Long-term treatment with high-dose of sildenafil in a thalassemic patient with pulmonary hypertension

We report a case of a 37-years-old man, affected by thalassemia major, hypogonadotropic hypogonadism, chronic HCV-hepatitis, diabetes mellitus, severe osteoporosis, prior septic pulmonary embolism and pulmonary artery hypertension was performed a long-term treatment with highdose of sildenafil (120 mg/die) with reduction of pulmonary arterial systolic pressure and of the dyspnea

Cognitive reserve modulates mental health in adulthood

Cognitive Reserve (CR) reflects acquired knowledge, skills, and abilities throughout life, and it is known for modulating cognitive efficiency in healthy and clinical populations. CR, which was initially proposed to explain individual differences in the clinical presentation of dementia, has subsequently been extended to healthy ageing, showing its role in cognitive efficiency also during middle age. Recently, CR has been linked to affective processes in psychiatric conditions such as schizophrenia, major depressive and anxiety symptoms, and psychological distress, suggesting its potential role in emotional expression and regulation. Whether the role of CR in mental health extends to non-pathological adults, and whether this is only relevant in older age is not yet clear. The aim of this work was therefore to explore the relationship between CR and mental health in healthy adults, with a focus on middle adulthood (40–60). In a sample of 96 participants, we found a positive association between CR and mental health outcomes, such that a higher cognitive reserve index corresponded to fewer mental health reported symptoms. Specifically, a higher CR reflecting professional activities was associated with lower stress levels, especially in middle agers. Taken together, these data therefore suggest that engaging occupations may help maintain a robust mental health, especially by reducing stress symptoms during middle age. These results broaden previous findings suggesting that CR relates to affective components of mental health in middle aged and older adults

Heme oxygenase-1 in central nervous system malignancies

Central nervous system tumors are the most common pediatric solid tumors and account for 20%-25% of all childhood malignancies. Several lines of evidence suggest that brain tumors show altered redox homeostasis that triggers the activation of various survival pathways, leading to disease progression and chemoresistance. Among these pathways, heme oxygenase-1 (HO-1) plays an important role. HO-1 catalyzes the enzymatic degradation of heme with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin. The biological effects of HO-1 in tumor cells have been shown to be cell-specific since, in some tumors, its upregulation promotes cell cycle arrest and cellular death, whereas, in other neoplasms, it is associated with tumor survival and progression. This review focuses on the role of HO-1 in central nervous system malignancies and the possibility of exploiting such a target to improve the outcome of well-established therapeutic regimens. Finally, several studies show that HO-1 overexpression is involved in the development and resistance of brain tumors to chemotherapy and radiotherapy, suggesting the use of HO-1 as an innovative therapeutic target to overcome drug resistance. The following keywords were used to search the literature related to this topic: nuclear factor erythroid 2 p45-related factor 2, heme oxygenase, neuroblastoma, medulloblastoma, meningioma, astrocytoma, oligodendroglioma, glioblastoma multiforme, and gliomas

A new generation photodetector for astroparticle physics: the VSiPMT

The VSiPMT (Vacuum Silicon PhotoMultiplier Tube) is an innovative design we proposed for a revolutionary photon detector. The main idea is to replace the classical dynode chain of a PMT with a SiPM (G-APD), the latter acting as an electron detector and amplifier. The aim is to match the large sensitive area of a photocathode with the performance of the SiPM technology. The VSiPMT has many attractive features. In particular, a low power consumption and an excellent photon counting capability. To prove the feasibility of the idea we first tested the performance of a special non-windowed SiPM by Hamamatsu (MPPC) as electron detector and current amplifier. Thanks to this result Hamamatsu realized two VSiPMT industrial prototypes. In this work, we present the results of a full characterization of the VSiPMT prototype

Early immune modulation by single-agent trastuzumab as a marker of trastuzumab benefit

