The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors

Alterations of human chromosome 8p occur frequently in many tumors. We identified a 1.5-Mb common region of allelic loss on 8p22 by allelotype analysis, cDNA selection allowed isolation of several genes, including FEZ1. The predicted Fez1 protein contained a leucine-zipper region with similarity to the DNA-binding domain of the cAMP-responsive activating-transcription factor 5. RNA blot analysis revealed that FEZ1 gene expression was undetectable in more than 60% of epithelial tumors. Mutations were found in primary esophageal cancers and in a prostate cancer cell line. Transcript analysis from several FEZ1-expressing tumors revealed truncated mRNAs, including a frameshift. Alteration and inactivation of the FEZ1 gene may play a role in various human tumors

FHIT gene therapy prevents tumor development in Fhit-deficient mice

The tumor suppressor gene FHIT spans a common fragile site and is highly susceptible to environmental carcinogens. FHIT inactivation and loss of expression is found in a large fraction of premaligant and malignant lesions. In this study, we were able to inhibit tumor development by oral gene transfer, using adenoviral or adenoassociated viral vectors expressing the human FHIT gene, in heterozygous Fhit+/- knockout mice, that are prone to tumor development after carcinogen exposure. We therefore suggest that FHIT gene therapy could be a novel clinical approach not only in treatment of early stages of cancer, but also in prevention of human cancer

Generalized Kaehler Potentials from Supergravity

We consider supersymmetric N=2 solutions with non-vanishing NS three-form. Building on worldsheet results, we reduce the problem to a single generalized Monge-Ampere equation on the generalized Kaehler potential K recently interpreted geometrically by Lindstrom, Rocek, Von Unge and Zabzine. One input in the procedure is a holomorphic function w that can be thought of as the effective superpotential for a D3 brane probe. The procedure is hence likely to be useful for finding gravity duals to field theories with non-vanishing abelian superpotential, such as Leigh-Strassler theories. We indeed show that a purely NS precursor of the Lunin-Maldacena dual to the beta-deformed N=4 super-Yang-Mills falls in our class.Comment: "38 pages. v3: improved exposition and minor mistakes corrected in sec. 4

Supersymmetric AdS_5 solutions of M-theory

We analyse the most general supersymmetric solutions of D=11 supergravity consisting of a warped product of five-dimensional anti-de-Sitter space with a six-dimensional Riemannian space M_6, with four-form flux on M_6. We show that M_6 is partly specified by a one-parameter family of four-dimensional Kahler metrics. We find a large family of new explicit regular solutions where M_6 is a compact, complex manifold which is topologically a two-sphere bundle over a four-dimensional base, where the latter is either (i) Kahler-Einstein with positive curvature, or (ii) a product of two constant-curvature Riemann surfaces. After dimensional reduction and T-duality, some solutions in the second class are related to a new family of Sasaki-Einstein spaces which includes T^{1,1}/Z_2. Our general analysis also covers warped products of five-dimensional Minkowski space with a six-dimensional Riemannian space.Comment: 40 pages. v2: minor changes, eqs. (2.22) and (D.12) correcte

Evaluating immunological and inflammatory changes of treatment-experienced people living with HIV switching from first-line triple cART regimens to DTG/3TC vs. B/F/TAF: the DEBATE trial

Background: The aim of this randomized clinical trial (RCT) was to compare immunological changes in virally suppressed people living with HIV (PLWH) switching from a three-drug regimen (3DR) to a two-drug regimen (2DR). Methods: An open-label, prospective RCT enrolling PLWH receiving a 3DR who switched to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir/lamivudine (DTG/3TC) was performed. Blood was taken at baseline and months 6 and 12. The primary outcome was the change in CD4+ or CD8+ T-cell counts and CD4/CD8 ratio over time points. The secondary outcomes were the changes in immunological and inflammatory parameters. Parametric mixed-linear models with random intercepts and slopes were fitted separately for each marker after controlling for potential confounders. Results: Between the two arms (33 PLWH each), there was no difference in CD4+ or CD8+ T cells, CD4/CD8 ratio, and IL-6 trajectories. PLWH switching to DTG/3TC had increased levels of both transitional memory and terminally differentiated CD4+ T cells (arm–time interaction p-value = 0.02) and to a lesser extent for the corresponding CD8+ T-cell subsets (p = 0.09). Significantly lower levels of non-classical monocytes were detected in the B/F/TAF arm at T6 (diff = −6.7 cells/mm3; 95% CI; −16, +2.6; p-value for interaction between arm and time = 0.03). All differences were attenuated at T12. Conclusion: No evidence for a difference in absolute CD4+ and CD8+ T-cell counts, CD4/CD8 ratio, and IL-6 trajectories by study arm over 12 months was found. PLWH on DTG/3TC showed higher levels of terminally differentiated and exhausted CD4+ and CD8+ T lymphocytes and non-classical monocytes at T6. Further studies are warranted to better understand the clinical impact of our results. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04054089

