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Background: The development of highly active drugs has improved the survival of melanoma patients, but elevated drug prices place a significant burden on health care systems. In Spain, the public health care system is transferred to the 17 autonomous communities (AACC). The objective of this study is to describe the situation of drug access for melanoma patients in Spain and how this decentralized system is affecting equity. Methods: From July to September 2023, a cross-sectional survey was sent to members of the Spanish Multidisciplinary Melanoma Group (GEM Group). The questionnaire consulted about the real access to new drugs in each hospital. The responses were collected anonymously and analyzed according to several variables, including the AACC. Results: The survey was answered by 50 physicians in 15 AACC. No major differences on access between AACC were observed for indications that are reimbursed by the Spanish Health Care System (adjuvant immunotherapy for stage IIIC–IIID and resected stage IV melanoma). Important differences in drug access were observed among AACC and among centers within the same AACC, for most of the EMA indications that are not reimbursed (adjuvant immunotherapy for stages IIB–IIC–IIIA–IIIB) or that are not fully reimbursed (ipilimumab plus nivolumab in advanced stage). Homogeneously, access to adjuvant targeted drugs, TIL therapy and T-VEC, is extremely low or non-existing in all AACC. Conclusions: For most indications that reimbursement is restricted out of the EMA indication, a great diversity on access was found throughout the different hospitals in Spain, including heterogeneity intra-AACC. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, delivering nanoparticles to hard-to-reach tumor sites remains a challenge in nanomedicine. Mesenchymal stem cells are an innovative strategy for targeting tumors, and genetic engineering could enable them to release antitumor agents and/or nanomaterials at tumor sites. Therefore, combining radiosensitizing agents with mesenchymal stem cells represents a promising strategy in the fight against cancer. Still, evaluating whether nanoparticles can modulate mesenchymal stem cells' behavior is essential. This study assessed the impact of new Fe3O4@Au nanoparticles on human pulmonary mesenchymal stem cells to determine whether they can be used as carriers for radiosensitizer agents to cancer sites. This study focused on the markers related to cell death, redox and proinflammatory status, and tumorigenesis. Background/Objectives: Metallic nanoparticles (NPs) exhibit interesting radiosensitizing effects, and finding a way to accurately deliver them appears to be crucial. Due to their tumor tropism, mesenchymal stem cells (MSCs) represent a strategic approach. Therefore, we aimed to evaluate the impact of core–shell Fe3O4@Au NPs on the functionality of human pulmonary MSCs (HPMSCs). Methods/Results: The results showed that 100 µg/mL Fe3O4@Au NPs, accumulated in HPMSCs (revealed by Prussian blue staining), did not alter cell viability as assessed by cell counting, MTT, and LDH assays. However, caspase 9 and Bcl2 gene expression, evaluated by RT-qPCR, was regulated 72 h after exposure to the NPs. Moreover, the NPs also decreased proinflammatory cytokine/chemokine secretions, except for CXCL8 (ELISA). These modulations were associated with the downregulation of AMPK gene expression at 24 h. In contrast, the NPs did not modulate VEGF, PI3K, or PDGF gene expression. Nevertheless, a decrease in VEGF secretion was observed after 24 h of exposure to the NPs. Interestingly, the Fe3O4@Au NPs did not modulate Nrf2 gene expression, but they did regulate the expression of the genes encoding Nox4 and HMOX-1. Additionally, the NPs increased ROS production, suggesting a redox imbalance. Conclusions: Finally, the Fe3O4@Au NPs did not affect the HPMSCs' viability or proangiogenic/tumorigenic markers. These findings are encouraging for investigating the effects of Fe3O4@Au NPs delivered by HPMSCs to tumor sites in combination with radiation. [ABSTRACT FROM AUTHOR]

Background Recently, mesenchymal stromal cells (MSCs) have gained recognition for their clinical utility in transplantation to induce tolerance and to improve/replace pharmacological immunosuppression. Cord blood (CB)-derived MSCs are particularly attractive for their immunological naivety and peculiar anti-inflammatory and anti-apoptotic properties. Objectives: The objective of this study was to obtain an inventory of CB MSCs able to support large-scale advanced therapy medicinal product (ATMP)-based clinical trials. Study design: We isolated MSCs by plastic adherence in a GMP-compliant culture system. We established a well-characterized master cell bank and expanded a working cell bank to generate batches of finished MSC(CB) products certified for clinical use. The MSC(CB) produced by our facility was used in approved clinical trials or for therapeutic use, following single-patient authorization as an immune-suppressant agent. Results: We show the feasibility of a well-defined MSC manufacturing process and describe the main indications for which the MSCs were employed. We delve into a regulatory framework governing advanced therapy medicinal products (ATMPs), emphasizing the need of stringent quality control and safety assessments. From March 2012 to June 2023, 263 of our Good Manufacturing Practice (GMP)-certified MSC(CB) preparations were administered as ATMPs in 40 subjects affected by Graft-vs.-Host Disease, nephrotic syndrome, or bronco-pulmonary dysplasia of the newborn. There was no infusion-related adverse event. No patient experienced any grade toxicity. Encouraging preliminary outcome results were reported. Clinical response was registered in the majority of patients treated under therapeutic use authorization. Conclusions: Our 10 years of experience with MSC(CB) described here provides valuable insights into the use of this innovative cell product in immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Abstract Systemic lupus erythematosus (SLE) is characterized by disruptions in cell death pathways and impaired clearance of apoptotic cells, resulting in immune dysregulation and tissue damage. This review explores the complex interplay of regulated cell death (RCD) mechanisms, including apoptosis, necroptosis, pyroptosis, NETosis, autophagy, and ferroptosis, in the pathogenesis of SLE. These pathways release autoantigens and danger signals, triggering autoimmune reactions and inflammation. Six various RCDs have mutual associates to support immune dysregulation and are associated with SLE. Apoptosis intrinsically induces immune tolerance by packaging dying cells into immunologically inert fragments. Deficiencies in apoptotic clearance will result in impaired tolerance. Necroptosis, pyroptosis, NETosis, and ferroptosis lead to cell membrane destruction, production of intracellular immunostimulatory components, and triggering a strong inflammatory immune reaction. Abnormal autophagic activity affects the development, differentiation, function, and metabolism of many immune cell subpopulations. Investigating the interconnections between cell death pathways and SLE sheds light on the disease's underlying mechanisms and provides opportunities for novel therapeutic interventions. The convergence of precision medicine and innovative strategies targeting these intricate pathways holds promise for expanding the landscape of SLE treatment.

