Psoriasis and Psoriatic Arthritis-Associated Genes, Cytokines, and Human Leukocyte Antigens.

In recent years, research has intensified in exploring the genetic basis of psoriasis (PsO) and psoriatic arthritis (PsA). Genome-wide association studies (GWASs), including tools like ImmunoChip, have significantly deepened our understanding of disease mechanisms by pinpointing risk-associated genetic loci. These efforts have elucidated biological pathways involved in PsO pathogenesis, particularly those related to the innate immune system, antigen presentation, and adaptive immune responses. Specific genetic loci, such as TRAF3IP2, REL, and FBXL19, have been identified as having a significant impact on disease development. Interestingly, different genetic variants at the same locus can predispose individuals to either PsO or PsA (e.g., IL23R and deletion of LCE3B and LCE3C), with some variants being uniquely linked to PsA (like HLA B27 on chromosome 6). This article aims to summarize known and new data on the genetics of PsO and PsA, their associated genes, and the involvement of the HLA system and cytokines.

Expression of BCL2, TP53, FOXA1, and GATA3 in pTa bladder cancer recurrence.

OBJECTIVES: In this study, we analyzed pTa bladder cancer (BC) for molecular markers BCL2, TP53, FOXA1, and GATA3 in relation to cancer recurrence. METHODS: We analyzed samples of 79 patients with the pTa stage of BC using a real-time polymerase chain reaction (real-time PCR) between September 2018 and September 2020. The expression levels of BCL2, TP53, FOXA1, and GATA3 were compared with homologous non-tumor bladder tissue. RESULTS: Expression of FOXA1, GATA3, and TP53 was significantly higher (p<0.01) in NMIBC samples compared to homologous non-tumor tissue. The expression of TP53 and FOXA1 in pTa was significantly lower (p<0.01) in the high-grade (HG) tumor when compared to the low-grade (LG) tumor. In contrast, the relative quantification (RQ) of GATA3 was significantly higher (p<0.01) in HG pTa. Patients with recurrence (pTa=33) had significantly higher expression of TP53, and GATA3 (p<0.01), and the gene of FOXA1 (p<0.01) had a significantly lower expression when compared to pTa tumors without recurrence. The expression of Bcl-2 was not statistically significant. CONCLUSION: Our results, indicate, that comparing expression levels of these genes in cancer and cancer-free tissue could provide valuable data, as patients with pTa BC recurrence within up to 54 months of follow-up had a significantly higher RQ of TP53, GATA3, and FOXA1 when compared to pTa BC patients without recurrence (Tab. 2, Fig. 8, Ref. 54). Text in PDF www.elis.sk Keywords: bladder cancer, gene expression, recurrence, GATA3, FOXA1, TP53, BCL2.

Current look at the most promising proteomic and glycomic biomarkers of bladder cancer.

BACKGROUND: Bladder cancer (BC) belongs to the most frequent cancer types. The diagnostic process is still long and costly, with a high percentage of false-positive or -negative results. Due to the cost and lack of effectiveness, older methods need to be supplemented or replaced by a newer more reliable method. In this regard, proteins and glycoproteins pose high potential. METHODS: We performed an online search in PubMed/Medline, Scopus, and Web of Science databases to find relevant studies published in English up until May 2023. If applicable, we set the AUC threshold to 0.90 and sensitivity/specificity (SN/SP) to 90%. FINDINGS: Protein and glycoprotein biomarkers are a demonstrably viable option in BC diagnostics. Cholinesterase shows promise in progression-free survival. BLCA-4, ORM-1 along with HTRA1 in the detection of BC. Matrix metallopeptidase 9 exhibits potential for stratification of muscle-invasive subtypes with high negative predictive value for aggressive phenotypes. Distinguishing non-muscle invasive subtypes benefits from Keratin 17. Neu5Gc-modified UMOD glycoproteins pose potential in BC diagnosis, while fibronectin, laminin-5, collagen type IV, and lamprey immunity protein in early detection of BC.

