Search Results (344)

Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers. Full article

Cardiovascular disease encompasses a wide group of conditions that affect the heart and blood vessels. Of these diseases, cardiomyopathies and arrhythmias specifically have been well-studied in their relationship to cardiac dyads, nanoscopic structures that connect electrical signals to muscle contraction. The proper development and positioning of dyads is essential in excitation–contraction (EC) coupling and, thus, beating of the heart. Three proteins, namely CMYA5, JPH2, and BIN1, are responsible for maintaining the dyadic cleft between the T-tubule and junctional sarcoplasmic reticulum (jSR). Various other dyadic proteins play integral roles in the primary function of the dyad—translating a propagating action potential (AP) into a myocardial contraction. Ca²⁺, a secondary messenger in this process, acts as an allosteric activator of the sarcomere, and its cytoplasmic concentration is regulated by the dyad. Loss-of-function mutations have been shown to result in cardiomyopathies and arrhythmias. Adeno-associated virus (AAV) gene therapy with dyad components can rescue dyadic dysfunction, which results in cardiomyopathies and arrhythmias. Overall, the dyad and its components serve as essential mediators of calcium homeostasis and excitation–contraction coupling in the mammalian heart and, when dysfunctional, result in significant cardiac dysfunction, arrhythmias, morbidity, and mortality. Full article

Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by autoantibody production and multi-organ involvement. Anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, has been approved for the treatment of SLE. Our aim was to investigate the long-term effects of inhibited type I IFN signaling on circulating follicular helper T subsets (T_FH), follicular regulatory T cells (T_FR), and B lymphocyte subpopulations, reflecting the ongoing germinal center reactions in SLE patients. Peripheral blood samples were obtained from ten SLE patients before the initiation of anifrolumab treatment, and at months 6 and 12 of the intervention period. Flow cytometry analysis was performed to assess the frequencies of circulating T_FH cell subsets, T_FR cells, and certain B cell subpopulations. Serological parameters, including autoantibody levels and complement components, were determined as part of the routine diagnostic evaluation. We observed a significant and sustained reduction in the percentage of activated circulating T_FH cells. Notably, the frequency of CXCR3⁻CCR6⁺ T_FH17 cells decreased, whereas the proportion of CXCR3⁺CCR6⁻ T_FH1 cells increased significantly. Furthermore, the proportion of the IgD⁻CD27⁻ double-negative B lymphocytes was also significantly reduced. These findings suggest that anifrolumab therapy attenuates T_FH cell activation, which may contribute to its clinical efficacy by modulating germinal center responses in SLE. Full article

Background: Soft tissue sarcomas (STSs) are a rare and heterogeneous group of mesenchymal tumors with limited response to current therapies, particularly in advanced stages. STS tumors were traditionally considered “cold” tumors, characterized by limited immune infiltration and low immunogenicity. However, emerging evidence is challenging this perception, highlighting a potentially critical role for the immune system in STS biology. Objective: Building on our previous findings suggesting impaired natural killer (NK) cell activity in STS patients, we aimed to perform an in-depth characterization of peripheral NK cells in STS. Methods: Peripheral blood samples from STS patients and sex- and age-matched healthy donors were analyzed to assess NK cell degranulation, IFNγ production, and receptor repertoire. Results: Functional assays revealed a notable reduction in both degranulation and IFNγ production in NK cells from STS patients. STS patients also exhibited dysregulated expression of activating and inhibitory NK cell receptors. Principal component analysis (PCA) identified CD27 and NKp44 as critical markers for distinguishing STS patients from healthy donors. Increased CD27 expression represents a shift towards a more regulatory NK cell phenotype, and we found that CD27 expression was negatively correlated with NK cell degranulation and IFNγ production. ROC curve analysis demonstrated strong potential to distinguish between the groups for both CD27 (AUC = 0.85) and NKp44 (AUC = 0.94). Conclusion: In conclusion, STS patients exhibited impaired NK cell function, altered receptor repertoire, and a shift towards a less cytotoxic and more regulatory phenotype. Full article

