Platelet-derived growth factor C and calpain-3 are modulators of human melanoma cell invasiveness.

The molecular mechanisms responsible for the elevated metastatic potential of malignant melanoma are still not fully understood. In order to shed light on the molecules involved in the acquisition by melanoma of a highly aggressive phenotype, we compared the gene expression profiles of two cell clones derived from the human cutaneous metastatic melanoma cell line M14: a highly invasive clone (M14C2/MK18) and a clone (M14C2/C4) with low ability to invade the extracellular matrix (ECM). The highly invasive phenotype of M14C2/MK18 cells was correlated with overexpression of neuropilin-1, activation of a vascular endothelial growth factor (VEGF)-A/VEGFR-2 autocrine loop and secretion of matrix metalloprotease-2. Moreover, in an in vivo murine model, M14C2/MK18 cells displayed a higher growth rate as compared with M14C2/C4 cells, even though in vitro both clones possessed comparable proliferative potential. Microarray analysis in M14C2/MK18 cells showed a strong upregulation of platelet-derived growth factor (PDGF)-C, a cytokine that contributes to angiogenesis, and downregulation of calpain-3, a calcium-dependent thiol-protease that regulates specific signalling cascade components. Inhibition of PDGF-C with a specific antibody resulted in a significant decrease in ECM invasion by M14C2/MK18 cells, confirming the involvement of PDGF-C in melanoma cell invasiveness. Moreover, the PDGF-C transcript was found to be upregulated in a high percentage of human melanoma cell lines (17/20), whereas only low PDGF-C levels were detected in a few melanocytic cultures (2/6). By contrast, inhibition of calpain-3 activity in M14C2/C4 control cells, using a specific chemical inhibitor, markedly increased ECM invasion, strongly suggesting that downregulation of calpain-3 plays a role in the acquisition of a highly invasive phenotype. The results indicate that PDGF-C upregulation and calpain-3 downregulation are involved in the aggressiveness of malignant melanoma and suggest that modulators of these proteins or their downstream effectors may synergise with VEGF‑A therapies in combating tumour-associated angiogenesis and melanoma spread

Boosting slow oscillations during sleep to improve memory function in elderly people: A review of the literature

Sleep represents a crucial time window for the consolidation of memory traces. In this view, some brain rhythms play a pivotal role, first of all the sleep slow waves. In particular, the neocortical slow oscillations (SOs), in coordination with the hippocampal ripples and the thalamocortical spindles, support the long-term storage of the declarative memories. The aging brain is characterized by a disruption of this complex system with outcomes on the related cognitive functions. In recent years, the advancement of the comprehension of the sleep-dependent memory consolidation mechanisms has encouraged the development of techniques of SO enhancement during sleep to induce cognitive benefits. In this review, we focused on the studies reporting on the application of acoustic or electric stimulation procedures in order to improve sleep-dependent memory consolidation in older subjects. Although the current literature is limited and presents inconsistencies, there is promising evidence supporting the perspective to non-invasively manipulate the sleeping brain electrophysiology to improve cognition in the elderly, also shedding light on the mechanisms underlying the sleep-memory relations during healthy and pathological aging

Changes of evening exposure to electronic devices during the COVID-19 lockdown affect the time course of sleep disturbances

