Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways

Quercetin, a bioflavonoid contained in several vegetables daily consumed, has been studied for long time for its antiinflammatory and anticancer properties. Quercetin interacts with multiple cancer-related pathways such as PI3K/AKT, Wnt/β-catenin and STAT3. These pathways are hyperactivated in primary effusion lymphoma (PEL), an aggressive B cell lymphoma whose pathogenesis is strictly linked to the oncogenic virus Kaposis' Sarcoma-associated Herpesvirus (KSHV). In this study, we found that quercetin inhibited PI3K/AKT/mTOR and STAT3 pathways in PEL cells, and as a consequence, it down-regulated the expression of the prosurvival cellular proteins such as c-FLIP, cyclin D1 and cMyc. It also reduced the release of IL-6 and IL-10 cytokines, leading to PEL cell death. Moreover, quercetin induced a prosurvival autophagy in these cells and increased the cytotoxic effect of bortezomib, a proteasomal inhibitor, against them. Interestingly, quercetin decreased also the expression of latent and lytic KSHV proteins involved in PEL tumorigenesis and up-regulated the surface expression of HLA-DR and calreticulin, rendering the dying cells more likely detectable by the immune system. The results obtained in this study indicate that quercetin, which does not exert any cytotoxicity against normal B cells, may represent a good candidate for the treatment of this aggressive B cell lymphoma, especially in combination with autophagy inhibitors or with bortezomib

EBV up-regulates PD-L1 on the surface of primary monocytes by increasing ROS and activating TLR signaling and STAT3

Programmed death ligand 1 (PD-L1) (also called B7-H1) is a membrane immune-modulatory protein whose overexpression on the surface of tumor cells as well as APCs impairs T-cell-mediated killing. Viruses that establish chronic infections have developed a number of strategies to escape from immune recognition including the up-regulation of PD-L1. This study shows for the first time that the human oncovirus EBV infects human primary monocytes using HLA-DR and induced a strong up-regulation of PD-L1 expression on their surface. Searching for the underlying mechanism/s leading to this immune suppressive effect, we found that EBV activated TLR signaling, increased intracellular ROS, and phosphorylated STAT3. Targeting these molecules partially reverted PD-L1 up-regulation that correlated with an altered cytokine production and a reduction of monocyte cell survival, strongly impairing the antiviral immune response

Choosing wisely: la lista del gruppo di studio Endocrinologia e Malattie del Metabolismo della Società Italiana di Patologia Clinica e Medicina di Laboratorio

Background.: The need to promote the appropriateness of diagnostic and therapeutic procedures increased in the recent years in the world and in Italy. Scientific societies participated from the beginning in defining modes and tools to support the members in the “translation” of this need in the clinical practice, for example defining lists of the diagnostic and therapeutic procedures with the highest risk of inappropriateness. The most relevant projects at international and national levels were, respectively, Choosing wisely e Slow Medicine. SIPMeL is supporting Slow Medicine and presented at 2015 SIPMel National Congress the list of the 5 procedures with the highest risk of inappropriateness in Laboratory Medicine. Methods.: In 2015 a survey has been carried out among the members of the Group of study Endocrinology-Metabolic diseases that were asked to vote (score 1–10) the five procedures with the highest risk of inappropriateness supporting their score with a short comment and essential references. Results.: The final list was obtained from the sum of the scores and includes: (1) optimal assessment of thyroid function; (2) optimal diagnostics of Cushing syndrome; (3) optimal diagnostics of pheocromocytoma; (4) optimal diagnostics for autoimmune thyroid disease; (5) assessment of 25 (OH) vitamin D. Conclusions.: The top five procedures have been presented at 2015 SIPMel National Congress and will be available in the Society website. We propose that also the other SIPMel groups of study prepare similar list and make them available within the Society and profession in a similar way

Laboratory diagnostics of adrenal diseases. Practice guidelines for pheochromocytoma and paraganglioma [La diagnostica di laboratorio delle malattie del surrene. Raccomandazioni pratiche per feocromocitoma e paraganglioma]

Pheochromocytoma is a catecholamine-producing neuroendocrine tumor derived from the neural crest. It is a rare tumor with an incidence in the general population of 2\u20138 cases per million population per year. Pheochromocytomas most commonly arise in the adrenal medulla but they can also occur extra-adrenally; these tumors are referred to as paragangliomas. The clinical presentation involves a constellation of signs and symptoms associated with catecholamine excess: hypertension (paroxysmal or sustained), sweating, pallor, headaches, palpitations, anxiety, dyspeptic complaints, paresthesias, visual disturbances, chest and abdominal pain