Hepatic PPARs: their role in liver physiology, fibrosis and treatment

Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease

Multipair approach to pairing in nuclei

The ground state of a general pairing Hamiltonian for a finite nuclear system is constructed as a product of collective, real, distinct pairs. These are determined sequentially via an iterative variational procedure that resorts to diagonalizations of the Hamiltonian in restricted model spaces. Different applications of the method are provided that include comparisons with exact and projected BCS results. The quantities that are examined are correlation energies, occupation numbers and pair transfer matrix elements. In a first application within the picket-fence model, the method is seen to generate the exact ground state for pairing strengths confined in a given range. Further applications of the method concern pairing in spherically symmetric mean fields and include simple exactly solvable models as well as some realistic calculations for middle-shell Sn isotopes. In the latter applications, two different ways of defining the pairs are examined: either with J=0 or with no well-defined angular momentum. The second choice reveals to be more effective leading, under some circumstances, to solutions that are basically exact.Comment: To appear in Physical Review

AB0563 AORTIC ROOT DILATION IN ASSOCIATED WITH THE REDUCTION OF CAPILLARY DENSITY OBSERVED AT NAILFOLD CAPILLAROSCOPY IN SSC PATIENTS

Background:Systemic sclerosis (SSc) in a chronic autoimmune disease characterized by endothelial dysfunction and diffuse microangiopathy, leading to tissue ischemia and inducing fibrosis of skin and visceral organs. Furthermore, it was demonstrated the impairment of wall elasticity of large-medium vessels, such as aorta and its branches (1). SSc-related microangiopathy of vasa vasorum of the aortic wall could also be supposed. However no data on this hypothesis are available in literature.SSc microangiopathy may be easily studied at the nailfold by means of videocapillaroscopy. Indeed, capillaroscopic findings are representative of the microvascular damage caused by SSc troughout the body.Objectives:we aimed to investigate the presence of aortic root dilation, classical sign of aortic wall damage, in a cohort of SSc patients, and to correlate these findings with the capillaroscopic patterns (early, active, and late, according to Cutolo's classification (2)).Methods:we recruited 125 SSc patients (M/F: 14/111, mean age 55+/-12.7 years, median disease duration 11 years) in 3 Rheumatology Centres in Sicily, Italy, from January to December 2019.Transthoracic echocardiogram with aortic root diameter measurement was carried out in all patients. Moreover, videocapillaroscopy with identification of early, active, or late SSc patterns was performed in the whole case series. Patients with early SSc pattern formed the subgroup 1, while those with the active or late patterns (both characterized by the reduction of capillary density) the subgroup 2.Results:we identified 8 (6.4%) SSc patients with aortic root dilation (diameter > 35 mm). Their age and their frequencies of cardiovascular risk factors were similar to the whole series. Moreover, videocapillaroscopy showed 62 (49.6%) early, 47 (37.6%) active, and 16 (12.8%) late SSc patterns.Aortic root dilation was observed in only one patient in the subgroup 1 (1/62, 1.6%), and in 7 cases of the subgroup 2 (7/63, 11.1%); p=0.03.Conclusion:in this multicentre study, we found that aortic root dilation is significantly associated with the reduction of capillary density at nailfold capillaroscopy (active or late SSc patterns). On the basis of these findings, we might argue that SSc-related microangiopathy of vasa vasorum could contribute to aortic wall damage, at least in a subset of SSc patients.References:[1]Bartoloni E, Pucci G, Cannarile F, Battista F, Alunno A, Giuliani M, Cafaro G, Gerli R, Schillaci G. Central hemodynamics and arterial stiffness in systemic sclerosis. Hypertension 2016; 68:1504-1511. 2.Cutolo M, Matucci-Cerinic M. Nailfold capillaroscopy and classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007; 25:663-665.Disclosure of Interests:Michele Colaci: None declared, Ylenia Dal Bosco: None declared, Claudia Schinocca: None declared, Maria Letizia Aprile: None declared, Giuliana Guggino Grant/research support from: Pfizer, Celgene, Speakers bureau: Celgene, Sandoz, Pfizer, Ilenia De Andres: None declared, Alessandra Azzurra Russo: None declared, Gianluca Sambataro: None declared, Domenico Sambataro: None declared, Lorenzo Malatino: None declare

New Frontiers in the Treatment of Patients with HER2+ Cancer and Brain Metastases: Is Radiotherapy Always Useful?

Brain metastases (BM) pose a significant challenge in the management of HER2+ breast cancer since almost 50% of patients with HER2+ breast cancer develop brain tumors. The complex process of brain metastases involves genetic mutations, adaptations and mechanisms to overcome the blood–brain barrier. While radiotherapy is still fundamental in local therapy, its use is associated with cognitive adverse effects and limited long-term control, necessitating the exploration of alternative treatments. Targeted therapies, including tyrosine kinase inhibitors, monoclonal antibodies, and antibody–drug conjugates, offer promising options for HER2+ breast cancer patients with BM. Clinical trials have demonstrated the efficacy of these agents in controlling tumor growth and improving patient outcomes, posing the question of whether radiotherapy is always the unique choice in treating this cancer. Ongoing research into novel anti-HER2 antibodies and innovative combination therapies holds promise for advancing treatment outcomes and enhancing patient care in this clinical scenario. This narrative review provides a comprehensive overview of traditional medical treatments, molecularly targeted therapy and investigational agents in the management of HER2+ breast cancer with BM, highlighting the evolving landscape and potential future directions in treatment strategies to improve patient survival and quality of life