The prevalence of obesity in children and adolescents is increasing, and it is recognised as a complex disorder that often begins in early childhood and persists throughout life. Both polygenic and monogenic obesity are influenced by a combination of genetic predisposition and environmental factors. Rare genetic obesity forms are caused by specific pathogenic variants in single genes that have a significant impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. Genetic testing is recommended for patients who exhibit rapid weight gain in infancy and show additional clinical features suggestive of monogenic obesity as an early identification allows for appropriate treatment, preventing the development of obesity-related complications, avoiding the failure of traditional treatment approaches. In the past, the primary recommendations for managing obesity in children and teenagers have been focused on making multiple lifestyle changes that address diet, physical activity, and behaviour, with the goal of maintaining these changes long-term. However, achieving substantial and lasting weight loss and improvements in body mass index (BMI) through lifestyle interventions alone is rare. Recently the progress made in genetic analysis has paved the way for innovative pharmacological treatments for different forms of genetic obesity. By understanding the molecular pathways that contribute to the development of obesity, it is now feasible to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms. Conclusion: However, additional preclinical research and studies in the paediatric population are required, both to develop more personalised prevention and therapeutic programs, particularly for the early implementation of innovative and beneficial management options, and to enable the translation of these novel therapy approaches into clinical practice. What is Known: • The prevalence of obesity in the paediatric population is increasing, and it is considered as a multifaceted condition that often begins in early childhood and persists in the adult life. Particularly, rare genetic forms of obesity are influenced by a combination of genetic predisposition and environmental factors and are caused by specific pathogenic variants in single genes showing a remarkable impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. • Patients who present with rapid weight gain in infancy and show additional clinical characteristics indicative of monogenic obesity should undergo genetic testing, which, by enabling a correct diagnosis, can prevent the development of obesity-related consequences through the identification for appropriate treatment. What is New: • In recent years, advances made in genetic analysis has made it possible to develop innovative pharmacological treatments for various forms of genetic obesity. In fact, it is now achievable to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms by understanding the molecular pathways involved in the development of obesity. • As demonstrated over the last years, two drugs, setmelanotide and metreleptin, have been identified as potentially effective interventions in the treatment of certain rare forms of monogenic obesity caused by loss-of-function mutations in genes involved in the leptin-melanocortin pathway. Recent advancements have led to the development of novel treatments, including liraglutide, semaglutide and retatrutide, that have the potential to prevent the progression of metabolic abnormalities and improve the prognosis of individuals with these rare and severe forms of obesity. However, extensive preclinical research and, specifically, additional studies in the paediatric population are necessary to facilitate the translation of these innovative treatment techniques into clinical practice. [ABSTRACT FROM AUTHOR]

The definition of “Metabolic Associated Fatty Liver Disease – MAFLD” has replaced the previous definition of Nonalcoholic Fatty Liver Disease (NAFLD), because cardiometabolic criteria have been added for the prevention of cardiological risk in these patients. This definition leads to an in-depth study of the bidirectional relationships between hepatic steatosis, Type 2 Diabetes Mellitus (T2DM), Cardiovascular Disease (CVD) and/or their complications. Lifestyle modification, which includes correct nutrition combined with regular physical activity, represents the therapeutic cornerstone of MAFLD. When therapy is required, there is not clear accord on how to proceed in an optimal way with nutraceutical or pharmacological therapy. Numerous studies have attempted to identify nutraceuticals with a significant benefit on metabolic alterations and which contribute to the improvement of hepatic steatosis. Several evidences are supporting the use of silymarin, berberine, curcumin, Nigella sativa, Ascophyllum nodosum, and Fucus vesiculosus, vitamin E, coenzyme Q10 and Omega-3. However, more evidence regarding the long-term efficacy and safety of these compounds are required. There is numerous evidence that highlights the use of therapies such as incretins or the use of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors or other similar therapies which, by assisting existing therapies for pathologies such as diabetes, hypertension, insulin resistance, have given a breakthrough in prevention and the reduction of cardiometabolic risk. This review gave an overview of the current therapeutic strategies that are expected to aid in the treatment and prevention of MAFLD.

