JAK Inhibitors in Rheumatoid Arthritis: Immunomodulatory Properties and Clinical Efficacy.

Rheumatoid arthritis (RA) is a highly prevalent autoimmune disorder. The pathogenesis of the disease is complex and involves various cellular populations, including fibroblast-like synoviocytes, macrophages, and T cells, among others. Identification of signalling pathways and molecules that actively contribute to the development of the disease is crucial to understanding the mechanisms involved in the chronic inflammatory environment present in affected joints. Recent studies have demonstrated that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway regulates the behaviour of immune cells and contributes to the progression of RA. Several JAK inhibitors, such as tofacitinib, baricitinib, upadacitinib, and filgocitinib, have been developed, and their efficacy and safety in patients with RA have been comprehensively investigated in a number of clinical trials. Consequently, JAK inhibitors have been approved and registered as a treatment for patients with RA. In this review, we discuss the involvement of JAK/STAT signalling in the pathogenesis of RA and summarise the potential beneficial effects of JAK inhibitors in cells implicated in the pathogenesis of the disease. Moreover, we present the most important phase 3 clinical trials that evaluated the use of these agents in patients.

Pathogenesis of Sarcopenia in Chronic Kidney Disease-The Role of Inflammation, Metabolic Dysregulation, Gut Dysbiosis, and microRNA.

Chronic kidney disease (CKD) is a progressive disorder associated with a decline in kidney function. Consequently, patients with advanced stages of CKD require renal replacement therapies, such as dialysis and kidney transplantation. Various conditions lead to the development of CKD, including diabetes mellitus, hypertension, and glomerulonephritis, among others. The disease is associated with metabolic and hormonal dysregulation, including uraemia and hyperparathyroidism, as well as with low-grade systemic inflammation. Altered homeostasis increases the risk of developing severe comorbidities, such as cardiovascular diseases or sarcopenia, which increase mortality. Sarcopenia is defined as a progressive decline in muscle mass and function. However, the precise mechanisms that link CKD and the development of sarcopenia are poorly understood. Knowledge about these linking mechanisms might lead to the introduction of precise treatment strategies that could prevent muscle wasting. This review discusses inflammatory mediators, metabolic and hormonal dysregulation, gut microbiota dysbiosis, and non-coding RNA alterations that could link CKD and sarcopenia.

Successful Treatment of Cutaneous Squamous Cell Cancer with Cemiplimab-A Report of Two Cases Demonstrating the Management of Pseudoprogression and Adverse Events.

Background: Cutaneous squamous cell carcinoma is a common malignancy, which frequently develops in the areas exposed to the sun. Patients with locally advanced disease in the head and neck region are frequently disqualified from surgical resection and require systemic treatment. Methods: In this report, we present the clinicopathological features and treatment of two patients who received cemiplimab, a monoclonal antibody targeting programmed cell death receptor 1 (PD-1). Results: An 80-year-old female and 82-year-old male patient were admitted to the hospital for the treatment of large tumors diagnosed as squamous cell carcinomas. In both patients, surgical treatment was not recommended due to the large dimensions of the tumors. These patients qualified for systemic treatment with cemiplimab. In the first patient, immunotherapy was interrupted due to adverse events. Nevertheless, a continuous regression of the tumor was observed despite treatment cessation. The second patient experienced a pseudoprogression, which is an increase in the tumor size caused by infiltration of immune cells. The treatment significantly reduced tumor size in both patients, which highly improved their quality of life. Conclusions: Cemiplimab offers clinical benefits in patients with cutaneous squamous cell carcinoma who are ineligible for surgical treatment. Systemic treatment can significantly improve the quality of life and reduce tumor diameters.

The role of adipokines in the pathogenesis of psoriasis - a focus on resistin, omentin-1 and vaspin.

BACKGROUND: Psoriasis is a chronic immune-mediated skin condition with several types of manifestation, including psoriatic arthritis. In recent years, studies have demonstrated multiple molecules and mechanisms that play important roles in the pathophysiology of psoriasis. Studies have been conducted to determine the role of adipokines, bioactive peptides secreted by the adipose tissue, in the pathogenesis of inflammatory diseases. These studies have shown that adipokines are dysregulated in psoriasis and their abnormal expression profile could contribute to the inflammatory mechanisms observed in psoriasis. AREAS COVERED: In this review, we discuss the immunomodulatory features of resistin, omentin-1, and vaspin, and discuss their potential involvement in the pathogenesis of psoriasis. EXPERT OPINION: The adipokines resistin, omentin, and vaspin appear to be promising therapeutic targets in psoriasis. It is important to seek to block the action of resistin, either by blocking its receptors or by blocking its systemic effects with antibodies. In the case of omentin and vaspin, substances that are receptor mimetics of these adipokines should be sought and studies conducted of their analogues for the treatment of psoriasis. To introduce these therapies into clinical practice, multicentre clinical trials are required to confirm their efficacy and safety after initial studies in animal models.

The Role of Mesenchymal Stromal Cells in the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterised by the formation of a hyperplastic pannus, as well as cartilage and bone damage. The pathogenesis of RA is complex and involves broad interactions between various cells present in the inflamed synovium, including fibroblast-like synoviocytes (FLSs), macrophages, and T cells, among others. Under inflammatory conditions, these cells are activated, further enhancing inflammatory responses and angiogenesis and promoting bone and cartilage degradation. Novel treatment methods for RA are greatly needed, and mesenchymal stromal cells (MSCs) have been suggested as a promising new regenerative and immunomodulatory treatment. In this paper, we present the interactions between MSCs and RA-FLSs, and macrophages and T cells, and summarise studies examining the use of MSCs in preclinical and clinical RA studies.

