Vista of the Future: Novel Immunotherapy Based on the Human V-Set Immunoregulatory Receptor for Digestive System Tumors.

While gastrointestinal tumors remain a multifactorial and prevalent group of malignancies commonly treated surgically in combination with chemotherapy and radiotherapy, advancements regarding immunotherapeutic approaches continue to occur. Entering a new era of immunotherapy focused on overcoming resistance to preceding therapies caused the emergence of new therapeutic strategies. A promising solution surfaces with a V-domain Ig suppressor of T-cell activation (VISTA), a negative regulator of a T-cell function expressed in hematopoietic cells. Due to VISTA's ability to act as both a ligand and a receptor, several therapeutic approaches can be potentially developed. A broad expression of VISTA was discovered on various tumor-growth-controlling cells, which proved to increase in specific tumor microenvironment (TME) conditions, thus serving as a rationale behind the development of new VISTA-targeting. Nevertheless, VISTA's ligands and signaling pathways are still not fully understood. The uncertain results of clinical trials suggest the need for future examining inhibitor agents for VISTA and implicating a double immunotherapeutic blockade. However, more research is needed before the breakthrough can be achieved. This review discusses perspectives and novel approaches presented in the current literature. Based on the results of the ongoing studies, VISTA might be considered a potential target in combined therapy, especially for treating gastrointestinal malignancies.

Effect of immunostimulation with bacterial lysate on the clinical course of allergic rhinitis and the level of γδT, iNKT and cytotoxic T cells in children sensitized to grass pollen allergens: A randomized controlled trial.

Background: There are many drugs for allergic rhinitis (AR), however, these drugs show variable clinical effectiveness and some side effects. Therefore, new methods of AR pharmacotherapy are being sought. Objectives: The objectives of this study were to evaluate the efficacy of polyvalent mechanical bacterial lysate (PMBL) therapy in improving the clinical course of grass pollen-induced AR (seasonal AR, SAR) in children and its effect on changes in the blood level of the γδT, iNKT and cytotoxic T cell subsets. Methods: Fifty children with SAR were enrolled in this study and were randomly assigned to either the PMBL group or the placebo group. The severity of SAR symptoms was assessed using the total nasal symptom score (TNSS) and visual analogue scale (VAS). During two visits (V1, V2), peak nasal inspiratory flow (PNIF) was measured and peripheral blood was collected for immunological analyses. The study also included 2 telephone contacts (TC1, TC2). Results: The severity of the nasal symptoms of SAR on the TNSS scale was revealed to have a significantly lower impact in the PMBL group vs the placebo group at measuring points TC1 and V2 (p = 0.01, p = 0.009, respectively). A statistically significantly lower mean severity of nasal symptoms of SAR on the VAS scale was recorded for children in the PMBL group compared to the placebo group at measuring points TC1, V2 and TC2 (p = 0.04, p = 0.04, p = 0.03, respectively). The compared groups do not show significant differences in terms of PNIF values at individual measuring points. There were no statistically significant changes in immune variables. For both groups, there was a statistically significant association between the level of Th1-like γδT cells and the severity of SAR symptoms expressed on the TNSS scale (p = 0.03) - the lower the level of Th1-like γδT cells, the higher the TNSS value. Conclusion: Administration of sublingual PMBL tablets during the grass pollen season proves to have a high efficacy in alleviating SAR symptoms in children sensitized to grass pollen allergens. Th1-like γδT cells may be used as potential markers for SAR severity in children. Clinical trial registration: ClinicalTrials.gov, identifier (NCT04802616).

The Crosstalk between the Gut Microbiota Composition and the Clinical Course of Allergic Rhinitis: The Use of Probiotics, Prebiotics and Bacterial Lysates in the Treatment of Allergic Rhinitis.

Although massive progress in discovering allergic rhinitis (AR) aetiology has been made in recent years, its prevalence is still rising and it significantly impacts patients' lives. That is why further and non-conventional research elucidating the role of new factors in AR pathogenesis is needed, facilitating discoveries of new treatment approaches. One of these factors is the gut microbiota, with its specific roles in health and disease. This review presents the process of gut microbiota development, especially in early life, focusing on its impact on the immune system. It emphasizes the link between the gut microbiota composition and immune changes involved in AR development. Specifically, it elucidates the significant link between bacteria colonizing the gut and the Th1/Th2 imbalance. Probiotics, prebiotics and bacterial lysates, which are medications that restore the composition of intestinal bacteria and indirectly affect the clinical course of AR, are also discussed.