Evaluating immunological and inflammatory changes of treatment-experienced people living with HIV switching from first-line triple cART regimens to DTG/3TC vs. B/F/TAF: the DEBATE trial

Background: The aim of this randomized clinical trial (RCT) was to compare immunological changes in virally suppressed people living with HIV (PLWH) switching from a three-drug regimen (3DR) to a two-drug regimen (2DR).Methods: An open-label, prospective RCT enrolling PLWH receiving a 3DR who switched to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir/lamivudine (DTG/3TC) was performed. Blood was taken at baseline and months 6 and 12. The primary outcome was the change in CD4+ or CD8+ T-cell counts and CD4/CD8 ratio over time points. The secondary outcomes were the changes in immunological and inflammatory parameters. Parametric mixed-linear models with random intercepts and slopes were fitted separately for each marker after controlling for potential confounders.Results: Between the two arms (33 PLWH each), there was no difference in CD4+ or CD8+ T cells, CD4/CD8 ratio, and IL-6 trajectories. PLWH switching to DTG/3TC had increased levels of both transitional memory and terminally differentiated CD4+ T cells (arm-time interaction p-value = 0.02) and to a lesser extent for the corresponding CD8+ T-cell subsets (p = 0.09). Significantly lower levels of non-classical monocytes were detected in the B/F/TAF arm at T6 (diff = -6.7 cells/mm(3); 95% CI; -16, +2.6; p-value for interaction between arm and time = 0.03). All differences were attenuated at T12.Conclusion: No evidence for a difference in absolute CD4+ and CD8+ T-cell counts, CD4/CD8 ratio, and IL-6 trajectories by study arm over 12 months was found. PLWH on DTG/3TC showed higher levels of terminally differentiated and exhausted CD4+ and CD8+ T lymphocytes and non-classical monocytes at T6. Further studies are warranted to better understand the clinical impact of our results

Non-Perturbative Superpotentials in F-theory and String Duality

We use open-closed string duality between F-theory on K3xK3 and type II strings on CY manifolds without branes to study non-perturbative superpotentials in generalized flux compactifications. On the F-theory side we obtain the full flux potential including D3-instanton contributions and show that it leads to an explicit and simple realization of the three ingredients of the KKLT model for stringy dS vacua. The D3-instanton contribution is highly non-trivial, can be systematically computed including the determinant factors and demonstrates that a particular flux lifts very effectively zero modes on the instanton. On the closed string side, we propose a generalization of the Gukov-Vafa-Witten superpotential for type II strings on generalized CY manifolds, depending on all moduli multiplets.Comment: 49 pages, harvmac, 1 figure; references & figures adde

The role of a Mediterranean diet on the risk of oral and pharyngeal cancer.

BACKGROUND: The Mediterranean diet has a beneficial role on various neoplasms, but data are scanty on oral cavity and pharyngeal (OCP) cancer. METHODS: We analysed data from a case-control study carried out between 1997 and 2009 in Italy and Switzerland, including 768 incident, histologically confirmed OCP cancer cases and 2078 hospital controls. Adherence to the Mediterranean diet was measured using the Mediterranean Diet Score (MDS) based on the major characteristics of the Mediterranean diet, and two other scores, the Mediterranean Dietary Pattern Adherence Index (MDP) and the Mediterranean Adequacy Index (MAI). RESULTS: We estimated the odds ratios (ORs), and the corresponding 95% confidence intervals (CI), for increasing levels of the scores (i.e., increasing adherence) using multiple logistic regression models. We found a reduced risk of OCP cancer for increasing levels of the MDS, the ORs for subjects with six or more MDS components compared with two or less being 0.20 (95% CI 0.14-0.28, P-value for trend <0.0001). The ORs for the highest vs the lowest quintile were 0.20 (95% CI 0.14-0.28) for the MDP score (score 66.2 or more vs less than 57.9), and 0.48 (95% CI 0.33-0.69) for the MAI score (score value 2.1 or more vs value less 0.92), with significant trends of decreasing risk for both scores. The favourable effect of the Mediterranean diet was apparently stronger in younger subjects, in those with a higher level of education, and in ex-smokers, although it was observed in other strata as well. CONCLUSIONS: Our study provides strong evidence of a beneficial role of the Mediterranean diet on OCP cancer