Study Objectives: During the coronavirus disease 2019 (COVID-19) lockdown, there was a worldwide increase in electronic devices' daily usage. Prolonged exposure to backlit screens before sleep influences the circadian system leading to negative consequences on sleep health. We investigated the relationship between changes in evening screen exposure and the time course of sleep disturbances during the home confinement period due to COVID-19. Methods: 2,123 Italians (mean age ± standard deviation, 33.1 ± 11.6) were tested longitudinally during the third and the seventh week of lockdown. The web-based survey evaluated sleep quality and insomnia symptoms through the Pittsburgh Sleep Quality Index and the Insomnia Severity Index. The second assessment survey inquired about intervening changes in backlit screen exposure in the two hours before falling asleep. Results: Participants who increased electronic device usage showed decreased sleep quality, exacerbated insomnia symptoms, reduced sleep duration, prolonged sleep onset latency, and delayed bedtime and rising time. In this subgroup, the prevalence of poor sleepers and individuals reporting moderate/severe insomnia symptoms increased. Conversely, respondents reporting decreased screen exposure exhibited improved sleep quality and insomnia symptoms. In this subgroup, the prevalence of poor sleepers and moderate/severe insomniacs decreased. Respondents preserving screen time habits did not show variations of the sleep parameters. Conclusions: Our investigation demonstrated a strong relationship between modifications of evening electronic device usage and time course of sleep disturbances during the lockdown period. Monitoring the potential impact of excessive evening exposure to backlit screens on sleep health is recommendable during the current period of restraining measures due to COVID-19

A Visible-Light Driven Esterification of Aldehydes Catalyzed by VOSO4

An esterification of the C-H bond of aldehydes promoted by oxidovanadium(IV) sulfate, (VOSO4)-O-IV, is reported. The process is mediated by visible-light, is carried out at room temperature, in absence of additives and using H2O2 as a benign oxidant. VOSO4 is a commercially available, earth-abundant metal (EAM(s)) salt, that does not require to be prepared. This report opens intriguing perspectives for the extended application of vanadium salts toward halogenation processes as well as for C-H activations and gives a contribution in the field of earth-abundant metals based-catalysis

Temozolomide and cisplatin in relapsed/refractory acute leukemia

Cisplatin depletes MGMT and increases the sensitivity of leukemia cells to temozolomide. We performed a phase I study of cisplatin and temozolomide in patients with relapsed and refractory acute leukemia. Fifteen patients had AML, 3 had ALL, and 2 had biphenotypic leukemia. The median number of prior chemotherapy regimens was 3 (1–5). Treatment was well tolerated up to the maximal doses of temozolomide 200 mg/m2/d times 7 days and cisplatin 100 mg/m2 on day 1. There was one complete remission in this heavily pretreated patient population. Five of 20 (25%) patients demonstrated a significant reduction in bone marrow blasts

Assessment of chemical stability of monoclonal antibody and antibody drug conjugate administered by pressurized intraperitoneal aerosol chemotherapy.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new therapeutic approach for patients with peritoneal cancer. So far, most published studies investigated the administration of established cytostatic agents through PIPAC. This study aimed to evaluate the effect of PIPAC on two breakthrough anti-cancer agents, specifically anti-PD1 pembrolizumab, and anti-HER2 antibody-drug conjugate (ADC) - trastuzumab-deruxtecan. We conducted systematic analyses on samples of pembrolizumab and trastuzumab-deruxtecan at clinically relevant concentrations before and after PIPAC administration using an experimental setup of a hermetic container system, mimicking the abdominal cavity and using identical features as in clinical use. We utilized a range of chromatographic and spectroscopic techniques to explore potential alterations in the primary, secondary, and tertiary structures of the drugs, focusing on post-translational modifications resulting from the aerosolization. Our findings indicate that PIPAC did not compromise the integrity of tested biopharmaceuticals. The size variants of both drugs, assessed by size exclusion chromatography (SEC), remained unchanged. Reversed-phase liquid chromatography (RPLC) and hydrophobic interaction chromatography (HIC) revealed no significant differences in hydrophobicity variants, the average drug-to-antibody ratio (DAR), or DAR distribution before and after PIPAC treatment. Circular dichroism (CD) spectroscopy confirmed that the secondary and tertiary structures were preserved. While pembrolizumab showed no change in charge variants post-PIPAC, trastuzumab-deruxtecan exhibited a non-negligible change in the quantity of charge variants on the monoclonal antibody itself, while the payload remained unchanged. This shift could possibly be related to the metallic composition of the CapnoPen® device (made of nickel and chromium) used in PIPAC and for these experiments. Together, our results suggest that PIPAC does not alter the structure of pembrolizumab and trastuzumab-deruxtecan, paving the way for future clinical trials

