Role of Sam68 in different types of cancer (Review).

Src­associated in mitosis 68 kDa protein (Sam68) is a protein encoded by the heteronuclear ribonucleoprotein particle K homology (KH) single domain­containing, RNA­binding, signal transduction­associated protein 1 (known as KHDRBS1) gene in humans. This protein contains binding sites for critical components in a variety of cellular processes, including the regulation of gene expression, RNA processing and cell signaling. Thus, Sam68 may play a role in a variety of diseases, including cancer. Sam68 has been widely demonstrated to participate in tumor cell proliferation, progression and metastasis to be involved in the regulation of cancer stem cell self­renewal. Based on the body of evidence available, Sam68 emerges as a promising target for this disease. The objectives of the present included summarizing the role of Sam68 in cancer murine models and cancer patients, unraveling the molecular mechanisms underlying its oncogenic potential and discussing the effectiveness of antitumor agents in reducing the malignant effects of Sam68 during tumorigenesis.

Role of Nutrients Regulating Myeloid Derived Suppressor Cells in Cancer: A Scoping Review.

Myeloid-derived suppressor cells (MDSCs) are immature cells with an immunosuppressive function. MDSCs have been related to inflammation in many settings, including infections, transplantation, obesity, aging, or cancer. In oncological settings, MDSCs participate in tumor immunoescape, growth, and metastasis. Certain nutrients can modify chronic inflammation by their interaction with MDSCs. Therefore, the possible influence of certain nutrients on immune surveillance by their actions on MDSCs and how this may affect the prognosis of cancer patients were evaluated in this scoping review. We identified seven papers, six of which were murine model studies and only one was a human clinical trial. Globally, a significant reduction in cancer growth and progression was observed after achieving a reduction in both MDSCs and their immunosuppressive ability with nutrients such as selected vegetables, icaritin, retinoic acid, curdlan, active vitamin D, soy isoflavones, and green tea. In conclusion, the consumption of certain nutrients may have effects on MDSCs, with beneficial results not only in the prevention of tumor development and growth but also in improving patients' response.

The Expression of Genes Related to Reverse Cholesterol Transport and Leptin Receptor Pathways in Peripheral Blood Mononuclear Cells Are Decreased in Morbid Obesity and Related to Liver Function.

Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells (PBMCs) from 86 patients with morbid obesity (MO) before and six months after Roux-en-Y gastric bypass (RYGB) and 38 non-obese subjects. In the LXRα pathway, LXRα, ABCA1, and ABCG1 mRNA expressions were decreased in MO compared to non-obese subjects (p < 0.001, respectively). Ob-Rb was decreased (p < 0.001), whereas Sam68 was increased (p < 0.001) in MO. RYGB did not change mRNA gene expressions. In the MO group, the LXRα pathway (LXRα/ABCA1/ABCG1) negatively correlated with obesity-related variables (weight, body mass index, and hip), inflammation (C-reactive protein), and liver function (alanine-aminotransferase, alkaline phosphatase, and fatty liver index), and positively with serum albumin. In the Ob-R pathway, Ob-Rb and Sam68 negatively correlated with alanine-aminotransferase and positively with albumin. The alteration of LXRα and Ob-R pathways may play an important role in NAFLD development in MO. It is possible that MO patients may require more than 6 months following RYBGB to normalize gene expression related to reverse cholesterol transport or leptin responsiveness.

Influence of the Surface Topography of Titanium Dental Implants on the Behavior of Human Amniotic Stem Cells.

The dental implant surface plays a crucial role in osseointegration. The topography and physicochemical properties will affect the cellular functions. In this research, four distinct titanium surfaces have been studied: machined acting (MACH), acid etched (AE), grit blasting (GBLAST), and a combination of grit blasting and subsequent acid etching (GBLAST + AE). Human amniotic mesenchymal (hAMSCs) and epithelial stem cells (hAECs) isolated from the amniotic membrane have attractive stem-cell properties. They were cultured on titanium surfaces to analyze their impact on biological behavior. The surface roughness, microhardness, wettability, and surface energy were analyzed using interferometric microscopy, Vickers indentation, and drop-sessile techniques. The GBLAST and GBLAST + AE surfaces showed higher roughness, reduced hydrophilicity, and lower surface energy with significant differences. Increased microhardness values for GBLAST and GBLAST + AE implants were attributed to surface compression. Cell viability was higher for hAMSCs, particularly on GBLAST and GBLAST + AE surfaces. Alkaline phosphatase activity enhanced in hAMSCs cultured on GBLAST and GBLAST + AE surfaces, while hAECs showed no mineralization signals. Osteogenic gene expression was upregulated in hAMSCs on GBLAST surfaces. Moreover, α2 and ß1 integrin expression enhanced in hAMSCs, suggesting a surface-integrin interaction. Consequently, hAMSCs would tend toward osteoblastic differentiation on grit-blasted surfaces conducive to osseointegration, a phenomenon not observed in hAECs.

