High prevalence of hepatitis C virus infection in patients with B-cell lymphoproliferative disorders in Italy.

Starting from the observation that a number of consecutive patients with non-Hodgkin's lymphoma (NHL) resulted positive for hepatitis C virus (HCV) antibodies on routine testing, we set up a survey for HCV contact prevalence in all patients with lymphoproliferative disorders (LPD) followed in our institution. We searched for HCV antibodies by a thirdgeneration ELISA technique, followed by a confirmation test (RIBA III); serum viral RNA and HCV genotype were investigated by a RT-PCR technique. We screened a total of 315 patients suffering from B-NHL (91), multiple myeloma (56), MGUS (48), chronic lymphocytic leukemia (57), Waldentrom's macroglobulinemia (13), Hodgkin's disease (HD)(43), and T-NHL (9). While only I of 52 patients with a non-B-LPD (HD or T-NHL) had signs of HCV contact (i.e., 1.9%, which is in the range of the normal population in the South of Italy), 59 of 263 patients with a B-LPD (22.4%) had HCV antibodies or RNA, or both, with no major differences among the various types of disorders, except for WM, in which the rate was higher (61.5%). The same prevalence was found for patients tested at diagnosis or during the follow-up, and in transfused or never-transfused patients. Only a few patients were aware of having a liver disease; one-half of HCV-positive patients never had transaminase increase. A review of data from Central and Northern Italy is included, showing similar findings; a report from Japan has confirmed such an association, while limited surveys in England have not revealed any correlation. These findings may have important biological and clinical implications

How does climate change affect a fishable resource? The case of the royal sea cucumber (Parastichopus regalis) in the central Mediterranean Sea

Holothurians or sea cucumbers are key organisms in marine ecosystems that, by ingesting large quantities of sediments, provide important ecosystem services. Among them, Parastichopus regalis (Cuvier, 1817) is one of the living sea cucumbers in the Mediterranean actively fished for human consumption mainly in Spain, where it is considered a gastronomic delicacy. In the Strait of Sicily (central Mediterranean Sea), this species is not exploited for commercial use even if it is used as bait by longline fishery. P. regalis is frequently caught by bottom trawling and discarded at sea by fishers after catch, and because of its capacity to resist air exposition (at least in cold months), it is reasonable to consider that it is not affected by fishing mortality. Having observed a significant decrease in abundance since 2018, the possible effects of some ecological factors related to current climate change (i.e., temperature and pH) were sought. Generalized additive models (GAMs) were applied to investigate the relationship among the abundance of P. regalis and environmental variables and fishing effort. Long time series of P. regalis densities (2008-2021) were extracted from the MEDITS bottom trawling survey and modeled as function of environmental parameters (i.e., salinity, dissolved oxygen, ammonium, pH, and chlorophyll alpha) and fishing effort (i.e., total number of fishing days per gross tonnage). Our results showed that this species prefers the soft bottoms (50-200 m) of the Adventure Bank and Malta Plateau, and its distribution changed over time with a slight deepening and a rarefaction of spatial distribution starting from 2011 and 2017, respectively. In addition, a positive relationship with pH concentration in surface waters during the larval dispersal phase (3-year lag before the survey) and nutrient concentration at sea bottom (1-year lag) has been found, suggesting that this species is sensitive to climate change and food availability. This study adds new knowledge about the population dynamics of an unexploited stock of P. regalis under fishing impact and environmental under climate change in fisheries management

Protective role of vitamin B6 (PLP) against DNA damage in Drosophila models of type 2 diabetes

Growing evidence shows that improper intake of vitamin B6 increases cancer risk and several studies indicate that diabetic patients have a higher risk of developing tumors. We previously demonstrated that in Drosophila the deficiency of Pyridoxal 5' phosphate (PLP), the active form of vitamin B6, causes chromosome aberrations (CABs), one of cancer prerequisites, and increases hemolymph glucose content. Starting from these data we asked if it was possible to provide a link between the aforementioned studies. Thus, we tested the effect of low PLP levels on DNA integrity in diabetic cells. To this aim we generated two Drosophila models of type 2 diabetes, the first by impairing insulin signaling and the second by rearing flies in high sugar diet. We showed that glucose treatment induced CABs in diabetic individuals but not in controls. More interestingly, PLP deficiency caused high frequencies of CABs in both diabetic models demonstrating that hyperglycemia, combined to reduced PLP level, impairs DNA integrity. PLP-depleted diabetic cells accumulated Advanced Glycation End products (AGEs) that largely contribute to CABs as α-lipoic acid, an AGE inhibitor, rescued not only AGEs but also CABs. These data, extrapolated to humans, indicate that low PLP levels, impacting on DNA integrity, may be considered one of the possible links between diabetes and cancer

Polydrug Use among IDUs in Tijuana, Mexico: Correlates of Methamphetamine Use and Route of Administration by Gender

Tijuana is situated on the Mexico–USA border adjacent to San Diego, CA, on a major drug trafficking route. Increased methamphetamine trafficking in recent years has created a local consumption market. We examined factors associated with methamphetamine use and routes of administration by gender among injection drug users (IDUs). From 2006–2007, IDUs ≥18 years old in Tijuana were recruited using respondent-driven sampling, interviewed, and tested for HIV, syphilis, and TB. Logistic regression was used to assess associations with methamphetamine use (past 6 months), stratified by gender. Among 1,056 participants, methamphetamine use was more commonly reported among females compared to males (80% vs. 68%, p < 0.01), particularly, methamphetamine smoking (57% vs. 34%; p < 0.01). Among females (N = 158), being aged >35 years (AOR, 0.2; 95% CI, 0.1–0.6) was associated with methamphetamine use. Among males (N = 898), being aged >35 years (AOR, 0.5; 95% CI, 0.3–0.6), homeless (AOR, 1.4 (0.9–2.2)), and ever reporting sex with another male (MSM; AOR, 1.9; 95% CI, 1.4–2.7) were associated with methamphetamine use. Among males, a history of MSM was associated with injection, while sex trade and >2 casual sex partners were associated with multiple routes of administration. HIV was higher among both males and females reporting injection as the only route of methamphetamine administration. Methamphetamine use is highly prevalent among IDUs in Tijuana, especially among females. Routes of administration differed by gender and subgroup which has important implications for tailoring harm reduction interventions and drug abuse treatment

MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sézary syndrome

Sézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma and its pathogenesis is still unknown. Diagnosis/prognosis may strongly ameliorate the management of SS individuals. Here, we profiled the expression of 470 microRNAs (miRNAs) in a cohort of 22 SS patients, and we identified 45 miRNAs differentially expressed between SS and controls. Using predictive analysis, a list of 19 miRNAs, including miR-21, miR-214, miR-486, miR-18a, miR-342, miR-31 and let-7 members were also found. Moreover, we defined a signature of 14 miRNAs including again miR-21, potentially able to discriminate patients with unfavorable and favorable outcome. We validated our data for miR-21, miR-214 and miR-486 by qRT-PCR, including an additional set of array-independent SS cases. In addition, we also provide an in vitro evidence for a contribution of miR-214, miR-486 and miR-21 to apoptotic resistance of CTCL cell line

Inositol 1,4,5- Trisphosphate Receptor Function in Drosophila Insulin Producing Cells

The Inositol 1,4,5- trisphosphate receptor (InsP3R) is an intracellular ligand gated channel that releases calcium from intracellular stores in response to extracellular signals. To identify and understand physiological processes and behavior that depends on the InsP3 signaling pathway at a systemic level, we are studying Drosophila mutants for the InsP3R (itpr) gene. Here, we show that growth defects precede larval lethality and both are a consequence of the inability to feed normally. Moreover, restoring InsP3R function in insulin producing cells (IPCs) in the larval brain rescues the feeding deficit, growth and lethality in the itpr mutants to a significant extent. We have previously demonstrated a critical requirement for InsP3R activity in neuronal cells, specifically in aminergic interneurons, for larval viability. Processes from the IPCs and aminergic domain are closely apposed in the third instar larval brain with no visible cellular overlap. Ubiquitous depletion of itpr by dsRNA results in feeding deficits leading to larval lethality similar to the itpr mutant phenotype. However, when itpr is depleted specifically in IPCs or aminergic neurons, the larvae are viable. These data support a model where InsP3R activity in non-overlapping neuronal domains independently rescues larval itpr phenotypes by non-cell autonomous mechanisms

The effect Akt2 deletion on tumor development in Pten+/− mice

The serine/threonine kinase Akt is frequently activated in human cancers and is considered an attractive therapeutic target. However, the relative contributions of the different Akt isoforms to tumorigenesis, and the effect of their deficiencies on cancer development are not well understood. We had previously shown that Akt1 deficiency is sufficient to markedly reduce the incidence of tumors in Pten+/− mice. Particularly, Akt1 deficiency inhibits endometrial carcinoma and prostate neoplasia in Pten+/− mice. Here, we analyzed the effect of Akt2 deficiency on the incidence of tumors in Pten+/− mice. Relative to Akt1, Akt2 deficiency had little-to-no effect on the incidence of prostate neoplasia, endometrial carcinoma, intestinal polyps and adrenal lesions in Pten+/− mice. However, Akt2 deficiency significantly decreased the incidence of thyroid tumors in Pten+/−, which correlates with the relatively high level of Akt2 expression in the thyroid. Thus, unlike Akt1 deletion, Akt2 deletion is not sufficient to markedly inhibit tumorigenesis in Pten+/− mice in most tested tissues. The relatively small effect of Akt2 deletion on the inhibition of tumorigenesis in Pten+/− mice could be explained, in part, by an insufficient decrease in total Akt activity, due to the relatively lower Akt2 versus Akt1 expression, and relatively high blood insulin levels in Pten+/−Akt2−/− mice. The relatively high blood insulin levels in Pten+/−Akt2−/− mice may elevate the activity of Akt1, and possibly Akt3, thus, limiting the reduction of total Akt activity and preventing this activity from dropping to a threshold level required to inhibit tumorigenesis

RhoH Regulates Subcellular Localization of ZAP-70 and Lck in T Cell Receptor Signaling

RhoH is an hematopoietic-specific, GTPase-deficient Rho GTPase that plays a role in T development. We investigated the mechanisms of RhoH function in TCR signaling. We found that the association between Lck and CD3ζ was impaired in RhoH-deficient T cells, due to defective translocation of both Lck and ZAP-70 to the immunological synapse. RhoH with Lck and ZAP-70 localizes in the detergent-soluble membrane fraction where the complex is associated with CD3ζ phosphorylation. To determine if impaired translocation of ZAP-70 was a major determinant of defective T cell development, Rhoh-/- bone marrow cells were transduced with a chimeric myristoylation-tagged ZAP-70. Myr-ZAP-70 transduced cells partially reversed the in vivo defects of RhoH-associated thymic development and TCR signaling. Together, our results suggest that RhoH regulates TCR signaling via recruitment of ZAP-70 and Lck to CD3ζ in the immunological synapse. Thus, we define a new function for a RhoH GTPase as an adaptor molecule in TCR signaling pathway