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Anna Sessa,1– 3 Sébastien Mulé,2– 4 Raffaele Brustia,2,3,5 Hélène Regnault,1,3 Athena Galletto Pregliasco,4 Rami Rhaiem,6,7 Vincent Leroy,1– 3 Daniele Sommacale,2,3,5 Alain Luciani,2– 4 Julien Calderaro,2,3,8 Giuliana Amaddeo1– 3 1Hepatology Department, APHP, Henri Mondor University Hospital, Créteil, France; 2Université Paris-Est Créteil, Faculté de Médecine, Créteil, France; 3Inserm, U955, Team 18, Créteil, France; 4Medical Imaging Department, AP-HP, Henri Mondor University Hospital, Créteil, France; 5Department of Digestive and Hepato-Pancreato-Biliary Surgery, AP-HP, Henri Mondor University Hospital, Créteil, France; 6Department of Hepato-Biliary Pancreatic and Digestive Oncological Surgery, Robert Debré University Hospital, Reims, France; 7Reims Champagne-Ardenne University, Reims, France; 8Department of Pathology, APHP, Henri Mondor University Hospital, Créteil, FranceCorrespondence: Giuliana Amaddeo; Anna Sessa, Hepatology Department, APHP, Henri Mondor University Hospital, 1 rue Gustave Eiffel, Créteil, 94000, France, Tel +33 149812353, Email giuliana.amaddeo@aphp.fr; asessa1990@gmail.comAbstract: The subject of this narrative review is macrotrabecular-massive hepatocellular carcinoma (MTM‐HCC). Despite their rarity, these tumours are of general interest because of their epidemiological and clinical features and for representing a distinct model of the interaction between the angiogenetic system and neoplastic cells. The MTM‐HCC subtype is associated with various adverse biological and pathological parameters (the Alfa-foetoprotein (AFP) serum level, tumour size, vascular invasion, and satellite nodules) and is a key determinant of patient prognosis, with a strong and independent predictive value for early and overall tumour recurrence. Gene expression profiling has demonstrated that angiogenesis activation is a hallmark feature of MTM-HCC, with overexpression of both angiopoietin 2 (ANGPT2) and vascular endothelial growth factor A (VEGFA).Keywords: hepatocellular carcinoma, macrotrabecular, angiopoietin 2 inhibitors, TP53, immunotherapy

Ground Source Heat Pumps (GSHP) are gaining interest for many applications and a very difficult task is to look at their affordability in urban environments with limited spaces. For this reason, the EU project GEO4CIVHIC has been funded. In order to set up different cases with different levels of retrofit and try to generalize results, the project focuses the activity on archetypes, i.e. buildings which may represent the usual type of building which may be found more frequently in urban environments around Europe. The analysis of the archetypes has been based on literature review and analysing the existing databases of buildings in Europe. The work allowed to determine a reference building for single family house and a building representing an apartment block for multi-users. In this latest case two types of possible uses have been examined: residential building and office building. In order to set up different levels of retrofit and cost-effective solutions, three different climates have been defined: warm climate, mild climate and cold climate. The climatic conditions do not only affect the energy demand of the building and the peak power needed for heating and cooling, but also determine different ways of buildings’ construction and define different levels of insulation. Last but not least, the buildings have been also subdivided into existing buildings, i.e. built up from 1960 to 2000 and historic buildings, i.e. buildings earlier than 1960. The paper presents the first step of the research which permitted to define the different archetypes, their dimensions and way they are constructed. Moreover, the different simulations allowed to define the energy needs of the buildings as well as the peak power for heating and cooling. This allows to create a matrix for the different levels of retrofit solutions which will be associated to related costs for a cost-benefit analysis to check the most achievable solutions.

