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Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1132-1146页

作者： Gian Luca Rampioni Vinciguerra Marina Capece Luca Reggiani Bonetti Giovanni Nigita Federica Calore Sydney Rentsch Paolo Magistri Roberto Ballarin Fabrizio di Benedetto Rosario distefano Roberto Cirombella Andrea Vecchione Barbara Belletti Gustavo Baldassarre Francesca Lovat Carlo M.Croce Department of Cancer Biology and Genetics and Comprehensive Cancer Center The Ohio State UniversityColumbus 43210 OHUSA Department of Clinical and Molecular Medicine Faculty of Medicine and PsychologySant’Andrea HospitalUniversity of Rome“Sapienza”Rome 00189Italy Department of diagnostic Clinic and Public Health MedicineUniversity of Modena and Reggio EmiliaModena 41100Italy Hepato-pancreato-biliary Surgery and Liver Transplantation Unit University of Modena and Reggio EmiliaModena 41100Italy division of Molecular Oncology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano 33081Italy

Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease,characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient *** aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor *** of the onco-suppressor miR-15a has been extensively documented in ***,we identified the transcription factor Fos-related antigen-2(Fra-2)as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient *** report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC ***,we discovered that miR-15a repressed IGF1R expression via Fra-2 *** miR-15a-low context,IGF1R hyperactivated mTOR,modulated the autophagic flux and sustained PDAC growth in nutrient *** a genetic mouse model,Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet ***,nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent ***,our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.

关键词： IGF1R Fra miR

enhancing sensitivity of triple-negative breast cancer to DNA-damaging therapy through chemical inhibition of the m6A methyltransferase MeTTL3

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Cancer Communications 2024年第2期44卷 282-286页

作者： Bianca Cesaro Alessia Iaiza Fabio Piscopo Marco Tarullo eleonora Cesari Dante Rotili Antonello Mai Alberto diana Michela Londero Luca Del Giacco Riccardo Masetti Alba di Leone Chiara Naro Silvia Masciarelli Giulia Fontemaggi Claudio Sette Francesco Fazi Alessandro Fatica Department of Anatomical HistologicalForensic&Orthopedic SciencesSection of Histology&Medical EmbryologySapienza University of RomeRomeItaly Department of Biology and Biotechnologies“Charles Darwin” Sapienza University of RomeRomeItaly GSTeP Organoids Research Core Facility Fondazione Policlinico A.Gemelli Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)RomeItaly Department of Drug Chemistry and Technologies Sapienza University of RomeRomeItaly Pasteur Institute Cenci-Bolognetti FoundationSapienza University of RomeRomeItaly Department of BioSciences University of MilanMilanItaly Multidisciplinary Breast Center Dipartimento Scienze della Salute della Donna e del Bambino e di SanitàPubblicaCatholic University of the Sacred HeartRomeItaly Department of Neuroscience Section of Human AnatomyCatholic University of the Sacred HeartRomeItaly Oncogenomic and epigenetic Unit IRCCS Regina Elena National Cancer InstituteRomeItaly

Dear editor,N 6-methyladenosine(m^(6)A)is a critical mRNA modi-fication catalyzed by the enzyme methyltransferase-like 3(MeTTL3),with implications in RNA ***3 upregulation is associated with cancer progres-sion,metast... 详细信息

关键词： cancer methyltransferase metastasis

Loss of CDKN1B induces an age-related clonal hematopoietic disorder via Notch2 activity dysregulation

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Cancer Communications 2023年第7期43卷 844-849页

作者： Ilenia Segatto Gian Luca Rampioni Vinciguerra Ilenia Pellarin Alessandra Dall’Acqua Stefania Berton Francesca Citron Sara D’Andrea Giorgia Mungo Davide Viotto Lorena Musco Arianna di Napoli Maria Antonietta Aloe Spiriti Vincenzo Canzonieri Valter Gattei Andrea Vecchione Barbara Belletti Gustavo Baldassarre division of Molecular Oncology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano(PN)Italy Department of Clinical and Molecular Medicine University of Rome“La Sapienza”Santo Andrea HospitalRomeItaly division of Pathology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano(PN)Italy division of Clinical and experimental Onco-Hematology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano(PN)Italy

