Hematological and Genetic Markers in the Rational Approach to Patients With HCV Sustained Virological Response With or Without Persisting Cryoglobulinemic Vasculitis

Background and Aims: Direct-acting antivirals (DAAs) usually lead to improvement/remission of cryoglobulinemic vasculitis (CV), although symptoms may persist/recur after a sustained virological response (SVR). We evaluated hematological and genetic markers in patients with HCV-SVR vasculitis with and without persisting/recurring symptoms to early predict the CV outcome. Approach and Results: Ninety-eight patients with HCV-CV were prospectively enrolled after a DAA-induced SVR: Group A: 52 with complete clinical response; Group B: 46 with symptom maintenance/recurrence. Monoclonal B-cell lymphocytosis, t(14;18) translocation, and abnormal free light chains κ/λ ratios were detected by flow cytometry or nested-PCR or nephelometry in 4% Group A versus 17% Group B (P = 0.04) patients, 17% Group A versus 40% Group B patients (P = 0.02), and 17% Group A versus 47% Group B (P = 0.003) patients, respectively. At least 1 out of 3 clonality markers was altered/positive in 29% of Group A versus 70% of Group B patients (P < 0.0001). When available, pretherapy samples were also tested for t(14;18) translocation (detected in 12/37 [32%] Group A and 21/38 [55%] Group B) and κ/λ ratios (abnormal in 5/35 [14%] Group A and 20/38 [53%] Group B) (P = 0.0006), whereas at least one clonality marker was detected/altered in 16/37 (43%) Group A and 30/38 (79%) Group B (P = 0.002). CV-associated single-nucleotide polymorphisms were tested by real-time PCR. Among them, notch4 rs2071286 T minor allele and TT genotype showed a higher frequency in Group B versus Group A (46% vs. 29%, P = 0.01, and 17% vs. 2%, P = 0.006, respectively). Conclusions: Hematological or genetic analyses could be used to foresee the CV clinical response after DAA therapy and could be valuable to assess a rational flowchart to manage CV during follow-up

Interference with Activator Protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation-sensitivity in breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Activator Protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2α and AP-2γ is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo- or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms.</p> <p>Methods</p> <p>We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant.</p> <p>Results</p> <p>We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo- and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed <it>Cell Death </it>and <it>Cell Adhesion and Migration </it>as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo- and radiation therapy, (i.e. <it>Ctgf, Nrp1</it>, <it>Tnfaip3, Gsta3</it>) and AP-2 and other main apoptosis players and to create a unique network.</p> <p>Conclusions</p> <p>Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo- and radiation-resistance of tumor cells by impairing the ability to induce apoptosis. Therefore, interference with AP-2 function could increase the sensitivity of tumor cells towards therapeutic intervention.</p

HEALTH RESORT MEDICINE IN ITALY AND TEACHING MEDICAL HYDROLOGY: THE STATE OF THE ART

Spa therapy, using mineral waters, muds, baths in mineral water and caves, is applied in 390 thermal stations, almost all in activity, standing in 185 thermal sites. In every region of Italy it is present one or more spa resorts. Toscana, Emilia-Romagna, Veneto, Campania are leader regions of thermalism. Overall 500 health resorts supply spa therapy, if we include also the hotels qualified to give some thermal therapies or thermal wellness. Each year about 1,500,000 people attend italian health resorts. So the thermal system of Italy needs of specialists in Thermal Medicine, who know very well the composition of mineral waters, their physical-chemical properties, their medical applications, alone or associated or alternated with medical therapy, physiotherapy and climatotherapy. Spa physicians also must know very well the contraindications of spa therapy and the possible collateral effects, albeit no frequent. Finally, university medical schools and spa resorts perform controlled and longitudinal-observational studies to evaluate the beneficial effects of spa therapy and the cost/benefit relationship of this therapy. These efforts are documented by researches and studies published in international medical journals. The teaching of Thermal Medicine actually comprises in Italy: 1) School of Specialization in Thermal Medicine. It is included in the Schools of Specialization of medical area, class of General Medical Clinic, which include Internal Medicine, Geriatry, Sport Medicine, Thermal Medicine, Medical Oncology, Community Medicine. They are two Schools of Specialization in Italy: one in Rome and one in Milano. National referee for the Schools is Prof. Antonio Fraioli. 2) Basic knowledge of Thermal Medicine are given to medical students mainly as seminarial activities. 3) Lectures of Thermal Medicine are present in the Schools of Specialization in Physical Medicine and Rehabilitation and Rheumatology. 4) A II level Master in spa medicine is working at Sapienza University of Roma 5) Chapters regarding Thermal Medicine and its therapeutical applications are included in the most important italian textbooks of Internal Medicine: Trattato Italiano di Medicina Interna – Teodori, Società Editrice Universo, Roma, 2004 and Strumenti di Medicina Interna-Terapia Medica, a cura di Negri M., UTET, Torino, 2011