@article{%a1.%Yb_41,

title = {Synthesis and biological activity evaluation of 3-(hetero) arylideneindolin-2-ones as potential c-Src inhibitors},

author = {Princiotto S and Musso L and Manetti F and Marcellini V and Maga G and Crespan E and Perini C and Zaffaroni N and Beretta GL and Dallavalle S},

url = {https://www.tandfonline.com/doi/full/10.1080/14756366.2022.2117317},

doi = {10.1080/14756366.2022.2117317},

year  = {2022},

date = {2022-09-05},

journal = {Journal of enzyme inhibition and medicinal chemistry},

volume = {37},

issue = {1},

pages = {2382-2394},

abstract = {Inhibition of c-Src is considered one of the most studied approaches to cancer treatment, with several heterocyclic compounds approved during the last 15 years as chemotherapeutic agents. Starting from the biological evaluation of an in-house collection of small molecules, indolinone was selected as the most promising scaffold. In this work, several functionalised indolinones were synthesised and their inhibitory potency and cytotoxic activity were assayed. The pharmacological profile of the most active compounds, supported by molecular modelling studies, revealed that the presence of an amino group increased the affinity towards the ATP-binding site of c-Src. At the same time, bulkier derivatizations seemed to improve the interactions within the enzymatic pocket. Overall, these data represent an early stage towards the optimisation of new, easy-to-be functionalised indolinones as potential c-Src inhibitors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybx,

title = {Autofluorescent Biomolecules in Diptera: From Structure to Metabolism and Behavior},

author = {Croce AC and Scolari F},

url = {https://www.mdpi.com/1420-3049/27/14/4458},

doi = {10.3390/molecules27144458},

year  = {2022},

date = {2022-08-30},

journal = {Molecules},

volume = {27},

issue = {14},

pages = {4458},

abstract = {Light-based phenomena in insects have long attracted researchers' attention. Surface color distribution patterns are commonly used for taxonomical purposes, while optically-active structures from Coleoptera cuticle or Lepidoptera wings have inspired technological applications, such as biosensors and energy accumulation devices. In Diptera, besides optically-based phenomena, biomolecules able to fluoresce can act as markers of bio-metabolic, structural and behavioral features. Resilin or chitinous compounds, with their respective blue or green-to-red autofluorescence (AF), are commonly related to biomechanical and structural properties, helpful to clarify the mechanisms underlying substrate adhesion of ectoparasites' leg appendages, or the antennal abilities in tuning sound detection. Metarhodopsin, a red fluorescing photoproduct of rhodopsin, allows to investigate visual mechanisms, whereas NAD(P)H and flavins, commonly relatable to energy metabolism, favor the investigation of sperm vitality. Lipofuscins are AF biomarkers of aging, as well as pteridines, which, similarly to kynurenines, are also exploited in metabolic investigations. Beside the knowledge available in Drosophila melanogaster, a widely used model to study also human disorder and disease mechanisms, here we review optically-based studies in other dipteran species, including mosquitoes and fruit flies, discussing future perspectives for targeted studies with various practical applications, including pest and vector control.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybw,

title = {Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response},

author = {Cristalli C and Manara MC and Valente S and Pellegrini E and Bavelloni A and De Feo A and Blalock WL and Di Bello E and Pineyro D and Merkel A and Esteller M and Tirado OM and Mai A and Scotlandi K},

url = {https://www.frontiersin.org/articles/10.3389/fendo.2022.876602/full},

doi = {10.3389/fendo.2022.876602},

year  = {2022},

date = {2022-08-30},

urldate = {2022-08-30},

journal = {Frontiers in endocrinology},

volume = {13},

pages = {876602},

abstract = {DNA methylation is an important component of the epigenetic machinery that regulates the malignancy of Ewing sarcoma (EWS), the second most common primary bone tumor in children and adolescents. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming and the DNMT1 enzyme has been demonstrated to have an important role in both maintaining the epigenome and controlling cell cycle. Here, we showed that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 induces a specific depletion of DNMT1 and affects EWS tumor proliferation through a mechanism that is independent on DNA methylation. Depletion of DNMT1 causes perturbation of the cell cycle, with an accumulation of cells in the G1 phase, and DNA damage, as revealed by the induction of γH2AX foci. These effects elicited activation of p53-dependent signaling and apoptosis in p53wt cells, while in p53 mutated cells, persistent micronuclei and increased DNA instability was observed. Treatment with MC3343 potentiates the efficacy of DNA damaging agents such as doxorubicin and PARP-inhibitors (PARPi). This effect correlates with increased DNA damage and synergistic tumor cytotoxicity, supporting the use of the DNMTi MC3343 as an adjuvant agent in treating EWS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_33,

title = {FT-IR Spectral Signature of Sensitive and Multidrug-Resistant Osteosarcoma Cell-Derived Extracellular Nanovesicles},

author = {Perut F and Graziani G and Roncuzzi L and Zini N and Avnet S and Baldini N},

url = {https://www.mdpi.com/2073-4409/11/5/778},

doi = {10.3390/cells11050778},

year  = {2022},

date = {2022-08-26},

journal = {Cells},

volume = {11},

issue = {5},

pages = {778},

abstract = {Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, the outcome is unsatisfactory, and multidrug resistance (MDR) is a pivotal process in OS treatment failure. OS-derived extracellular vesicles (EVs) promote drug resistance to chemotherapy and target therapy through different mechanisms. The aim of this study was to identify subpopulations of osteosarcoma-EVs by Fourier transform infrared spectroscopy (FT-IR) to define a specific spectral signature for sensitive and multidrug-resistant OS-derived EVs. EVs were isolated from sensitive and MDR OS cells as well as from mesenchymal stem cells by differential centrifugation and ultracentrifugation. EVs size, morphology and protein expression were characterized. FT-IR/ATR of EVs spectra were acquired in the region of 400-4000 cm-1 (resolution 4 cm-1, 128 scans). The FT-IR spectra obtained were consistently different in the EVs compared to cells from which they originate. A specific spectral signature, characterized by a shift and a new band (1601 cm-1), permitted to clearly distinguish EVs isolated by sensitive and multidrug-resistant OS cells. Our data suggest that FT-IR spectroscopy allows to characterize and define a specific spectral signature for sensitive and MDR OS-derived EVs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_31,

title = {A Single mtDNA Deletion in Association with a LMNA Gene New Frameshift Variant: A Case Report},

author = {Montano V and Mancuso M and Simoncini C and Torri F and Chico L and Ali G and Rocchi A and Baldinotti F and Caligo MA and Lattanzi G and Mattioli E and Cenacchi G and Barison A and Siciliano G and Ricci G},

url = {https://content.iospress.com/articles/journal-of-neuromuscular-diseases/jnd220802},

