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Background: Platinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting remains unclear., Materials and Methods: We evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates., Results: Of 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009)., Conclusion: CG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Among novel psychoactive substances, synthetic cannabinoid receptor agonists (SCRA) seem to have the widest diffusion in the population with no limitation to any particular demographic group. Information on drug consumption relies mostly on anonymized surveys and less on clinical or analytical data; notwithstanding, the huge efforts constantly made to enroll subjects to gather epidemiological data. In the present study, we collected 66 oral fluid samples from volunteers in a drug rehabilitation center in 2019 and early 2020. A liquid chromatography-mass spectrometry method previously developed and validated by our Unit was applied to detect SCRA (n = 10) in oral fluid. Results proved the presence of synthetic cannabinoids at a positivity rate of almost 20%, with detection frequency HU211(5/13) > UR144/JWH122 (3/13) > JWH019/JWH081/AM2201 (1/13). Concentrations were in the range < LOQ -0.36 ng/ml. Synthetic cannabinoids consumption had not been declared by any volunteer. This study enabled for the unprecedent detection of synthetic cannabinoids use in the territory of Parma (Italy) in a high-risk subpopulation. The identified SCRA proved the persistence into the market of the "first-generation" JWH family into the Italian territory and the marketing of relatively new ones (AM-2201). Public health consequences represented by NPS consumption are still scarce; therefore, further studies are needed to understand the real diffusion in the population., (© 2022 American Academy of Forensic Sciences.)

The aim of this study was to examine mortality risk and causes of death for natives and non-natives in a cohort of heroin population of treated in Northern Italy. Crude Mortality Rates (CMRs) were 12.78 per 1,000 Person Years (PY), Standardized Mortality Rate (SMR) was 9.93. Mortality has been decreasing over time, was higher for patients who accessed the treatment services before 2001 and has been increasing with age. CMRs and SMRs were higher among natives, while non-natives were distinguished by higher CMRs and SMRs for suicide. The natives were at greater risk of death than non-natives both injecting and non-injecting, but the mortality risk was not statistically significant in the different periods of first admission. Among non-native patients, older on average, there was a lower proportion of injecting, and a higher quota of people unemployed than among Italian natives. We highlight differences between the various areas of origin concerning consumption patterns and risk of death. The results of the study highlight a particular sub-population of heroin users, the non-natives, who as compared with the Italians, have less invasive consumption styles, reach the health services later but benefit from fewer medical controls.

Background: Studies have highlighted 2 different groups of cocaine users (CUs): "socially integrated" (stable living conditions, regular employment, use cocaine alone or in combination with other psychoactive substances) and "socially marginalized" (socioeconomic and health problems, former or current heroin users, many injecting cocaine). These differences are also found in the elevated mortality risk for CUs, higher among subjects with cocaine and heroin use. This study targeted residents in Northern Italy who turned to a public treatment center for drug addiction following problems caused by primary cocaine use between 1982 and 2016., Objectives: To estimate mortality risk for subjects who have never used heroin (CUs) compared to that of subjects who have used heroin (HCUs)., Method: Retrospective cohort study. We selected 1,993 subjects; 18,015 Person Years (PY)., Results: Over time, the quota of subjects injecting cocaine and using heroin decreased, while patients not using heroin increased. Both new patients and crude mortality rates (CMR) decreased during the years 2009-2012 and increased in the following period. CMRs were 5.55 per 1,000 PY, higher for HCUs, men and subjects aged over 44 years. Standardized mortality rates were 3.49, higher for women, injecting cocaine and HCUS. Among CUs, most of the deaths were from injury excluding drug related and tumors; among HCUs, from drug-related causes and diseases of the cardiovascular system., Conclusion: The study results show a change in the characteristics of SERD clients being treated for primary cocaine use, which are reflected both in mortality risk and causes of death. After a long period of a decrease, mortality risk increased in the period after the economic recession. Aspects concerning the effects of the economic recession on the problematic consumption of cocaine and on the risk of death are discussed., (© 2019 S. Karger AG, Basel.)

The elastin binding protein (EBP), a spliced variant of lysosomal β-galactosidase, is the primary receptor of elastin peptides that have been linked to emphysema, aneurysm and cancer progression. The sequences recognized by EBP share the XGXXPG consensus pattern found in numerous matrix proteins, notably in elastin where the VGVAPG motif is repeated. To delineate the elastin binding site of human EBP, we built a homology model of this protein and docked VGVAPG on its surface. Analysis of this model suggested that Gln-97 and Asp-98 were required for interaction with VGVAPG because they contribute to the definition of a pocket thought to represent the elastin binding site of EBP. Additionally, we proposed that Leu-103, Arg-107, and Glu-137 were essential residues because they could interact with VGVAPG itself. Site-directed mutagenesis experiments at these key positions validated our model. This work therefore provides the first structural data concerning the interaction of the VGVAPG with its cognate receptor. The present structural data should now allow the development of EBP-specific antagonists.

Elastin peptides regulate proliferation, chemotaxis and protease expression. The aim of this work was to assess their influence on apoptosis. Human skin fibroblast cell death was induced using C(2)-ceramide in the presence or absence of elastin peptides. We show that ceramide-induced apoptosis could be blocked by elastin peptides. Using pharmacological inhibitors, we show that elastin peptide treatment leads to activation of the anti-apoptotic protein Akt that phosphorylates the pro-apoptotic protein Bad, the Foxo3a transcription factor and caspase-9. Importantly, the anti-apoptotic effects of elastin peptides were persistent in time. Our results suggest that elastin peptides could be potent cell survival factors.

The binding of elastin peptides on the elastin receptor complex leads to the formation of intracellular signals but how this is achieved remains totally unknown. Using pharmacological inhibitors of the enzymatic activities of its subunits, we show here that the elastin peptide-driven ERK1/2 activation and subsequent pro-MMP-1 production, observed in skin fibroblasts when they are cultured in the presence of these peptides, rely on a membrane-bound sialidase activity. As lactose blocked this effect, the elastin receptor sialidase subunit, Neu-1, seemed to be involved. The use of a catalytically inactive form of Neu-1 and the small interfering RNA-mediated decrease of Neu-1 expression strongly support this view. Finally, we report that N-acetyl neuraminic acid can reproduce the effects of elastin peptides on both ERK1/2 activation and pro-MMP-1 production. Altogether, our results indicate that the enzymatic activity of the Neu-1 subunit of the elastin receptor complex is responsible for its signal transduction, presumably through sialic acid generation from undetermined substrates.