Promising Immunomodulatory Effects of Bacterial Lysates in Allergic Diseases.

In light of an escalating prevalence of allergic disorders, it is crucial to fully comprehend their pathophysiology and etiology. Such knowledge would play a pivotal role in the search for new therapeutic approaches concerning not only diseases' symptoms, but also their underlying causes. The hygiene hypothesis indicates a high correlation between limited exposure to pathogens in early childhood and the risk of developing allergic disorders. Bearing in mind the significance of respiratory and digestive systems' mucous membrane's first-line exposure to pathogens as well as its implications on the host's immune response, a therapy targeted at aforesaid membranes could guarantee promising and extensive treatment outcomes. Recent years yielded valuable information about bacterial lysates (BLs) known for having immunomodulatory properties. They consist of antigen mixtures obtained through lysis of bacteria which are the most common etiologic agents of respiratory tract infections. They interact with dendritic cells located in the mucous membranes of the upper respiratory tract and the gastrointestinal tract by toll-like receptors. The dendritic cells present acquired antigens resulting in innate immune response development on the release of chemokines, both stimulating monocytes and NK cells maturation and promoting polymorphonuclear neutrophil migration. Moreover, they influence the adaptive immune system by stimulating an increase of specific antibodies against administered bacterial antigens. The significance of BLs includes not only an anti-inflammatory effect on local infections but also restoration of Th1/Th2 balance, as demonstrated mainly in animal models. They decrease Th2-related cytokine levels (IL-4, IL-13) and increase Th1-related cytokine levels (IFN-γ). The reestablishment of the balance of the immune response leads to lowering atopic reactions incidence which, in addition to reduced risk of inflammation, provides the alleviation and improvement of clinical manifestations of allergic disorders. In this review, we hereby describe mechanisms of BLs action, considering their significant immunomodulatory role in innate immunity. The correlation between local, innate, and adaptive immune responses and their impact on the clinical course of allergic disorders are discussed as well. To conclude our review, we present up-to-date literature regarding the outcomes of BLs implemented in atopic dermatitis, allergic rhinitis, and asthma prevention and treatment, especially in children.

Perspectives for the Use of Bacterial Lysates for the Treatment of Allergic Rhinitis: A Systematic Review.

Bacterial lysates (BLs) are mixtures of bacterial antigens that have been used for many decades to minimize the risk of recurrent respiratory tract infections in both pediatric and adult populations. Research on the use of BLs is also conducted in allergology. Biomedical databases were searched for articles on the use of BLs in the treatment of allergic rhinitis (AR). After rejecting ineligible articles, six remaining reports were reviewed. Based on this review, it can be concluded that adding BL to standard therapy for seasonal or perennial AR reduces the severity of nasal symptoms and the need for antiallergic medications in both children and adults. Concurrently, these formulations have a high safety profile. An analysis of studies shows that the first effects of BLs therapy appear at the earliest 2-6 weeks after the start of treatment and persist at least 3 months after treatment.

Congenital Hypothyroidism in Preterm Newborns - The Challenges of Diagnostics and Treatment: A Review.