doi = {10.3233/JND-220802},

year  = {2022},

date = {2022-08-25},

journal = {Journal of neuromuscular diseases},

volume = {9},

issue = {3457-462},

abstract = {Background: Proximal muscle weakness may be the presenting clinical feature of different types of myopathies, including limb girdle muscular dystrophy and primary mitochondrial myopathy. LGMD1B is caused by LMNA mutation. It is characterized by progressive weakness and wasting leading to proximal weakness, cardiomyopathy, and hearth conduction block. Objective: In this article, we describe the case of a patient who presented with limb-girdle weakness and a double trouble scenario -mitochondrial DNA single deletion and a new LMNA mutation. Methods: Pathophysiological aspects were investigated with muscle biopsy, Western Blot analysis, NGS nuclear and mtDNA analysis and neuromuscular imaging (muscle and cardiac MRI). Results: Although secondary mitochondrial involvement is possible, a "double trouble" syndrome can not be excluded. Conclusion: Implication deriving from hypothetical coexistence of two different pathological conditions or the possible secondary mitochondrial involvement are discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_29,

title = {Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase},

author = {Joseph CR and Dusi S and Giannattasio M and Branzei D},

url = {https://www.nature.com/articles/s41467-022-30215-9},

doi = {10.1038/s41467-022-30215-9},

year  = {2022},

date = {2022-08-25},

journal = {Nature communications},

volume = {13},

issue = {1},

pages = {2480},

abstract = {DNA damage tolerance (DDT), activated by replication stress during genome replication, is mediated by translesion synthesis and homologous recombination (HR). Here we uncover that DDK kinase, essential for replication initiation, is critical for replication-associated recombination-mediated DDT. DDK relies on its multi-monoSUMOylation to facilitate HR-mediated DDT and optimal retention of Rad51 recombinase at replication damage sites. Impairment of DDK kinase activity, reduced monoSUMOylation and mutations in the putative SUMO Interacting Motifs (SIMs) of Rad51 impair replication-associated recombination and cause fork uncoupling with accumulation of large single-stranded DNA regions at fork branching points. Notably, genetic activation of salvage recombination rescues the uncoupled fork phenotype but not the recombination-dependent gap-filling defect of DDK mutants, revealing that the salvage recombination pathway operates preferentially proximal to fork junctions at stalled replication forks. Overall, we uncover that monoSUMOylated DDK acts with Rad51 in an axis that prevents replication fork uncoupling and mediates recombination-dependent gap-filling.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_28,

title = {Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies},

author = {Gorski M and Rasheed H and Teumer A and Thomas LF and Graham SE and Sveinbjornsson G and Winkler TW and Gunther F and Stark KJ and Chai JF and Tayo BO and Wuttke M and Li Y and Tin A and Ahluwalia TS and Ärnlöv J and Åsvold BO and Bakker SJL and Banas B and Bansal N and Biggs ML and Biino G and {et al}},

url = {https://www.sciencedirect.com/science/article/pii/S0085253822004549?via%3Dihub},

doi = {10.1016/j.kint.2022.05.021},

year  = {2022},

date = {2022-08-25},

journal = {Kidney international},

volume = {102},

issue = {3},

pages = {624-639},

abstract = {Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_36,

title = {Editorial: Novel Insights Into Female Post-Mating Physiology in Insects},

author = {Scolari F and Khamis FM and Perez-Staples D},

url = {https://www.frontiersin.org/articles/10.3389/fphys.2022.877222/full},

doi = {10.3389/fphys.2022.877222},

year  = {2022},

date = {2022-08-24},

journal = {Frontiers in physiology},

volume = {13},

pages = {877222},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybz,

title = {epg5 knockout leads to the impairment of reproductive success and courtship behaviour in a zebrafish model of autophagy-related diseases},

author = {Fontana CM and Locatello L and Sabatelli P and Facchinello N and Lidron E and Maradonna F and Carnevali O and Rasotto MB and Dalla Valle L},

url = {https://www.sciencedirect.com/science/article/pii/S2319417021000342?via%3Dihub},

doi = {10.1016/j.bj.2021.04.002},

year  = {2022},

date = {2022-08-24},

journal = {Biomedical journal},

volume = {45},

issue = {2},

pages = {377-386},

abstract = {Background: Dysregulation of the autophagic flux is linked to a wide array of human diseases, and recent findings highlighted the central role of autophagy in reproduction, as well as an association between impairment of autophagy and behavioural disorders. Here we deepened on the possible multilevel link between impairment of the autophagic processes and reproduction at both the physiological and the behavioural level in a zebrafish mutant model. Methods: Using a KO epg5 zebrafish line we analysed male breeding success, fertility rate, offspring survival, ejaculate quality, sperm and testes morphology, and courtship behaviour. To this aim physiological, histological, ultrastructural and behavioural analyses on epg5+/+ and mutant epg5-/- males coupled to WT females were applied. Results: We observed an impairment of male reproductive performance in mutant epg5-/- males that showed a lower breeding success with a reduced mean number of eggs spawned by their WT female partners. The spermatogenesis and the ability to produce fertilising ejaculates were not drastically impaired in our mutant males, whereas we observed a reduction of their courtship behaviour that might contribute to explain their lower overall reproductive success. Conclusion: Collectively our findings corroborate the hypothesis of a multilevel link between the autophagic process and reproduction. Moreover, by giving a first glimpse on behavioural disorders associated to epg5 KO in model zebrafish, our results open the way to more extensive behavioural analyses, also beyond the reproductive events, that might serve as new tools for the molecular screening of autophagy-related multisystemic and neurodegenerative diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yby,

title = {Development of a Short Questionnaire for the Screening for Vitamin D Deficiency in Italian Adults: The EVIDENCe-Q Project},

author = {{De Giuseppe R} and Tomasinelli CE and Cena H and Braschi V and Giampieri F and Preatoni G and Centofanti D and Princis MP and Bartoletti E and Biino G},

url = {https://www.mdpi.com/2072-6643/14/9/1772},

doi = {10.3390/nu14091772},

year  = {2022},

date = {2022-08-23},

journal = {Nutrients},

volume = {14},

issue = {9},

pages = {1772},

abstract = {Background: To develop and validate a questionnaire for the screening of Vitamin D in Italian adults (Evaluation Vitamin D dEficieNCy Questionnaire, EVIDENCe-Q). Methods: 150 participants, attending the 11Clinical Nutrition and Dietetics Operative Unit, Internal Medicine and Endocrinology, Istituti Clinici Scientifici Maugeri IRCCS, of Pavia were enrolled. Demographic variables and serum levels of vitamin D were recorded. The EVIDENCe-Q included information regarding factors affecting the production, intake, absorption and metabolism of Vitamin D. The EVIDENCe-Q score ranged from 0 (the best status) to 36 (the worst status). Results: Participants showed an inadequate status of Vitamin D, according to the current Italian reference values. A significant difference (p < 0.0001) in the EVIDENCe-Q score was found among the three classes of vitamin D status (severe deficiency, deficiency and adequate), being the mean score higher in severe deficiency and lower in the adequate one. A threshold value for EVIDENCe-Q score of 23 for severe deficiency, a threshold value of 21 for deficiency and a threshold value of 20 for insufficiency were identified. According to these thresholds, the prevalence of severe deficiency, deficiency and insufficiency was 22%, 35.3% and 43.3% of the study population, respectively. Finally, participants with EVIDENCe-Q scores <20 had adequate levels of vitamin D. Conclusions: EVIDENCe-Q can be a useful and easy screening tool for clinicians in their daily practice at a reasonable cost, to identify subjects potentially at risk of vitamin D deficiency and to avoid unwarranted supplementation and/or costly blood testing},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_38,