In 2023 there are still even 75% of patients over the target of low-density lipoprotein cholesterol (LDL-C), and hypercholesterolemia is the most common and the worst monitored cardiovascular risk factor. How it is possible, considering the knowledge we have on the role of cholesterol in the process of atherosclerosis, atherosclerotic cardiovascular disease (ASCVD) and its complications, on the methods of lipid disorders diagnosis, prevention, and treatment. Nowadays, almost 4 million deaths per year are attributed to LDL-C, and even 2/3 of all CVD deaths to ASCVD, therefore hypothetically we should easily prevent few to several million of deaths with early diagnosis, and early and intensive non-pharmacological and pharmacological therapies. Moreover, lipidology is now, besides oncology, the area with the highest number of new and ongoing trials with new effective and safe medications that have already appeared and will soon be available. Therefore, we have no doubt that year 2023 should be called the year of new and prospective lipid lowering therapies (LLTs). In this State-of-the-Art paper we summarized the most important trials, studies, and recommendations on the new and prospective LLTs, with suitable graphical summaries that might be helpful for the physicians in their practice with a look to the nearest future with prospective therapies being still under investigation. Let’s hope all those medications helps to render dyslipidemia a rare disease in next few years.

Obesity has become a global epidemic, contributing to the development of numerous chronic diseases, including diabetes, chronic kidney disease (CKD) and cardiovascular disorders. MicroRNAs (miRNAs) have emerged as key regulators in various biological processes, including metabolism, inflammation, and tissue remodeling, making them pivotal players in obesity-related pathologies. This review aims to provide comprehensive insights into the roles of miRNAs in obesity, with a particular emphasis on their involvement in the pathogenesis of CKD and cardiovascular disorders. We highlight the involvement of specific miRNAs in adipose tissue development, energy homeostasis, inflammation, and insulin resistance, contributing to the pathogenesis of obesity. Moreover, we explore the impact of miRNAs on renal fibrosis and inflammation, giving clues on their roles in the development and progression of CKD. Additionally, we discuss the influence of miRNAs on endothelial dysfunction, atherosclerosis, and cardiac remodeling, emphasizing their contribution to obesity-related cardiovascular disorders. Understanding the regulatory functions of miRNAs in these interconnected conditions holds promise for improved diagnosis, prognosis, and therapeutic interventions. Indeed, miRNAs are potential diagnostic biomarkers for obesity-related diseases, although challenges remain to be elucidated before their clinical translation. Furthermore, we highlight the emerging strategies that target miRNAs as therapeutic interventions to mitigate the detrimental effects of obesity on kidney and cardiovascular health.

Background Recently, mesenchymal stromal cells (MSCs) have gained recognition for their clinical utility in transplantation to induce tolerance and to improve/replace pharmacological immunosuppression. Cord blood (CB)-derived MSCs are particularly attractive for their immunological naivety and peculiar anti-inflammatory and anti-apoptotic properties. Objectives: The objective of this study was to obtain an inventory of CB MSCs able to support large-scale advanced therapy medicinal product (ATMP)-based clinical trials. Study design: We isolated MSCs by plastic adherence in a GMP-compliant culture system. We established a well-characterized master cell bank and expanded a working cell bank to generate batches of finished MSC(CB) products certified for clinical use. The MSC(CB) produced by our facility was used in approved clinical trials or for therapeutic use, following single-patient authorization as an immune-suppressant agent. Results: We show the feasibility of a well-defined MSC manufacturing process and describe the main indications for which the MSCs were employed. We delve into a regulatory framework governing advanced therapy medicinal products (ATMPs), emphasizing the need of stringent quality control and safety assessments. From March 2012 to June 2023, 263 of our Good Manufacturing Practice (GMP)-certified MSC(CB) preparations were administered as ATMPs in 40 subjects affected by Graft-vs.-Host Disease, nephrotic syndrome, or bronco-pulmonary dysplasia of the newborn. There was no infusion-related adverse event. No patient experienced any grade toxicity. Encouraging preliminary outcome results were reported. Clinical response was registered in the majority of patients treated under therapeutic use authorization. Conclusions: Our 10 years of experience with MSC(CB) described here provides valuable insights into the use of this innovative cell product in immune-mediated diseases.