Dear editor,The tumor suppressor gene CDKN1B,encoding for the p27^(Kip1)(p27)protein,defines the smallest region of deletion on chromosome 12p13 described in clonal hematopoietic disorders(CHDs)[1].Among them,myelodysplastic syndromes(MDSs)display typical onset in the elderly and an indolent behavior that may evolve in acute myeloid leukemia(AML)[2].Recent evidences support a model of parallel clonal evolution at the stem or progenitor cell level and implicate the need of more preclinical,translational and clinical research to identify better ways to timely target clones that may evolve toward malignancy[3,4].

关键词： hematopoietic clinical acute

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Neural Regeneration Research 2013年第17期8卷 1615-1622页

作者： Letteria Spadaro Lilla Bonanno Giuseppe di Lorenzo Placido Bramanti Silvia Marino istituto di ricovero e cura a carattere scientifico Centro Neurolesi "Bonino Pulejo" Via Provinciale Palermo

Parkinson＇s disease has a negative impact on health-related quality of life in Parkinson＇s disease patients. Depression, cognitive impairment, coping strategies, dyskinesia, gait disorders and complications of dopaminergic drugs are the variables that most affect health-related quality of life. The ecological model of human development focuses attention on both individual and social environmental factors as targets for health interventions. From this perspective, the aim of this cross-sectional survey was to evaluate the influence of gender, family size and perceived autonomy on health-related quality of life in Parkinson＇s disease patients in nOrtheastern Sicily, Italy. Ninety Parkinson＇s disease patients, attending the Movement disorders Clinic at IRCCS Centro Neurolesi ＂Bonino-Pulejo＂（Messina）, were consecutively enrolled. The Unified Parkinson disease Rating Scale motor subscale （UPDRS-Ⅲ） scores, the Parkinson disease Questionnaire-39 Item scores （as a disease-specific measure of health-related quality of life）, scores on the Short Form （36） Health Survey Questionnaire （as a generic measure）, and answers to a brief checklist were recorded. A total of 85 Parkinson＇s disease patients （49% males and 51% females; mean age 70.8 ± 8.6 years mean UPDRS-Ⅲ 24.15 ± 6.55; mean disease duration 5.52 ± 4.65 years） completed the booklet of questionnaires. In the multivariate regression analysis, we included clinical and social variables as independent predictors of health-related quality of life. Our results suggest a potential compounding effect of ecological intrapersonal and interpersonal levels on health-related quality of life outcomes. Gender, self-evaluated autonomy and family size significantly impacted health-related quality of life. If quality of life is used as an indicator of treatment outcomes, an ecological perspective of the case history will be important to disclose relevant prognostic information and trigger personalized health care interventions.

关键词： neural regeneration neurodegenerative disease health-related quality of life Parkinson's disease ecological model Parkinson's disease Questionnaire-39 Items social variables the UnifiedParkinson disease Rating Scale motor subscales caregiver grants-supported paper

Anxiety,depression,and quality of life in Parkinson's disease:the implications of multidisciplinary treatment

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Neural Regeneration Research 2021年第3期16卷 587-590页

作者： Viviana Lo Buono Rosanna Palmeri Simona De Salvo Matteo Berenati Agata Greco Rosella Ciurleo Chiara Sorbera Vincenzo Cimino Francesco Corallo Placido Bramanti Silvia Marino Giuseppe di Lorenzo Lilla Bonanno Department of Neurobioimaging Istituto di Ricovero e Cura a Carattere Scientifico IRCCS Centro Neurolesi Bonino-PulejoMessinaItaly