title = {Revisiting the Function of p21CDKN1A in DNA Repair: The Influence of Protein Interactions and Stability},

author = {Ticli G and Cazzalini O and Stivala LA and Prosperi E},

url = {https://www.mdpi.com/resolver?pii=ijms23137058},

doi = {10.3390/ijms23137058},

year  = {2022},

date = {2022-08-19},

journal = {International journal of molecular sciences},

volume = {23},

issue = {13},

pages = {7058},

abstract = {The p21 protein is an important player in the maintenance of genome stability through its function as a cyclin-dependent kinase inhibitor, leading to cell-cycle arrest after genotoxic damage. In the DNA damage response, p21 interacts with specific proteins to integrate cell-cycle arrest with processes such as transcription, apoptosis, DNA repair, and cell motility. By associating with Proliferating Cell Nuclear Antigen (PCNA), the master of DNA replication, p21 is able to inhibit DNA synthesis. However, to avoid conflicts with this process, p21 protein levels are finely regulated by pathways of proteasomal degradation during the S phase, and in all the phases of the cell cycle, after DNA damage. Several lines of evidence have indicated that p21 is required for the efficient repair of different types of genotoxic lesions and, more recently, that p21 regulates DNA replication fork speed. Therefore, whether p21 is an inhibitor, or rather a regulator, of DNA replication and repair needs to be re-evaluated in light of these findings. In this review, we will discuss the lines of evidence describing how p21 is involved in DNA repair and will focus on the influence of protein interactions and p21 stability on the efficiency of DNA repair mechanisms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_30,

title = {The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer},

author = {Mazzeschi M and Sgarzi M and Romaniello D and Gelfo V and Cavallo C and Ambrosi F and Morselli A and Miano C and Laprovitera N and Girone C and Ferracin M and Santi S and Rihawi K and Ardizzoni A and Fiorentino M and D'Uva G and Győrffy B and Palmer R and Lauriola M},

url = {https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02309-1},

doi = {10.1186/s13046-022-02309-1},

year  = {2022},

date = {2022-08-19},

journal = {Journal of experimental & clinical cancer research},

volume = {41},

issue = {1},

pages = {113},

abstract = {Background: In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). Methods: In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use. Results: ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo. Conclusions: Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_40,

title = {Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature},

author = {Valenti AC and Albini A and Imberti JF and Vitolo M and Bonini N and Lattanzi G and Schnabel RB and Boriani G},

url = {https://www.mdpi.com/2079-7737/11/4/530},

doi = { doi: 10.3390/biology11040530},

year  = {2022},

date = {2022-08-18},

journal = {Biology (Basel)},

volume = {11},

issue = {4},

abstract = {Cardiolaminopathies are a heterogeneous group of disorders which are due to mutations in the genes encoding for nuclear lamins or their binding proteins. The whole spectrum of cardiac manifestations encompasses atrial arrhythmias, conduction disturbances, progressive systolic dysfunction, and malignant ventricular arrhythmias. Despite the prognostic significance of cardiac involvement in this setting, the current recommendations lack strong evidence. The aim of our work was to systematically review the current data on the main cardiovascular outcomes in cardiolaminopathies. We searched PubMed/Embase for studies focusing on cardiovascular outcomes in LMNA mutation carriers (atrial arrhythmias, ventricular arrhythmias, sudden cardiac death, conduction disturbances, thromboembolic events, systolic dysfunction, heart transplantation, and all-cause and cardiovascular mortality). In total, 11 studies were included (1070 patients, mean age between 26-45 years, with follow-up periods ranging from 2.5 years up to 45 ± 12). When available, data on the EMD-mutated population were separately reported (40 patients). The incidence rates (IR) were individually assessed for the outcomes of interest. The IR for atrial fibrillation/atrial flutter/atrial tachycardia ranged between 6.1 and 13.9 events/100 pts-year. The IR of atrial standstill ranged between 0 and 2 events/100 pts-year. The IR for malignant ventricular arrhythmias reached 10.2 events/100 pts-year and 15.6 events/100 pts-year for appropriate implantable cardioverter-defibrillator (ICD) interventions. The IR for advanced conduction disturbances ranged between 3.2 and 7.7 events/100 pts-year. The IR of thromboembolic events reached up to 8.9 events/100 pts-year. Our results strengthen the need for periodic cardiological evaluation focusing on the early recognition of atrial arrhythmias, and possibly for the choice of preventive strategies for thromboembolic events. The frequent need for cardiac pacing due to advanced conduction disturbances should be counterbalanced with the high risk of malignant ventricular arrhythmias that would justify ICD over pacemaker implantation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_39,

title = {Collagen VI ablation in zebrafish causes neuromuscular defects during developmental and adult stages},

author = {Tonelotto V and Consorti C and Facchinello N and Trapani V and Sabatelli P and Giraudo C and Spizzotin M and Cescon M and Bertolucci C and Bonaldo P},

url = {https://www.sciencedirect.com/science/article/pii/S0945053X22000981?via%3Dihub},

doi = {10.1016/j.matbio.2022.08.004},

year  = {2022},

date = {2022-08-18},

journal = {Matrix biology},

abstract = {Collagen VI (COL6) is an extracellular matrix protein exerting multiple functions in different tissues. In humans, mutations of COL6 genes cause rare inherited congenital disorders, primarily affecting skeletal muscles and collectively known as COL6-related myopathies, for which no cure is available yet. In order to get insights into the pathogenic mechanisms underlying COL6-related diseases, diverse animal models were produced. However, the roles exerted by COL6 during embryogenesis remain largely unknown. Here, we generated the first zebrafish COL6 knockout line through CRISPR/Cas9 site-specific mutagenesis of the col6a1 gene. Phenotypic characterization during embryonic and larval development revealed that lack of COL6 leads to neuromuscular defects and motor dysfunctions, together with distinctive alterations in the three-dimensional architecture of craniofacial cartilages. These phenotypic features were maintained in adult col6a1 null fish, which displayed defective muscle organization and impaired swimming capabilities. Moreover, col6a1 null fish showed autophagy defects and organelle abnormalities at both embryonic and adult stages, thus recapitulating the main features of patients affected by COL6-related myopathies. Mechanistically, lack of COL6 led to increased BMP signaling, and direct inhibition of BMP activity ameliorated the locomotor col6a1 null embryos. Finally performance of, treatment with salbutamol, a beta2-adrenergic receptor agonist, elicited a significant amelioration of the neuromuscular and motility defects of col6a1 null fish embryos. Altogether, these findings indicate that this newly generated zebrafish col6a1 null line is a valuable in vivo tool to model COL6-related myopathies and suitable for drug screenings aimed at addressing the quest for effective therapeutic strategies for these disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_37,

