Correlation between IL-12 and IL-2 blood levels in the metastatic neoplastic disease: a possible inhibitory feedback system regulating their secretion

Despite the great importance of IL-2 and IL-12 in activating the anticancer immune response in humans, cancer-related physiopathology of their secretion needs to be better investigated. IL-2 blood levels have been proven to decrease in the advanced neoplastic disease, whereas preliminary data would suggest an enhanced secretion of IL-12 in metastatic cancer patients. This study was performed to analyze IL-2 levels in relation to those of IL-12 in metastatic solid neoplasms. The study included 40 untreated metastatic cancer patients. Serum levels of both IL-2 and IL-12 were measured by ELISA. Abnormally low blood levels of IL-2 and elevated values of IL-12 were observed in 16/40 and in 18/40 patients, respectively. Moreover, patients with IL-2 deficiency showed significantly higher mean levels of IL-12 than patients with normal values of IL-2. This preliminary result, by showing an increased secretion of IL-12 in advanced cancer patients with IL-2 endogenous deficiency, would suggest the existance of a possible feedback mechanism operating between macrophage release of IL-12 and T lymphocyte secretion of IL-2.     

Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter

The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was tested on mice lacking the dopamine (DA) transporter (DAT-/- mice). Striatal tissue DA content and glial fibrillary acidic protein (GFAP) mRNA expression were assessed as markers of MPTP neurotoxicity. MPTP (30 mg/kg, s.c., b.i.d.) produced an 87% decrease in tissue DA levels and a 29-fold increase in the level of GFAP mRNA in the striatum of wild-type animals 48 h after administration. Conversely, there were no significant changes in either parameter in DAT-/- mice. Heterozygotes demonstrated partial sensitivity to MPTP administration as shown by an intermediate value (48%) of tissue DA loss. Direct intrastriatal infusion of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+; 10 mM), via a microdialysis probe produced a massive efflux of DA in wild-type mice (>320-fold). In the DAT-/- mice the same treatment produced a much smaller increase in extracellular DA (sixfold), which is likely secondary to tissue damage due to the implantation of the dialysis probe. These observations show that the DAT is a mandatory component for expression of MPTP toxicity in vivo.     

TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase

Tumor microenvironments are often characterized by an increase in oxidative stress levels. We studied the response to oxidative stimulation in human primary (IGR39) or metastatic (IGR37) cell lines obtained from the same patient, performing patch-clamp recordings, intracellular calcium ([Ca²⁺]_i) imaging, and RT-qPCR gene expression analysis. In IGR39 cells, chloramine-T (Chl-T) activated large K⁺ currents (KROS) that were partially sensitive to tetraethylammonium (TEA). A large fraction of KROS was inhibited by paxilline—a specific inhibitor of large-conductance Ca²⁺-activated BK channels. The TEA-insensitive component was inhibited by senicapoc—a specific inhibitor of the Ca²⁺-activated KCa3.1 channel. Both BK and KCa3.1 activation were mediated by an increase in [Ca²⁺]_i induced by Chl-T. Both KROS and [Ca²⁺]_i increase were inhibited by ACA and clotrimazole—two different inhibitors of the calcium-permeable TRPM2 channel. Surprisingly, IGR37 cells did not exhibit current increase upon the application of Chl-T. Expression analysis confirmed that the genes encoding BK, KCa3.1, and TRPM2 are much more expressed in IGR39 than in IGR37. The potassium currents and [Ca²⁺]_i increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.     

Hypoxia Enhances the Expression of RNASET2 in Human Monocyte-Derived Dendritic Cells: Role of PI3K/AKT Pathway

Hypoxia is a key component of the tumor microenvironment (TME) and promotes not only tumor growth and metastasis, but also negatively affects infiltrating immune cells by impairing host immunity. Dendritic cells (DCs) are the most potent antigen-presenting cells and their biology is weakened in the TME in many ways, including the modulation of their viability. RNASET2 belongs to the T2 family of extracellular ribonucleases and, besides its nuclease activity, it exerts many additional functions. Indeed, RNASET2 is involved in several human pathologies, including cancer, and it is functionally relevant in the TME. RNASET2 functions are not restricted to cancer cells and its expression could be relevant also in other cell types which are important players in the TME, including DCs. Therefore, this study aimed to unravel the effect of hypoxia (2% O₂) on the expression of RNASET2 in DCs. Here, we showed that hypoxia enhanced the expression and secretion of RNASET2 in human monocyte-derived DCs. This paralleled the HIF-1α accumulation and HIF-dependent and -independent signaling, which are associated with DCs’ survival/autophagy/apoptosis. RNASET2 expression, under hypoxia, was regulated by the PI3K/AKT pathway and was almost completely abolished by TLR4 ligand, LPS. Taken together, these results highlight how hypoxia- dependent and -independent pathways shape RNASET2 expression in DCs, with new perspectives on its implication for TME and, therefore, in anti-tumor immunity.     

The Seniors’ Outdoor Survey (SOS Tool): comparing ratings and reliability between Italy and the USA

To test applicability of an environmental assessment instrument in new settings, the ratings and reliability of the SOS Tool were compared in diverse settings with a similar climate: Milan, Italy; and Bryan/College Station, Texas, USA. This instrument evaluates physical environment support for outdoor usage by residents at senior facilities. Two trained raters assigned ratings (using a 1–7 scale) to the 60 instrument items at each setting (Italy: 94 outdoor spaces, 67 facilities; US: 22 outdoor spaces, 12 facilities). Overall mean ratings were similar across both sites (6% difference), and three of the five domains had comparable mean ratings. Mean inter-rater reliability was good in both settings but higher in Italy (ICC = .97 versus .82). Despite geographic/cultural differences, mean ratings for most items and domains were surprisingly similar between Italy and the US. This finding, and the high inter-rater reliability found in both settings, suggest this instrument may be useful in a wide range of settings.     

Current criticalities and innovation perspectives in flash memory design automation

With reference to technological, architectural, and market considerations, the specific areas of design methodology and automation in flash memory design are analyzed in this paper. For each of the activities identified as critical, we show the design process key constraints and specifications, which drive the change in methodology, tools, and flows. We go through a brief survey of the solutions adopted in the recent past as well as the new emerging areas of intervention. The analysis covers: 1) design methodology, floorplanning, full-custom layout design and Rtl2Layout automation integration; 2) analog-digital mixed full-chip simulation and architectural exploration; 3) statistical analog circuital simulation; 4) mixed-signal design to test approaches; and 5) IC and package design integration.