The importance of arterial stiffness in pediatric patients with type 1 diabetes mellitus: What's new?

Youths with type 1 diabetes (T1D) exhibits higher levels of pulse wave velocity (PWV) compared to healthy controls. Higher PWV in T1D subjects is associated with increased hazard of progression in albuminuria, decline in eGFR, cardiovascular (CV) events and mortality. In the recently published work by Georeli et al., increased PWV was associated with poor glycemic control as expressed by time-in-range (TIR) < 50 % in T1D children, adolescents and young adults. This finding is of great interest, since it is well known that glycemic control, as measured by TIR, is an important contributor of CV risk. The duration of TIR < 50 % is not reported by the authors, but is of importance, knowing that CGM provide data for the last 3-6 months, depending on the CGM model. In conclusion, PWV looks promising for risk stratification in T1D, but its exact role in T1D still remains to be fully explored.

Gastrointestinal adverse events associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the EudraVigilance and VigiAccess databases.

BACKGROUND: This study aimed to provide an overview of gastrointestinal (GI) adverse events associated with immune checkpoint inhibitors (ICIs) using two pharmacovigilance databases, EudraVigilance and VigiAccess. RESEARCH DESIGN AND METHODS: Data was collected from the date of ICI's marketing authorization until 30 November 2023. Reporting odds ratio (ROR) was used as a measure of ADR reporting disproportionality for signal detection. RESULTS: Overall, across both databases, EudraVigilance and VigiAccess, a total of 76,606 ADR reports were analyzed. In EudraVigilance, colitis (12,581) and diarrhea (12,108) were the most reported GI adverse events, with similar findings in VigiAccess. Furthermore, in both databases, the most ADR reports were associated with nivolumab and pembrolizumab. Durvalumab (ROR:3.96,95%CI:3.65-4.28), ipilimumab (ROR:1.95,95%CI:1.89-2.01), nivolumab (ROR:1.05,95%CI:1.02-1.07), and atezolizumab (ROR:1.04,95%CI:1.01-1.07) demonstrated higher risks of GI events compared to other ICIs. EudraVigilance analysis identified dysphagia, ascites, hematochezia, and gastroesophageal reflux disease as potential signals associated with ICI therapy. Majority of ADR reports (87.2%) comprised serious GI adverse events, a portion of which was associated with fatal outcomes (14.5%). Atezolizumab (14.9%) and pembrolizumab (11.9%) were linked to a higher incidence of fatal outcomes compared to other ICIs. CONCLUSION: The differential risk profiles of ICIs-associated-GI adverse events underscore the importance of personalized therapy in oncology.

Correction: Al Khatib et al. Inhaled Medicines for Targeting Non-Small Cell Lung Cancer. Pharmaceutics 2024, 15, 2777.

In the original publication [...].

A comprehensive review of PRAME and BAP1 in melanoma: Genomic instability and immunotherapy targets.

In a thorough review of the literature, the complex roles of PRAME (preferentially expressed Antigen of Melanoma) and BAP1 (BRCA1-associated protein 1) have been investigated in uveal melanoma (UM) and cutaneous melanoma. High PRAME expression in UM is associated with poor outcomes and correlated with extraocular extension and chromosome 8q alterations. BAP1 mutations in the UM indicate genomic instability and a poor prognosis. Combining PRAME and BAP1 immunohistochemical staining facilitates effective risk stratification. Mechanistically, both genes are associated with genomic instability, making them promising targets for cancer immunotherapy. Hypomethylation of PRAME, specifically in its promoter regions, is critical for UM progression and contributes to epigenetic reprogramming. Additionally, miR-211 regulation is crucial in melanoma and has therapeutic potential. The way PRAME changes signaling pathways provides clues about the cause of cancer due to genomic instability related to modifications in DNA repair. Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in cells expressing PRAME could lead to potential therapeutic applications. Pathway enrichment analysis underscores the significance of PRAME and BAP1 in melanoma pathogenesis.