Rheumatoid Synovial Fluid and Acidic Extracellular pH Modulate the Immunomodulatory Activity of Urine-Derived Stem Cells.

Urine-derived stem cells (UdSCs) possess a remarkable anti-inflammatory and immune-modulating activity. However, the clinical significance of UdSCs in autoimmune inflammatory diseases such as rheumatoid arthritis (RA) is yet to be explored. Hence, we tested the UdSCs response to an articular RA microenvironment. To simulate the inflamed RA joint more authentically in vitro, we treated cells with rheumatoid synovial fluids (RASFs) collected from RA patients, serum deprivation, acidosis (pH 7.0 and 6.5), and their combinations. Firstly, the RASFs pro-inflammatory status was assessed by cytokine quantification. Then, UdSCs were exposed to the RA environmental factors for 48 h and cell proliferation, gene expression and secretion of immunomodulatory factors were evaluated. The immunosuppressive potential of pre-conditioned UdSCs was also assessed via co-cultivation with activated peripheral blood mononuclear cells (PBMCs). In all experimental conditions, UdSCs' proliferation was not affected. Conversely, extracellular acidosis considerably impaired the viability/proliferation of adipose tissue-derived stem cells (ATSCs). In the majority of cases, exposure to RA components led to the upregulated expression of IL-6, TSG6, ICAM-1, VCAM-1, and PD-L1, all involved in immunomodulation. Upon RASFs and acidic stimulation, UdSCs secreted higher levels of immunomodulatory cytokines: IL-6, IL-8, MCP-1, RANTES, GM-CSF, and IL-4. Furthermore, RASFs and combined pretreatment with RASFs and acidosis promoted the UdSCs-mediated immunosuppression and the proliferation of activated PBMCs was significantly inhibited. Altogether, our data indicate that the RA microenvironment certainly has the capacity to enhance UdSCs' immunomodulatory function. For potential preclinical/clinical applications, the intra-articular injection might be a reasonable approach to maximize UdSCs' therapeutic efficiency in the RA treatment.

Tissue Engineering and Stem Cell Therapy in Neurogenic Bladder Dysfunction: Current and Future Perspectives.

Tissue engineering (TE) is a rapidly evolving biomedical discipline that can play an important role in treating neurogenic bladder dysfunction and compensating for current conventional options' shortcomings. This review aims to analyze the current status of preclinical and clinical trials and discuss what could be expected in the future based on the current state of the art. Although most preclinical studies provide promising results on the effectiveness of TE and stem cell therapies, the main limitations are mainly the very slow translation of preclinical trials to clinical trials, lack of quality research on neurogenic preconditions of neurogenic bladder dysfunction outside of the spinal cord injury and varying therapeutic methods of the existing research that lacks a standardized approach.

Application and Technical Principles of Catheter High-Frequency Jet Ventilation.

The aim of this publication is to analyze the topic of high-frequency jet ventilation (HFJV), namely catheter HFJV (C-HFJV), from a mathematical-physical as well as a clinical point of view. There are known issues with applying anesthesia and artificial lung ventilation (ALV) during surgical procedures in the upper airways, e.g., during bronchoscopy or tracheostomy. The principles, advantages, and disadvantages of HFJV are discussed in context with basic physical principles to clarify the proper use of this method. The basic technical principles of catheter construction, as well as its functional properties from a biophysical point of view, are introduced. Also, the placement of the catheter in the airways, the set-up of the HFJV ventilator, and the indications as well as the risks and contraindications of the use of C-HFJV are analyzed. This leads to the explanation of potentially optimal techniques for C-HFJV applications. In this article, we present the positive effects of C-HFJV even with complications such as bacterial or viral pneumonia, including COVID-19. In conclusion, we offer recommendations for clinical practice obtained from a literature review and from our rich clinical experience.

The Immunomodulatory Role of Cell-Free Approaches in SARS-CoV-2-Induced Cytokine Storm-A Powerful Therapeutic Tool for COVID-19 Patients.