title = {DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective},

author = {Secchi M and Lodola C and Garbelli A and Bione S and Maga G},

url = {https://www.mdpi.com/2072-6694/14/15/3820},

doi = {10.3390/cancers14153820},

year  = {2022},

date = {2022-08-18},

journal = {Cancers (Basel)},

volume = {14},

issue = {15},

pages = {3820},

abstract = {RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_35,

title = {A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids},

author = {Ramdas S and Judd J and {………} and Biino G and {……..} and {et al.}},

url = {https://www.sciencedirect.com/science/article/pii/S0002929722002658?via%3Dihub},

doi = {10.1016/j.ajhg.2022.06.012},

year  = {2022},

date = {2022-08-18},

journal = {American journal of human genetics},

volume = {109},

issue = {8},

pages = {1366-1387},

abstract = {A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_34,

title = {Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells},

author = {Piazzi M and Bavelloni A and Cenni V and Salucci S and Bartoletti Stella A and Tomassini E and Scotlandi K and Blalock WL and Faenza I},

url = {https://www.mdpi.com/1420-3049/27/9/2742},

doi = {10.3390/molecules27092742},

year  = {2022},

date = {2022-08-18},

journal = {Molecules},

volume = {27},

issue = {9},

pages = {2742},

abstract = {Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_32,

title = {MCD Diet Rat Model Induces Alterations in Zinc and Iron during NAFLD Progression from Steatosis to Steatohepatitis},

author = {Palladini G and Di Pasqua LG and Cagna M and Croce AC and Perlini S and Mannucci B and Profumo A and Ferrigno A and Vairetti M},

url = {https://www.mdpi.com/1422-0067/23/12/6817},

doi = {10.3390/ijms23126817},

year  = {2022},

date = {2022-08-18},

journal = {International journal of molecular sciences},

volume = {23},

issue = {12},

pages = {6817},

abstract = {We evaluate the effects of the methionine-choline-deficient (MCD) diet on serum and hepatic zinc (Zn) and iron (Fe) and their relationships with matrix metalloproteinases (MMPs) and their modulators (TIMPs and RECK) as well as hepatic fatty acids using male Wistar rats fed 2-, 4- and 8-week MCD diets. Serum and hepatic Zn decrease after an 8-week MCD diet. Serum Fe increases after an 8-week MCD diet and the same occurs for hepatic Fe. An increase in hepatic MMP activity, associated with a decrease in RECK and TIMPs, is found in the MCD 8-week group. Liver Fe shows a positive correlation versus MMPs and RECK, and an inverse correlation versus TIMPs. A positive correlation is found comparing liver Zn with stearic, vaccenic and arachidonic acids, and an inverse correlation is found with linolenic and docosatetraenoic acids. An opposite trend is found between liver Fe versus these fatty acids. During NAFLD progression from steatosis to steatohepatitis, MCD rats exhibit an increase in Zn and a decrease in Fe levels both in serum and tissue associated with alterations in hepatic MMPs and their inhibitors, and fatty acids. The correlations detected between Zn and Fe versus extracellular matrix modulators and fatty acids support their potential role as therapeutic targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_27,

title = {Ambra1 deficiency impairs mitophagy in skeletal muscle},

author = {Gambarotto L and Metti S and Chrisam M and Cerqua C and Sabatelli P and Armani A and Zanon C and Spizzotin M and Castagnaro S and Strappazzon F and Grumati P and Cescon M and Braghetta P and Trevisson E and Cecconi F and Bonaldo P.},

url = {https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13010},

doi = {10.1002/jcsm.13010},

year  = {2022},

date = {2022-08-18},

journal = {Journal of cachexia, sarcopenia and muscle},

volume = {13},

issue = {4},

pages = {2211-2224},

abstract = {Background: Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well-known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full-body Ambra1 deficiency. Methods: To establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria-targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle-specific Ambra1 knockout (Ambra1fl/fl :Mlc1f-Cre) mice. Mitochondria-enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux. Results: Our data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild-type muscles is sufficient to enhance mitochondria clearance through the autophagy-lysosome system. Consistently with this, Ambra1-deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6-7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6-7 mice; P < 0.01) and Parkin (n = 6-7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1-deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild-type muscles (n = 4; P < 0.05). Histologically, Ambra1-deficient muscles of both 3- and 6-month-old animals display a significant decrease of myofibre cross-sectional area and a 52% reduction in oxidative fibres (n = 6-7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle. Conclusions: Our study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybu,

title = {Multiple lipid nanoparticles as antimicrobial drug delivery systems},

author = {{Ben Khalifa R} and Cacciatore I and Dimmito MP and  Ciulla M and Grande R and Puca V and Robuffo I and De Laurenzi V and Chekir-Ghedira L and Di Stefano A and Marinelli L},

url = {https://www.sciencedirect.com/science/article/pii/S1773224721005670?via%3Dihub},

doi = {10.1016/j.jddst.2021.102887},

year  = {2022},

date = {2022-08-17},

journal = {Journal of drug delivery science and technology},

volume = {67},

pages = {102887},

abstract = {The present work aimed at investigating formulations based on multiple lipid nanoparticles (MLNs) containing carvacrol (CAR) and vancomycin hydrochloride (VAN) co-loaded (CAR-VAN-MLNs) as therapeutical strategy useful to improve the antibiotic activity of VAN. Drug-loaded MLNs were prepared by the ultra-sonication technique and investigated for both physico-chemical and antimicrobial properties. Results revealed that all the formulations possessed particle size lower than 150 nm and negatively charged surfaces, as suggested by the ?-potential values. The encapsulation efficiencies were higher than 70% and 21% for CAR and VAN, respectively. Moreover, differential scanning calorimetry analysis confirmed the effective drug loading, while stability studies indicated that the prepared formulations remained stable for about one month when stored at 4 oC. Finally, in vitro studies revealed a sustained drug release during the time. The morphological MLNs characterization, performed by transmission electron microscopy analysis, showed a spherical shape of the produced nanoparticles. Antimicrobial studies suggested that the co-encapsulation improved VAN antibiotic activity against Staphylococcus aureus with a possible greater advantage during systemic therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybv,

title = {Small Extracellular Vesicles from Inflamed Adipose Derived Stromal Cells Enhance the NF-κB-Dependent Inflammatory/Catabolic Environment of Osteoarthritis. },

author = {Cavallo C and Merli G and Zini N and {D'Adamo} S and Cattini L and Guescini M and Grigolo B and Di Martino A and Santi S and Borzì RM and Filardo G},