Abstract Background One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. Methods/Design The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. Discussion The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia. Trial Registration Clincaltrials.gov Identifier: NCT00395915

Are first and second generation antipsychotics equally effective and safe for people with first-episode non-affective psychosis?METHODDesign: Randomised controlled trial.Allocation: Unclear.Blinding: Unclear.Follow-up period: Six weeks (treatment period only).Setting: One outpatient and one inpatient clinic at a university hospital, Cantabria, Spain; enrolment February 2001 to February 2005.Patients: 182 adults (15-60 years old; 93% antipsychotic naive) with non-affective psychotic disorder (DSM-IV) and psychotic symptoms of moderate severity or greater (Scale for the Assessment of Positive Symptoms). Exclusions: DSM-IV mental retardation, DSM-IV drug dependence, or >/= 6 weeks' total lifetime adequate antipsychotic treatment.Intervention: Haloperidol (3-9 mg/day; mean modal dose 5.4 mg/day) risperidone (3-6 mg/day; mean modal dose4 mg/day), or olanzapine (5-20 mg/day; mean modal dose 15.3 mg/day).Outcomes: Response (>/= 40% reduction in Brief Psychiatric Rating Scale score), adverse events including treatment-emergent parkinsonism (Simpson-Angus Scale >3) and akathisia (Barnes Akathisia Scale global score >/= 2).Patient follow-up: 95% included in last observation carried forward analyses.MAIN RESULTSAll treatments showed similar effectiveness in inducing response by the sixth week (% responders: 57.1% with haloperidol vs 52.5% with risperidone vs 63.6% with olanzapine; p = 0.476). Haloperidol increased parkinsonism compared with the second generation antipsychotics (46.6% with haloperidol vs 5.5% with olanzapine vs 24.6% with risperidone; p<0.001). Haloperidol also increased akathisia (55.4% with haloperidol vs 26.2% with risperidone vs 5.5% with olanzapine; p<0.001). Olanzapine increased weight gain compared to the other antipsychotics (% people with >/= 4 kg weight gain: 47% with olanzapine vs 23% with risperidone vs 9% with haloperidol; p<0.001). Olanzapine and haloperidol increased somnolence compared with risperidone (46% with olanzapine vs 46% with haloperidol vs 23% with risperidone; p = 0.012).CONCLUSIONSHaloperidol, risperidone and olanzapine are similarly effective for first-episode non-affective psychosis. Haloperidol increases parkinsonism and akathisia, while olanzapine increases weight gain. Both olanzapine and haloperidol increase somnolence. [ABSTRACT FROM AUTHOR]

The link between the gut environment and the prostate has recently been proposed as a potential therapeutic approach for treating benign prostatic hyperplasia (BPH). Therefore, this study examined the advantages of a novel oral probiotic supplement to improve intestinal health and treat BPH. A 3D intestinal barrier model that simulated oral intake was used to analyse the combined regulative abilities of Bifidobacterium longum and Bifidobacterium psychaerophilum . Then, a co-culture prostatic model was used to investigate the biological consequences of the combination under conditions mimicking BPH. The results show the connection between the gut microbiome and prostate disease since the probiotics successfully modulate the primary mechanism involved in the pathogenesis of BPH. Indeed, after the intestinal passage, the mediators released from B. longum and B. psychaerophilum induced a substantial decrease in reactive oxidative species of about 6 times and inflammation (about 5 times regarding interleukine-6 and 10) and a sharp increase in testosterone and serotonin levels (about 95%). Further, proliferation and BPH principal mediators (such as androgen and dihydrotestosterone) were highly affected and nearly restored to physiological levels. Thus, BPH can be directly affected by probiotic supplementation; specifically, B. longum and B. psychaerophilum , in combination, seem able to promote the mitigation of this disease.

