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Loss of CYLD promotes splenic marginal zone lymphoma
Full text linkSplenic marginal zone lymphoma (SMZL) is a distinct clinical and pathological entity among marginal zone lymphomas. Genetic and microenvironmental factors leading to aberrant activation of the NF-κB pathway have been implicated in SMZL pathogenesis. CYLD is a negative regulator of NF-κB and other signaling pathways acting as a deubiquitinase of regulatory molecules and has been reported as a tumor suppressor in different types of cancer, including B-cell malignancies. To assess whether CYLD is implicated in the natural history of SMZL, we profiled primary cells from patients with SMZL and SMZL cell lines for CYLD expression and functionality. We report that CYLD is downregulated in patients with SMZL and that CYLD ablation in vitro leads to NF-κB pathway hyperactivation, promoting the proliferation of SMZL cells. In addition, we found that CYLD deficiency was associated with increased migration of SMZL cells in vitro, through CCR7 receptor signaling, and with increased dissemination in vivo. CYLD loss was sufficient to induce BcR signaling, conferring increased resistance to ibrutinib treatment in vitro. In summary, our work uncovers a novel role of CYLD as a key regulator in SMZL pathogenesis, dissemination, and resistance to targeted agents. On these grounds, CYLD could be proposed as a novel target for patient stratification and personalized interventions
Zygoma Bone Shell Technique: A Proof-of-Concept Surgical Protocol in Human Cadaver for Bone Reconstruction After Zygomatic Implant Failure
Full text linkObjectivesThis article aims to present a proof-of-concept surgical technique for immediate reconstruction of zygoma anatomy following implant failure and complications, illustrating the related clinical steps in a cadaver specimen. Zygomatic implants represent a paradigm shift, addressing challenges posed by severe maxillary bone atrophy and partial or complete maxillectomy, not suitable for conventional dental implant placement. Despite documented high survival rates, intra- and postoperative complications can occur and lead to implant failure, resulting in severe defects extended up to entire height of zygomatic bone pyramid. Such defects may infringe immediate or delayed new implant placement, requiring complex surgical procedures to restore integrity of zygomatic bone anatomy.Material and MethodsThe three-dimensional reconstruction of zygomatic bone defect was achieved by specific form of guided bone regeneration or shell technique, using a thin cortical plate harvested from external oblique line of the mandible. After a meticulous mechanical debridement of bone defect resulting from implant removal, a thin cortical bone block was harvested from the mandibular ramus. The cleared bone defect was filled with autogenous bone chips and thin bone shell was secured above with a bone fixation screw.ResultsZygoma Bone Shell technique was able to restore contours of zygomatic pyramid ridge. The comparable composition between mandibular and zygomatic bone, particularly in the cortical region allowed an anatomical resemblance that facilitates optimal structural compatibility, fostering seamless integration of bone graft into zygomatic area.ConclusionsWithin limitations of this proof-of-concept, zygoma bone shell technique may offer a viable surgical procedure for immediate bone reconstruction after zygomatic implant failure. Translating the previously reported clinical outcomes of bone shell technique, it may be used same day of failing implant removal to achieve reconstruction of zygomatic anatomy with limited risk of postoperative complications. Further clinical studies are needed to confirm its predictability, reliability and anticipated benefits
Technological Advances in Healthcare and Medical Deontology: Towards a Hybrid Clinical Methodology
