on Grain Quality and Protein Composition of Durum Wheat (Triticum durum Desf.)

The reduction of atmosphere emission of SO2 and the massive use of fertilizers high in nitrogen and phosphorus resulted in a decrease of the sulphur content in the soil. In durum wheat cultivation, sulphur supply plays a key role not only for plant growth, but also for grain quality. Sulphur is an essential macronutrient primarily used to synthesize methionine and cysteine and it is also involved in establishing protein structures by disulphide bonds. The aim of this study was to evaluate the effect of sulphur nutrition on grain quality and protein composition of durum wheat cultivars grown under water deficit conditions, typical of Mediterranean areas. To this purpose, in the 2003-2004 and 2004-2005 crop seasons a field trial was carried out by comparing two water regimes (irrigated and rainfed), two sulphur fertilizer levels and two durum wheat cultivars. Under our experimental conditions, an increase in protein and gluten content in the rainfed treatment and a positive effect of sulphur fertilization on quality parameters were observed. Few changes were observed in protein composition in response to sulphur fertilization

Effect of sulphur fertilization on grain quality and protein composition of durum wheat (Triticum durum, Desf.)

The reduction of atmosphere emission of SO2 and the massive use of fertilizers high in nitrogen and phosphorus resulted in a decrease of the sulphur content in the soil. In durum wheat cultivation, sulphur supply plays a key role not only for plant growth, but also for grain quality. Sulphur is an essential macronutrient primarily used to synthesize methionine and cysteine and it is also involved in establishing protein structures by disulphide bonds. The aim of this study was to evaluate the effect of sulphur nutrition on grain quality and protein composition of durum wheat cultivars grown under water deficit conditions, typical of Mediterranean areas. To this purpose, in the 2003-2004 and 2004-2005 crop seasons a field trial was carried out by comparing two water regimes (irrigated and rainfed), two sulphur fertilizer levels and two durum wheat cultivars. Under our experimental conditions, an increase in protein and gluten content in the rainfed treatment and a positive effect of sulphur fertilization on quality parameters were observed. Few changes were observed in protein composition in response to sulphur fertilization

Effect of Sulphur Fertilization on Grain Quality and Protein Composition of Durum Wheat (Triticum durum Desf.)

The reduction of atmosphere emission of SO2 and the massive use of fertilizers high in nitrogen and phosphorus resulted in a decrease of the sulphur content in the soil. In durum wheat cultivation, sulphur supply plays a key role not only for plant growth, but also for grain quality. Sulphur is an essential macronutrient primarily used to synthesize methionine and cysteine and it is also involved in establishing protein structures by disulphide bonds. The aim of this study was to evaluate the effect of sulphur nutrition on grain quality and protein composition of durum wheat cultivars grown under water deficit conditions, typical of Mediterranean areas. To this purpose, in the 2003-2004 and 2004-2005 crop seasons a field trial was carried out by comparing two water regimes (irrigated and rainfed), two sulphur fertilizer levels and two durum wheat cultivars. Under our experimental conditions, an increase in protein and gluten content in the rainfed treatment and a positive effect of sulphur fertilization on quality parameters were observed. Few changes were observed in protein composition in response to sulphur fertilization

Patients with hematological malignancies and serological signs of prior resolved hepatitis B

Hepatitis B virus (HBV) infection affects a large part of the world population. Within the different virological HBV categories that have been identified, patients with occult HBV infection represent a peculiar group. These individuals harbor a replication competent virus, inhibited in its replicative function. Accordingly, cases of reactivations have been observed in immunosuppressed individuals who lose immunological control over the infection. Patients with hematological malignancies (HM) are treated with intense myelo- and immunosuppressive chemotherapy regimens which favor HBV reactivation. This event can have severe consequences, such as hepatitis flare, hepatic failure and even death. In addition, it can lead to delays or interruptions of curative treatments, resulting in a decreased disease free and overall survival. In this review, we will examine the event of HBV reactivation in patients with signs of resolved HBV infection undergoing treatment for HM and propose possible management strategies