During ageing, the brain is vulnerable to a growing imbalance of the antioxidant defence system, resulting in increased oxidative stress. This condition may be mainly responsible for cognitive decline, resulting in synaptic transmission disruptions and the onset of neuronal dysfunction. In this context, developing efficient preventive and therapeutic strategies against increased oxidative stress and decreased antioxidant defence mechanisms should be considered a public health priority to promote healthy ageing. Therefore, the current study explored the benefits of a novel combination of green tea, saffron, trans-Reveratrol, and citicoline, called MIX, on improving intracellular processes to ameliorate the mechanisms linked to cognitive decline under oxidative stress conditions. First, the ability of MIX to cross the blood-brain barrier (BBB) was evaluated in an in vitro model, analysing TEER value and the specific tight junctions; second, the CCF-STTG1 cell line was pretreated with 200  µ M H 2 O 2 for 30 min to explore the effects of the single active compounds and their combination under oxidative stress conditions. Our results demonstrated for the first time the synergistic effects of the new combination to improve the absorption rate of individual agents through the BBB and maintain its integrity. Subsequently, further research was done to assess the positive role of the combination to counteract oxidative damage; as expected, MIX restored the neurodegenerative state activated by 200  µ M H 2 O 2 , reducing mitochondrial damage, and improving survival pathways. Additionally, MIX acted as a regulator of both cellular energy metabolism and apoptosis, reducing the inflammatory state activated by oxidative stress. Finally, MIX can balance neurotrophin production to prevent mitochondrial disruption. In conclusion, MIX counteracted the adverse effects of brain oxidative stress, suggesting that this new proposed formulation prevents the molecular mechanisms underlying the onset of cognitive decline, even in support of conventional therapy., Competing Interests: The authors declare that they have no competing interests. Francesca Uberti is a cofounder of noiVita Srls. Dr. Stefania Battaglia and Dr. Valeria Curti are employees of Kolinpharma S.p.A., a nutraceutical company that produces and commercialises food supplements. These authors report no involvement of the company in the research that could have influenced the outcome of this work., (Copyright © 2024 Simone Mulè et al.)

Palmitoylethanolamide (PEA) is a highly lipophilic molecule with low solubility, making absorption difficult. Recent techniques like micronisation, ultra-micronisation and combining PEA with solvents have improved their bioavailability and stability. Our study analysed particle size differences and absorption kinetics using specific solvents (PEAΩ and PEA DynoΩ) over time (0.5 h-6 h) in a dose-dependent manner (200 mg-1800 mg). The results showed that PEAΩ and PEA DynoΩ achieved 82-63% absorption at 3 h, compared to 30-60% for micronised, ultra-micronised PEA and a commercial product, highlighting the optimal dose range of 300 mg-600 mg. In addition, a 3D model of the peripheral nerve was utilised to explain the efficacy after gut passage and support the most effective dose (300 mg or 600 mg) achieved at the gut level. PEAΩ and PEA DynoΩ, which are associated with better intestinal bioavailability compared to PEA-micronised, PEA ultra-micronised and a commercial product, have allowed not only a reduction in the inflammatory context but also an improvement of peripheral nerve well-being by increasing specific markers like MPZ (26-36% vs. 8-15%), p75 (25-32% vs. 13-16%) and NRG1 (22-29.5% vs. 11-14%). These results highlight the potential of advanced PEA formulations to overcome solubility challenges and maintain in vitro efficacy, modulating peripheral nerve well-being.

Neuropathy affects 7-10% of the general population and is caused by a lesion or disease of the somatosensory system. The limitations of current therapies highlight the necessity of a new innovative approach to treating neuropathic pain (NP) based on the close correlation between oxidative stress, inflammatory process, and antioxidant action. The advantageous outcomes of a novel combination composed of Hop extract, Propolis, Ginkgo Biloba, Vitamin B, and palmitoylethanolamide (PEA) used as a treatment was evaluated in this study. To assess the absorption and biodistribution of the combination, its bioavailability was first examined in a 3D intestinal barrier model that replicated intestinal absorption. Further, a 3D nerve tissue model was developed to study the biological impacts of the combination during the essential pathways involved in NP. Our findings show that the combination could cross the intestinal barrier and reach the peripheral nervous system, where it modulates the oxidative stress, inflammation levels, and myelination mechanism (increased NRG, MPZ, ERB, and p75 levels) under Schwann cells damaging. This study proves the effectiveness of Ginkgo Biloba, Propolis, Hop extract, Vitamin B, and PEA in avoiding nerve damage and suggests a potential alternative nutraceutical treatment for NP and neuropathies.