The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists in the Management of Obesity-Related Heart Failure with Preserved Ejection Fraction: Benefits beyond What Scales Can Measure?

Obesity is a significant predisposing factor for heart failure with preserved ejection fraction (HFpEF). Although a substantial proportion of individuals with HFpEF also have obesity, those with obesity are under-represented in clinical trials for heart failure. In turn, current guidelines provided limited recommendations for the medical management of this patient population. Both obesity and diabetes induce a pro-inflammatory state that can contribute to endothelial dysfunction and coronary microvascular impairment, finally resulting in HFpEF. Additionally, obesity leads to increased epicardial and chest wall adiposity, which enhances ventricular interdependence. This condition is further aggravated by plasma and blood volume expansion and excessive vasoconstriction, ultimately worsening HFpEF. Despite the well-documented benefits of GLP-1 receptor agonists in subjects with diabetes, obesity, or both, their role in obesity-related HFpEF remains unclear. In light of the recently published literature, this review aims to investigate the potential mechanisms and synthesize the available clinical evidence regarding the role of GLP-1 receptor agonists in patients with obesity-related HFpEF.

Effects of Glucagon-Like Peptide 1 Receptor Agonists on Atrial Fibrillation Recurrence After Catheter Ablation: A Systematic Review and Meta-analysis.

INTRODUCTION: Despite the technological advancements in catheter ablation strategies, the recurrence of atrial fibrillation (AF) post-ablation remains a concern that requires further investigation. Glucagon-like peptide 1 (GLP-1) receptor agonists have shown a significant effect on weight reduction, which in turn is associated with freedom from AF recurrence in both patients who are obese and not obese undergoing ablation. Therefore, we aimed to summarize the available evidence on the efficacy of GLP-1 receptor agonists in maintaining sinus rhythm post-ablation. METHODS: Medline, Cochrane Library, and Scopus were searched until June 9, 2024. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled using DerSimonian-Laird random effects meta-analysis. RESULTS: Three propensity score-matched studies (n = 6031 participants) were analyzed. Over a 12-months follow-up, the use of GLP-1 receptor agonists was associated with a significant reduction in AF recurrence compared to controls, hazard ratio (HR) = 0.549, 95% confidence interval (CI) = [0.315, 0.956], P = 0.034; I2 = 57%. No significant heterogeneity was observed (Q statistic = 4.6, heterogeneity P = 0.1). CONCLUSION: The use of GLP-1 receptor agonists is associated with a lower risk of AF recurrence in patients receiving AF ablation therapy. Further large-scale randomized trials are necessary to explore the efficacy of GLP-1 receptor agonists in maintaining ablation outcomes over the long term.

Diabetes and its Silent Partner: A Critical Review of Hyperinsulinemia and its Complications.

In this complex realm of diabetes, hyperinsulinemia is no longer regarded as just a compensatory response to insulin resistance but rather has evolved into an integral feature. This comprehensive review provides a synthesis of the current literature, including various aspects associated with hyperinsulinemia in diabetic complications. Hyperinsulinemia has been shown to be more than just a compensatory mechanism, and the key findings demonstrate how hyperinsulinism affects the development of cardiovascular events as well as microvascular complications. Additionally, recognizing hyperinsulinemia as a modifiable factor, the diabetes management paradigm shifts towards cognitive ones that consider the use of lifestyle modifications in combination with newer pharmacotherapies and precision medicine approaches. These findings have crucial implications for the clinical work, requiring a careful appreciation of hyperinsulinemia's changing aspects as well as incorporation in personalized treatment protocol. In addition, the review focuses on bigger issues related to public health, showing that prevention and early diagnosis will help reduce the burden of complications. Research implications favor longitudinal studies, biomarker discovery, and the study of emerging treatment modalities; clinical practice should adopt global evaluations, patient education, and precision medicine adaptation. Finally, this critical review provides an overview of the underlying processes of hyperinsulinemia in diabetes and its overall health effects.