Background/Objectives: Hemorrhage remains a leading cause of early mortality in trauma patients, and timely transfusion guided by a structured massive transfusion protocol (MTP) is critical for improving outcomes. Although regional trauma centers have been established, standardized MTPs remain insufficiently developed in many settings. This study aimed to evaluate current MTP practices across five major trauma centers within a national trauma care system. Methods: Participating institutions provided written protocols and completed a structured survey addressing key domains, including activation criteria, transfusion strategies, laboratory monitoring, adjunct therapies, termination processes, and performance improvement measures. Findings were analyzed and compared against established international recommendations. Results: All centers had implemented MTPs and were capable of delivering initial blood products within 15 min. However, considerable variation was observed in activation triggers, transfusion ratios, and laboratory monitoring protocols. None of these centers maintained thawed plasma or whole blood in immediate readiness. Only one of five centers had a formal performance improvement monitoring system. Tranexamic acid was included in all institutional protocols. Conclusions: This review highlights significant variability and critical gaps in MTP implementation across trauma centers. Inconsistent activation criteria, the absence of essential components, and limited quality monitoring may compromise the efficacy of current practices. To improve patient outcomes, a standardized, evidence-based MTP framework should be developed and implemented nationwide. Full article

Due to advances in molecular technologies and the expanding knowledge of biomarkers, their use in patient screening, diagnosis, prognosis, and targeted therapy is continuously increasing. Biomarker characteristics play a crucial role across all areas of medical research/practice. Biomarkers often reflect changes in the biochemical composition of biofluids, which can be qualitatively and quantitatively analyzed using methods such as high-performance liquid chromatography (HPLC) at various stages of clinical intervention. This study focuses on establishing physiological reference ranges for selected biochemical and metabolomic indicators by analyzing blood serum samples from domestic sheep. A total of sixty samples are examined using standard biochemical assays and HPLC, resulting in the determination of experimental reference values for twenty-one biochemical and eight metabolomic parameters. Reliable and reproducible preclinical testing is essential before any diagnostic method can be introduced into clinical use. A thorough understanding of the safety and efficacy of such methods in animal models is a prerequisite for initiating human trials. Species selection and the definition of physiological biomarker ranges are therefore critical components in the development of effective preclinical protocols. This work contributes to the foundation needed for further clinical testing by establishing reference values for relevant biomarkers in a commonly used animal model. Full article

Westernization of traditional diets has been implicated in the rising burden of overweight/obesity and type 2 diabetes, especially in developing countries. In recent times, diet therapy is increasingly being recognized as an essential component of diabetes care. This study assessed the effect of diet therapy on body composition, antioxidant nutrient intake, and glycemic status in individuals living with type 2 diabetes (ILWT2D). In this prospective observational cohort study, 45 ILWT2D who were receiving diet therapy (personalized dietary counseling) in addition to standard medical treatment (intervention group) were compared with 45 ILWT2D receiving only standard medical treatment (comparator group). Antioxidant micronutrient intake was assessed using a 24-h dietary recall. Body composition indices, including body mass index (BMI), percentage body fat (%BF), and visceral fat (VF), were assessed. Participants’ fasting blood glucose (FBG), glycated hemoglobin (HbA1C) levels, and blood pressure (BP) were measured. All measurements were performed before and after a three-month period. There were significant improvements in BMI (27.8 ± 6.0 kg/m² vs. 26.9 ± 5.5 kg/m², p = 0.003), %BF (37.8 ± 11.9% vs. 35.5 ± 10.5%, p < 0.001), visceral fat (9.8 ± 3.4 vs. 9.1 ± 3.2, p < 0.001), systolic BP (136.9 ± 19.9 mmHg vs. 124.6 ± 13.0 mmHg, p < 0.001), FBG (8.8 ± 2.8 mmol/L vs. 6.7 ± 1.5 mmol/L, p < 0.001), and HbA1c (7.3 ± 1.0% vs. 6.4 ± 0.8%, p < 0.001) in the intervention group from baseline to endline, but not in the comparator group. In contrast, %BF increased within the comparator group (39.9 ± 7.8 vs. 40.7 ± 7.4; p = 0.029). Vitamin A intake increased significantly (227.5 ± 184.3 µg vs. 318.8 ± 274.7 µg, p = 0.038) within the intervention group but not in the comparator group (174.9 ± 154.3 µg, 193.7 ± 101.4 µg, p = 0.54). There were no significant changes in zinc, copper, selenium, and vitamin C intakes (p > 0.05) in the intervention group from the baseline to endline, unlike those in the comparator group who showed a significant increase in the intake of these nutrients. There was a significant increase in vitamin A intake among the ILWT2D who received dietary counseling as an intervention compared to those who did not. Additionally, the ILWT2D who received dietary counseling had significant improvements in their body composition (BMI, body fat, and visceral fat) and systolic blood pressure, compared to those who did not. The ILWT2D who received the intervention had significantly better glycemic control (FBG and HbA1c) than their counterparts who did not. Thus, this study suggests the potential of diet therapy as a viable non-pharmacological treatment approach for individuals living with type 2 diabetes. Full article