Placental apoptosis increased by hypoxia inducible factor-1 stabilization is counteracted by leptin†.

During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed toward the relevance of hypoxia as modulator of trophoblast cell death. Previous reports have shown that leptin, a placental cytokine, promotes cell survival in both cell culture and placental explant models. The aim of this work is to establish the role of leptin in apoptosis under hypoxic condition in trophoblast cells. In this study, we evaluated the effect of cobalt chloride, a hypoxia mimicking agent that stabilizes the expression of hypoxia-inducible factor-1 alpha, on Swan-71 and human placental explants. Hypoxia chamber was also used to generate 2% oxygen. Apoptosis was determined by the presence of apoptotic nucleus, fragmentation of DNA and Caspase-3 and PARP-1 cleavage. The pro-apoptotic proteins BAX, BID, BAD, and BAK and the anti-apoptotic effectors BCL-2, B-cell lymphoma-extra-large, and myeloid cell leukemia-1 were also analyzed. We found that hypoxia-inducible factor-1 alpha stabilization increased the appearance of apoptotic nucleus, fragmentation of DNA, and Caspase-3 and PARP-1 cleavage. Hypoxia mimicking conditions enhanced the expression of pro-apoptotic effectors BAX, BID, BAD, and BAK. Hypoxia-inducible factor-1 alpha stabilization also downregulated the level of BCL-2, B-cell lymphoma-extra-large, and myeloid cell leukemia-1. All these apoptotic parameters changes were reversed with leptin treatment. Moreover, we showed that leptin action on apoptosis modulation involves PI3K and MAPK signaling pathways. Obtained data demonstrate that hypoxia-inducible factor-1 alpha stabilization induces apoptosis in human placenta and leptin counteracts this effect, reinforcing its role as a survival cytokine.

Impact of obesity­associated myeloid­derived suppressor cells on cancer risk and progression (Review).

Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low­grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid­derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abilities. Obesity­associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity­associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipocytes, plays in MDSC­driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity­related cancer.

Increasing the complexity of lipoprotein characterization for cardiovascular risk in type 2 diabetes.

The burden of cardiovascular disease is particularly high among individuals with diabetes, even when LDL cholesterol is normal or within the therapeutic target. Despite this, cholesterol accumulates in their arteries, in part, due to persistent atherogenic dyslipidaemia characterized by elevated triglycerides, remnant cholesterol, smaller LDL particles and reduced HDL cholesterol. The causal link between dyslipidaemia and atherosclerosis in T2DM is complex, and our contention is that a deeper understanding of lipoprotein composition and functionality, the vehicle that delivers cholesterol to the artery, will provide insight for improving our understanding of the hidden cardiovascular risk of diabetes. This narrative review covers three levels of complexity in lipoprotein characterization: 1-the information provided by routine clinical biochemistry, 2-advanced nuclear magnetic resonance (NMR)-based lipoprotein profiling and 3-the identification of minor components or physical properties of lipoproteins that can help explain arterial accumulation in individuals with normal LDLc levels, which is typically the case in individuals with T2DM. This document highlights the importance of incorporating these three layers of lipoprotein-related information into population-based studies on ASCVD in T2DM. Such an attempt should inevitably run in parallel with biotechnological solutions that allow large-scale determination of these sets of methodologically diverse parameters.

CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes.

Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.

Tissue-specific early and late activated lymphocytes immunophenotype in chronic rhinosinusitis with nasal polyps.

KEY POINTS: T-cell activation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is enriched by late cytotoxic T cells. The proportion of early and intermediate activated cytotoxic T cells decreases in nasal polyps of patients with CRSwNP. Our results identify late activated cytotoxic T cells as potential biomarkers or therapeutic targets for patients with CRSwNP.

Cancer Nano-Immunotherapy: The Novel and Promising Weapon to Fight Cancer.

Cancer is a complex disease that, despite advances in treatment and the greater understanding of the tumor biology until today, continues to be a prevalent and lethal disease. Chemotherapy, radiotherapy, and surgery are the conventional treatments, which have increased the survival for cancer patients. However, the complexity of this disease together with the persistent problems due to tumor progression and recurrence, drug resistance, or side effects of therapy make it necessary to explore new strategies that address the challenges to obtain a positive response. One important point is that tumor cells can interact with the microenvironment, promoting proliferation, dissemination, and immune evasion. Therefore, immunotherapy has emerged as a novel therapy based on the modulation of the immune system for combating cancer, as reflected in the promising results both in preclinical studies and clinical trials obtained. In order to enhance the immune response, the combination of immunotherapy with nanoparticles has been conducted, improving the access of immune cells to the tumor, antigen presentation, as well as the induction of persistent immune responses. Therefore, nanomedicine holds an enormous potential to enhance the efficacy of cancer immunotherapy. Here, we review the most recent advances in specific molecular and cellular immunotherapy and in nano-immunotherapy against cancer in the light of the latest published preclinical studies and clinical trials.