In 2023 there are still even 75% of patients over the target of low-density lipoprotein cholesterol (LDL-C), and hypercholesterolemia is the most common and the worst monitored cardiovascular risk factor. How it is possible, considering the knowledge we have on the role of cholesterol in the process of atherosclerosis, atherosclerotic cardiovascular disease (ASCVD) and its complications, on the methods of lipid disorders diagnosis, prevention, and treatment. Nowadays, almost 4 million deaths per year are attributed to LDL-C, and even 2/3 of all CVD deaths to ASCVD, therefore hypothetically we should easily prevent few to several million of deaths with early diagnosis, and early and intensive non-pharmacological and pharmacological therapies. Moreover, lipidology is now, besides oncology, the area with the highest number of new and ongoing trials with new effective and safe medications that have already appeared and will soon be available. Therefore, we have no doubt that year 2023 should be called the year of new and prospective lipid lowering therapies (LLTs). In this State-of-the-Art paper we summarized the most important trials, studies, and recommendations on the new and prospective LLTs, with suitable graphical summaries that might be helpful for the physicians in their practice with a look to the nearest future with prospective therapies being still under investigation. Let's hope all those medications helps to render dyslipidemia a rare disease in next few years. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) presents a complex interplay of both innate and adaptive immune responses that drive a variety of pathological manifestations. Recent studies highlight the role of immune-mediated pathogenesis, pinpointing the involvement of antibodies against tissue transglutaminases (TG2, TG3, TG6), specific HLA molecules (DQ2/8), and the regulatory role of interleukin-15, among other cellular and molecular pathways. These aspects illuminate the systemic nature of CD, reflecting its wide-reaching impact that extends beyond gastrointestinal symptoms to affect other physiological systems and giving rise to a range of pathological landscapes, including refractory CD (RCD) and, in severe cases, enteropathy-associated T cell lymphoma. The existing primary therapeutic strategy, a gluten-free diet (GFD), poses significant challenges, such as low adherence rates, necessitating alternative treatments. Emerging therapies target various stages of the disease pathology, from preventing immunogenic gluten peptide absorption to enhancing intestinal epithelial integrity and modulating the immune response, heralding potential breakthroughs in CD management. As the understanding of CD deepens, novel therapeutic avenues are emerging, paving the way for more effective and sophisticated treatment strategies with the aim of enhancing the quality of life of CD patients. This review aims to delineate the immunopathology of CD and exploring its implications on other systems, its complications and the development of novel treatments. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a major healthcare issue worldwide. However, the prevalence of pediatric CKD has never been systematically assessed and consistent information is lacking in this population. The current definition of CKD is based on glomerular filtration rate (GFR) and the extent of albuminuria. Given the physiological age-related modification of GFR in the first years of life, the definition of CKD is challenging per se in the pediatric population, resulting in high risk of underdiagnosis in this population, treatment delays and untailored clinical management. The advent and spreading of massive-parallel sequencing technology has prompted a profound revision of the epidemiology and the causes of CKD in children, supporting the hypothesis that CKD is much more frequent than currently reported in children and adolescents. This acquired knowledge will eventually converge in the identification of the molecular pathways and cellular response to damage, with new specific therapeutic targets to control disease progression and clinical features of children with CKD. In this review, we will focus on recent innovations in the field of pediatric CKD and in particular those where advances in knowledge have become available in the last years, with the aim of providing a new perspective on CKD in children and adolescents. [ABSTRACT FROM AUTHOR]

Obesity has become a global epidemic, contributing to the development of numerous chronic diseases, including diabetes, chronic kidney disease (CKD) and cardiovascular disorders. MicroRNAs (miRNAs) have emerged as key regulators in various biological processes, including metabolism, inflammation, and tissue remodeling, making them pivotal players in obesity-related pathologies. This review aims to provide comprehensive insights into the roles of miRNAs in obesity, with a particular emphasis on their involvement in the pathogenesis of CKD and cardiovascular disorders. We highlight the involvement of specific miRNAs in adipose tissue development, energy homeostasis, inflammation, and insulin resistance, contributing to the pathogenesis of obesity. Moreover, we explore the impact of miRNAs on renal fibrosis and inflammation, giving clues on their roles in the development and progression of CKD. Additionally, we discuss the influence of miRNAs on endothelial dysfunction, atherosclerosis, and cardiac remodeling, emphasizing their contribution to obesity-related cardiovascular disorders. Understanding the regulatory functions of miRNAs in these interconnected conditions holds promise for improved diagnosis, prognosis, and therapeutic interventions. Indeed, miRNAs are potential diagnostic biomarkers for obesity-related diseases, although challenges remain to be elucidated before their clinical translation. Furthermore, we highlight the emerging strategies that target miRNAs as therapeutic interventions to mitigate the detrimental effects of obesity on kidney and cardiovascular health. [ABSTRACT FROM AUTHOR]

The history of fetal surgery is one of constant evolution. Over the last 50 years, fetal surgery has progressed from a mere idea to an internationally respected innovative field of surgery. This article aims to provide a historical review of how the enterprise of maternal-fetal surgery came to be its modern version. This review is less focused on the history of specific therapies for a relatively small number of conditions, and more on how the whole field of maternal-fetal surgery evolved. The various internal and external influences that steered the field's evolution are discussed in chronologic order. Since the start of modern fetal surgery in the 1980s, large paradigm shifts have characterized the growth of the field as a whole. Innovative interventions are now based on physiologic manipulation as opposed to simple anatomic repair, fetoscopy has become the more frequently preferred surgical approach, and rigorous scientific evaluation with randomized controlled trials is now the standard expected by the community. In a very similar fashion to when the field first began in the early 1980s, recently community's leaders have risen to protect the integrity of maternal-fetal surgery by publishing ethical guidelines for innovation and clinical practice. This incredible history of innovation, rigorous science and ethical contemplation is the foundation on which modern maternal-fetal surgery rests.

Now that ovarian tissue cryopreservation (OTC) has become standard of care for patients receiving gonadotoxic therapies, discussion has turned toward offering OTC to pediatric patients with Turner syndrome outside of research. Although patients with Turner syndrome have unmet fertility needs and the authors support efforts for fertility preservation in these individuals, safety and efficacy data about OTC in this population are limited. Building on longstanding debates around offering experimental therapies as research or outside of research (as "innovative therapy"), we considered the suitability of offering OTC for patients with Turner syndrome as innovative therapy. On the basis of pathophysiology and preliminary research data, we argue that there is significant uncertainty about whether the risk-benefit profile of OTC for patients with Turner syndrome is favorable. This reduces the weight of arguments in favor of offering it as innovative therapy. Furthermore, as Turner syndrome is rare, widespread availability of OTC could make it difficult to develop generalizable knowledge. The benefits of innovative therapy for acquiring experience from use in humans and avoiding research-related procedures are of limited importance too, as OTC is already an established procedure, and current studies involve limited procedures that restrict access. OTC should therefore only be offered to patients with Turner syndrome in research settings until additional data suggest that the risk-benefit profile is likely favorable. [ABSTRACT FROM AUTHOR]

Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus [MRSA] stands as an enduring threat within healthcare landscapes, characterized by its ability to rapidly evolve and develop resistance to conventional antibiotics. This comprehensive review embarks on a journey through the historical landscape of MRSA, elucidating its initial emergence and subsequent evolution of resistance mechanisms over time. The narrative unfolds to underscore the profound impact of MRSA on patient outcomes and healthcare systems globally. Current trends in MRSA therapies come under meticulous scrutiny, spotlighting the limitations and challenges associated with existing treatment modalities. This analysis underscores the critical need for transformative and innovative therapeutic strategies to effectively combat the ever-growing spectre of drug resistance in MRSA from the exploration of novel antibiotics designed to overcome resistance mechanisms to the promising potential of phage therapy and immunotherapies. Amidst the exploration of innovative therapies, the review identifies and discusses emerging issues and challenges in MRSA management. Insights are provided into the intricate web of obstacles hindering the adoption and implementation of new therapeutic strategies. Furthermore, the socio-economic implications of MRSA and drug resistance are brought to the forefront, emphasizing the broader impact on public health and healthcare systems. In parallel, historical perspectives on MRSA research illuminate key milestones in scientific understanding and technological advancements. The evolution of research strategies and their impact on our ability to comprehend and combat MRSA is examined, providing context for the current state of the field. In conclusion, this review summarizes major findings and drawing implications for the future of MRSA treatment. Recommendations for further research and clinical practice are outlined, encapsulating a holistic overview of the resilient efforts against resistance in the ongoing battle against MRSA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: In a context of intensive clinical development and innovation in oncology, the French National Cancer Institute has developed a horizon scanning focused on emerging anticancer drugs since 2019. This tool aims to provide further insight to national authorities responsible of the access to medicines and policymakers., Methods: EMERGINCaRE is based on an annual cycle initiated by the identification of clinical developments of interest from a database, one to three years prior European marketing authorization. Clinical developments are ranked and prioritized using a scoring approach. Scores are based on public information about developments collected by the Institute and on the evaluation carried out by clinicians who were asked to analyse and identify the most impacting drugs. A national steering committee prioritizes several high-score developments each year., Results: Seventy-five developments were analysed during the 2023 cycle. Among these developments, 50 are related to drugs for solid tumors and 25 for hematological malignancies. At the end of this cycle, six developments, including two concerning Advanced Therapy Medicinal Products, were prioritized. Half of these prioritized developments evaluate a drug for a poor prognosis cancer., Discussion: Among the developments evaluated with a high clinical impact score, some drugs were finally approved for the clinical situation concerned. As first public Horizon Scanning in France, the methodology of EMERGINCaRE has been refined and deadlines have been optimized to provide annually the information generated by this system to interested public institutions., (Copyright © 2024. Published by Elsevier Masson SAS.)

Abstract In 2001, Fondazione Telethon and the Italian muscular dystrophy patient organisation Unione Italiana Lotta alla Distrofia Muscolare joined their efforts to design and launch a call for grant applications specifically dedicated to clinical projects in the field of neuromuscular disorders. This strategic initiative, run regularly over the years and still ongoing, aims at supporting research with impact on the daily life of people with a neuromuscular condition and is centred on macro-priorities identified by the patient organisation. It is investigator-driven, and all proposals are peer-reviewed for quality and feasibility. Over the years, this funding program contributed to strengthening the activities of the Italian neuromuscular clinical network, reaching many achievements in healthcare research. Moreover, it has been an enabling factor for innovative therapy experimentation at international level and prepared the clinical ground to make therapies available to Italian patients. The ultimate scope of healthcare research is to ameliorate the delivery of care. In this paper, the achievements of the funded studies are analysed also from this viewpoint, to ascertain to which extent they have fulfilled the original goals established by the patient organisation. The evidence presented indicates that this has been a highly fruitful program. Factors that contributed to its success, lessons learned, challenges, and issues that remain to be addressed are discussed to provide practical examples of an experience that could inspire also other organizations active in the field of rare disease research.

Osteoarthritis (OA) is a chronic debilitating disorder causing pain and gradual degeneration of joints. Among various cell therapies, mesenchymal stem cell (MSC) therapy appears to provide encouraging results. Human amniotic suspension allografts (HASA) have anti-inflammatory and chondroregenerative potential and represent a promising treatment strategy. The purpose of the present study was to prospectively assess the safety, clinical effectiveness, and feasibility of intra-articular injections of human amniotic suspension allograft (HASA) in unilateral knee OA in order to assess the improvement of symptoms and delay the necessity for invasive surgical procedures. A total of 25 symptomatic patients, affected by knee OA were treated with 3 mL of HASA. Clinical evaluations before the treatment and after 3, 6, and 12 months were performed through International Knee Documentation Committee (IKDC) score and Visual Analogue Scale (VAS) scores. Adverse events were recorded. No severe complications were noted during the treatment and the follow-up period. A statistically significant improvement from basal evaluation to the 3-, 6-, and 12-month follow-up visits was observed. The present pilot study indicates that a single intra-articular injection of HASA seems safe and able to provide positive clinical outcomes, potentially offering a new minimally invasive therapeutic option for patients with knee OA. [ABSTRACT FROM AUTHOR]