Procoagulant platelets are a specialized subset of activated platelets that externalize phosphatidylserine (PS) on their surface, facilitating the assembly of tenase and prothrombinase complexes and enhancing thrombin generation and clot formation. Although procoagulant platelet formation shares certain features with nucleated cell death pathways, such as mitochondrial dysfunction, calcium (Ca²⁺) overload, membrane blebbing, and microvesiculation, it differs in key molecular mechanisms, notably lacking nuclei and caspase-dependent deoxyribonucleic acid (DNA) fragmentation. Interestingly, molecular components of nucleated cell death pathways in platelets can promote thrombus formation without impacting platelet lifespan. Under pathological conditions, excessive platelet activation may result in platelet lysis, resembling the complete activation of nucleated cell death pathways and contribute to thrombocytopenia. This review compares procoagulant platelet formation with various nucleated cell death pathways, including necrosis, necroptosis, pyroptosis, and ferroptosis, and explores their role in pathological thrombosis and blood clotting. A deeper understanding of mechanisms may help in developing targeted therapies to prevent aberrant blood clotting, platelet death and thrombocytopenia. Full article

Introduction: The vascular architecture of the vocal folds plays a critical role in sustaining the dynamic demands of phonation. Disruptions in this microvascular system are linked to various pathological conditions, including Reinke’s edema, hemorrhage, and laryngeal carcinoma. This review explores the structural and functional components of vocal fold microvascularization, with emphasis on pericytes, endothelial interactions, and neurovascular regulation. Materials and Methods: A systematic review of the literature was conducted using databases such as PubMed, Scopus, Web of Science, and Embase. Keywords included “pericytes”, “Reinke’s edema”, and “vocal fold microvascularization”. Selected studies were peer-reviewed and met criteria for methodological quality and relevance to laryngeal microvascular physiology and pathology. Results: The vocal fold vasculature is organized in a parallel, tree-like pattern with distinct arterioles, capillaries, and venules. Capillaries dominate the superficial lamina propria, while transitional vessels connect to deeper arterioles surrounded by smooth muscle. Pericytes, present from birth, form tight associations with endothelial cells and contribute to capillary stability, vessel remodeling, and mechanical protection during vibration. Their thick cytoplasmic processes suggest a unique adaptation to the biomechanical stress of phonation. Arteriovenous anastomoses regulate perfusion by shunting blood according to functional demand. Furthermore, neurovascular control is mediated by noradrenergic fibers and neuropeptides such as VIP and CGRP, modulating vascular tone and glandular secretion. The limited lymphatic presence in the vocal fold mucosa contributes to edema accumulation while also restricting carcinoma spread, offering both therapeutic challenges and advantages. Conclusions: A deeper understanding of vocal fold microvascularization enhances clinical approaches to voice disorders and laryngeal disease, offering new perspectives for targeted therapies and regenerative strategies. Full article