Tirzepatide: unveiling a new dawn in dual-targeted diabetes and obesity management.

INTRODUCTION: Incretin-based therapies have emerged as effective treatments for type 2 diabetes (T2D) and obesity. However, not all patients achieve optimal outcomes with existing treatments, highlighting the need for more effective solutions. AREAS COVERED: We present a comprehensive evaluation of Tirzepatide (TZP), a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonist, for managing obesity and T2D. We conducted a systematic search of Cochrane, PubMed, Scopus, and Web of Science databases from inception to April 2024. The focus of the review is on the development and therapeutic potential of TZP, with detailed exploration on pharmacodynamics, pharmacokinetics, clinical efficacy, and safety. Furthermore, it reviews TZP's impacts on glycemic control, weight management, and its potential cardiovascular (CV) benefits. EXPERT OPINION: TZP represents a significant advancement in the dual-targeted approach to treating T2D and obesity. Its unique mechanism of action offers superior efficacy in reducing glycemic levels and body weight compared to existing therapies. New data suggesting improvements in CV outcomes indicate that TZP could set a new standard in the treatment paradigm. While long-term data on efficacy and safety are still forthcoming, current evidence positions TZP as a promising option for patients who have not reached their therapeutic goals with existing treatments.

Deciphering Depression: Epigenetic Mechanisms and Treatment Strategies.

Depression, a significant mental health disorder, is under intense research scrutiny to uncover its molecular foundations. Epigenetics, which focuses on controlling gene expression without altering DNA sequences, offers promising avenues for innovative treatment. This review explores the pivotal role of epigenetics in depression, emphasizing two key aspects: (I) identifying epigenetic targets for new antidepressants and (II) using personalized medicine based on distinct epigenetic profiles, highlighting potential epigenetic focal points such as DNA methylation, histone structure alterations, and non-coding RNA molecules such as miRNAs. Variations in DNA methylation in individuals with depression provide opportunities to target genes that are associated with neuroplasticity and synaptic activity. Aberrant histone acetylation may indicate that antidepressant strategies involve enzyme modifications. Modulating miRNA levels can reshape depression-linked gene expression. The second section discusses personalized medicine based on epigenetic profiles. Analyzing these patterns could identify biomarkers associated with treatment response and susceptibility to depression, facilitating tailored treatments and proactive mental health care. Addressing ethical concerns regarding epigenetic information, such as privacy and stigmatization, is crucial in understanding the biological basis of depression. Therefore, researchers must consider these issues when examining the role of epigenetics in mental health disorders. The importance of epigenetics in depression is a critical aspect of modern medical research. These findings hold great potential for novel antidepressant medications and personalized treatments, which would significantly improve patient outcomes, and transform psychiatry. As research progresses, it is expected to uncover more complex aspects of epigenetic processes associated with depression, enhance our comprehension, and increase the effectiveness of therapies.

Therapeutic Advances in Obesity: How Real-World Evidence Impacts Affordability Beyond Standard of Care.

Obesity is currently considered a global epidemic, with rising prevalence worldwide and rather pessimistic projections. Based on its close interconnection with various co-morbidities, such as diabetes mellitus and cardiovascular disease, obesity is associated with significant increases in morbidity and mortality, while it also poses a substantial economic burden for national healthcare systems. Apparently, the majority of individuals classified as obese do not achieve adequate weight loss with the adoption of a healthy lifestyle intervention, including dietary modification and physical activity. Fortunately, during the last decade, a significant progress in pharmacotherapy of obesity has been observed, with the introduction of agents that have gained approval from regulatory authorities, namely semaglutide, liraglutide and tirzepatide, due to their impressive results in body weight reduction, alongside their beneficial, pleiotropic effects. The aim of the present review article is to discuss on evidence retrieved from real-world studies regarding the efficacy of those agents in obesity treatment, with emphasis on cost-effectiveness data, towards an effort to tackle efficiently the progression of obesity epidemic.