Preterm newborns are forced to adapt to harsh extrauterine conditions and endure numerous adversities despite their incomplete growth and maturity. The inadequate thyroid hormones secretion as well as the impaired regulation of hypothalamus-pituitary-thyroid axis may lead to hypothyroxinemia. Two first weeks after birth are pivotal for brain neurons development, synaptogenesis and gliogenesis. The decreased level of thyroxine regardless of cause may lead to delayed mental development. Congenital hypothyroidism (CH) is a disorder highly prevalent in premature neonates and it originates from maternal factors, perinatal and labor complications, genetic abnormalities, thyroid malformations as well as side effects of medications and therapeutic actions. Because of that, the prevention is not fully attainable. CH manifests clinically in a few distinctive forms: primary, permanent or transient, and secondary. Their etiologies and implications bear little resemblance. Therefore, the exact diagnosis and differentiation between the subtypes of CH are crucial in order to plan an effective treatment. Hypothyroxinemia of prematurity indicates dynamic changes in thyroid hormone levels dependent on neonatal postmenstrual age, which directly affects patient's maintenance and wellbeing. The basis of a successful treatment relies on an early and accurate diagnosis. Neonatal screening is a recommended method of detecting CH in preterm newborns. The preferred approach involves testing serum TSH and fT4 concentrations and assessing their levels according to the cut-off values. The possible benefits also include the evaluation of CH subtype. Nevertheless, the reference range of thyroid hormones varies all around the world and impedes the introduction of universal testing recommendations. Unification of the methodology in neonatal screening would be advantageous for prevention and management of CH. Current guidelines recommend levothyroxine treatment of CH in preterm infants only when the diagnose is confirmed. Moreover, they underline the importance of the re-evaluation among preterm born infants due to the frequency of transient forms of hypothyroidism. However, results from multiple clinical trials are mixed and depend on the newborn's gestational age at birth. Some benefits of treatment are seen especially in the preterm infants born <29 weeks' gestation. The discrepancies among trials and guidelines create an urgent need to conduct more large sample size studies that could provide further analyses and consensus. This review summarizes the current state of knowledge on congenital hypothyroidism in preterm infants. We discuss screening and treatment options and demonstrate present challenges and controversies.

Coacervate Thermoresponsive Polysaccharide Nanoparticles as Delivery System for Piroxicam.

Low water solubility frequently compromises the therapeutic efficacy of drugs and other biologically active molecules. Here, we report on coacervate polysaccharide nanoparticles (CPNs) that can transport and release a model hydrophobic drug, piroxicam, to the cells in response to changes in temperature. The proposed, temperature-responsive drug delivery system is based on ionic derivatives of natural polysaccharides-curdlan and hydroxypropyl cellulose. Curdlan was modified with trimethylammonium groups, while the anionic derivative of hydroxypropyl cellulose was obtained by the introduction of styrenesulfonate groups. Thermally responsive nanoparticles of spherical shape and average hydrodynamic diameter in the range of 250-300 nm were spontaneously formed in water from the obtained ionic polysaccharides as a result of the coacervation process. Their morphology was visualized using SEM and AFM. The size and the surface charge of the obtained objects could be tailored by adjusting the polycation/polyanion ratio. Piroxicam (PIX) was effectively entrapped inside the nanoparticles. The release profile of the drug from the CPNs-PIX was found to be temperature-dependent in the range relevant for biomedical applications.

Postoperative depression in patients after coronary artery bypass grafting (CABG) - a review of the literature.

<b>Introduction:</b> Ischemic heart disease is the most common cause of death in the world. The lives of patients with vascular defects can be saved by coronary artery bypass grafting (CABG). However, it is associated with an increased risk of developing depression after surgery. <br><b>Meterial and Methods:</b> The aim of the study is to present the results of the latest research on postoperative depression after CABG, including studies describing the course of the disease, its consequences for the patient's prognosis and treatment. The publications available on the PubMed platform published after 2011 were reviewed. <br><b>Results:</b> Depression before and after CABG affects 30-40% of patients, mostly women. Established after surgery and untreated, it persists for many years. The level of anxiety in patients decreases systematically after surgery. Indicators that may correlate with the patient's postoperative depression, including cortisol, high sensitivity C-reactive protein (hsCRP) and oxidative stress biomarkers, are being investigated. The occurrence of depression in patients after CABG has a number of negative consequences. Those include: weaker response to treatment, greater chance of relapse, and increased readmission frequency and mortality. Treatment of patients with this disorder involves the use of antidepressants (most often SSRIs - selective serotonin reuptake inhibitor) and/or various types of psychotherapy with cognitive behavioral therapy (CBT) at the forefront. <br><b>Conclusions:</b> Depression following CABG decreases the quality of life and worsens patient prognosis. It is necessary to detect this condition early after surgery and to apply treatment, taking into account the cardiological disorders of the patient.

Postoperative depression in patients after coronary artery bypass grafting (CABG) - a review of the literature.