BACKGROUND: Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. We analysed BC samples before and after treatment with 1 cycle of trastuzumab according to the response to trastuzumab. METHODS: Gene expression profiles of pre- and post-treatment tumour samples from 17 HER2-positive BC patients were analysed on the Illumina platform. Tumour-associated immune pathways and blood counts were analysed with regard to the response to trastuzumab. HER2-positive murine models with differential responses to trastuzumab were used to reproduce and better characterise these data. RESULTS: Patients who responded to single-agent trastuzumab had basal tumour biopsies that were enriched in immune pathways, particularly the MHC-II metagene. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. Trastuzumab increased the MHC-II-positive cell population, primarily macrophages, only in the tumour microenvironment of responsive mice. In patients who benefited from complete trastuzumab therapy and in mice that harboured responsive tumours circulating neutrophil levels declined, but this cell subset rose in nonresponsive tumours. CONCLUSIONS: Short treatment with trastuzumab induces local and systemic immunomodulation that is associated with clinical outcomes

Bortezomib modulates CHIT1 and YKL40 in monocyte-derived osteoclast and in myeloma cells

Osteolytic bone disease is a common manifestation of multiple myeloma (MM) that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients.It results from increased osteolytic activity and decrease osteoblastic function. Activation of mammalian chitinases CHIT1 and YKL40 is associated with osteoclast (OCs) differentiation and bone digestion. In the current study, we investigated the effect of two Bortezomib’s concentration (BO) (2.5 nM and 5nM) on osteoclastogenesis by analyzing regulation of chitinase expression. OCs exposition to BO was able to inhibit the expression of different OCs markers such as RANK, CTSK, TRAP and MMP9. In addition BO-treatment reduced CHIT1 enzymatic activity and both CHIT1 and YKL40 mRNA expression levels and cytoplasmatic and secreted protein. Moreover, immunofluorescence evaluation of mature OCs showed that BO was able to translocate YKL40 into the nucleus, while CHIT1 remained into the cytoplasm. Since MM cell lines such as U266, SKM-M1 and MM1 showed high levels of CHIT1 activity, we analyzed bone resorption ability of U266 using dentin disc assay resorption pits. Silencing chitinase proteins in U266 cell line with specific siRNAs, resulted in pits number reduction on dentine discs. In conclusion, we showed that BO decreases osteoclastogenesis and reduces bone resorption in OCs and U266 cell line by modulating the chitinases CHIT1 and YKL40. These results indicate that chitinases may be a therapeutic target for bone disease in MM patients

Liver Transplantation for Unresectable Intrahepatic Cholangiocarcinoma: The Role of Sequencing Genetic Profiling

: Intrahepatic cholangiocarcinoma (iCCA) is a rare and aggressive primary liver tumor, characterized by a range of different clinical manifestations and by increasing incidence and mortality rates even after curative treatment with radical resection. In recent years, growing attention has been devoted to this disease and some evidence supports liver transplantation (LT) as an appropriate treatment for intrahepatic cholangiocarcinoma; evolving work has also provided a framework for better understanding the genetic basis of this cancer. The aim of this study was to provide a clinical description of our series of patients complemented with Next-Generation Sequencing genomic profiling. From 1999 to 2021, 12 patients who underwent LT with either iCCA or a combined hepatocellular and cholangiocellular carcinoma (HCC-iCCA) were included in this study. Mutations were observed in gene activating signaling pathways known to be involved with iCCA tumorigenesis (KRAS/MAPK, P53, PI3K-Akt/mTOR, cAMP, WNT, epigenetic regulation and chromatin remodeling). Among several others, a strong association was observed between the Notch pathway and tumor size (point-biserial rhopb = 0.93). Our results are suggestive of the benefit potentially derived from molecular analysis to improve our diagnostic capabilities and to devise new treatment protocols, and eventually ameliorate long-term survival of patients affected by iCCA or HCC-iCCA

Long-term treatment with high-dose of sildenafil in a thalassemic patient with pulmonary hypertension

We report a case of a 37-years-old man, affected by thalassemia major, hypogonadotropic hypogonadism, chronic HCV-hepatitis, diabetes mellitus, severe osteoporosis, prior septic pulmonary embolism and pulmonary artery hypertension was performed a long-term treatment with highdose of sildenafil (120 mg/die) with reduction of pulmonary arterial systolic pressure and of the dyspnea