Metabolic vulnerabilities in cancer: A new therapeutic strategy.

Cancer metabolism is now a key area for therapeutic intervention, targeting unique metabolic reprogramming crucial for tumor growth and survival. This article reviews the therapeutic potential of addressing metabolic vulnerabilities through glycolysis and glutaminase inhibitors, which disrupt cancer cell metabolism. Challenges such as tumor heterogeneity and adaptive resistance are discussed, with strategies including personalized medicine and predictive biomarkers to enhance treatment efficacy. Additionally, integrating diet and lifestyle changes with metabolic targeting underscores a holistic approach to improving therapy outcomes. The article also examines the benefits of incorporating these strategies into standard care, highlighting the potential for more tailored, safer treatments. In conclusion, exploiting metabolic vulnerabilities promises a new era in oncology, positioning metabolic targeting at the forefront of personalized cancer therapy and transforming patient care.

Customizable Microfluidic Devices: Progress, Constraints, and Future Advances.

The field of microfluidics encompasses the study of fluid behavior within micro-channels and the development of miniature systems featuring internal compartments or passageways tailored for fluid control and manipulation. Microfluidic devices capitalize on the unique chemical and physical properties exhibited by fluids at the microscopic scale. In contrast to their larger counterparts, microfluidic systems offer a multitude of advantages. Their implementation facilitates the investigation and utilization of reduced sample, solvent, and reagent volumes, thus yielding decreased operational expenses. Owing to their compact dimensions, these devices allow for the concurrent execution of multiple procedures, leading to expedited experimental timelines. Over the past two decades, microfluidics has undergone remarkable advancements, evolving into a multifaceted discipline. Subfields such as organ-on-a-chip and paper-based microfluidics have matured into distinct fields of study. Nonetheless, while scientific progress within the microfluidics realm has been notable, its translation into autonomous end-user applications remains a frontier to be fully explored. This paper sets forth the central objective of scrutinizing the present research paradigm, prevailing limitations, and potential prospects of customizable microfluidic devices. Our inquiry revolves around the latest strides achieved, prevailing constraints, and conceivable trajectories for adaptable microfluidic technologies. We meticulously delineate existing iterations of microfluidic systems, elucidate their operational principles, deliberate upon encountered limitations, and provide a visionary outlook toward the future trajectory of microfluidic advancements. In summation, this work endeavors to shed light on the current state of microfluidic systems, underscore their operative intricacies, address incumbent challenges, and unveil promising pathways that chart the course toward the next frontier of microfluidic innovation.

Nanomaterial-Driven Precision Immunomodulation: A New Paradigm in Therapeutic Interventions.

Immunotherapy is a rapidly advancing field of research in the treatment of conditions such as cancer and autoimmunity. Nanomaterials can be designed for immune system manipulation, with precise targeted delivery and improved immunomodulatory efficacy. Here, we elaborate on various strategies using nanomaterials, including liposomes, polymers, and inorganic NPs, and discuss their detailed design intricacies, mechanisms, and applications, including the current regulatory issues. This type of nanomaterial design for targeting specific immune cells or tissues and controlling release kinetics could push current technological frontiers and provide new and innovative solutions for immune-related disorders and diseases without off-target effects. These materials enable targeted interactions with immune cells, thereby enhancing the effectiveness of checkpoint inhibitors, cancer vaccines, and adoptive cell therapies. Moreover, they allow for fine-tuning of immune responses while minimizing side effects. At the intersection of nanotechnology and immunology, nanomaterial-based platforms have immense potential to revolutionize patient-centered immunotherapy and reshape disease management. By prioritizing safety, customization, and compliance with regulatory standards, these systems can make significant contributions to precision medicine, thereby significantly impacting the healthcare landscape.