No full textThe rapid advancements in healthcare technologies are reshaping the medical landscape, prompting a reconsideration of clinical methodologies and their ethical foundations. This article explores the need for an updated approach to medical deontology, emphasizing the transition from traditional practices to a hybrid clinical methodology that integrates both human expertise and technological innovations. With the increasing use of Artificial Intelligence, data analytics, and advanced medical tools, healthcare professionals are presented with new ethical and professional challenges. These challenges demand a reevaluation of professional responsibility, highlighting the importance of scientific evidence in decision-making while mitigating the influence of economic and ideological factors. By framing medical practice within a systemic and integrated perspective, this article proposes a model that moves beyond the reductionist and anti-reductionist dualism, fostering a more realistic understanding of healthcare. This new paradigm necessitates the evolution of the Medical Code of Ethics, integrating the concept of "medical intelligence" to address the complexities of data management and its ethical implications. The article ultimately advocates for a dynamic and adaptive approach that aligns medical practice with emerging technologies, ensuring that patient care remains person-centered and ethically grounded in a rapidly changing healthcare environment
Effects of cognitive rehabilitation and exercise on brain structure in progressive multiple sclerosis: results from the CogEx trial
No full textBACKGROUND: We previously showed increased cortical grey matter (GM) volume in CogEx trial participants who performed cognitive rehabilitation (CR). Here, we explore combined CR and aerobic exercise (EX) effects on regional changes in brain volumes and white matter (WM) integrity. METHODS: Seventy-three patients were randomized into four groups receiving a combination of CR and EX or their sham versions: CR + EX, CR + EX-sham, EX + CR-sham, and CR-sham + EX-sham. A diagnosis of progressive multiple sclerosis (PMS) and impaired information processing speed were required for inclusion. Participants attended a 12-week intervention twice/week. Assessments were performed at baseline, week-12 (W12), and nine months post-baseline (M9). Structural MRI scans were acquired with a standardized protocol, and voxelwise variations of brain volumes and WM fractional anisotropy (FA) were analyzed. RESULTS: Baseline regional brain volumes and WM FA were comparable between groups. Voxelwise analyses at W12 and M9 revealed generalized volume reductions in all groups. We found different patterns of volumetric changes in the left inferior temporal gyrus between CR + EX and CR-sham + EX-sham, and in the right cerebellum crus II between EX + CR-sham and CR + EX-sham. WM FA values remained stable throughout the trial and no longitudinal between-group differences were found. CONCLUSIONS: Our analysis showed a decrease in brain volumes and limited effects of the combined CR + EX intervention, indicating that the previously found cortical GM increase was not superimposable at voxel level. Methodological and sampling differences between the studies could explain these discrepancies. In few cognitively relevant areas, the combined CR interventions might have affected patterns of volume changes, while EX modified cerebellar motor regions. CLINICAL TRIAL REGISTRATION: The main trial was registered on ClinicalTrials.gov (NCT03679468; registration date: 20 Sep 2018)
Testing for causal effect for binary data when propensity scores are estimated through Bayesian Networks
No full textThis paper proposes a new statistical approach for assessing treatment effect using Bayesian Networks (BNs). The goal is to draw causal inferences from observational data with a binary outcome and discrete covariates. The BNs are here used to estimate the propensity score, which enables flexible modeling and ensures maximum likelihood properties. When the propensity score is estimated by BNs, two point estimators are considered—Hájek and Horvitz–Thompson—based on inverse probability weighting, and their main distributional properties are derived for constructing confidence intervals and testing hypotheses about the absence of the treatment effect. Empirical evidence is presented to show the good behavior of the proposed methodology through a simulation study mimicking the characteristics of a real dataset of prostate cancer patients from Milan San Raffaele Hospital
Towards a Unified Set of Diagnostic Criteria for Multiple Sclerosis