Currently, there is still no effective and definitive cure for the coronavirus disease 2019 (COVID-19) caused by the infection of the novel highly contagious severe acute respiratory syndrome virus (SARS-CoV-2), whose sudden outbreak was recorded for the first time in China in late December 2019. Soon after, COVID-19 affected not only the vast majority of China's population but the whole world and caused a global health public crisis as a new pandemic. It is well known that viral infection can cause acute respiratory distress syndrome (ARDS) and, in severe cases, can even be lethal. Behind the inflammatory process lies the so-called cytokine storm (CS), which activates various inflammatory cytokines that damage numerous organ tissues. Since the first outbreak of SARS-CoV-2, various research groups have been intensively trying to investigate the best treatment options; however, only limited outcomes have been achieved. One of the most promising strategies represents using either stem cells, such as mesenchymal stem cells (MSCs)/induced pluripotent stem cells (iPSCs), or, more recently, using cell-free approaches involving conditioned media (CMs) and their content, such as extracellular vesicles (EVs) (e.g., exosomes or miRNAs) derived from stem cells. As key mediators of intracellular communication, exosomes carry a cocktail of different molecules with anti-inflammatory effects and immunomodulatory capacity. Our comprehensive review outlines the complex inflammatory process responsible for the CS, summarizes the present results of cell-free-based pre-clinical and clinical studies for COVID-19 treatment, and discusses their future perspectives for therapeutic applications.

Effects of the COVID-19 pandemic on mental health, anxiety, and depression.

BACKGROUND: The COVID-19 pandemic affected everyone around the globe. Depending on the country, there have been different restrictive epidemiologic measures and also different long-term repercussions. Morbidity and mortality of COVID-19 affected the mental state of every human being. However, social separation and isolation due to the restrictive measures considerably increased this impact. According to the World Health Organization (WHO), anxiety and depression prevalence increased by 25% globally. In this study, we aimed to examine the lasting effects of the COVID-19 pandemic on the general population. METHODS: A cross-sectional study using an anonymous online-based 45-question online survey was conducted at Comenius University in Bratislava. The questionnaire comprised five general questions and two assessment tools the Zung Self-Rating Anxiety Scale (SAS) and the Zung Self-Rating Depression Scale (SDS). The results of the Self-Rating Scales were statistically examined in association with sex, age, and level of education. RESULTS: A total of 205 anonymous subjects participated in this study, and no responses were excluded. In the study group, 78 (38.05%) participants were male, and 127 (61.69%) were female. A higher tendency to anxiety was exhibited by female participants (p = 0.012) and the age group under 30 years of age (p = 0.042). The level of education has been identified as a significant factor for changes in mental state, as participants with higher levels of education tended to be in a worse mental state (p = 0.006). CONCLUSIONS: Summarizing two years of the COVID-19 pandemic, the mental state of people with higher levels of education tended to feel worse, while females and younger adults felt more anxiety.

Exploring the Three-Dimensional Frontier: Advancements in MSC Spheroids and Their Implications for Breast Cancer and Personalized Regenerative Therapies.

To more accurately replicate the in vivo three-dimensional (3D) mesenchymal stem cell (MSC) niche and enhance cellular phenotypes for superior in vivo treatments, MSC functionalization through in vitro 3D culture approaches has gained attention. The organization of MSCs in 3D spheroids results in altered cell shape, cytoskeleton rearrangement, and polarization. Investigations have revealed that the survival and secretory capability of MSCs are positively impacted by moderate hypoxia within the inner zones of MSC spheroids. The spheroid hypoxic microenvironment enhances the production of angiogenic and anti-apoptotic molecules, including HGF, VEGF, and FGF-2. Furthermore, it upregulates the expression of hypoxia-adaptive molecules such as CXCL12 and HIF-1, inhibiting MSC death. The current review focuses on the latest developments in fundamental and translational research concerning three-dimensional MSC systems. This emphasis extends to the primary benefits and potential applications of MSC spheroids, particularly in the context of breast cancer and customized regenerative therapies.