url = {https://www.hindawi.com/journals/sci/2022/9376338/},

doi = {10.1155/2022/9376338},

year  = {2022},

date = {2022-08-11},

urldate = {2022-08-11},

journal = {Stem cells international},

volume = {2022},

pages = {9376338},

abstract = {The last decade has seen exponentially growing efforts to exploit the effects of adipose derived stromal cells (ADSC) in the treatment of a wide range of chronic degenerative diseases, including osteoarthritis (OA), the most prevalent joint disorder. In the perspective of developing a cell-free advanced therapy medicinal product, a focus has been recently addressed to the ADSC secretome that lends itself to an allogeneic use and can be further dissected for the selective purification of small extracellular vesicles (sEVs). sEVs can act as "biological drug carriers" to transfer information that mirror the pathophysiology of the providing cells. This is important in the clinical perspective where many OA patients are also affected by the metabolic syndrome (MetS). ADSC from MetS OA patients are dysfunctional and "inflammatory" primed within the adipose tissue. To mimic this condition, we exposed ADSC to IL-1β, and then we investigated the effects of the isolated sEVs on chondrocytes and synoviocytes, either cultured separately or in co-culture, to tease out the effects of these "IL-1β primed sEVs" on gene and protein expression of major inflammatory and catabolic OA markers. In comparison with sEVs isolated from unstimulated ADSC, the IL-1β primed sEVs were able to propagate NF-κB activation in bystander joint cells. The effects were more prominent on synoviocytes, possibly because of a higher expression of binding molecules such as CD44. These findings call upon a careful characterization of the "inflammatory fingerprint" of ADSC to avoid the transfer of an unwanted message as well as the development of in vitro "preconditioning" strategies able to rescue the antiinflammatory/anticatabolic potential of ADSC-derived sEVs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybt,

title = {In Vitro Neurotoxicity of Flumethrin Pyrethroid on SH-SY5Y Neuroblastoma Cells: Apoptosis Associated with Oxidative Stress},

author = {Barrios-Arpi L and Arias Y and Lopez-Torres B and Ramos-Gonzalez M and Ticli G and Prosperi E and Rodríguez J-L},

url = {https://www.mdpi.com/2305-6304/10/3/131#cite},

doi = {10.3390/toxics10030131},

year  = {2022},

date = {2022-07-20},

journal = {Toxics},

volume = {10},

issue = {3},

pages = {131},

abstract = {Pyrethroids are neurotoxicants for animals, showing a pattern of toxic action on the nervous system. Flumethrin, a synthetic pyrethroid, is used against ectoparasites in domestic animals, plants, and for public health. This compound has been shown to be highly toxic to bees, while its effects on other animals have been less investigated. However, in vitro studies to evaluate cytotoxicity are scarce, and the mechanisms associated with this effect at the molecular level are still unknown. This study aimed to investigate the oxidative stress and cell death induction in SH-SY5Y neuroblastoma cells in response to flumethrin exposure (1–1000 µM). Flumethrin induced a significant cytotoxic effect, as evaluated by MTT and LDH leakage assays, and produced an increase in the biomarkers of oxidative stress as reactive oxygen species and nitric oxide (ROS and NO) generation, malondialdehyde (MDA) concentration, and caspase-3 activity. In addition, flumethrin significantly increased apoptosis-related gene expressions (Bax, Casp-3, BNIP3, APAF1, and AKT1) and oxidative stress and antioxidative (NFκB and SOD2) mediators. The results demonstrated, by biochemical and gene expression assays, that flumethrin induces oxidative stress and apoptosis, which could cause DNA damage. Detailed knowledge obtained about these molecular changes could provide the basis for elucidating the molecular mechanisms of flumethrin-induced neurotoxicity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybs,

title = {Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line},

author = {Avolio F and Martinotti S and Khavinson VK and Esposito JE and Giambuzzi G and Marino A and Mironova E and Pulcini R and Robuffo I and Bologna G and Simeone P and Lanuti P and Guarnieri S and Trofimova S and Procopio AD and Toniato E},

url = {https://www.mdpi.com/1422-0067/23/7/3607},

doi = {10.3390/ijms23073607},

year  = {2022},

date = {2022-07-20},

journal = {International journal of molecular sciences},

volume = {23},

issue = {7},

pages = {3607},

abstract = {This study evaluates the effects of five different peptides, the Epitalon® tetrapeptide, the Vilon® dipeptide, the Thymogen® dipeptide, the Thymalin® peptide complex, and the Chonluten® tripeptide, as regulators of inflammatory and proliferative processes in the human monocytic THP-1, which is a human leukemia monocytic cell line capable of differentiating into macrophages by PMA in vitro. These peptides (Khavinson Peptides®), characterized by Prof. Khavinson from 1973 onwards, were initially isolated from animal tissues and found to be organ specific. We tested the capacity of the five peptides to influence cell cultures in vitro by incubating THP-1 cells with peptides at certain concentrations known for being effective on recipient cells in culture. We found that all five peptides can modulate key proliferative patterns, increasing tyrosine phosphorylation of mitogen-activated cytoplasmic kinases. In addition, the Chonluten tripeptide, derived from bronchial epithelial cells, inhibited in vitro tumor necrosis factor (TNF) production of monocytes exposed to pro-inflammatory bacterial lipopolysaccharide (LPS). The low TNF release by monocytes is linked to a documented mechanism of TNF tolerance, promoting attenuation of inflammatory action. Therefore, all peptides inhibited the expression of TNF and pro-inflammatory IL-6 cytokine stimulated by LPS on terminally differentiated THP-1 cells. Lastly, by incubating the THP1 cells, treated with the peptides, on a layer of activated endothelial cells (HUVECs activated by LPS), we observed a reduction in cell adhesion, a typical pro-inflammatory mechanism. Overall, the results suggest that the Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocyte, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb,

title = {Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells},

author = {Corradi G and Bassani B and Simonetti G and Sangaletti S and Vadakekolathu J and Fontana MC and Pazzaglia M and Gulino A and Tripodo C and Cristiano G and Bandini L and Ottaviani E and Ocadlikova D and Piccioli M and Martinelli G and Colombo MP and Rutella S and Cavo M and Ciciarello M and Curti A},

url = {https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-21-3594/694419/Release-of-IFN-by-Acute-Myeloid-Leukemia-Cells?redirectedFrom=fulltext},

doi = {10.1158/1078-0432.CCR-21-3594},

year  = {2022},

date = {2022-05-30},

urldate = {2022-05-30},

journal = {Clinical cancer research},

volume = {Clincanres.359},

pages = {2021},

abstract = {Purpose: The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Tregs) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFN-γ released by AML cells in BM Tregs induction and its impact on AML prognosis. Experimental design: BM aspirates from AML patients were subdivided according to IFNG expression. Gene expression profiles in INFGhigh and IFNGlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFN-g release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell co-cultures. In mice, AML cells silenced for IFN-γ expression were injected intrabone. Results: IFNGhigh AMLsamples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. By contrast, in AML patients, high IFNG expression associated with poor overall survival. Notably, IFN-g release by AML cells positively correlated with a higher BM suppressive Tregs' frequency. In co-culture experiments, IFNGhigh AML cells modified MSC transcriptome by up-regulating IFN-γ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFN-γ release by AML cells on MSC-derived Treg induction. Invivo, the genetic ablation of IFN-γ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment. Conclusions: IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybr,

title = {Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma},

author = {Chiarini F and Paganelli F and Balestra T and Capanni C and Fazio A and Manara MC and Landuzzi L and Petrini S and Evangelisti C and Lollini PL and Martelli AM and Lattanzi G and Scotlandi K},

url = {https://www.nature.com/articles/s41419-022-04729-5},

doi = {10.1038/s41419-022-04729-5},

year  = {2022},

date = {2022-05-30},

urldate = {2022-05-30},

journal = {Cell death & disease},

volume = {13},

issue = {4},

pages = {346},

abstract = {Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybq,

title = {Sex disparities in DNA damage response pathways: Novel determinants in cancer formation and therapy},