Objectives: An increasing number of innovative therapies (e.g., gene- and cell-based treatments) have been developed in the past 20 years. Despite the significant clinical potential of these therapies, access delays may arise because of differing perspectives of manufacturers and payers regarding issues such as the value of the product, clinical and financial uncertainties, and sustainability.Managed entry agreements (MEAs) can enable access to treatments that would not be reimbursed by conventional methods because of such concerns. However, although MEA typologies exist, there is currently no structured process to come to agreements on MEAs, which can be difficult to decide upon and implement.To facilitate more structured MEA negotiations, we propose a conceptual "value-based negotiation framework" with corresponding application tools.Methods: The framework was developed based on an iterative process of scientific literature review and expert input.Results: The framework aims to (i) systematically identify and prioritize manufacturer and payer concerns about a new treatment, and (ii) select a mutually acceptable combination of MEA terms that can best address priority concerns, with the lowest possible implementation burden.Conclusions: The proposed framework will be tested in practice, and is a step toward supporting payers and manufacturers to engage in more structured, transparent negotiations to balance the needs of both sides, and enabling quicker, more transparent MEA negotiations and patient access to innovative products. [ABSTRACT FROM AUTHOR]

Objectives: An increasing number of innovative therapies (e.g., gene- and cell-based treatments) have been developed in the past 20 years. Despite the significant clinical potential of these therapies, access delays may arise because of differing perspectives of manufacturers and payers regarding issues such as the value of the product, clinical and financial uncertainties, and sustainability. Managed entry agreements (MEAs) can enable access to treatments that would not be reimbursed by conventional methods because of such concerns. However, although MEA typologies exist, there is currently no structured process to come to agreements on MEAs, which can be difficult to decide upon and implement. To facilitate more structured MEA negotiations, we propose a conceptual "value-based negotiation framework" with corresponding application tools. Methods: The framework was developed based on an iterative process of scientific literature review and expert input. Results: The framework aims to (i) systematically identify and prioritize manufacturer and payer concerns about a new treatment, and (ii) select a mutually acceptable combination of MEA terms that can best address priority concerns, with the lowest possible implementation burden. Conclusions: The proposed framework will be tested in practice, and is a step toward supporting payers and manufacturers to engage in more structured, transparent negotiations to balance the needs of both sides, and enabling quicker, more transparent MEA negotiations and patient access to innovative products. [ABSTRACT FROM AUTHOR]

We present a description of pediatric pneumology biological medications and other target therapies. The article aims at introducing the importance of a molecular approach to improve treatments. The first item treated was T2-High asthma and its current biological treatment and prescribing indications to propose a flow-chart to guide the clinical choice. Molecular rationales of such treatments are used to introduce a more general description of the biological and molecular approach to target therapies application. We introduce a general interpretation approach to neutrophilic asthma using the molecular plausibility one in order to propose possible future treatments mainly targeting interleukin-1 (IL-1), IL-17, IL-12, and IL-23. Indeed, cytokines can be excellent targets for several biological treatments. Downregulation of specific cytokines can be crucial in treating autoinflammatory and rheumatological diseases with a pulmonary involvement. Such conditions, although rare, should be early recognized as they can involve significant improvement with a properly targeted therapy. We face these conditions in a cherry-picking fashion picturing SAVI (STING-associated vasculopathy with onset in infancy), CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), and COPA (coat proteins alpha syndrome) syndrome pulmonary involvement. Such examples are functional to introduce molecular-based approach for patients with rare conditions. Molecular plausibility can be highly valuable in treating patients with not-approved but possibly highly effective therapies. Due to the rarity of these conditions, we stress the concept of basket trials using the example of cytokinin-directed immunosuppressive treatment. Lastly, we provide an example of augmentative therapy using the alpha1 antitrypsin deficiency as a model. In summary, the article presents a collection of the most recent achievements and some possible future developments of target therapies for pediatric pulmonary conditions.

Retinitis pigmentosa (RP) is a collection of retinal disorders characterized by the progressive degeneration of photoreceptor cells, leading to significant visual impairment and, in severe cases, blindness. RP affects individuals worldwide and can be inherited through various genetic patterns, making it a genetically diverse condition. Despite considerable advancements in diagnostic methods and supportive therapies, there is currently no cure for RP. The focus of existing management strategies is on slowing the progression of the disease and improving the quality of life for those affected. This comprehensive review explores the latest therapeutic approaches in the management of RP, highlighting advancements in genetic therapies, such as gene augmentation and editing, as well as cell-based treatments including stem cell transplantation and induced pluripotent stem cell (iPSC) technologies. Emerging methods like optogenetics and pharmacological interventions designed to preserve retinal function are also discussed. Additionally, the review examines technological innovations, including retinal prosthetics and the use of artificial intelligence, which hold the potential to revolutionize RP treatment. The challenges and limitations associated with these novel therapies, such as safety concerns, accessibility issues, and regulatory hurdles, are critically evaluated. By providing an overview of current research and future directions, this review aims to inform clinicians and researchers about the state of the art in RP treatment and the prospects for achieving significant therapeutic advancements., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Pawar et al.)