Biomarkers of Bladder Cancer: Cell-Free DNA, Epigenetic Modifications and Non-Coding RNAs.

Bladder cancer (BC) is the 10th most frequent cancer in the world. The initial diagnosis and surveillance of BC require a combination of invasive and non-invasive methods, which are costly and suffer from several limitations. Cystoscopy with urine cytology and histological examination presents the standard diagnostic approach. Various biomarkers (e.g., proteins, genes, and RNAs) have been extensively studied in relation to BC. However, the new trend of liquid biopsy slowly proves to be almost equally effective. Cell-free DNA, non-coding RNA, and other subcellular structures are now being tested for the best predictive and diagnostic value. In this review, we focused on published gene mutations, especially in DNA fragments, but also epigenetic modifications, and non-coding RNA (ncRNA) molecules acquired by liquid biopsy. We performed an online search in PubMed/Medline, Scopus, and Web of Science databases using the terms "bladder cancer", in combination with "markers" or "biomarkers" published until August 2022. If applicable, we set the sensitivity and specificity threshold to 80%. In the era of precision medicine, the development of complex laboratory techniques fuels the search and development of more sensitive and specific biomarkers for diagnosis, follow-up, and screening of BC. Future efforts will be focused on the validation of their sensitivity, specificity, predictive value, and their utility in everyday clinical practice.

Anxiety and Depression: What Do We Know of Neuropeptides?

In modern society, there has been a rising trend of depression and anxiety. This trend heavily impacts the population's mental health and thus contributes significantly to morbidity and, in the worst case, to suicides. Modern medicine, with many antidepressants and anxiolytics at hand, is still unable to achieve remission in many patients. The pathophysiology of depression and anxiety is still only marginally understood, which encouraged researchers to focus on neuropeptides, as they are a vast group of signaling molecules in the nervous system. Neuropeptides are involved in the regulation of many physiological functions. Some act as neuromodulators and are often co-released with neurotransmitters that allow for reciprocal communication between the brain and the body. Most studied in the past were the antidepressant and anxiolytic effects of oxytocin, vasopressin or neuropeptide Y and S, or Substance P. However, in recent years, more and more novel neuropeptides have been added to the list, with implications for the research and development of new targets, diagnostic elements, and even therapies to treat anxiety and depressive disorders. In this review, we take a close look at all currently studied neuropeptides, their related pathways, their roles in stress adaptation, and the etiology of anxiety and depression in humans and animal models. We will focus on the latest research and information regarding these associated neuropeptides and thus picture their potential uses in the future.

Selected Biomarkers of Depression: What Are the Effects of Cytokines and Inflammation?

Depression is one of the leading mental illnesses worldwide and lowers the quality of life of many. According to WHO, about 5% of the worldwide population suffers from depression. Newer studies report a staggering global prevalence of 27.6%, and it is rising. Professionally, depression belonging to affective disorders is a psychiatric illness, and the category of major depressive disorder (MDD) comprises various diagnoses related to persistent and disruptive mood disorders. Due to this fact, it is imperative to find a way to assess depression quantitatively using a specific biomarker or a panel of biomarkers that would be able to reflect the patients' state and the effects of therapy. Cytokines, hormones, oxidative stress markers, and neuropeptides are studied in association with depression. The latest research into inflammatory cytokines shows that their relationship with the etiology of depression is causative. There are stronger cytokine reactions to pathogens and stressors in depression. If combined with other predisposing factors, responses lead to prolonged inflammatory processes, prolonged dysregulation of various axes, stress, pain, mood changes, anxiety, and depression. This review focuses on the most recent data on cytokines as markers of depression concerning their roles in its pathogenesis, their possible use in diagnosis and management, their different levels in bodily fluids, and their similarities in animal studies. However, cytokines are not isolated from the pathophysiologic mechanisms of depression or other psychiatric disorders. Their effects are only a part of the whole pathway.