Sleep-related declarative memory consolidation in children and adolescents with developmental dyslexia

Sleep has a crucial role in memory processes, and maturational changes in sleep electro-physiology are involved in cognitive development. Albeit both sleep and memory alterations have been observed in Developmental Dyslexia (DD), their relation in this population has been scarcely investigated, particularly concerning topographical aspects. The study aimed to compare sleep topography and associated sleep-related declarative memory consolidation in participants with DD and normal readers (NR). Eleven participants with DD and 18 NR (9–14 years old) underwent a whole-night polysomnography. They were administered a word pair task before and after sleep to assess for declarative memory consolidation. Memory performance and sleep features (macro and microstructural) were compared between the groups, and the intercorrelations between consolidation rate and sleep measures were assessed. DD showed a deeper worsening in memory after sleep compared to NR and reduced slow spindles in occipito-parietal and left fronto-central areas. Our results suggest specific alterations in local sleep EEG (i.e., sleep spindles) and in sleep-dependent memory consolidation processes in DD. We highlight the importance of a topographical approach, which might shed light on potential alteration in regional cortical oscillation dynamics in DD. The latter might represent a target for therapeutic interventions aimed at enhancing cognitive functioning in DD

Evaluation of biomimetic hyaluronic-based hydrogels with enhanced endogenous cell recruitment and cartilage matrix formation

Biomaterials play a pivotal role in cell-free cartilage repair approaches, where cells must migrate through the scaffold, fill the defect, and then proliferate and differentiate facilitating tissue remodeling. Here we used multiple assays to test the influence of chemokines and growth factors on cell migration and cartilage repair in two different hyaluronan (HA)-based hydrogels. We first investigated bone marrow Mesenchymal Stromal Cells (BMSC) migration in vitro, in response to different concentrations of platelet-derived growth factor-BB (PDGF-BB), chemokine ligand 5 (CCL5/RANTES) and stromal cell-derived factor 1 (SDF-1), using a 3D spheroid-based assay. PDGF-BB was selected as most favourable chemotactic agent, and MSC migration was assessed in the context of physical impediment to cell recruitment by testing Fibrin-HA and HA-Tyramine hydrogels of different cross-linking densities. Supplementation of PDGF-BB stimulated progressive migration of MSC through the gels over time. We then investigated in situ cell migration into the hydrogels with and without PDGF-BB, using a cartilage-bone explant model implanted subcutaneously in athymic mice. In vivo studies show that when placed into an osteochondral defect, both hydrogels supported endogenous cell infiltration and provided an amenable microenvironment for cartilage production. These processes were best supported in Fibrin-HA hydrogel in the absence of PDGF-BB. This study used an advanced preclinical testing platform to select an appropriate microenvironment provided by implanted hydrogels, demonstrating that HA-based hydrogels can promote the initial and critical step of endogenous cell recruitment and circumvent some of the clinical challenges in cartilage tissue repair. Statement of significance: The challenge of articular cartilage repair arises from its complex structure and architecture, which confers the unique mechanical behavior of the extracellular matrix. The aim of our research is to identify biomaterials for implants that can support migration of endogenous stem and progenitor cell populations from cartilage and bone tissue, in order to permanently replace damaged cartilage with the original hyaline structure. Here, we present an in vitro 3D spheroid-based migration assay and an osteochondral defect model, which provide the opportunity to assess biomaterials and biomolecules, and to get stronger experimental evidence of the not well-characterized dynamic process of endogenous cells colonization in an osteochondral defect. Furthermore, the delicate step of early cell migration into biomaterials towards functional tissue engineering is reproduced. These tests can be used for pre-clinical testing of newly developed material designs in the field of scaffold engineering