Molecular mechanisms of hepatitis C virus–induced hepatocellular carcinoma

n/

Allogeneic versus Autologous: ethical issues in umbilical cord blood use

OBJECTIVE. To analyse some ethical issues involved in umbilical cord blood (UCB) collection, storage and use. MATERIALS AND METHODS. Ethical issues were addressed in the light of the wellknown fundamental ethical principles for biomedicine: beneficence/non maleficence, respect for autonomy and justice. Specific issues that have been debated concerning the clinical utility of autologous use compared with allogeneic use for transplantation, the validity of informed consent, especially in private UCB banking, and finally the controversial question of private UCB banking for-profit compared to public UCB banking non-profit. RESULTS. Our ethical analysis has highlighted that the allogeneic UCB use for transplantation, compared to autologous UCB use, seems to fulfil the principle of beneficence/non maleficence as it provides “logistic” and clinical benefits and it decreases risks; the acquisition of informed consent requires some counselling, particularly for autologous collection; finally, public UCB banking seems to fulfil the criteria for justice more than private ones. CONCLUSION. Present and future therapeutic UCB possibilities for treating a wide variety of diseases need to increase the number of UCB units available. For this purpose, a “gift” culture and a “solidarity chain” between donors and recipients are requested. Moreover, in recent years, a further and emerging model of bank seems usable, i.e. “hybrid” banking

Allogeneic versus Autologous: ethical issues in umbilical cord blood use

OBJECTIVE. To analyse some ethical issues involved in umbilical cord blood (UCB) collection, storage and use. MATERIALS AND METHODS. Ethical issues were addressed in the light of the wellknown fundamental ethical principles for biomedicine: beneficence/non maleficence, respect for autonomy and justice. Specific issues that have been debated concerning the clinical utility of autologous use compared with allogeneic use for transplantation, the validity of informed consent, especially in private UCB banking, and finally the controversial question of private UCB banking for-profit compared to public UCB banking non-profit. RESULTS. Our ethical analysis has highlighted that the allogeneic UCB use for transplantation, compared to autologous UCB use, seems to fulfil the principle of beneficence/non maleficence as it provides “logistic” and clinical benefits and it decreases risks; the acquisition of informed consent requires some counselling, particularly for autologous collection; finally, public UCB banking seems to fulfil the criteria for justice more than private ones. CONCLUSION. Present and future therapeutic UCB possibilities for treating a wide variety of diseases need to increase the number of UCB units available. For this purpose, a “gift” culture and a “solidarity chain” between donors and recipients are requested. Moreover, in recent years, a further and emerging model of bank seems usable, i.e. “hybrid” banking

The role of miRNA-133b and its target gene SIRT1 in FAP-derived desmoid tumor.

Signaling pathways have a key role in driving the uncontrolled development of familial adenomatous polyposis (FAP)- associated and sporadic desmoid tumors (DTs). The relationship between the Wnt/b-catenin signaling pathway and DTs has been extensively studied, but no reliable biomarkers able to detect their histological subtype have been identified for the accurate diagnosis. In this study we studied the differences in miRNA expression between sporadic (20 patients) and FAP-associated DTs (7 patients) using microarray confirmed by quantitative PCR (qPCR). The analysis showed 19 dysregulated miRNAs. Among them miR-133b levels were significantly lower in FAP-associated DT than in sporadic DT. Therefore, two mRNAs, associated to miR-133b and β-catenin expression, the SIRT1 and ELAVL1were analyzed. The qPCR analysis showed that SIRT1 mRNA levels were significantly up-regulated in FAP-associated DT than in sporadic DT, whereas no differences in ELAVL1 expression was observed between these two DT types. In addition, a negative correlation was observed between miR-133b and SIRT1 in FAP-associated DTs, but not in sporadic DTs. The miR-133b-SIRT1-β-catenin axis may represent a novel mechanism underlying progression of FAP-associated D

health technology assessment processes for nanotechnologies the ethical domain

The ethical assessment of the use of technologies is generally considered a component of the health technology assessment (HTA) processes. HTA is a multidisciplinary process that summarizes information about medical, economic, organizational, ethical, psychological, social and legal issues related to the implementation of a certain health technology in health care system and its main purpose is to inform policymaking. Unlike the other technologies nanotechnologies pose different risks and, therefore, new bioethical implications should be assessed. So, the ethical assessment of nanotechnologies within the HTA processes could be more problematic. The article intends to debate this complexity

Health technology assessment of pathogen reduction technologies applied to plasma for clinical use

