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Role of copper in central nervous system physiology and pathology

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Neural Regeneration Research 2025年第4期20卷 1058-1068页

作者： Martina Locatelli Cinthia Farina Institute of Experimental Neurology Division of NeuroscienceIstituto di Ricovero e Cura a Carattere Scientifico(IRCCS)San Raffaele Scientific InstituteMilanItaly Vita-salute san raffaele university MilanItaly

Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

关键词： astrocytes central nervous system copper cuprizone multiple sclerosis myelin neurodegenerative disorders

Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

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Neural Regeneration Research 2025年第4期20卷 1009-1014页

作者： Antonio Masone Chiara Zucchelli Enrico Caruso Giovanna Musco Roberto Chiesa Laboratory of Prion Neurobiology Department of NeuroscienceIstituto di Ricerche Farmacologiche Mario Negri IRCCSMilanItaly Biomolecular NMR Unit Division of Genetics and Cell BiologyIRCCS Ospedale San RaffaeleMilanItaly Department of Biotechnology and Life Sciences University of InsubriaVareseItaly

PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.

关键词： anti-prion drug anti-PrPC antibody antisense oligonucleotide neurodegeneration pharmacological chaperone porphyrin prion disease PrPC degrader PrPC shedding zinc finger repressor

Improving performance of robotic liver resections with high technical complexity by Robo-Lap approach

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Hepatobiliary Surgery and Nutrition 2023年第6期12卷 981-986页

作者： Francesca Ratti Rebecca Marino Luca Aldrighetti Hepatobiliary Surgery Division IRCCS Ospedale San RaffaeleMilanItaly Vita-salute san raffaele university MilanItaly

Introduction The hybrid robotic-laparoscopic technique has been described-in the field of hepatic surgery-in order to overcome procedural challenges related to the lack of the robotic ultrasonic dissector(1-4):Robo-Lap approach hence combines the use of the robotic platform(specifically robotic bipolar forceps for coagulation and scissors)with the laparoscopic dissector handled by the surgeon at the table.

关键词： robotic handle approach

Endoscopic ultrasound radiofrequency ablation of pancreatic insulinoma in elderly patients:Three case reports

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World Journal of Clinical Cases 2022年第19期10卷 6514-6519页

作者： Gemma Rossi Maria Chiara Petrone Gabriele Capurso Stefano Partelli Massimo Falconi Paolo Giorgio Arcidiacono Division of Pancreato-Biliary Endoscopy and Endosonography Pancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSVita-Salute San Raffaele UniversityMilano 20132Italy Department of Pancreatic Surgery Pancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSVita-Salute San Raffaele UniversityMilano 20132Italy

BACKGROUND Endoscopic ultrasound(EUS)-guided radiofrequency ablation(RFA)has recently been proposed as a local treatment for functional pancreatic neuroendocrine neoplasms in patients unfit for surgery,in order to obtain clinical syndrome regression.Data on the safety and long-term effectiveness of this approach are scarce,and EUS-RFA procedures are not standardized.CASE SUMMARY The present case series reports 3 elderly patients with a pancreatic insulinoma and comorbidities,locally treated by EUS-guided RFA with clinical success in terms of hypoglycemic symptoms.RFA procedures were performed during deep sedation,under EUS control with a 19 G needle,an electrode 5-mm in size at a power of 30 W and multiple RFA applications during the same session in order to treat the whole area of the lesions.Immediate relief of symptoms was evident in 2 patients after the first EUS-RFA,while in the third patient a second endoscopic treatment was needed.All 3 patients are symptom-free without need of medications after 24 mo of follow-up with imaging follow-up showing no disease recurrence.A single adverse event of intraprocedural bleeding occurred,which was successfully treated endoscopically.CONCLUSION EUS-RFA represents an effective and safe alternative to surgery for the treatment of insulinomas in elderly patients at high surgical risk.However,larger multicenter studies withlonger follow-up are needed in order to better assess its safety and clinical success.

