MicroRNAs as a Potential New Preventive Approach in the Transition from Asymptomatic to Symptomatic Multiple Myeloma Disease

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bonemarrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact onMMtumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions

Using increased trust in medical researchers to increase minority recruitment: The RECRUIT cluster randomized clinical trial

While extensive literature exists on barriers and strategies to increase minority participation in clinical trials, progress is limited. Few strategies were evaluated in randomized trials. We studied the impact of RECRUIT, a trust-based, cluster randomized minority recruitment trial layered on top of four traditional NIH-funded parent trials (BMT CTN, CABANA, PACES, STEADY-PD III; fifty specialty sites). RECRUIT was conducted from July 2013 through April 2017. Intervention sites implemented trust-based approaches customized to individual sites, promoting relationships between physician-investigators and minority-serving physicians and their minority patients. Control sites implemented only parent trials\u27 recruitment procedures. Adjusting for within-site clustering, we detected no overall intervention effect, odds ratio 1.3 (95% confidence limits 0.7,2.4). Heterogeneity among parent trials may have obscured the effect. Of the four parent trials, three enrolled more minorities in intervention versus control sites. CABANA odds ratio = 4.2 (adjusted 95%CL 1.5,11.3). PACES intervention sites enrolled 63% (10/16) minorities; control sites enrolled one participant in total, a minority, yielding an incalculable odds ratio. STEADY-PD III odds ratio = 2.2 (adjusted 95%CL 0.6,8.5). BMT CTN odds ratio \u3c 1, 0.8 (adjusted 95%CL 0.4,1.8). In conclusion, RECRUIT findings suggest the unique trust-based intervention increased minority recruitment to intervention trials in (3/4) of studied trials. Physician-investigators\u27 participation was critical to recruitment success. Lack of commitment to minority recruitment remained a barrier for some physician-investigators, especially in control sites. We recommend prospective physician investigators commit to minority recruitment activities prior to selection as site investigators and trial funding include some compensation for minority recruitment efforts.TRIAL REGISTRATION ClinicalTrials.govNCT01911208

MicroRNAs as a Potential New Preventive Approach in the Transition from Asymptomatic to Symptomatic Multiple Myeloma Disease

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bone marrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact on MM tumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions

microRNAs as Biomarkers of Endothelial Dysfunction and Therapeutic Target in the Pathogenesis of Atrial Fibrillation

The pathophysiology of atrial fibrillation (AF) may involve atrial fibrosis/remodeling and dysfunctional endothelial activities. Despite the currently available treatment approaches, the progression of AF, its recurrence rate, and the high mortality risk of related complications underlay the need for more advanced prognostic and therapeutic strategies. There is increasing attention on the molecular mechanisms controlling AF onset and progression points to the complex cell to cell interplay that triggers fibroblasts, immune cells and myofibroblasts, enhancing atrial fibrosis. In this scenario, endothelial cell dysfunction (ED) might play an unexpected but significant role. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level. In the cardiovascular compartment, both free circulating and exosomal miRNAs entail the control of plaque formation, lipid metabolism, inflammation and angiogenesis, cardiomyocyte growth and contractility, and even the maintenance of cardiac rhythm. Abnormal miRNAs levels may indicate the activation state of circulating cells, and thus represent a specific read-out of cardiac tissue changes. Although several unresolved questions still limit their clinical use, the ease of accessibility in biofluids and their prognostic and diagnostic properties make them novel and attractive biomarker candidates in AF. This article summarizes the most recent features of AF associated with miRNAs and relates them to potentially underlying mechanisms

The Leading Role of the Immune Microenvironment in Multiple Myeloma: A New Target with a Great Prognostic and Clinical Value

Multiple myeloma (MM) is a plasma cell (PC) malignancy whose development flourishes in the bone marrow microenvironment (BMME). The BMME components’ immunoediting may foster MM progression by favoring initial immunotolerance and subsequent tumor cell escape from immune surveillance. In this dynamic process, immune effector cells are silenced and become progressively anergic, thus contributing to explaining the mechanisms of drug resistance in unresponsive and relapsed MM patients. Besides traditional treatments, several new strategies seek to re-establish the immunological balance in the BMME, especially in already-treated MM patients, by targeting key components of the immunoediting process. Immune checkpoints, such as CXCR4, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), PD-1, and CTLA-4, have been identified as common immunotolerance steps for immunotherapy. B-cell maturation antigen (BCMA), expressed on MMPCs, is a target for CAR-T cell therapy, antibody-(Ab) drug conjugates (ADCs), and bispecific mAbs. Approved anti-CD38 (daratumumab, isatuximab), anti-VLA4 (natalizumab), and anti-SLAMF7 (elotuzumab) mAbs interfere with immunoediting pathways. New experimental drugs currently being evaluated (CD137 blockers, MSC-derived microvesicle blockers, CSF-1/CSF-1R system blockers, and Th17/IL-17/IL-17R blockers) or already approved (denosumab and bisphosphonates) may help slow down immune escape and disease progression. Thus, the identification of deregulated mechanisms may identify novel immunotherapeutic approaches to improve MM patients’ outcomes

Mast Cells and Interleukins

Mast cells play a critical role in inflammatory diseases and tumor growth. The versatility of mast cells is reflected in their ability to secrete a wide range of biologically active cytokines, including interleukins, chemokines, lipid mediators, proteases, and biogenic amines. The aim of this review article is to analyze the complex involvement of mast cells in the secretion of interleukins and the role of interleukins in the regulation of biological activities of mast cells

Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer’s disease (AD). Indeed, the proposed definition of Alzheimer’s disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated

The Complexity of the Tumor Microenvironment in Hepatocellular Carcinoma and Emerging Therapeutic Developments

This review explores various aspects of the HCC TME, including both cellular and non-cellular components, to elucidate their roles in tumor development and progression. Specifically, it highlights the significance of cancer-associated fibroblasts (CAFs) and their contributions to tumor progression, angiogenesis, immune suppression, and therapeutic resistance. Moreover, this review emphasizes the role of immune cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T-cells (Tregs), in shaping the immunosuppressive microenvironment that promotes tumor growth and immune evasion. Furthermore, we also focused only on the non-cellular components of the HCC TME, including the extracellular matrix (ECM) and the role of hypoxia-induced angiogenesis. Alterations in the composition of ECM and stiffness have been implicated in tumor invasion and metastasis, while hypoxia-driven angiogenesis promotes tumor growth and metastatic spread. The molecular mechanisms underlying these processes, including the activation of hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) signaling, are also discussed. In addition to elucidating the complex TME of HCC, this review focuses on emerging therapeutic strategies that target the TME. It highlights the potential of second-line treatments, such as regorafenib, cabozantinib, and ramucirumab, in improving overall survival for advanced HCC patients who have progressed on or were intolerant to first-line therapy. Furthermore, this review explores the implications of the Barcelona Clinic Liver Cancer (BCLC) staging and classification system in guiding HCC management decisions. The BCLC system, which incorporates tumor stage, liver function, and performance status, provides a framework for treatment stratification and prognosis prediction in HCC patients. The insights gained from this review contribute to the development of novel therapeutic interventions and personalized treatment approaches for HCC patients, ultimately improving clinical outcomes in this challenging disease