No full textObjective: The 2017 McDonald criteria continued the separation of diagnostic criteria for relapsing–remitting multiple sclerosis (RRMS) and primary progressive MS (PPMS) for historical, rather than biological, reasons. We aimed to explore the feasibility of a single, unified set of diagnostic criteria when applied to patients with suspected PPMS. Methods: We retrospectively identified patients evaluated for suspected PPMS at 5 European centers. The 2017 McDonald PPMS criteria was the gold standard against which the 2017 McDonald RRMS dissemination in space (DIS) and dissemination in time criteria were evaluated. We also investigated modified RRMS DIS criteria, including: (i) optic nerve lesions; (ii) ≥2 spinal cord lesions; and (iii) higher fulfilment of DIS criteria alone (lesions in ≥3 regions) without dissemination in time/positive cerebrospinal fluid, for a diagnosis of PPMS. Results: A total of 282 patients were diagnosed with PPMS using the 2017 McDonald criteria, and 40 with alternate disorders. The 2017 McDonald RRMS DIS criteria and the modified DIS criteria including the optic nerve or ≥2 spinal cord lesions performed well in PPMS diagnosis when combined with dissemination in time/positive cerebrospinal fluid (sensitivity 92.9–95.4%, specificity 95%, accuracy 93.2–95.3%). A diagnosis of PPMS based on high fulfillment of modified RRMS DIS criteria had high specificity, but low sensitivity. A diagnostic algorithm applicable to patients evaluated for suspected MS is proposed. Interpretation: The 2017 McDonald RRMS criteria and modifications to DIS criteria, currently under consideration, performed well in PPMS diagnosis. Forthcoming revisions to the McDonald criteria should consider a single, unified set of diagnostic criteria for MS. ANN NEUROL 2024
Profilo di Franz Brentano
Full text linkObiettivo di questo profilo è di fornire una presentazione sinottica di alcuni tra i principali contributi di Franz Brentano al dibattito filosofico contemporaneo, in particolare per quanto riguarda gli ambiti della filosofia della psicologia e della filosofia della mente
How to handle polypharmacy in heart failure. A clinical consensus statement of the Heart Failure Association of the ESC
No full text: The multiplicity of coexisting comorbidities affecting patients with heart failure (HF), together with the availability of multiple treatments improving prognosis in HF with reduced ejection fraction, has led to an increase in the number of prescribed medications to each patient. Polypharmacy is defined as the regular use of multiple medications, and over the last years has become an emerging aspect of HF care, particularly in older and frailer patients who are more frequently on multiple treatments, and are therefore more likely exposed to tolerability issues, drug-drug interactions and practical difficulties in management. Polypharmacy negatively affects adherence to treatment, and is associated with a higher risk of adverse drug reactions, impaired quality of life, more hospitalizations and worse prognosis. It is important to adopt and implement strategies for the management of polypharmacy from other medical disciplines, including medication reconciliation, therapeutic revision and treatment prioritization. It is also essential to develop new HF-specific strategies, with the primary goal of avoiding the use of redundant treatments, minimizing adverse drug reactions and interactions, and finally improving adherence. This clinical consensus statement document from the Heart Failure Association of the European Society of Cardiology proposes a rationale, pragmatic and multidisciplinary approach to drug prescription in the current era of multimorbidity and 'multi-medication' in HF
Evaluation of the efficacy and safety of gene therapy strategies for liver metabolic diseases
No full textThe liver is a major metabolic organ involved in many genetic diseases. Over the years in vivo liver-directed gene therapy strategies have been developed as therapeutic approaches. Gene addition based on adeno-associated viral vectors (AAVs) has become an approved drug for the inherited coagulation disease hemophilia. However, other strategies, such as gene editing, are being developed to modify the hepatocyte genome. With CRISPR/Cas9-based gene editing it is possible to obtain targeted transgene insertions maintained upon hepatocyte proliferation. Transgene maintenance is fundamental for the treatment of metabolic disorders that have rapid manifestation and decline. Two of these metabolic disorders are Maple syrup urine disease (MSUD) and Progressive familial