Although existing clinical evidence shows that the transfusion of blood components is becoming increasingly safe, the risk of transmission of known and unknown pathogens, new pathogens or re-emerging pathogens still persists. Pathogen reduction technologies may offer a new approach to increase blood safety. The study is the output of collaboration between the Italian National Blood Centre and the Post-Graduate School of Health Economics and Management, Catholic University of the Sacred Heart, Rome, Italy. A large, multidisciplinary team was created and divided into six groups, each of which addressed one or more HTA domains.Plasma treated with amotosalen + UV light, riboflavin + UV light, methylene blue or a solvent/detergent process was compared to fresh-frozen plasma with regards to current use, technical features, effectiveness, safety, economic and organisational impact, and ethical, social and legal implications. The available evidence is not sufficient to state which of the techniques compared is superior in terms of efficacy, safety and cost-effectiveness. Evidence on efficacy is only available for the solvent/detergent method, which proved to be non-inferior to untreated fresh-frozen plasma in the treatment of a wide range of congenital and acquired bleeding disorders. With regards to safety, the solvent/detergent technique apparently has the most favourable risk-benefit profile. Further research is needed to provide a comprehensive overview of the cost-effectiveness profile of the different pathogen-reduction techniques. The wide heterogeneity of results and the lack of comparative evidence are reasons why more comparative studies need to be performed

High levels of trim5a are associated with xenophagy in hiv‐1‐infected long‐term nonprogressors

Autophagy is a lysosomal‐dependent degradative mechanism essential in maintaining cellular homeostasis, but it is also considered an ancient form of innate eukaryotic fighting against invading microorganisms. Mounting evidence has shown that HIV‐1 is a critical target of autoph-agy that plays a role in HIV‐1 replication and disease progression. In a special subset of HIV‐1‐infected patients that spontaneously and durably maintain extremely low viral replication, namely, long‐term nonprogressors (LTNP), the resistance to HIV‐1‐induced pathogenesis is ac-companied, in vivo, by a significant increase in the autophagic activity in peripheral blood mon-onuclear cells. Recently, a new player in the battle of autophagy against HIV‐1 has been identified, namely, tripartite motif protein 5α (TRIM5α). In vitro data demonstrated that TRIM5α directly recognizes HIV‐1 and targets it for autophagic destruction, thus protecting cells against HIV‐1 in-fection. In this paper, we analyzed the involvement of this factor in the control of HIV‐1 infection through autophagy, in vivo, in LTNP. The results obtained showed significantly higher levels of TRIM5α expression in cells from LTNP with respect to HIV‐1‐infected normal progressor patients. Interestingly, the colocalization of TRIM5α and HIV‐1 proteins in autophagic vacuoles in LTNP cells suggested the participation of TRIM5α in the autophagy containment of HIV‐1 in LTNP. Al-together, our results point to a protective role of TRIM5α in the successful control of the chronic viral infection in HIV‐1‐controllers through the autophagy mechanism. In our opinion, these findings could be relevant in fighting against HIV‐1 disease, because autophagy inducers might be employed in combination with antiretroviral drugs

Prioritization of high-cost new drugs for HCV: making sustainability ethical

Hepatitis C virus (HCV) infection is a major health problem worldwide. Chronic HCV infection may in the long run cause cirrhosis, hepatic decompensation and hepatocellular carcinoma, with an ultimate disease burden of at least 350,000 deaths per year worldwide. The new generation of highly effective direct acting antivirals (DAA) to treat HCV infection brings major promises to infected patients in terms of exceedingly high rates of sustained virological response (SVR) but also of tolerability, allowing even the sickest patients to be treated. Even in the face of the excellent safety and efficacy and wide theoretical applicability of these regimens, their introduction is currently facing cost and access issues denying their use to many patients in need. Health systems in all countries are facing a huge problem of distributive justice, since while they should guarantee individual rights, among which the right to health in its broader sense, therefore not limited to healing, but extended to quality of life, they must also grant equal access to the healthcare resources and keep the distribution system sustainable. In the face of a disease with a relatively unpredictable course, where many but not of all chronically infected will eventually die of liver disease, selective allocation of this costly resource is debatable. In most countries the favorite solution has been a stratification of patients for prioritization of treatment, which means allowing Interferon-free DAA treatment only in patients with advanced fibrosis or cirrhosis, while keeping on hold persons with lesser stages of liver disease. In this report, we will perform an ethical assessment addressing the issues linked to access to new therapies, prioritization and eligibility criteria, analyzing the meaning of the term “distributive justice” and the different approaches that can guide us (individualistic libertarianism, social utilitarianism and egalitarianism) on this specific matter. Even if over time the price of new DAA will be reduced through competition and eventual patent expiration, the phenomenon of high drug costs will go on in the next decades and we need adequate tools to face the problems of distributive justice that come with it

Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75

Transglutaminase type 2 (TG2) is a multifunctional enzyme that plays a key role in mitochondria homeostasis under stressful cellular conditions. TG2 interactome analysis reveals an enzyme interaction with GRP75 (glucose-regulated protein 75). GRP75 localizes in mitochondria-associated membranes (MAMs) and acts as a bridging molecule between the two organelles by assembling the IP3R-GRP75-VDAC complex, which is involved in the transport of Ca2+ from the endoplasmic reticulum (ER) to mitochondria. We demonstrate that the TG2 and GRP75 interaction occurs in MAMs. The absence of the TG2-GRP75 interaction leads to an increase of the interaction between IP3R-3 and GRP75; a decrease of the number of ER-mitochondria contact sites; an impairment of the ER-mitochondrial Ca2+ flux; and an altered profile of the MAM proteome. These findings indicate TG2 is a key regulatory element of the MAMs