Background/Objectives: While adenovirus (Ad) therapies have been proven to be effective in local administration, systemic Ad treatments have shown limited success due to pre-existing antibodies in the human blood that neutralize the virus. We developed a liposome coating procedure that protects the Ad from pre-existing neutralizing antibodies in human blood. To assess the in vivo stability of the liposomes, the present study used a novel in vivo method to quantitatively assess the protective capabilities of liposome-encapsulated Ad (DfAd) from neutralizing antibodies. Methods: The assay systemically administers DfAd with a green fluorescent protein transgene (DfAd-GFP) into pre-immunized mice and allows it to circulate in the presence of neutralizing antibodies; the infected blood is extracted and used to transduce HEK293 cells, which emits fluorescence in the presence of protected, un-neutralized Ad. Results: The PEGylated liposome formulation provides 12× protection in vivo relative to unencapsulated Ads. In vitro optimization of the liposome coating reveals a strong correlation between the structural stability of liposomes and protection against anti-Ad neutralizing antibodies, where DSPE-PEG2000-carboxylic acid (DSPE-PEG2000-CA) is a critical component for liposome stability and increasing protection against antibody neutralization of the encapsulated Ad. Conclusions: The findings in the present study confirm that the DfAd liposome can protect against neutralizing antibodies in blood circulation. The novel in vivo assay for liposome protection against neutralizing antibodies and in vitro experiments in the present study provide new tools and insights toward designing liposome–Ad complexes for the systemic treatment of cancer. Full article

Background: Cardiac autonomic neuropathy (CAN) is a common yet frequently underdiagnosed complication of diabetes. While our previous study demonstrated the utility of multiscale cross-approximate entropy (MS-CXApEn) in detecting early CAN, the present study further investigates the use of frequency-domain coherence analysis between systolic blood pressure (SBP) and R-R intervals (RRI) and evaluates the effects of insulin treatment on autonomic function in diabetic rats. Methods: At the onset of diabetes induced by streptozotocin (STZ), rats were assessed for cardiovascular autonomic function both before and after insulin treatment. Spectral and coherence analyses were performed to evaluate baroreflex function and autonomic regulation. Parameters assessed included low-frequency power (LFP) and high-frequency power (HFP) of heart rate variability, coherence between SBP and RRI at low and high-frequency bands (LF_Coh and HF_Coh), spontaneous and phenylephrine-induced baroreflex sensitivity (BRS_spn and BRS_phe), HRV components derived from fast Fourier transform, and MS-CXApEn at multiple scales. Results: Compared to normal controls (LF_Coh: 0.14 ± 0.07, HF_Coh: 0.19 ± 0.06), early diabetic rats exhibited a significant reduction in both LF_Coh (0.08 ± 0.04, p < 0.05) and HF_Coh (0.16 ± 0.10, p > 0.05), indicating impaired autonomic modulation. Insulin treatment led to a recovery of LF_Coh (0.11 ± 0.04) and HF_Coh (0.24 ± 0.12), though differences remained statistically insignificant (p > 0.05 vs. normal). Additionally, low-frequency LFP increased at the onset of diabetes and decreased after insulin therapy in most rats significantly, while MS-CXApEn at all scale levels increased in the early diabetic rats, and MS-CXApEn_large declined following hyperglycemia correction. The BRS_spn and BRS_phe showed no consistent trend. Conclusions: Coherence analysis provides valuable insights into autonomic dysfunction in early diabetes. The significant reduction in LF_Coh in early diabetes supports its role as a potential marker for CAN. Although insulin treatment partially improved coherence, the lack of full recovery suggests persistent autonomic impairment despite glycemic correction. These findings underscore the importance of early detection and long-term management strategies for diabetic CAN. Full article