Association Analysis of GDF5 and Contributing Factors in Developmental Dysplasia of the Hip in Infants.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a developmental disorder which is reported to be associated with hip instability. When untreated, it can lead to irreversible joint damage. DDH is known to be a multifactorial disease involving genetic, mechanical and environmental factors. The greatest causative potential is attributed to the genetic component. Growth Differentiation Factor 5 (GDF5) is among the most studied genes associated with processes of regeneration and maintenance of joints. The aim of this work was to analyse the association of SNP rs143383 in the GDF5 gene and the occurrence of DDH, along with association with various contributing factors in the Caucasian population. MATERIAL AND METHODS: A total of 118 samples were analysed for the presence of the mutation. DNA was isolated from all individuals from peripheral blood. SNP rs143383 in the GDF5 gene was genotyped using the TaqMan assay. A standard chi-square test was used to compare allele and genotype distributions in patients and healthy controls. RESULTS: The association analysis of genotypes of DDH and rs143383 revealed a significant association. Also, the association of GDF5 and selected contributing factors was statistically significant in female gender (p=0.002), family history (p<0.001), count of pregnancy (p=0.009), laterality of hip involvement and initial US examination. CONCLUSIONS: 1. The results indicate an important effect of rs143383 polymorphism in the GDF5 gene on DDH development. 2. However, our results also suggest that rs143383 is not the only contributing factor in the genetic component of DDH.

Genetic Study of IL6, GDF5 and PAPPA2 in Association with Developmental Dysplasia of the Hip.

BACKGROUND: Developmental dysplasia of the hip (DDH) is one of the most prevalent skeletal disorders. DDH is considered a pathologic condition with polygenic background, but environmental and mechanic factors significantly contribute to its multifactorial etiology. Inheritance consistent with autosomal dominant type has also been observed. Single-nucleotide polymorphisms (SNPs) in various genes mostly related to formation of connective tissue are studied for a possible association with DDH. METHODS: We genotyped three SNPs, rs1800796 located in the promoter region of the IL6 gene, rs143383 located in the 5' untranslated region (UTR) of the GDF5 gene and rs726252 located in the fifth intron of the PAPPA2 gene. The study consisted of 45 subjects with DDH and 85 controls from all regions of Slovakia. RESULTS: Association between DDH occurrence and studied genotypes affected by aforementioned polymorphisms was confirmed in the case of rs143383 in the GDF5 gene (p = 0.047), where the T allele was over-expressed in the study group. Meanwhile, in the matter of IL6 and PAPPA2, we found no association with DDH (p = 0.363 and p = 0.478, respectively). CONCLUSIONS: These results suggest that there is an association between DDH and GDF5 polymorphisms and that the T allele is more frequently presents in patients suffering from DDH.

Genetics of developmental dysplasia of the hip.

In the last decade, the advances in the molecular analyses and sequencing techniques allowed researchers to study developmental dysplasia of the hip (DDH) more thoroughly. Certain chromosomes, genes, loci and polymorphisms are being associated with variable severity of this disorder. The wide range of signs and symptoms is dependent either on isolated or systemic manifestation. Phenotypes of isolated cases range from only a mild ligamental laxity, through subluxation, to a complete dislocation of the femoral head. Systemic manifestation is connected to various forms of skeletal dysplasia and other malformations characterized by significant genetic aberrations. To reveal the background of DDH heredity, multiple studies focused on large sample sizes with an emphasis on the correlation between genotype, phenotype and continuous clinical examination. Etiological risk factors that have been observed and documented in patients include genetic, environmental, and mechanical factors, which significantly contribute to the familial or nonfamilial occurrence and phenotypic variability of this disorder. Still, the multifactorial etiology and pathogenesis of DDH are not yet sufficiently clarified, explained, or understood. Formation of connective tissue, osteogenesis, chondrogenesis, and all other affected pathways and variations in the function of their individual elements contribute to the creation of the pathology in a developing human body. This review article presents an up-to-date list of known DDH associated genes, their products, and functional characteristics.

Developmental Dysplasia of the Hip: A Review of Etiopathogenesis, Risk Factors, and Genetic Aspects.