In 2001, Fondazione Telethon and the Italian muscular dystrophy patient organisation Unione Italiana Lotta alla Distrofia Muscolare joined their efforts to design and launch a call for grant applications specifically dedicated to clinical projects in the field of neuromuscular disorders. This strategic initiative, run regularly over the years and still ongoing, aims at supporting research with impact on the daily life of people with a neuromuscular condition and is centred on macro-priorities identified by the patient organisation. It is investigator-driven, and all proposals are peer-reviewed for quality and feasibility. Over the years, this funding program contributed to strengthening the activities of the Italian neuromuscular clinical network, reaching many achievements in healthcare research. Moreover, it has been an enabling factor for innovative therapy experimentation at international level and prepared the clinical ground to make therapies available to Italian patients. The ultimate scope of healthcare research is to ameliorate the delivery of care. In this paper, the achievements of the funded studies are analysed also from this viewpoint, to ascertain to which extent they have fulfilled the original goals established by the patient organisation. The evidence presented indicates that this has been a highly fruitful program. Factors that contributed to its success, lessons learned, challenges, and issues that remain to be addressed are discussed to provide practical examples of an experience that could inspire also other organizations active in the field of rare disease research. [ABSTRACT FROM AUTHOR]

• This article investigates market formation in a global health transition. • Market formation activities are interlinked with other innovation system functions. • Structural couplings link innovation systems components along geographical scales and locations. • We learn lessons from the market formation of a new generation of antimalarial therapies. • Lessons are important for future drug transitions under the pressure of drug resistance. Transition studies have started to focus on market formation in innovation systems. This article investigates market formation in a global health transition that was instigated by drug-resistant malaria. We explore how markets for Artemisinin-based Combination Therapies (ACT) in the Greater Mekong Subregion (GMS) were formed at multiple geographical scales and locations. The study reveals the role of public institutes, academia and partnerships in early innovation system development. It demonstrates how transnational organizations created a supportive global landscape for ACT development and deployment. It then reveals how these advancements led to the formation of public-sector and private-sector ACT markets in the GMS. We illustrate how market formation activities took place on global, national and local scales and how structural couplings enabled the functioning of this global innovation system. The lessons learned are particularly relevant now that drug-resistant malaria has once more emerged in the GMS, urgently calling for new therapies and associated end-user markets. [ABSTRACT FROM AUTHOR]

Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.

Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues. [ABSTRACT FROM AUTHOR]

Currently, Brazil lacks a national asthma management program and is burdened with nearly 200,000 hospitalizations due to the disease per year and approximately 5 deaths per day. The purpose of this article was to analyze the current issues surrounding severe asthma in Brazil, as the status of diagnosis and treatment is largely unknown, and to provide feasible recommendations to elicit imminent action. A panel of Brazilian medical experts in the field of severe asthma was provided with a series of relevant questions to address prior to a multi-day conference. Within this conference, each narrative was discussed and edited by the entire group. Through numerous rounds of discussion consensus was achieved. In order to overcome barriers to adequate asthma treatment, this panel recommends specific initiatives that can be implemented in the short-term to decrease the burden of severe asthma in Brazil. With increasing healthcare costs and limited resources globally, there is an opportunity to implement these recommendations in other countries in order to achieve adequate asthma care. Severe asthma is a heterogeneous and complex disease with various phenotypes that requires strict attention for diagnosis and management. Although this disease affects only a small proportion of the population with asthma, it poses a great burden to healthcare systems. Thus, barriers to diagnosis, treatment, and management should be overcome as quickly and efficiently as possible. [ABSTRACT FROM AUTHOR]

Diffusion and reimbursement of healthcare strategies, drugs or medical devices are based on decisions made by public authorities and health authorities. In a situation of restricted resources and strict budget restrictions, decisions on innovative and costly health products must take into account not only efficacy and safety data, but also efficiency data. In France, generate health economics data to inform on efficiency can be obtain by different processes, resulting in an opportunity to develop, structure and finance health economic evaluation. However, the diversity of sources of funding and the specific requirements of each process make them difficult to understand. The aim of this article is to provide an overview of these sources, while highlighting their advantages and limitations. It also points the need to facilitate interaction between manufacturers, public authorities and the health economic evaluation organisations of health care institutions. The issue is to be able to mobilize the most appropriate system to produce relevant data at the most appropriate time., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The definition of "Metabolic Associated Fatty Liver Disease - MAFLD" has replaced the previous definition of Nonalcoholic Fatty Liver Disease (NAFLD), because cardiometabolic criteria have been added for the prevention of cardiological risk in these patients. This definition leads to an in-depth study of the bidirectional relationships between hepatic steatosis, Type 2 Diabetes Mellitus (T2DM), Cardiovascular Disease (CVD) and/or their complications. Lifestyle modification, which includes correct nutrition combined with regular physical activity, represents the therapeutic cornerstone of MAFLD. When therapy is required, there is not clear accord on how to proceed in an optimal way with nutraceutical or pharmacological therapy. Numerous studies have attempted to identify nutraceuticals with a significant benefit on metabolic alterations and which contribute to the improvement of hepatic steatosis. Several evidences are supporting the use of silymarin, berberine, curcumin, Nigella sativa , Ascophyllum nodosum , and Fucus vesiculosus , vitamin E, coenzyme Q10 and Omega-3. However, more evidence regarding the long-term efficacy and safety of these compounds are required. There is numerous evidence that highlights the use of therapies such as incretins or the use of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors or other similar therapies which, by assisting existing therapies for pathologies such as diabetes, hypertension, insulin resistance, have given a breakthrough in prevention and the reduction of cardiometabolic risk. This review gave an overview of the current therapeutic strategies that are expected to aid in the treatment and prevention of MAFLD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Al Hashmi, Giglio, Pantea Stoian, Patti, Al Waili, Al Rasadi, Ciaccio and Rizzo.)