author = {Cardano M and Buscemi G and Zannini L},

url = {https://www.sciencedirect.com/science/article/pii/S2589004222001456?via%3Dihub},

doi = {10.1016/j.isci.2022.103875},

year  = {2022},

date = {2022-05-30},

journal = {iScience},

volume = {25},

issue = {3},

pages = {103875},

abstract = {Cancer incidence and survival are different between men and women. Indeed, females have a lesser risk and a better prognosis than males in many tumors unrelated to reproductive functions. Although the reasons for these disparities are still unknown, they constitute an important starting point for the development of personalized cancer therapies. One of the mechanisms that fuels carcinogenesis is the accumulation of defects in DNA damage response (DDR) pathways, a complex signaling cascade that senses DNA lesions and, depending on the severity, coordinates transient cell-cycle arrest, DNA replication, repair, apoptosis, and senescence, preventing genomic instability and cancer. Recently, evidence of sexual dimorphisms is emerging in these pathways, therefore providing new opportunities for precision medicine. Here, we will discuss current knowledge about sexual disparities in the DDR, their role in tumorigenesis and cancer progression, and the importance of considering sex contribution in both research and cancer therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybo,

title = {Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line},

author = {Avolio F and Martinotti S and Khavinson VK and Esposito JE and Giambuzzi G and Marino A and Mironova E and Pulcini R and Robuffo I and Bologna G and Simeone P and Lanuti P and Guarnieri S and Trofimova S and Procopio AD and Toniato E.},

url = {https://www.mdpi.com/1422-0067/23/7/3607

},

doi = {10.3390/ijms23073607},

year  = {2022},

date = {2022-05-30},

journal = {International journal of molecular sciences},

volume = {23},

issue = {7},

pages = {3607},

abstract = {This study evaluates the effects of five different peptides, the Epitalon® tetrapeptide, the Vilon® dipeptide, the Thymogen® dipeptide, the Thymalin® peptide complex, and the Chonluten® tripeptide, as regulators of inflammatory and proliferative processes in the human monocytic THP-1, which is a human leukemia monocytic cell line capable of differentiating into macrophages by PMA in vitro. These peptides (Khavinson Peptides®), characterized by Prof. Khavinson from 1973 onwards, were initially isolated from animal tissues and found to be organ specific. We tested the capacity of the five peptides to influence cell cultures in vitro by incubating THP-1 cells with peptides at certain concentrations known for being effective on recipient cells in culture. We found that all five peptides can modulate key proliferative patterns, increasing tyrosine phosphorylation of mitogen-activated cytoplasmic kinases. In addition, the Chonluten tripeptide, derived from bronchial epithelial cells, inhibited in vitro tumor necrosis factor (TNF) production of monocytes exposed to pro-inflammatory bacterial lipopolysaccharide (LPS). The low TNF release by monocytes is linked to a documented mechanism of TNF tolerance, promoting attenuation of inflammatory action. Therefore, all peptides inhibited the expression of TNF and pro-inflammatory IL-6 cytokine stimulated by LPS on terminally differentiated THP-1 cells. Lastly, by incubating the THP1 cells, treated with the peptides, on a layer of activated endothelial cells (HUVECs activated by LPS), we observed a reduction in cell adhesion, a typical pro-inflammatory mechanism. Overall, the results suggest that the Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocyte, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Yb_63,

title = {Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population},

author = {Bacalini MG and Palombo F and Garagnani P and Giuliani C and Fiorini C and Caporali L and Stanzani Maserati M and Capellari S and Romagnoli M and De Fanti S and Benussi L and Binetti G and Ghidoni R and Galimberti D and Scarpini E and Arcaro M and Bonanni E and Siciliano G and Maestri M and Guarnieri B and {Italian Multicentric Group on clock genes and actigraphy in AD} and Martucci M and Monti D and Carelli V and Franceschi C and La Morgia C and Santoro A},

url = {https://link.springer.com/article/10.1007%2Fs11357-021-00477-0},

doi = {10.1007/s11357-021-00477-0},

year  = {2022},

date = {2022-04-29},

urldate = {2022-04-29},

journal = {Geroscience},

volume = {44},

number = {881},

issue = {2},

pages = {896},

abstract = {Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb,

title = {Dynamic susceptibility MR perfusion imaging of the brain: not a question of contrast agent molarity},

author = {Panara V and Chiacchiaretta P and Rapino M and Maruotti V and Parenti M and Piccirilli E and Pizzi AD and Caulo M},

url = {https://link.springer.com/article/10.1007%2Fs00234-021-02807-7},

doi = {10.1007/s00234-021-02807-7},

year  = {2022},

date = {2022-04-13},

urldate = {2022-04-13},

journal = {Neuroradiology},

volume = {64},

issue = {4},

pages = {685-692},

abstract = {Purpose: Dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI) is increasingly used in clinical neuroimaging for a range of conditions. More highly concentrated GBCAs (e.g., gadobutrol) are often preferred for DSC imaging because it is thought that more Gd is present in the volume of interest during first pass for a given equivalent injection rate. However, faster injection of a less viscous GBCA (e.g., gadoteridol) might generate a more compact and narrower contrast bolus thus obviating any perceived benefit of higher Gd concentration. This preliminary study aimed to analyze and compare DSC examinations in the healthy brain hemisphere of patients with brain tumors using gadobutrol and gadoteridol administered at injection rates of 4 and 6 mL/s. Methods: Thirty-nine brain tumor patients studied with DSC-PWI were evaluated. A simplified gamma-variate model function was applied to calculate the mean peak, area under the curve (AUC), and full-width at half-maximum (FHWM) of concentration-time curves derived from ΔR2* signals at four different regions-of-interest (ROIs). Qualitative assessment of the derived CBV maps was also performed independently by 2 neuroradiologists. Results: No qualitative or quantitative differences between the two GBCAs were observed when administered at a flow rate of 4 mL/s. At a flow rate of 6 mL/s, gadoteridol showed lower FWHM values. Conclusion: Gadobutrol and gadoteridol are equivalent for clinical assessment of qualitative CBV maps and quantitative perfusion parameters (FHWM) at a flow rate of 4 mL/s. At 6 mL/s, gadoteridol produces a narrower bolus shape and potentially improves quantitative assessment of perfusion parameters.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_44,

title = {The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment},

author = {Capanni C and Schena E and Di Giampietro ML and Montecucco A and Mattioli E and Lattanzi G},