As one of the most frequent skeletal anomalies, developmental dysplasia of the hip (DDH) is characterized by a considerable range of pathology, from minor laxity of ligaments in the hip joint to complete luxation. Multifactorial etiology, of which the candidate genes have been studied the most, poses a challenge in understanding this disorder. Candidate gene association studies (CGASs) along with genome-wide association studies (GWASs) and genome-wide linkage analyses (GWLAs) have found numerous genes and loci with susceptible DDH association. Studies put major importance on candidate genes associated with the formation of connective tissue (COL1A1), osteogenesis (PAPPA2, GDF5), chondrogenesis (UQCC1, ASPN) and cell growth, proliferation and differentiation (TGFB1). Recent studies show that epigenetic factors, such as DNA methylation affect gene expression and therefore could play an important role in DDH pathogenesis. This paper reviews all existing risk factors affecting DDH incidence, along with candidate genes associated with genetic or epigenetic etiology of DDH in various studies.

Expression of E-cadherin, Ki-67, and p53 in urinary bladder cancer in relation to progression, survival, and recurrence.

Although the incidence varies with age and gender, urothelial bladder cancer is a relatively frequently occurring malignancy with variable clinical behavior that often has high recurrence rates. In this study, we analyzed the tumor tissues of 224 patients with pTa, pT1, and pT2 urinary bladder cancer. We performed a histomorphologic analysis and immunohistochemistry for p53, Ki-67, and E-cadherin, which were selected as markers of the malignant process. For pTa and pT1, univariate analyses of cancer-specific survival (CSS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method, the log-rank test and Cox regression. Multivariate analysis was performed by a Cox regression analysis. Ki-67 (P<0.001) was significantly associated with CSS, but the highest association was shown for E-cadherin (P<0.001). For pT1 and pTa, the Kaplan-Meier analysis and the log-rank test revealed significantly worse PFS for patients with higher levels of Ki-67 (P<0.001) and lower levels of E-cadherin (P<0.001). Based on these obtained results, it can be clearly stated that Ki-67 and E-cadherin expression levels are associated with CSS, PFS and RFS. The clinical utility of these markers is valuable for pTa and pT1 urinary bladder cancer and should be further verified with prospective multi-center trials.

Developmental Dysplasia of Hip: Perspectives in Genetic Screening.

Development dysplasia of the hip (DDH) is a complex developmental disorder despite being a relatively common condition mainly caused by incompatibility of the femoral head and the abnormal joint socket. Development dysplasia of the hip describes a wide spectrum of disorders ranging from minor acetabular dysplasia to irreducible dislocation of the hip. Modern medicine still suffers from lack of information about screening and precise genetic examination. Genome wide linkage and association studies have brought significant progress to DDH diagnosis. Association studies managed to identify many candidate (susceptible) genes, such as PAPPA2, COL2A1, HOXD9, GDF-5, and TGFB1, which play a considerable role in the pathogenesis of DDH. Early detection of DDH has a big chance to help in preventing further disability and improve the psychological health and quality of life in those children. This emphasizes the importance to establish a universal screening program along with the genetic counseling.

Identification of Prognostic and Predictive Osteosarcoma Biomarkers.

Both adolescents and children suffer from osteosarcoma, localized in the metaphysis of the long bones. This is the most common primary high-grade bone tumor in this patient group. Early tumor detection is the key to ensuring effective treatment. Improved osteosarcoma outcomes in clinical trials have been contingent on biomarker discovery and an evolving understanding of molecules and their complex interactions. In this review, we present a short overview of biomarkers for osteosarcoma, and highlight advances in osteosarcoma-related biomarker research. Many studies show that several biomarkers undergo critical changes with osteosarcoma progression. Growing knowledge about osteosarcoma-related markers is expected to positively impact the development of therapeutics for osteosarcoma, and ultimately of clinical care. It has also become important to develop new biomarkers, which can identify vulnerable patients who should be treated with more intensive and aggressive therapy after diagnosis.