关键词： Endoscopic ultrasound Radiofrequency ablation Insulinomas Neuroendocrine neoplasms Ablative therapies Case report

Poke And Delayed Drink Intertemporal Choice Task(POKE-ADDICT):An open-source behavioral apparatus for intertemporal choice testing in rodents

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Animal Models and Experimental Medicine 2023年第6期6卷 619-626页

作者： Andrea Stefano Moro Daniele Saccenti Alessia Seccia Mattia Ferro Antonio Malgaroli Jacopo Lamanna Department of Psychology Sigmund Freud UniversityMilanItaly Center for Behavioral Neuroscience and Communication(BNC) Vita-Salute San Raffaele UniversityMilanItaly Transcranial Magnetic Stimulation Unit Italian Psychotherapy ClinicsMilanItaly Faculty of Psychology Vita-Salute San Raffaele UniversityMilanItaly san raffaele Turro IRCCS Ospedale San RaffaeleMilanItaly

Advancements in neuroscience research present opportunities and challenges,requiring substantial resources and funding.To address this,we describe here“Poke And Delayed Drink Intertemporal Choice Task(POKE-ADDICT)”,an open-source,versatile,and cost-effective apparatus for intertemporal choice testing in rodents.This allows quantification of delay discounting(DD),a cross-species phenomenon observed in decision making which provides valuable insights into higher-order cognitive functioning.In DD,the subjective value of a delayed reward is reduced as a function of the delay for its receipt.Using our apparatus,we implemented an effective intertemporal choice paradigm for the quantification of DD based on an adjusting delayed amount(ADA)algorithm using mango juice as a reward.Our paradigm requires limited training,a few 3D-printed parts and inexpensive electrical components,including a Raspberry Pi control unit.Furthermore,it is compatible with several in vivo procedures and the use of nose pokes instead of levers allows for faster task learning.Besides the main application described here,the apparatus can be further extended to implement other behavioral tests and protocols,including standard operant conditioning.In conclusion,we describe a versatile and cost-effective design based on Raspberry Pi that can support research in animal behavior,decision making and,more specifically,delay discounting.

关键词： decision making delay discounting intertemporal choice open source

Endoluminal vacuum-assisted therapy to treat rectal anastomotic leakage:A critical analysis

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World Journal of Gastroenterology 2022年第14期28卷 1394-1404页

作者： Andrea Vignali Paola De Nardi Department of Gastrointestinal Surgery IRCCS San Raffaele Scientific InstituteMilano 20132Italy Department of Surgery Vita-Salute UniversityMilano 20132Italy

Endoluminal vacuum-assisted therapy(EVT)has been introduced recently to treat colorectal anastomotic leaks in clinically stable non-peritonitic patients.Its application has been mainly reserved to low colorectal and colo-anal anastomoses.The main advantage of this new procedure is to ensure continuous drainage of the abscess cavity,to promote and to accelerate the formation of granulation tissue resulting in a reduction of the abscess cavity.The reported results are promising allowing a higher preservation of the anastomosis when compared to conventional treatments that include trans-anastomotic tube placement,percutaneous drainage,endoscopic clipping of the anastomotic defect or stent placement.Nevertheless,despite this procedure is gaining acceptance among the surgical community,indications,inclusion criteria and definitions of success are not yet standardized and extremely heterogeneous,making it difficult to reach definitive conclusions and to ascertain which are the real benefits of this new procedure.Moreover,long-term and functional results are poorly reported.The present review is focused on critically analyzing the theoretical benefits and risks of the procedure,short-and long-term functional results and future direction in the application of EVT.

关键词： Anastomotic leakage Rectal surgery Endoluminal vacuum therapy Endosponge Complications

Feasibility of therapeutic endoscopic ultrasound in the bridge-to-surgery scenario:The example of pancreatic adenocarcinoma

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World Journal of Gastroenterology 2022年第10期28卷 976-984页

作者： Giuseppe Vanella Domenico Tamburrino Gabriele Capurso Michiel Bronswijk Michele Reni Giuseppe Dell'Anna Stefano Crippa Schalk Van der Merwe Massimo Falconi Paolo Giorgio Arcidiacono Pancreatobiliary Endoscopy and EUS Division Pancreas Translational&Clinical Research CenterIRCCS San Raffaele Scientific InstituteVita-Salute San Raffaele UniversityMilan 20132Italy Pancreatic Surgery Unit Pancreas Translational&Clinical Research CenterIRCCS San Raffaele Scientific InstituteVita-Salute San Raffaele UniversityMilan 20132Italy Department of Gastroenterology and Hepatology University Hospital GasthuisbergUniversity of LeuvenLeuven 3000Belgium Department of Gastroenterology and Hepatology Imelda HospitalBonheiden 2820Belgium Department of Medical Oncology Pancreas Translational&Clinical Research CenterIRCCS San Raffaele Scientific InstituteMilan 20132Italy