url = {https://www.frontiersin.org/articles/10.3389/fcell.2022.1018102/full},

doi = {10.3389/fcell.2022.1018102},

year  = {2022},

date = {2022-03-31},

journal = {Frontiers in cell and developmental biology},

volume = {10},

abstract = {Lamin A is a main constituent of the nuclear lamina and contributes to nuclear shaping, mechano-signaling transduction and gene regulation, thus affecting major cellular processes such as cell cycle progression and entry into senescence, cellular differentiation and stress response. The role of lamin A in stress response is particularly intriguing, yet not fully elucidated, and involves prelamin A post-translational processing. Here, we propose prelamin A as the tool that allows lamin A plasticity during oxidative stress response and permits timely 53BP1 recruitment to DNA damage foci. We show that while PCNA ubiquitination, p21 decrease and H2AX phosphorylation occur soon after stress induction in the absence of prelamin A, accumulation of non-farnesylated prelamin A follows and triggers recruitment of 53BP1 to lamin A/C complexes. Then, the following prelamin A processing steps causing transient accumulation of farnesylated prelamin A and maturation to lamin A reduce lamin A affinity for 53BP1 and favor its release and localization to DNA damage sites. Consistent with these observations, accumulation of prelamin A forms in cells under basal conditions impairs histone H2AX phosphorylation, PCNA ubiquitination and p21 degradation, thus affecting the early stages of stress response. As a whole, our results are consistent with a physiological function of prelamin A modulation during stress response aimed at timely recruitment/release of 53BP1 and other molecules required for DNA damage repair. In this context, it becomes more obvious how farnesylated prelamin A accumulation to toxic levels alters timing of DNA damage signaling and 53BP1 recruitment, thus contributing to cellular senescence and accelerated organismal aging as observed in progeroid laminopathies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_46,

title = {Privileged Scaffold Decoration for the Identification of the First Trisubstituted Triazine with Anti-SARS-CoV-2 Activity},

author = {Cesarini S and Vicenti I and Poggialini F and Secchi M and Giammarino F and Varasi I and Lodola C and Zazzi M and Dreassi E and Maga G and Botta L and Saladino R},

url = {https://www.mdpi.com/1420-3049/27/24/8829},

doi = {10.3390/molecules27248829},

year  = {2022},

date = {2022-03-25},

journal = {Molecules},

volume = {27},

issue = {24},

pages = {8829},

abstract = {Current therapy against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are based on the use of Remdesivir 1, Molnupiravir 2, and the recently identified Nirmatrelvir 3. Unfortunately, these three drugs showed some limitations regarding potency and possible drug-drug interactions. A series of derivatives coming from a decoration approach of the privileged scaffold s-triazines were synthesized and evaluated against SAR-CoV-2. One derivative emerged as the hit of the series for its micromolar antiviral activity and low cytotoxicity. Mode of action and pharmacokinetic in vitro preliminary studies further confirm the role as candidates for a future optimization campaign of the most active derivative identified with this work.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_43,

title = {Screening Questionnaire for Vitamin D Insufficiency in Children with Obesity},

author = {Calcaterra V and Cena H and Biino G and Grazi R and Bortoni G and Braschi V and Tomasinelli CE and Schneider L and Zuccotti G},

url = {https://www.mdpi.com/2227-9067/9/11/1685},

doi = {https://www.mdpi.com/2227-9067/9/11/1685},

year  = {2022},

date = {2022-03-25},

urldate = {2022-03-25},

journal = {Children (Basel)},

volume = {9},

issue = {11},

pages = {1685},

abstract = {"Non-invasive screening tools to identify children at high risk of vitamin D (VitD) deficiency are proactive measures in preventive care. Recently, a validated questionnaire (Evaluation dEficieNCy Questionnaire, EVIDENCe-Q) for identifying newly diagnosed VitD-insufficient adults has been developed. We tested the EVIDENCe-Q modified for children with obesity and evaluated the correlation between VitD and questionnaire scores to adapt this tool to the pediatric population. We enrolled 120 children with obesity (BMI ≥ 2). Clinical evaluation and VitD levels were considered. The modified EVIDENCe-Q included information regarding factors affecting control of VitD, with scores ranging between 0 (best) and 36 (worst). VitD and adiposity indices were inversely correlated. The threshold values for identifying severe deficiency (<10 mg/dL), deficiency (<20 mg/dL) and insufficiency (<30 mg/dL) were scores of 21, 19 and 23, respectively. According to those thresholds, the prevalence of severe deficiency, deficiency and insufficiency was 47.5%, 69.2% and 23.3%, respectively; the best accuracy was obtained with a questionnaire score cut-off of 19 for the VitD deficiency level. A novel simple screening tool such as the modified EVIDENCe-Q would be useful in clinical practice to identify potential cases of hypovitaminosis D and select at-risk patients. Considering the limited accuracy and specificity of our results, for the pediatric population a dedicated tool should be created. Phases of childhood and the role of adipose tissue could be considered in the definition of a questionnaire intended for pediatric patients with obesity.

"},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_45,

title = {3D ECM-rich environment sustains the identity of naive human iPSCs},

author = {Cesare E and Urciuolo A and Stuart HT and Torchio E and Gesualdo A and Laterza C and Gagliano O and Martewicz S and Cui M and Manfredi A and Di Filippo L and Sabatelli P and Squarzoni S and Zorzan I and Betto RM and Martello G and Cacchiarelli D and Luni C and Elvassore N},

url = {https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00458-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590922004581%3Fshowall%3Dtrue},

doi = {10.1016/j.stem.2022.11.011},

year  = {2022},

date = {2022-03-24},

urldate = {2022-03-24},

journal = {Cell stem cell},

volume = {29},

issue = {12},

pages = {1703-1717},

abstract = {The establishment of in vitro naive human pluripotent stem cell cultures opened new perspectives for the study of early events in human development. The role of several transcription factors and signaling pathways have been characterized during maintenance of human naive pluripotency. However, little is known about the role exerted by the extracellular matrix (ECM) and its three-dimensional (3D) organization. Here, using an unbiased and integrated approach combining microfluidic cultures with transcriptional, proteomic, and secretome analyses, we found that naive, but not primed, hiPSC colonies are characterized by a self-organized ECM-rich microenvironment. Based on this, we developed a 3D culture system that supports robust long-term feeder-free self-renewal of naive hiPSCs and also allows direct and timely developmental morphogenesis simply by modulating the signaling environment. Our study opens new perspectives for future applications of naive hiPSCs to study critical stages of human development in 3D starting from a single cell.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybm,

title = {Novel Perceptions on Chemical Profile and Biopharmaceutical Properties of Mentha spicata Extracts: Adding Missing Pieces to the Scientific Puzzle},

author = {Zengin G and Ak G and Ceylan R and Uysal S and Llorent-Martínez E and Di Simone SC and Rapino M and Acquaviva A and Libero ML and Chiavaroli A and Recinella L and Leone S and Brunetti L and Cataldi A and Orlando G and Menghini L and Ferrante C and Balaha M and di Giacomo V},

url = {https://www.mdpi.com/2223-7747/11/2/233},

doi = {10.3390/plants11020233},

year  = {2022},

date = {2022-03-21},

journal = {Plants (Basel)},

volume = {11},

issue = {2},

pages = {233},

abstract = {Mentha spicata is one of the most popular species in the genus, and it is of great interest as a gastrointestinal and sedative agent in the folk medicine system. In this study, different M. spicata extracts, obtained by the use of four solvents (hexane, chloroform, acetone and acetone/water) were chemically characterized using HPLC-ESI-MS n, which allowed for identification of 27 phenolic compounds. The extracts' antioxidant and enzyme inhibitory properties were investigated. In addition, neuroprotective effects were evaluated in hypothalamic HypoE22 cells, and the ability of the extracts to prevent the hydrogen peroxide-induced degradation of dopamine and serotonin was observed. The best antioxidant effect was achieved for all the extraction methods using acetone/water as a solvent. These extracts were the richest in acacetin, eriodictyol, hesperidin, sagerinic acid, naringenin, luteolin, chlorogenic acid, chrysoeriol and apigenin. The intrinsic antioxidant and enzyme inhibition properties of the acetone/water extract could also explain, albeit partially, its efficacy in preventing prostaglandin E2 overproduction and dopamine depletion (82.9% turnover reduction) in HypoE22 cells exposed to hydrogen peroxide. Thus, our observations can provide a scientific confirmation of the neuromodulatory and neuroprotective effects of M. spicata.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybl,