The Complex Connection between Obesity and Cancer: Signaling Pathways and Therapeutic Implications.

Obesity has emerged as an important global health challenge, significantly influencing the incidence and progression of various cancers. This comprehensive review elucidates the complex relationship between obesity and oncogenesis, focusing particularly on the role of dysregulated signaling pathways as central mediators of this association. We delve into the contributions of obesity-induced alterations in key signaling cascades, including PI3K/AKT/mTOR, JAK/STAT, NF-κB, and Wnt/ß-catenin to carcinogenesis. These alterations facilitate unchecked cellular proliferation, chronic inflammation and apoptosis resistance. Epidemiological evidence links obesity with increased cancer susceptibility and adverse prognostic outcomes, with pronounced risks for specific cancers such as breast, colorectal, endometrial and hepatic malignancies. This review synthesizes data from both animal and clinical studies to underscore the pivotal role of disrupted signaling pathways in shaping innovative therapeutic strategies. We highlight the critical importance of lifestyle modifications in obesity management and cancer risk mitigation, stressing the benefits of dietary changes, physical activity, and behavioral interventions. Moreover, we examine targeted pharmacological strategies addressing aberrant pathways in obesity-related tumors and discuss the integration of cutting-edge treatments, including immunotherapy and precision medicine, into clinical practice.

Evaluation of Solubility, Dissolution Rate, and Oral Bioavailability of ß-Cyclodextrin and Hydroxypropyl ß-Cyclodextrin as Inclusion Complexes of the Tyrosine Kinase Inhibitor, Alectinib.

This study aims to improve the solubility and dissolution rate of alectinib (ALB), a tyrosine kinase inhibitor commonly used for treating non-small-cell carcinoma (NSCLC). Given ALB's low solubility and bioavailability, complexation with ß-cyclodextrin (ßCD) and hydroxy propyl ß-cyclodextrin (HPßCD) was evaluated. Some of the different preparation methods used with varying ALB-to-CD ratios led to the formation of complexes that were characterized using Fourier-Transform Infrared (FTIR) techniques and Differential Scanning Calorimetry (DSC) to prove complex formation. The encapsulation efficiency was also determined. The simulations were carried out for ALB's interactions with ßCD and HPßCD. This study identified the most soluble complex (ALB-HPßCD; 1:2 ratio) and evaluated its dissolution. The bioavailability of the ALB-HPßCD complex was evaluated in Wistar rats relative to free ALB. Pharmacokinetic profiles revealed increased Cmax (240 ± 26.95 ng/mL to 474 ± 50.07 ng/mL) and AUC0-48 (5946.75 ± 265 ng.h/mL to 10520 ± 310 ng.h/mL) with no change in the elimination rate constant. In conclusion, the complexation of ALB-HPßCD manages to increase in vitro solubility, the dissolution rate, and oral bioavailability, providing a favorable approach to improving ALB administration.

Doxorubicin conjugates: a practical approach for its cardiotoxicity alleviation.

INTRODUCTION: Doxorubicin (DOX) emerges as a cornerstone in the arsenal of potent chemotherapeutic agents. Yet, the clinical deployment of DOX is tarnished by its proclivity to induce severe cardiotoxic effects, culminating in heart failure and other consequential morbidities. In response, a panoply of strategies has undergone rigorous exploration over recent decades, all aimed at attenuating DOX's cardiotoxic impact. The advent of encapsulating DOX within lipidic or polymeric nanocarriers has yielded a dual triumph, augmenting DOX's therapeutic efficacy while mitigating its deleterious side effects. AREAS COVERED: Recent strides have spotlighted the emergence of DOX conjugates as particularly auspicious avenues for ameliorating DOX-induced cardiotoxicity. These conjugates entail the fusion of DOX through physical or chemical bonds with diminutive natural or synthetic moieties, polymers, biomolecules, and nanoparticles. This spectrum encompasses interventions that impinge upon DOX's cardiotoxic mechanism, modulate cellular uptake and localization, confer antioxidative properties, or refine cellular targeting. EXPERT OPINION: The endorsement of DOX conjugates as a compelling stratagem to mitigate DOX-induced cardiotoxicity resounds from this exegesis, amplifying safety margins and the therapeutic profile of this venerated chemotherapeutic agent. Within this ambit, DOX conjugates stand as a beacon of promise in the perpetual pursuit of refining chemotherapy-induced cardiac compromise.