Anxiety and depression in Parkinson's disease(PD)reduce well-being of the *** alterations influence motor skills and cognitive performance;moreover,they contribute significantly and independently to worsen rehabilitative treatment *** investigated anxiety,depression,and quality of life in PD patients subjected to multidisciplinary rehabilitative *** self-controlled study included 100 PD patients(49 males and 51 females with the mean age of 64.66 years)admitted to 60 days hospitalization rehabilitative program,between January 2017 and December ***,cognitive,linguistic abilities,and functional independence were evaluated at admission(T0 baseline visit)and 60 days after(T1)the multidisciplinary rehabilitation including motor exercises,speech therapies,and cognitive *** multidisciplinary rehabilitation improved functional status in PD patients and exerted its positive effects on mood,motor abilities,autonomy in the activities of daily life,perception of quality of life,cognitive performance and speech ***-motor symptoms may worsen severe disability and reduce quality of *** are often poorly recognized and inadequately ***,multidisciplinary rehabilitative training represents an optimal strategy to improve disease *** study was approved by Istituito di ricovero e cura a carattere scientifico(IRCCS)Centro Neurolesi"Bonino-Pulejo"ethical Committee(approval No.6/2016)in June 2016.

关键词： anxiety depression multidisciplinary rehabilitation Parkinson's disease

Polyphenols-gut microbiota interplay and brain neuromodulation

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Neural Regeneration Research 2018年第12期13卷 2055-2059页

作者： Stefania Filosa Francesco di Meo Stefania Crispi Institute of Biosciences and Bioresources National Research Council National Research Council via P. Castellino Naples Italy istituto di ricovero e cura a carattere scientifico neuromed Pozzilli Italy

Increasing evidence suggests that food ingested polyphenols can have beneficial effects in neuronal protection acting against oxidative stress and inflammatory injury. Moreover, polyphenols have been reported to promote cognitive functions. Biotransformation of polyphenols is needed to obtain metabolites active in brain and it occurs through their processing by gut microbiota. Polyphenols metabolites could directly act as neurotransmitters crossing the blood-brain barrier or indirectly by modulating the cerebrovascular system. The microbiota-gut-brain axis is considered a neuroendocrine system that acts bidirectionally and plays an important role in stress responses. The metabolites produced by microbiota metabolism can modulate gut bacterial composition and brain biochemistry acting as neurotransmitters in the central nervous system. Gut microbiota composition can be influenced by dietary ingestion of natural bioactive molecules such as probiotics, prebiotics and polyphenol. Microbiota composition can be altered by dietary changes and gastrointestinal dysfunctions are observed in neurodegenerative diseases. In addition, several pieces of evidence support the idea that alterations in gut microbiota and enteric neuroimmune system could contribute to onset and progression of these age-related disorders. The impact of polyphenols on microbiota composition strengthens the idea that maintaining a healthy microbiome by modulating diet is essential for having a healthy brain across the lifespan. Moreover, it is emerging that they could be used as novel therapeutics to prevent brain from neurodegeneration.

关键词： polyphenols gut-microbiota gut-brain axis metagenomic neurodegeneration neurotransmitters prebiotics probiotics

Topical delivery of nerve growth factor for treatment of ocular and brain disorders

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Neural Regeneration Research 2021年第9期16卷 1740-1750页

作者： Gemma eftimiadi Marzia Soligo Luigi Manni Daniela di Giuda Maria Lucia Calcagni Antonio Chiaretti Institute of Pediatrics Fondazione Policlinico Universitario Agostino GemelliIstituto di Ricovero e Cura a Carattere Scientifico(IRCCS)RomeItaly Institute of Translational Pharmacology Consiglio Nazionale delle Ricerche(CNR)RomeItaly Institute of Nuclear Medicine Fondazione Policlinico Universitario Agostino GemelliIstituto di Ricovero e Cura a Carattere Scientifico(IRCCS)RomeItaly