Circulating myeloid-derived suppressor cells may be a useful biomarker in the follow-up of unvaccinated COVID-19 patients after hospitalization.

SARS-CoV-2 infection is the cause of the disease named COVID-19, a major public health challenge worldwide. Differences in the severity, complications and outcomes of the COVID-19 are intriguing and, patients with similar baseline clinical conditions may have very different evolution. Myeloid-derived suppressor cells (MDSCs) have been previously found to be recruited by the SARS-CoV-2 infection and may be a marker of clinical evolution in these patients. We have studied 90 consecutive patients admitted in the hospital before the vaccination program started in the general population, to measure MDSCs and lymphocyte subpopulations at admission and one week after to assess the possible association with unfavorable outcomes (dead or Intensive Care Unit admission). We analyzed MDSCs and lymphocyte subpopulations by flow cytometry. In the 72 patients discharged from the hospital, there were significant decreases in the monocytic and total MDSC populations measured in peripheral blood after one week but, most importantly, the number of MDSCs (total and both monocytic and granulocytic subsets) were much higher in the 18 patients with unfavorable outcome. In conclusion, the number of circulating MDSCs may be a good marker of evolution in the follow-up of unvaccinated patients admitted in the hospital with the diagnosis of COVID-19.

Expression of nutrient transporters in placentas affected by gestational diabetes: role of leptin.

Gestational diabetes mellitus (GDM) is the most frequent pathophysiological state of pregnancy, which in many cases produces fetuses with macrosomia, requiring increased nutrient transport in the placenta. Recent studies by our group have demonstrated that leptin is a key hormone in placental physiology, and its expression is increased in placentas affected by GDM. However, the effect of leptin on placental nutrient transport, such as transport of glucose, amino acids, and lipids, is not fully understood. Thus, we aimed to review literature on the leptin effect involved in placental nutrient transport as well as activated leptin signaling pathways involved in the expression of placental transporters, which may contribute to an increase in placental nutrient transport in human pregnancies complicated by GDM. Leptin appears to be a relevant key hormone that regulates placental transport, and this regulation is altered in pathophysiological conditions such as gestational diabetes. Adaptations in the placental capacity to transport glucose, amino acids, and lipids may underlie both under- or overgrowth of the fetus when maternal nutrient and hormone levels are altered due to changes in maternal nutrition or metabolic disease. Implementing new strategies to modulate placental transport may improve maternal health and prove effective in normalizing fetal growth in cases of intrauterine growth restriction and fetal overgrowth. However, further studies are needed to confirm this hypothesis.

Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells.

Breast cancer (BC) continues to be the most diagnosed tumor in women and a very heterogeneous disease both inter- and intratumoral, mainly given by the variety of molecular profiles with different biological and clinical characteristics. Despite the advancements in early detection and therapeutic strategies, the survival rate is low in patients who develop metastatic disease. Therefore, it is mandatory to explore new approaches to achieve better responses. In this regard, immunotherapy arose as a promising alternative to conventional treatments due to its ability to modulate the immune system, which may play a dual role in this disease since the relationship between the immune system and BC cells depends on several factors: the tumor histology and size, as well as the involvement of lymph nodes, immune cells, and molecules that are part of the tumor microenvironment. Particularly, myeloid-derived suppressor cell (MDSC) expansion is one of the major immunosuppressive mechanisms used by breast tumors since it has been associated with worse clinical stage, metastatic burden, and poor efficacy of immunotherapies. This review focuses on the new immunotherapies in BC in the last five years. Additionally, the role of MDSC as a therapeutic target in breast cancer will be described.

Knowing the myeloid-derived suppressor cells: Another enemy of sarcomas patients.

Sarcomas are heterogeneous and aggressive malignant tumors with variable responses to current standard treatments being usually incurable for those patients with metastatic and unresectable diseases. The lack of curative strategies has led to develop new therapies in the treatment of sarcomas where the role of immune system is an evolving field. Most sarcomas often exhibit an immunosuppressive microenvironment, which reduces their capacity to trigger an immune response. Therefore, sarcomas are broadly considered as an "immune cold" tumor, although some studies have described a great immune heterogeneity across sarcoma subtypes. Sarcoma cells, like other tumors, evade their immune destruction through a variety of mechanisms, including expansion and recruitment of myeloid derived suppressor cells (MDSCs). MDSCs are immature myeloid cells that have been correlated with a reduction of the therapeutic efficacy, including immunotherapy, tumor progression and worst prognosis. Consequently, different strategies have been developed in recent years to target MDSCs in cancer treatments. This chapter discusses the role of MDSCs in sarcomas and their current potential as a therapeutic target in these malignancies.