title = {Early Morphological Changes of the Rectus Femoris Muscle and Deep Fascia in Ullrich Congenital Muscular Dystrophy},

author = {Sabatelli P and Merlini L and Di Martino A and Cenni V and Faldini C},

url = {https://www.mdpi.com/1660-4601/19/3/1252},

doi = {International journal of environmental research and public health},

year  = {2022},

date = {2022-03-21},

journal = {International journal of environmental research and public health},

volume = {19},

issue = {3},

pages = {1252},

abstract = {Ullrich congenital muscular dystrophy (UCMD) is a severe form of muscular dystrophy caused by the loss of function of collagen VI, a critical component of the muscle-tendon matrix. Magnetic resonance imaging of UCMD patients' muscles shows a peculiar rim of abnormal signal at the periphery of each muscle, and a relative sparing of the internal part. The mechanism/s involved in the early fat substitution of muscle fiber at the periphery of muscles remain elusive. We studied a muscle biopsy of the rectus femoris/deep fascia (DF) of a 3-year-old UCMD patient, with a homozygous mutation in the COL6A2 gene. By immunohistochemical and ultrastructural analysis, we found a marked fatty infiltration at the interface of the muscle with the epimysium/DF and an atrophic phenotype, primarily in fast-twitch fibers, which has never been reported before. An unexpected finding was the widespread increase of interstitial cells with long cytoplasmic processes, consistent with the telocyte phenotype. Our study documents for the first time in a muscle biopsy the peculiar pattern of outside-in muscle degeneration followed by fat substitution as already shown by muscle imaging, and an increase of telocytes in the interstitium of the deep fascia, which highlights a potential involvement of this structure in the pathogenesis of UCMD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybk,

title = {Telomere dysfunction in ageing and age-related diseases},

author = {Rossiello F and Jurk D and Passos JF and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/s41556-022-00842-x},

doi = {10.1038/s41556-022-00842-x},

year  = {2022},

date = {2022-03-21},

volume = {24},

issue = {2},

pages = {135-147},

abstract = {Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybj,

title = {Exosomes Recovered From the Plasma of COVID-19 Patients Expose SARS-CoV-2 Spike-Derived Fragments and Contribute to the Adaptive Immune Response},

author = {Pesce E and Manfrini N and Cordiglieri C and Santi S and Bandera A and Gobbini A and Gruarin P and Favalli A and Bombaci M and Cuomo A and Collino F and Cricri' G and Ungaro R and Lombardi A and Mangioni D and Muscatello A and Aliberti S and Blasi F and Gori A and Abrignani S and De Francesco R and Biffo S and Grifantini R},

url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-85123854300&partnerID=q2rCbXpz},

doi = {10.3389/fimmu.2021.785941},

year  = {2022},

date = {2022-03-21},

journal = {Frontiers in immunology},

volume = {12},

pages = {7859},

abstract = {Coronavirus disease 2019 (COVID-19) is an infectious disease caused by beta-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has rapidly spread across the globe starting from February 2020. It is well established that during viral infection, extracellular vesicles become delivery/presenting vectors of viral material. However, studies regarding extracellular vesicle function in COVID-19 pathology are still scanty. Here, we performed a comparative study on exosomes recovered from the plasma of either MILD or SEVERE COVID-19 patients. We show that although both types of vesicles efficiently display SARS-CoV-2 spike-derived peptides and carry immunomodulatory molecules, only those of MILD patients are capable of efficiently regulating antigen-specific CD4+ T-cell responses. Accordingly, by mass spectrometry, we show that the proteome of exosomes of MILD patients correlates with a proper functioning of the immune system, while that of SEVERE patients is associated with increased and chronic inflammation. Overall, we show that exosomes recovered from the plasma of COVID-19 patients possess SARS-CoV-2-derived protein material, have an active role in enhancing the immune response, and possess a cargo that reflects the pathological state of patients in the acute phase of the disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybi,

title = {Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4},

author = {Kannan A and Cuartas J and Gangwani P and Branzei D and Gangwani L},

url = {https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab464/6511590},

doi = {10.1093/brain/awab464},

year  = {2022},

date = {2022-03-21},

journal = {Brain},

abstract = {Mutation in the Senataxin (SETX) gene causes an autosomal dominant neuromuscular disorder, amyotrophic lateral sclerosis 4 (ALS4), characterized by degeneration of motor neurons, muscle weakness and atrophy. SETX is an RNA-DNA helicase that mediates resolution of co-transcriptional RNA-DNA hybrids (R-loops). The process of R-loop resolution is essential for the normal functioning of cells, including neurons. The molecular basis of ALS4 pathogenesis and the mechanism of R-loop resolution are unclear. We report that the zinc finger protein ZPR1 binds to RNA-DNA hybrids, recruits SETX onto R-loops and is critical for R-loop resolution. ZPR1 deficiency disrupts the integrity of R-loop resolution complexes (RLRC) containing SETX and causes increased R-loop accumulation throughout gene transcription. We uncover that SETX is a downstream target of ZPR1 and that overexpression of ZPR1 can rescue RLRC assembly in SETX-deficient cells but not vice versa. To uncover the mechanism of R-loop resolution, we examined the function of SETX-ZPR1 complexes using two genetic motor neuron disease models with altered R-loop resolution. Notably, chronic low levels of SETX-ZPR1 complexes onto R-loops result in a decrease of R-loop resolution activity causing an increase in R-loop levels in spinal muscular atrophy (SMA). ZPR1 overexpression increases recruitment of SETX onto R-loops, decreases R-loops and rescues the SMA phenotype in motor neurons and patient cells. Strikingly, interaction of SETX with ZPR1 is disrupted in ALS4 patients that have heterozygous SETX (L389S) mutation. ZPR1 fails to recruit the mutant SETX homodimer but recruits the heterodimer with partially disrupted interaction between SETX and ZPR1. Interestingly, disruption of SETX-ZPR1 complexes causes increase in R-loop resolution activity leading to fewer R-loops in ALS4. Modulation of ZPR1 levels regulates R-loop accumulation and rescues the pathogenic R-loop phenotype in ALS4 patient cells. These findings originate a new concept, "opposite alterations in a cell biological activity (R-loop resolution) result in similar pathogenesis (neurodegeneration) in different genetic motor neuron disorders". We propose that ZPR1 collaborates with SETX and may function as a molecular brake to regulate SETX-dependent R-loop resolution activity critical for the normal functioning of motor neurons.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}