Neurotrophins are a family of proteins that support neuronal proliferation, survival, and differentiation in the central and peripheral nervous systems, and are regulators of neuronal plasticity. Nerve growth factor is one of the best-described neurotrophins and has advanced to clinical trials for treatment of ocular and brain diseases due to its trophic and regenerative properties. Prior trials over the past few decades have produced conflicting results, which have principally been ascribed to adverse effects of systemic nerve growth factor administration, together with poor penetrance of the blood-brain barrier that impairs drug delivery. Contrastingly, recent studies have revealed that topical ocular and intranasal nerve growth factor administration are safe and effective, suggesting that topical nerve growth factor delivery is a potential alternative to both systemic and invasive intracerebral delivery. The therapeutic effects of local nerve growth factor delivery have been extensively investigated for different ophthalmic diseases, including neurotrophic keratitis, glaucoma, retinitis pigmentosa, and dry eye disease. Further, promising pharmacologic effects were reported in an optic glioma model, which indicated that topically administered nerve growth factor diffused far beyond where it was topically applied. These findings support the therapeutic potential of delivering topical nerve growth factor preparations intranasally for acquired and degenerative brain disorders. Preliminary clinical findings in both traumatic and non-traumatic acquired brain injuries are encouraging, especially in pediatric patients, and clinical trials are ongoing. The present review will focus on the therapeutic effects of both ocular and intranasal nerve growth factor delivery for diseases of the brain and eye.

关键词： Alzheimer's disease eye drops group B streptococcus meningitis glioma intranasal delivery neurotrophic keratitis nerve growth factor proNGF stroke traumatic brain injury

efficacy of a therapeutic strategy for eradication of Helicobacter pylori infection

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World Journal of Gastroenterology 2012年第33期18卷 4542-4548页

作者： Giuliana Sereni Francesco Azzolini Lorenzo Camellini Debora Formisano Francesco Decembrino Veronica Iori Cristiana Tioli Maurizio Cavina Francesco di Mario Giuliano Bedogni Romano Sassatelli Unit of Gastroenterology and digestive endoscopy Arcispedale Santa Maria Nuova Istituto di Ricovero e Cura a Carattere Scientifico 42123 Reggio Emilia Italy Statistics and Clinical epidemiology Unit Arcispedale Santa Maria Nuova Istituto di Ricovero e Cura a Carattere Scientifico 42123 Reggio Emilia Italy Unit of Gastroenterology Ospedale S. Maria di Ca' Foncello 31100 Treviso Italy

AIM: To determine the efficacy of our therapeutic strategy for Helicobacter pylori (H. pylori) eradication and to identify predictive factors for successful eradication. MeTHODS: From April 2006 to June 2010, we retrospectively assessed 2428 consecutive patients (1025 men, 1403 women; mean age 55 years, age range 18-92 years) with gastric histology positive for H. pylori infection referred to our unit for 13-C urea breath test(UBT), after first-line therapy with proton pump inhibitor (PPI) b.i.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d. for 7 d. Patients who were still positive to UBT were recommended a second-line therapy (PPI b.i.d. + amoxicillin 1 g b.i.d. + tinidazole 500 mg b.i.d. for 14 d). Third choice treatment was empirical with PPI b.i.d. + amoxicillin 1 g b.i.d. + levofloxacin 250 mg b.i.d. for 14 d. ReSULTS: Out of 614 patients, still H. pylori-positive after first-line therapy, only 326 and 19 patients respectively rechecked their H. pylori status by UBT after the suggested second and third-line regimens. "Per protocol" eradication rates for first, second and thirdline therapy were 74.7% (95% CI: 72.7%-76.4%), 85.3% (95% CI: 81.1%-89.1%) and 89.5% (95% CI: 74.9%-103%) respectively. The overall percentage of patients with H. pylori eradicated after two treatments was 97.8% (95% CI: 97.1%-98.4%), vs 99.9% (95% CI: 99.8%-100%) after three treatments. The study found that eradication therapy was most effective in patients with ulcer disease (P especially in those with duodenal ulcer. Smoking habits did not significantly affect the eradication rate. CONCLUSION: First-line therapy with amoxicillin and clarithromycin produces an H. pylori eradication rate comparable or superior to other studies and secondline treatment can still be triple therapy with amoxicillin and tinidazole.