intrahepatic cholestasis type 2 (PFIC2). MSUD is caused by mutations in one of four different genes, we are concentrating on DBT, while PFIC2 is due to mutations of ABCB11. Gene editing may become a therapeutic strategy for MSUD and PFIC2, by integrating transgene cDNA in the first intron of DBT and ABCB11 genes, respectively, to maintain as much as possible physiological gene regulation. In this work, we tested different integration strategies and demonstrated that donor DNAs with short homology arms are the most efficient in integrating and expressing the transgene. Then, we showed that the coadministration of lipid nanoparticles (LNPs) and AAVs resulted in the highest integration rate. However, to develop gene editing for PFIC2 it is important to consider liver fibrosis, which causes alteration of liver architecture and metabolism. Here, we exploited two chemically induced and two genetic mouse models with different types and grades of liver fibrosis. We report that both pericentral and periportal fibrosis partially inhibited lentiviral vector (LV) and LNP-mediated hepatocyte gene transfer, while the efficiency of AAV-mediated transduction was reduced only in the presence of periportal fibrosis. Gene transfer was less impacted when liver fibrosis was milder. We also investigated the biodistribution of LV transduction among different organs and liver cell types, and the zonation in the liver lobule of LV-, AAV-, and LNP-mediated gene transfer. Overall, this work informs about the optimal strategy and timeframe of in vivo liver-directed genome editing for the treatment of MSUD and PFIC-2 and sheds light on the impact of liver fibrosis on hepatic gene transfer.Il fegato è un importante organo metabolico coinvolto in molte malattie genetiche. Nel corso degli anni sono state sviluppate come approcci terapeutici strategie di terapia genica dirette al fegato. L'aggiunta di geni basata su vettori virali adeno-associati (AAV) è diventata un farmaco approvato per l’emofilia, patologia ereditaria della coagulazione. Tuttavia, altre strategie per modificare il genoma degli epatociti, come l'editing genetico, sono in fase di sviluppo. Con l'editing genetico basato su CRISPR/Cas9 è possibile ottenere inserimenti mirati di transgeni che sono mantenuti durante la proliferazione degli epatociti. Il mantenimento dei transgeni è fondamentale per il trattamento di disturbi metabolici che hanno una rapida manifestazione e declino. Due di questi disturbi metabolici sono la malattia delle urine a sciroppo d'acero (MSUD) e la colestasi intraepatica familiare progressiva di tipo 2 (PFIC2). MSUD è causata da mutazioni in uno di quattro geni, noi ci stiamo concentrando su DBT, mentre PFIC2 è dovuta a mutazioni in ABCB11. L'editing genetico potrebbe diventare una strategia terapeutica per MSUD e PFIC2, integrando il cDNA del transgene nel primo introne dei geni DBT e ABCB11, rispettivamente, per mantenere il più possibile la regolazione fisiologica. In questo lavoro, abbiamo testato diverse strategie di integrazione e dimostrato che i DNA donatori con bracci di omologia corti sono i più efficienti nell'integrare ed esprimere il transgene. Quindi, abbiamo dimostrato che la co-somministrazione di nanoparticelle lipidiche (LNP) e AAV risulta nel più alto tasso di integrazione. Tuttavia, per sviluppare l'editing genetico per PFIC2 è importante considerare la fibrosi epatica, che causa alterazioni dell'architettura e del metabolismo del fegato. Qui, abbiamo sfruttato due modelli murini indotti chimicamente e due genetici con diversi tipi e gradi di fibrosi epatica. Riportiamo che sia la fibrosi pericentrale che quella periportale hanno inibito parzialmente il trasferimento genico agli epatociti mediato da vettori lentivirali (LV) e LNP, mentre l'efficienza della trasduzione mediata da AAV è stata ridotta solo in presenza di fibrosi periportale. Il trasferimento genico era meno impattato quando la fibrosi epatica era più lieve. Abbiamo anche studiato la biodistribuzione della trasduzione dei LV nei diversi organi e cellule epatiche e la zonazione nel lobulo epatico del trasferimento genico mediato da LV, AAV e LNP. Nel complesso, questo lavoro dà informazioni sulla strategia ottimale e sulla tempistica dell'editing genomico diretto al fegato per il trattamento di MSUD e PFIC-2 e fa luce sull'impatto della fibrosi epatica sul trasferimento genico agli epatociti