Asthma is a chronic and multifaceted respiratory condition that affects over 300 million individuals across the globe. It is characterized by persistent inflammation of the airways, which leads to episodes of wheezing, breathlessness, chest tightness, and coughing. The most prevalent form of asthma is classified as Type 2 or T2-high asthma. In this variant, the immune response is heavily driven by eosinophils, mast cells, and T-helper 2 (Th2) cells. These components release a cascade of cytokines, including interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13). This release promotes several processes: the production of immunoglobulin E (IgE), which is integral to allergic responses; the recruitment of eosinophils—white blood cells that contribute to inflammation and tissue damage. Conversely, non-Type 2 or T2-low asthma is typically associated with a different inflammatory profile characterized by neutrophilic inflammation. This type of asthma is driven by T-helper 1 (Th1) and T-helper 17 (Th17) immune responses, which are often present in older adults, smokers, and those suffering from more severe manifestations of the disease. Among asthmatic patients, approximately 80–85% of cases are classified as T2-high asthma, while only 15–20% are T2-low asthma. Treatment of asthma focuses heavily on controlling inflammation. Inhaled corticosteroids remain the cornerstone therapy for managing T2-high asthma. For more severe or treatment-resistant cases, biologic therapies targeting specific inflammatory pathways, such as anti-IgE (omalizumab), anti-IL-5 (mepolizumab, benralizumab), and anti-IL-4/IL-13 (dupilumab), have shown great promise. For T2-low asthma, macrolide antibiotics like azithromycin and other novel therapies are being explored. This article reviews the safety, efficacy, and indications of the currently approved biologics and discusses potential novel biologics for asthma. Full article

Red blood cells (RBCs) have traditionally been excluded from orthobiologic formulations due to inflammation, oxidative stress, and hemolysis concerns. However, emerging evidence suggests that RBCs may play an active role in regenerative medicine, contributing to immune modulation, vascular support, and oxidative balance. Their interactions with macrophages, involvement in nitric oxide signaling, and release of extracellular vesicles suggest they may influence tissue repair more than previously assumed. Despite these potential benefits, RBC retention in orthobiologic preparations like platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) remains controversial, with most protocols favoring their removal in the absence of robust translational clinical data. This review explores the biological functions of RBCs in regenerative medicine, their potential contributions to PRP and BMAC, and the challenges associated with their inclusion. While concerns about hemolysis and inflammation persist, controlled studies are needed to determine whether selective RBC retention could enhance musculoskeletal healing in some scenarios. Future research should focus on optimizing RBC processing techniques and evaluating their impact on clinical applications. Addressing these gaps will clarify whether RBCs represent an overlooked but valuable component in regenerative therapies or their exclusion remains justified. Full article

Hypertension (HTN) is prevalent among patients with type 2 diabetes mellitus (T2DM), and both conditions are well-established risk factors for cardiovascular diseases (CVDs) and microvascular complications. To mitigate the risk of CVD, a comprehensive management approach for both blood pressure (BP) and glycaemic control is essential. The current therapeutic strategy should be structured around five pillars aimed at confirming HTN, establishing the 10-year CVD risk and its components and focusing on pharmacological treatment alongside lifestyle interventions to achieve BP targets. In clinical practice, the recommended BP target is 120–129/70–79 mmHg, while an optimal target of ≤120/70 mmHg is being explored under research conditions. Further, BP control should be re-evaluated in cases of resistant or uncontrolled HTN, in conjunction with antidiabetic therapies that have demonstrated cardiovascular and renal protective benefits. This five-pillar approach offers a comprehensive and evolving perspective on BP management in patients with T2DM, although certain aspects continue to be refined as new evidence emerges. Full article

The blood–brain barrier (BBB) is a semi-permeable membrane in physiological conditions, but in pathologies like multiple sclerosis (MS) and ischemic stroke (IS), its permeability increases. In this review, we focus on neutrophils and their interaction with cellular components of the BBB: endothelial cells (EC), pericytes (PC), and astrocytes (AC). Nowadays, neutrophils receive more attention, mostly due to advanced research techniques that show the complexity of their population. Additionally, neutrophils have the ability to secrete extracellular vesicles (EVs), reactive oxygen species (ROS) and cytokines, which both destroy and restore the BBB. Astrocytes, PCs, and ECs also have dual roles in the pathogenesis of MS and IS. The interaction between neutrophils and cellular components of the BBB provides us with a wider insight into the pathogenesis of common diseases in the central nervous system. Further, we comprehensively review knowledge about the influence of neutrophils on the BBB in the context of MS and IS. Moreover, we describe new therapeutic strategies for patients with MS and IS like cell-based therapies and therapies that use the neutrophil function. Full article