关键词： Helicobacter pylori eradication treatment Rescue therapy eradication rate Triple therapy Firstline therapy Second-line therapy

Polymorphism AGT2(rs4762)is involved in the development of dermatologic events:Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib

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World Journal of Hepatology 2022年第7期14卷 1438-1458页

作者： Víctor Sapena Massimo Iavarone Loreto Boix Floriana Facchetti Maria Guarino Marco Sanduzzi Zamparelli Alessandro Granito esther Samper Mario Scartozzi Josep Corominas Giorgia Marisi Alba Díaz Andrea Casadei-Gardini Laura Gramantieri Pietro Lampertico Filomena Morisco Ferran Torres Jordi Bruix María Reig Barcelona Clinic Liver Cancer Group Liver UnitHospital Clínic de BarcelonaInstitut d'Investigacions Biomèdiques August Pi SunyerCentro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelona 08036Spain Universidad de Barcelona Barcelona 08036Spain division of Gastroenterology and Hepatology Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca’Granda Ospedale Maggiore PoliclinicoMilano 20122Italy Department of Clinical Medicine and Surgery Gastroenterology UnitUniversity of Naples Federico IINaples 80131Italy Gastroenterology and Hepatology Unit Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica CàGranda Ospedale Maggiore PoliclinicoUniversity of MilanMilan 20100Italy Department of Clinical Medicine and Surgery Gastroenterology UnitUniversity of Naples"Federico II"Napoli 80100Italy Department of Clinical Medicine and Surgery Gastroenterology and HepatologyFederico II University of NaplesNaples 80131Italy division of Internal Medicine Hepatobiliary and Immunoallergic DiseasesIstituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero-Universitaria di BolognaBologna 40139Italy Department of Medical and Surgical Sciences University of BolognaBologna 40139Italy Department of Medical Oncology University of CagliariCagliari 45698Italy Biosciences Laboratory Istituto di Ricovero e Cura a Carattere Scientifico di Natura PubblicaIstituto Romagnolo per lo Studio dei Tumori“Dino Amadori”Meldola 47014Italy Department of Pathology Hospital Clínic de BarcelonaUniversitat de BarcelonaBarcelona 08036Spain School of Medicine Vita-Salute San Raffaele UniversityMilan 20132Italy Unit of Oncology UniversitàVita-SaluteIstituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica-San Raffaele Scientific InstituteMilan 20132Italy division of Internal Medicine Hepatobiliary and Immunoallergic DiseasesIstituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Aziend

BACKGROUND Dermatologic adverse events(DAes)are associated with a better outcome in patients with hepatocellular carcinoma(HCC)irrespective of the therapeutic agent *** exact mechanisms associated with the development of DAes are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors(TKIs)to the skin or an immune-mediated reaction triggered by the oncologic *** is the case in other conditions,individual genetic variants may partially explain a higher risk of *** To evaluate the contribution of several gene variants to the risk of developing DAes in HCC patients treated with *** We first analyzed 27 single-nucleotide polymorphisms(SNPs)from 12 genes selected as potential predictors of adverse event(Ae)development in HCC patients treated with sorafenib[Barcelona Clinic Liver Cancer 1(BCLC1)cohort].Three additional cohorts were analyzed for AGT1(rs699)and AGT2(rs4762)polymorphisms-initially identified as predictors of DAes:BCLC2(n=79),Northern Italy(n=221)and Naples(n=69)cohorts,*** relation between SNPs and DAes and death were assessed by univariate and multivariate Cox regression models,and presented with hazard ratios and their 95%confidence intervals(95%CI).ReSULTS The BCLC1 cohort showed that patients with arterial hypertension(AHT)(HR=1.61;P value=0.007)and/or AGT SNPs had an increased risk of ***,AGT2(rs4762)AA genotype was found to be linked to a statistically significant increased probability of DAes(HR=5.97;P value=0.0201,AA vs GG)in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage,eCOG-PS,diabetes and *** value of this genetic marker was externally validated in the cohort combining the BCLC1,BCLC2 and Naples cohorts[HR=3.12(95%CI:1.2-8.14),P value=0.0199,AGT2(rs4762)AA vs AG genotype and HR=2.73(95%CI:1.18-6.32)P value=0.0188,AGT2(rs4762)AA vs GG genotype].None of the other gene variants tested were found to be associated with the risk of D

关键词： HCC early DAe Single-nucleotide polymorphisms AGT1(rs699) AGT2(rs4762),Tyrosine kinase inhibitors