Increased Functional Connectivity in the Default Mode Network in Mild Cognitive Impairment: A Maladaptive Compensatory Mechanism Associated with Poor Semantic Memory Performance

Semantic memory decline and changes of default mode network (DMN) connectivity have been reported in mild cognitive impairment (MCI). Only a few studies, however, have investigated the role of changes of activity in the DMN on semantic memory in this clinical condition. The present study aimed to investigate more extensively the relationship between semantic memory impairment and DMN intrinsic connectivity in MCI. Twenty-one MCI patients and 21 healthy elderly controls matched for demographic variables took part in this study. All participants underwent a comprehensive semantic battery including tasks of category fluency, visual naming and naming from definition for objects, actions and famous people, word-association for early and late acquired words and reading. A subgroup of the original sample (16 MCI patients and 20 healthy elderly controls) was also scanned with resting state functional magnetic resonance imaging and DMN connectivity was estimated using a seed-based approach. Compared with healthy elderly, patients showed an extensive semantic memory decline in category fluency, visual naming, naming from definition, words-association, and reading tasks. Patients presented increased DMN connectivity between the medial prefrontal regions and the posterior cingulate and between the posterior cingulate and the parahippocampus and anterior hippocampus. MCI patients also showed a significant negative correlation of medial prefrontal gyrus connectivity with parahippocampus and posterior hippocampus and visual naming performance. Our findings suggest that increasing DMN connectivity may contribute to semantic memory deficits in MCI, specifically in visual naming. Increased DMN connectivity with posterior cingulate and medio-temporal regions seems to represent a maladaptive reorganization of brain functions in MCI, which detrimentally contributes to cognitive impairment in this clinical population

Second- and Third-Line Chemotherapy in Advanced Gastric Cancer: a Real-Life Clinical Picture

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Contribution of pulmonary function tests (PFTs) to the diagnosis and follow up of connective tissue diseases

Introduction: Connective Tissue Diseases (CTDs) are systemic autoimmune conditions characterized by frequent lung involvement. This usually takes the form of Interstitial Lung Disease (ILD), but Obstructive Lung Disease (OLD) and Pulmonary Artery Hypertension (PAH) can also occur. Lung involvement is often severe, representing the first cause of death in CTD. The aim of this study is to highlight the role of Pulmonary Function Tests (PFTs) in the diagnosis and follow up of CTD patients. Main body: Rheumatoid Arthritis (RA) showed mainly an ILD with a Usual Interstitial Pneumonia (UIP) pattern in High-Resolution Chest Tomography (HRCT). PFTs are able to highlight a RA-ILD before its clinical onset and to drive follow up of patients with Forced Vital Capacity (FVC) and Carbon Monoxide Diffusing Capacity (DL CO ). In the course of Scleroderma Spectrum Disorders (SSDs) and Idiopathic Inflammatory Myopathies (IIMs), DL CO appears to be more sensitive than FVC in highlighting an ILD, but it can be compromised by the presence of PAH. A restrictive respiratory pattern can be present in IIMs and Systemic Lupus Erythematosus due to the inflammatory involvement of respiratory muscles, the presence of fatigue or diaphragm distress. Conclusions: The lung should be carefully studied during CTDs. PFTs can represent an important prognostic tool for diagnosis and follow up of RA-ILD, but, on their own, lack sufficient specificity or sensitivity to describe lung involvement in SSDs and IIMs. Several composite indexes potentially able to describe the evolution of lung damage and response to treatment in SSDs are under investigation. Considering the potential severity of these conditions, an HRCT jointly with PFTs should be performed in all new diagnoses of SSDs and IIMs. Moreover, follow up PFTs should be interpreted in the light of the risk factor for respiratory disease related to each disease

Extension of random-phase approximation preserving energy weighted sum rules: an application to a 3-level Lipkin model

A limitation common to all extensions of random-phase approximation including only particle-hole configurations is that they violate to some extent the energy weighted sum rules. Considering one such extension, the improved RPA (IRPA), already used to study the electronic properties of metallic clusters, we show how it can be generalized in order to eliminate this drawback. This is achieved by enlarging the configuration space, including also elementary excitations corresponding to the annihilation of a particle (hole) and the creation of another particle (hole) on the correlated ground state. The approach is tested within a solvable 3-level model.Comment: 2 figure

The Consistency and Quality of ChatGPT Responses Compared to Clinical Guidelines for Ovarian Cancer: A Delphi Approach

Introduction: In recent years, generative Artificial Intelligence models, such as ChatGPT, have increasingly been utilized in healthcare. Despite acknowledging the high potential of AI models in terms of quick access to sources and formulating responses to a clinical question, the results obtained using these models still require validation through comparison with established clinical guidelines. This study compares the responses of the AI model to eight clinical questions with the Italian Association of Medical Oncology (AIOM) guidelines for ovarian cancer. Materials and Methods: The authors used the Delphi method to evaluate responses from ChatGPT and the AIOM guidelines. An expert panel of healthcare professionals assessed responses based on clarity, consistency, comprehensiveness, usability, and quality using a five-point Likert scale. The GRADE methodology assessed the evidence quality and the recommendations’ strength. Results: A survey involving 14 physicians revealed that the AIOM guidelines consistently scored higher averages compared to the AI models, with a statistically significant difference. Post hoc tests showed that AIOM guidelines significantly differed from all AI models, with no significant difference among the AI models. Conclusions: While AI models can provide rapid responses, they must match established clinical guidelines regarding clarity, consistency, comprehensiveness, usability, and quality. These findings underscore the importance of relying on expert-developed guidelines in clinical decision-making and highlight potential areas for AI model improvement