<b>Introduction:</b> Ischemic heart disease is the most common cause of death in the world. The lives of patients with vascular defects can be saved by coronary artery bypass grafting (CABG). However, it is associated with an increased risk of developing depression after surgery. <br><b>Meterial and Methods:</b> The aim of the study is to present the results of the latest research on postoperative depression after CABG, including studies describing the course of the disease, its consequences for the patient's prognosis and treatment. The publications available on the PubMed platform published after 2011 were reviewed. <br><b>Results:</b> Depression before and after CABG affects 30-40% of patients, mostly women. Established after surgery and untreated, it persists for many years. The level of anxiety in patients decreases systematically after surgery. Indicators that may correlate with the patient's postoperative depression, including cortisol, high sensitivity C-reactive protein (hsCRP) and oxidative stress biomarkers, are being investigated. The occurrence of depression in patients after CABG has a number of negative consequences. Those include: weaker response to treatment, greater chance of relapse, and increased readmission frequency and mortality. Treatment of patients with this disorder involves the use of antidepressants (most often SSRIs - selective serotonin reuptake inhibitor) and/or various types of psychotherapy with cognitive behavioral therapy (CBT) at the forefront. <br><b>Conclusions:</b> Depression following CABG decreases the quality of life and worsens patient prognosis. It is necessary to detect this condition early after surgery and to apply treatment, taking into account the cardiological disorders of the patient.

A Hybrid System for Magnetic Hyperthermia and Drug Delivery: SPION Functionalized by Curcumin Conjugate.

Cancer is among the leading causes of death worldwide, thus there is a constant demand for new solutions, which may increase the effectiveness of anti-cancer therapies. We have designed and successfully obtained a novel, bifunctional, hybrid system composed of colloidally stabilized superparamagnetic iron oxide nanoparticles (SPION) and curcumin containing water-soluble conjugate with potential application in anticancer hyperthermia and as nanocarriers of curcumin. The obtained nanoparticulate system was thoroughly studied in respect to the size, morphology, surface charge, magnetic properties as well as some biological functions. The results revealed that the obtained nanoparticles, ca. 50 nm in diameter, were the agglomerates of primary particles with the magnetic, iron oxide cores of ca. 13 nm, separated by a thin layer of the applied cationic derivative of chitosan. These agglomerates were further coated with a thin layer of the sodium alginate conjugate of curcumin and the presence of both polymers was confirmed using thermogravimetry. The system was also proven to be applicable in magnetic hyperthermia induced by the oscillating magnetic field. A high specific absorption rate (SAR) of 280 [W/g] was registered. The nanoparticles were shown to be effectively uptaken by model cells. They were found also to be nontoxic in the therapeutically relevant concentration in in vitro studies. The obtained results indicate the high application potential of the new hybrid system in combination of magnetic hyperthermia with delivery of curcumin active agent.

Lysozyme adsorption at a silica surface using simulation and experiment: effects of pH on protein layer structure.

Hen Egg White Lysozyme (HEWL) is a widely used exemplar to study protein adsorption on surfaces and interfaces. Here we use fully atomistic Molecular Dynamics (MD) simulations, Multi-Parametric Surface Plasmon Resonance (MP-SPR), contact angle and zeta potential measurements to study HEWL adsorption at a silica surface. The simulations provide a detailed description of the adsorption mechanism and indicate that at pH7 the main adsorption driving force is electrostatics, supplemented by weaker hydrophobic forces. Moreover, they reveal the preferred orientation of the adsorbed protein and show that its structure is only slightly altered at the interface with the surface. This provides the basis for interpreting the experimental results, which indicate the surface adsorbs a close-packed monolayer at about pH10 where the surface has a large negative zeta potential and the HEWL is positively charged. At higher pH, the adsorption amount of the protein layer is greatly reduced due to the loss of charge on the protein. At lower pH, the smaller zeta potential of the surface leads to lower HEWL adsorption. These interpretations are complemented by the contact angle measurements that show how the hydrophobicity of the surface is greatest when the surface coverage is highest. The simulations provide details of the hydrophobic residues exposed to solution by the adsorbed HEWL, completing the picture of the protein layer structure.