Human amniotic epithelial stem cells: Hepatic differentiation and regenerative properties in liver disease treatment.

The placenta and the extraembryonic tissues represent a valuable source of cells for regenerative medicine. In particular, the amniotic membrane possesses cells with stem cells characteristics that have attracted research attention. Human amniotic epithelial cells (hAECs) have unique and desirable features that position them over other stem cells, not only because of the unlimited potential supplied of, the easy access to placental tissues, and the minimal ethical and legal barriers associated, but also due to the embryonic stem cells markers expression and their ability to differentiate into the three germ layers. In addition, they are non-tumorigenic and have immunomodulatory and anti-inflammatory properties. Hepatic failure is one of the major causes of morbidity and mortality worldwide. Organ transplantation is the best way to treat acute and chronic liver failure, but there are several associated obstacles. Stem cells have been highlighted as alternative hepatocytes source because of their potential for hepatogenic differentiation. HAECs, in particular, have some properties that make them suitable for hepatocyte differentiation. In this work, we review the general characteristics of the epithelial stem cells isolated from human amniotic membrane as well as their ability to differentiate to hepatic cells. We also revise their regenerative properties, with the focus on their potential application in the liver disease treatment.

Treatment of hypertriglyceridaemia with icosapent ethyl in patients with high/very high cardiovascular risk. Consensus document of the Sociedad Española de Cardiología [Spanish Society of Cardiology] and the Sociedad Española de Diabetes [Spanish Diabetes Society].

The Working Groups of Cardiovascular Pharmacotherapy of the Sociedad Española de Cardiología and Cardiovascular Disease of the Sociedad Española de Diabetes have prepared a consensus document on the treatment of hypertriglyceridaemia in patients with high/very-high-cardiovascular risk with icosapent ethyl, a highly purified and stable eicosapentaenoic acid ethyl ester. This document is necessary since there are differences among the three main omega-3 fatty acids and there is large-scale clinical evidence with icosapent ethyl that demonstrates that in addition to its efficacy in lowering triglyceridaemia, it reduces the risk of cardiovascular events in both patients with atherosclerotic cardiovascular disease and in those with type 2 diabetes, with a good safety profile. The number needed to treat to avoid a major cardiovascular event is analysed, comparing it with other pivotal studies of pharmacological intervention in cardiovascular prevention, and an estimate of the Spanish population likely to be treated with ethyl icosapent is carried out. These recommendations are of interest to all clinicians who manage patients with lipid metabolism disorders, cardiovascular disease and diabetes.

Dendritic cells: the yin and yang in disease progression.

Dendritic cells (DCs) are antigen presenting cells that link innate and adaptive immunity. DCs have been historically considered as the most effective and potent cell population to capture, process and present antigens to activate naïve T cells and originate favorable immune responses in many diseases, such as cancer. However, in the last decades, it has been observed that DCs not only promote beneficial responses, but also drive the initiation and progression of some pathologies, including inflammatory bowel disease (IBD). In line with those notions, different therapeutic approaches have been tested to enhance or impair the concentration and role of the different DC subsets. The blockade of inhibitory pathways to promote DCs or DC-based vaccines have been successfully assessed in cancer, whereas the targeting of DCs to inhibit their functionality has proved to be favorable in IBD. In this review, we (a) described the general role of DCs, (b) explained the DC subsets and their role in immunogenicity, (c) analyzed the role of DCs in cancer and therapeutic approaches to promote immunogenic DCs and (d) analyzed the role of DCs in IBD and therapeutic approaches to reduced DC-induced inflammation. Therefore, we aimed to highlight the "yin-yang" role of DCs to improve the understand of this type of cells in disease progression.

Obesity and Risk for Lymphoma: Possible Role of Leptin.

Obesity, which is considered a pandemic due to its high prevalence, is a risk factor for many types of cancers, including lymphoma, through a variety of mechanisms by promoting an inflammatory state. Specifically, over the last few decades, obesity has been suggested not only to increase the risk of lymphoma but also to be associated with poor clinical outcomes and worse responses to different treatments for those diseases. Within the extensive range of proinflammatory mediators that adipose tissue releases, leptin has been demonstrated to be a key adipokine due to its pleotropic effects in many physiological systems and diseases. In this sense, different studies have analyzed leptin levels and leptin/leptin receptor expressions as a probable bridge between obesity and lymphomas. Since both obesity and lymphomas are prevalent pathophysiological conditions worldwide and their incidences have increased over the last few years, here we review the possible role of leptin as a promising proinflammatory mediator promoting lymphomas.