Alzheimer’s disease is a multifactorial pathology, for which no cure is currently available. Nowadays, researchers are moving towards a new hypothesis of the onset of the illness, linking it to a metabolic impairment. This innovative approach will lead to the identification of new targets for the preparation of new effective drugs. Peroxisome proliferator-activated receptors and their ligands are the ideal candidates to reach the necessary breakthrough to defeat this complicate disease.

Introduction: In today's dynamic world, research in biomedicine and healthcare is constantly evolving toward an integrated approach that takes into account the physical, mental and spiritual aspects of health. This thesis presents the latest trends in physiotherapy, focusing on innovative approaches and their associated challenges. Aim: The purpose of this paper is to present the latest research developments in physiotherapy, such as dry needling, electroacupuncture, virtual reality and fascial therapy, highlighting their holistic approach to the patient. The challenges of implementing and proving the effectiveness of these innovations are also analyzed. Material and methods: The literature review used databases: PubMed, Google Scholar, using the keywords: "holistic physiotherapy", "dry needling", "fascial release", "VR", "electroacupuncture", "VR rehabilitation", "Dn therapy". Inclusion criteria: articles based on randomized clinical trials from the last 5 years, excluding case reports and meta-analyses. Of the 60 papers, 20 were selected by subjecting them to methodological evaluation on the PEDro scale. Results: One of the latest research trends is the growing importance of holistic medicine, combining ancient traditions from the Middle East with modern standards. Analysis of the research papers indicates that the implementation of Dn, electroacupuncture, MFR and VR in the treatment of patients has significant effects that affect different levels, covering physical, mental and motivational aspects. The papers evaluated on the PEDro scale received an average score of 8.5/11, with the lowest score of 6/11. Conclusions: Research in biomedicine and holistic health care is moving toward the integration of modern technologies and a better understanding of the complex mechanisms of health and disease. Despite the introduction of new methods to support therapies, challenges remain in accessing innovative therapies, reducing health disparities and educating the society. While research confirms the effectiveness of the techniques discussed, there is a need for further, more solid research into their effectiveness, the extent of impact and long-term prognosis. [ABSTRACT FROM AUTHOR]

The limit of phage therapy, inherent to bacteriophage, lies in a narrow spectrum of action. Keywords: multi-drug resistant Enterobacterales; innovative therapies; association of antibiotics; plasmids; biofilm; phages EN multi-drug resistant Enterobacterales innovative therapies association of antibiotics plasmids biofilm phages 1 3 3 09/16/21 20210914 NES 210914 In the field of infectious diseases multidrug-resistant (MDR) Gram-negative bacteria such as I Enterobacterales i , I Acinetobacter baumannii i , I Pseudomonas aeruginosa i , and I Aeromonas hydrophila i constitute an important issue for establishing correct and appropriate therapies in patients admitted to both Intensive Care Units and General Medicine centers including respiratory care wards. Multi-drug resistant Enterobacterales, association of antibiotics, plasmids, biofilm, phages, innovative therapies. [Extracted from the article]

Skin wound healing is a complex and dynamic process that aims to restore lesioned tissues. Collagen-based skin substitutes are a promising treatment to promote wound healing by mimicking the native skin structure. Recently, collagen from marine organisms has gained interest as a source for producing biomaterials for skin regenerative strategies. This preliminary study aimed to describe the application of a collagen-based skin-like scaffold (CBSS), manufactured with collagen extracted from sea urchin food waste, to treat experimental skin wounds in a large animal. The wound-healing process was assessed over different time points by the means of clinical, histopathological, and molecular analysis. The CBSS treatment improved wound re-epithelialization along with cell proliferation, gene expression of growth factors (VEGF-A), and development of skin adnexa throughout the healing process. Furthermore, it regulated the gene expression of collagen type I and III, thus enhancing the maturation of the granulation tissue into a mature dermis without any signs of scarring as observed in untreated wounds. The observed results (reduced inflammation, better re-epithelialization, proper development of mature dermis and skin adnexa) suggest that sea urchin-derived CBSS is a promising biomaterial for skin wound healing in a “blue biotechnologies” perspective for animals of Veterinary interest.

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals that promise improvement in the atheromatous plaque from a molecular point of view, because have actions on the exposure of the LDL-Receptor (LDL-R), on endothelial dysfunction, activation of macrophages, on lipid oxidation, formations on foam cells, and deposition extracellular lipids. Atheroma plaque reduction both as a result of LDL-Cholesterol (LDL-C) intensive lowering and reducing inflammation and other residual risk factors is an integral part of the management of atherosclerotic disease, and the use of valid therapeutic alternatives appear to be appealing avenues to solving the problem.

Children and adolescents with acute leukemia have certainly a high chance of recovery, and much higher than adults, from the first line of treatment with conventional chemotherapy, but if a relapse occurs, subsequent survival remains poor, whether in lymphoblastic or myeloblastic subtypes. The accumulation of treatments is responsible for severe acute toxicities, long-term sequelae and a significant risk of secondary cancer. The exponential growth of new targeted therapies with small molecules, monoclonal antibodies and adoptive immunotherapy gives great hope for the most serious diseases. The large number of these new drugs raises the question of their respective place in new therapeutic strategies in the face of conventional chemotherapy and hematopoietic stem cell transplantation procedures, including in economic terms. [ABSTRACT FROM AUTHOR]