Advances in glioblastoma multiforme: Integrating therapy and pathology perspectives.

Glioblastoma, a highly lethal form of brain cancer, is characterized by its aggressive growth and resistance to conventional treatments, often resulting in limited survival. The response to therapy is notably influenced by various patient-specific genetic factors, underscoring the disease's complexity. Despite the utilization of diverse treatment modalities such as surgery, radiation, and chemotherapy, many patients experience local relapse, emphasizing the critical need for improved therapeutic strategies to effectively target these formidable tumors. Recent years have witnessed a surge in interest in natural products derived from plants, particularly alkaloids, for their potential anticancer effects. Alkaloids have shown promise in cancer chemotherapy by selectively targeting crucial signaling pathways implicated in tumor progression and survival. Specifically, they modulate the NF-κB and MAPK pathways, resulting in reduced tumor growth and altered gene expression across various cancer types. Additionally, alkaloids exhibit the capacity to induce cell cycle arrest, further impeding tumor proliferation in several malignancies. This review aims to delineate recent advances in understanding the pathology of glioblastoma multiforme (GBM) and to explore the potential therapeutic implications of alkaloids in managing this deadly disease. By segregating discussions on GBM pathology from those on alkaloid-based therapies, we provide a structured overview of the current challenges in GBM treatment and the promising opportunities presented by alkaloid-based interventions. Furthermore, we briefly discuss potential future directions in GBM research and therapy beyond alkaloids, including emerging treatment modalities or areas of investigation that hold promise for improving patient outcomes. In conclusion, our efforts offer hope for enhanced outcomes and improved quality of life for GBM patients through alkaloid-based therapies. By integrating insights from pathology and therapeutic perspectives, we underscore the significance of a comprehensive approach in addressing this devastating disease.

Unraveling the tumor microenvironment: Insights into cancer metastasis and therapeutic strategies.

This comprehensive review delves into the pivotal role of the tumor microenvironment (TME) in cancer metastasis and therapeutic response, offering fresh insights into the intricate interplay between cancer cells and their surrounding milieu. The TME, a dynamic ecosystem comprising diverse cellular and acellular elements, not only fosters tumor progression but also profoundly affects the efficacy of conventional and emerging cancer therapies. Through nuanced exploration, this review illuminates the multifaceted nature of the TME, elucidating its capacity to engender drug resistance via mechanisms such as hypoxia, immune evasion, and the establishment of physical barriers to drug delivery. Moreover, it investigates innovative therapeutic approaches aimed at targeting the TME, including stromal reprogramming, immune microenvironment modulation, extracellular matrix (ECM)-targeting agents, and personalized medicine strategies, highlighting their potential to augment treatment outcomes. Furthermore, this review critically evaluates the challenges posed by the complexity and heterogeneity of the TME, which contribute to variable therapeutic responses and potentially unintended consequences. This underscores the need to identify robust biomarkers and advance predictive models to anticipate treatment outcomes, as well as advocate for combination therapies that address multiple facets of the TME. Finally, the review emphasizes the necessity of an interdisciplinary approach and the integration of cutting-edge technologies to unravel the intricacies of the TME, thereby facilitating the development of more effective, adaptable, and personalized cancer treatments. By providing critical insights into the current state of TME research and its implications for the future of oncology, this review highlights the dynamic and evolving landscape of this field.