Upfront resection is becoming a rarer indication for pancreatic ductal adenocarcinoma,as biologic behavior and natural history of the disease has boosted indications for neoadjuvant treatments.Jaundice,gastric outlet obstruction and acute cholecystitis can frequently complicate this window of opportunity,resulting in potentially deleterious chemotherapy discontinuation,whose resumption relies on effective,prompt and long-lasting management of these complications.Although therapeutic endoscopic ultrasound(t-EUS)can potentially offer some advantages over comparators,its use in potentially resectable patients is primal and has unfairly been restricted for fear of potential technical difficulties during subsequent surgery.This is a narrative review of available evidence regarding EUS-guided choledochoduodenostomy,gastrojejunostomy and gallbladder drainage in the bridge-to-surgery scenario.Proof-ofconcept evidence suggests no influence of t-EUS procedures on outcomes of eventual subsequent surgery.Moreover,the very high efficacy-invasiveness ratio over comparators in managing pancreatic cancer-related symptoms or complications can provide a powerful weapon against chemotherapy discontinuation,potentially resulting in higher subsequent resectability.Available evidence is discussed in this short paper,together with technical notes that might be useful for endoscopists and surgeons operating in this scenario.No published evidence supports restricting t-EUS in potential surgical candidates,especially in the setting of pancreatic cancer patients undergoing neoadjuvant chemotherapy.Bridge-to-surgery tEUS deserves further prospective evaluation.

关键词： Endosonography Gastrojejunostomy Choledochoduodenostomy Gallbladder drainage Pancreatic cancer Pancreatic surgery

Multidisciplinary management of patients diagnosed with von Hippel-Lindau disease: A practical review of the literature for clinicians

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Asian Journal of Urology 2022年第4期9卷 430-442页

作者： Alessandro Larcher Federico Belladelli Giuseppe Fallara Isaline Rowe Umberto Capitanio Laura Marandino Daniele Raggi Jody Filippo Capitanio Michele Bailo Rosangela Lattanzio Costanza Barresi Sonia Francesca Calloni Maurizio Barbera Valentina Andreasi Giorgia Guazzarotti Giovanni Pipitone Paola Carrera Andrea Necchi Pietro Mortini Francesco Bandello Andrea Falini Stefano Partelli Massimo Falconi Francesco De Cobelli Andrea Salonia Ospedale san raffaele VHL Research Program MilanItaly URI-Urological Research Institute Department of UrologyDivision of Experimental OncologyIRCCS Ospedale San RaffaeleMilanItaly Universita Vita-salute san raffaele MilanItaly Department of Oncology IRCCS Ospedale San RaffaeleMilanItaly Department of Neurosurgery IRCCS Ospedale San RaffaeleMilanItaly Department of Ophthalmology IRCCS Ospedale San RaffaeleMilanItaly Department of Neuroradiology IRCCS Ospedale San RaffaeleMilanItaly Pancreas Translational&Clinical Research Center OSR ENETS Center of ExcellenceUnit of Pancreatic SurgeryIRCCS Ospedale San RaffaeleMilanItaly Department of Radiology IRCCS Ospedale San RaffaeleMilanItaly Service of Laboratory Medicine Molecular Genetics Service and Clinical Genomics

Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau(VHL)syndrome.Methods:A non-systematic narrative review of original articles,meta-analyses,and random-ized trials was conducted,including articles in the pre-clinical setting to support relevant find-ings.Results:VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma.Affected individuals inherit a germline mutation in one VHL allele,and any somatic event that disrupt the other allele can trigger mutations,chromosomal rearrange-ments,or epigenetic regulations leading to oncogenesis.From a clinical perspective,patients continuously develop multiple primary tumors.Conclusion:Because VHL is considered a rare disease,very limited evidence is available for diagnosis,surveillance,active treatment with local or systemic therapy and follow-up.

关键词： Von Hippel-Lindau disease Rare tumor Genetic syndrome Clear cell renal cell carcinoma

Advancing the field of rare genitourinary tumors:Challenges and opportunities

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Asian Journal of Urology 2022年第4期9卷 347-348,F0002页

作者： Philippe E.Spiess Andrea Necchi Department of Genitourinary Oncology and Tumor Biology Moffitt Cancer CenterTampaUSA Vita salute san raffaele university and Urological Research Institute IRCCS San Raffaele Hospital and Scientific InstituteMilanItaly

Firstly,I would like to congratulate the editorial team of the Asion Journol of Urology for dedicating a speclial isue of the joumal to this important toplc.With recent advances in our fundamental understanding of the... 详细信息

关键词： urinary tumors rare