The gut-brain axis is a bidirectional relationship between the microbiota and the brain; genes related to the brain and gut synaptic formation are similar. Research on the causal effects of gut microbiota on human behavior, brain development, and function, as well as the underlying molecular processes, has emerged in recent decades. Probiotics have been shown in several trials to help reduce anxiety and depressive symptoms. Because of this, probiotic combinations have been tested in in vitro models to see whether they might modulate the gut and alleviate depression and anxiety. Therefore, we sought to determine whether a novel formulation might affect the pathways controlling anxiety and depression states and alter gut barrier activities in a 3D model without having harmful side effects. Our findings indicate that B. bifidum novaBBF7 10 mg/mL, B. longum novaBLG2 5 mg/mL, and L. paracasei TJB8 10 mg/mL may influence the intestinal barrier and enhance the synthesis of short-chain fatty acids. Additionally, the probiotics studied did not cause neuronal damage and, in combination, exert a protective effect against the condition of anxiety and depression triggered by L-Glutamate. All these findings show that probiotics can affect gut function to alter the pathways underlying anxiety and depression.

This review aims to argue how using probiotics can improve anxiety and depressive behaviour without adverse effects, also exploring the impact of postbiotics on it. Specifically, probiotics have drawn more attention as effective alternative treatments, considering the rising cost of antidepressant and anti-anxiety drugs and the high risk of side effects. Depression and anxiety disorders are among the most common mental illnesses in the world's population, characterised by low mood, poor general interest, and cognitive or motor dysfunction. Thus, this study analysed published literature on anxiety, depression, and probiotic supplementation from PubMed and Scopus, focusing on the last twenty years. This study focused on the effect of probiotics on mental health as they have drawn more attention because of their extensive clinical applications and positive impact on various diseases. Numerous studies have demonstrated how the gut microbiota might be critical for mood regulation and how probiotics can affect host health by regulating the gut-brain axis. By comparing the different works analysed, it was possible to identify a strategy by which they are selected and employed and, at the same time, to assess how the effect of probiotics can be optimised using postbiotics, an innovation to improve mental well-being in humans., Competing Interests: All the authors declare no conflict of interest., (© 2024 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Chronic oxidative stress has been consistently linked to age-related diseases, conditions, and degenerative syndromes. Specifically, the brain is the organ that significantly contributes to declining quality of life in ageing. Since the body cannot completely counteract the detrimental effects of oxidative stress, nutraceuticals' antioxidant properties have received significant attention in recent years. This study assesses the potential health benefits of a novel combination of glutathione, vitamin D3, and N-acetylcysteine. To examine the combination's absorption and biodistribution and confirm that it has no harmful effects, the bioavailability of the mixture was first evaluated in a 3D model that mimicked the intestinal barrier. Further analyses on the blood-brain barrier was conducted to determine the antioxidant effects of the combination in the nervous system. The results show that the combination reaches the target and successfully crosses the blood-brain and intestinal barriers, demonstrating enhanced advantages on the neurological system, such as a reduction (about 10.5%) in inflammation and enhancement in cell myelination (about 20.4%) and brain tropism (about 18.1%) compared to the control. The results support the cooperative effect of N-acetylcysteine, vitamin D3, and glutathione to achieve multiple health benefits, outlining the possibility of an alternative nutraceutical approach.

Background: Peripheral neuropathy is caused by a malfunction in the axons and myelin sheaths of peripheral nerves and motor and sensory neurons. In this context, nonpharmacological treatments with antioxidant potential have attracted much attention due to the issues that some conventional pharmaceutical therapy can generate. Most of these treatments contain lipoic acid, but issues have emerged regarding its use. Considering this, the present study evaluated the beneficial effects of nutraceuticals based on Gastrodiae elata dry extract 10:1 or lipoic acid in combination with other substances (such as citicholine, B vitamins, and acetyl L-carnitine)., Method: To assess the combination's absorption and biodistribution and exclude cytotoxicity, its bioavailability was first examined in a 3D intestinal barrier model that replicated oral ingestion. Subsequently, a 3D model of nerve tissue was constructed to investigate the impacts of the new combination on the significant pathways dysregulated in peripheral neuropathy., Results: Our findings show that the novel combination outperformed in initial pain relief response and in recovering the mechanism of nerve healing following Schwann cell injury by successfully crossing the gut barrier and reaching the target site., Conclusion: This article describes a potential alternative nutraceutical approach supporting the effectiveness of combinations with Gastrodiae elata extract in decreasing neuropathy and regulating pain pathways.