The Role of MicroRNA in the Pathogenesis of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked progressive disorder associated with muscle wasting and degeneration. The disease is caused by mutations in the gene that encodes dystrophin, a protein that links the cytoskeleton with cell membrane proteins. The current treatment methods aim to relieve the symptoms of the disease or partially rescue muscle functionality. However, they are insufficient to suppress disease progression. In recent years, studies have uncovered an important role for non-coding RNAs (ncRNAs) in regulating the progression of numerous diseases. ncRNAs, such as micro-RNAs (miRNAs), bind to their target messenger RNAs (mRNAs) to suppress translation. Understanding the mechanisms involving dysregulated miRNAs can improve diagnosis and suggest novel treatment methods for patients with DMD. This review presents the available evidence on the role of altered expression of miRNAs in the pathogenesis of DMD. We discuss the involvement of these molecules in the processes associated with muscle physiology and DMD-associated cardiomyopathy.

A Rare Case of Primary Pulmonary Diffuse Large B-Cell Lymphoma Transformed from Marginal Zone Mucosa-Associated Lymphoid Tissue Lymphoma.

Primary pulmonary lymphoma is a rare neoplasm characterized by the proliferation of lymphoid tissue affecting the lungs. The most common subtype is marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). Rarely, a MALT lymphoma transforms into a diffuse large B-cell lymphoma (DLBCL). Treatment options include chemotherapy, radiotherapy, immunotherapy, and surgery. Here, we describe a patient with a primary pulmonary MALT lymphoma transforming into DLBCL. The purpose of this case report is to raise awareness of the relevant clinical and imaging features and to emphasize the need for a multidisciplinary approach to optimal management. In addition, we screened the PubMed and Embase databases for similar reports with a confirmed presence of transforming lymphoma within the lungs.

Placental Expression of Glucose and Zinc Transporters in Women with Gestational Diabetes.

Background/Objectives: Gestational diabetes (GDM) is a metabolic disorder with altered glucose levels diagnosed in pregnant women. The pathogenesis of GDM is not fully known, but it is thought to be caused by impaired insulin production and insulin resistance induced by diabetogenic factors. The placenta may play an important role in the development of GDM. Glucose transporters (GLUTs) are responsible for the delivery of glucose into the foetal circulation. Placental zinc transporters regulate insulin and glucagon secretion, as well as gluconeogenesis and glycolysis. The aim of this study was to investigate the placental expression of GLUT3, GLUT4, GLUT7 and SLC30A8 in women with GDM. Furthermore, we evaluated whether the expression profiles of these transporters were correlated with clinical parameters. Methods: This study included 26 patients with GDM and 28 patients with normal glucose tolerance (NGT). Results: The placental expression of GLUT3 was significantly reduced in the GDM group, while the placental expression of GLUT4, GLUT7 and SLC30A8 was significantly upregulated in the GDM group. GLUT3 expression correlated significantly with body mass index (BMI) increase during pregnancy and body mass increase during pregnancy, while GLUT4 expression correlated negatively with BMI at birth. Conclusions: These results suggest the involvement of GLUT3 and GLUT4, GLUT7 and SLC30A8 in the pathogenesis of GDM.

Non-Coding RNA as Biomarkers and Their Role in the Pathogenesis of Gastric Cancer-A Narrative Review.

Non-coding RNAs (ncRNAs) represent a broad family of molecules that regulate gene expression, including microRNAs, long non-coding RNAs and circular RNAs, amongst others. Dysregulated expression of ncRNAs alters gene expression, which is implicated in the pathogenesis of several malignancies and inflammatory diseases. Gastric cancer is the fifth most frequently diagnosed cancer and the fourth most common cause of cancer-related death. Studies have found that altered expression of ncRNAs may contribute to tumourigenesis through regulating proliferation, apoptosis, drug resistance and metastasis. This review describes the potential use of ncRNAs as diagnostic and prognostic biomarkers. Moreover, we discuss the involvement of ncRNAs in the pathogenesis of gastric cancer, including their interactions with the members of major signalling pathways.

The Role of Stem Cells in the Treatment of Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of death and include several vascular and cardiac disorders, such as atherosclerosis, coronary artery disease, cardiomyopathies, and heart failure. Multiple treatment strategies exist for CVDs, but there is a need for regenerative treatment of damaged heart. Stem cells are a broad variety of cells with a great differentiation potential that have regenerative and immunomodulatory properties. Multiple studies have evaluated the efficacy of stem cells in CVDs, such as mesenchymal stem cells and induced pluripotent stem cell-derived cardiomyocytes. These studies have demonstrated that stem cells can improve the left ventricle ejection fraction, reduce fibrosis, and decrease infarct size. Other studies have investigated potential methods to improve the survival, engraftment, and functionality of stem cells in the treatment of CVDs. The aim of the present review is to summarize the current evidence on the role of stem cells in the treatment of CVDs, and how to improve their efficacy.

The Role of Alarmins in the Pathogenesis of Rheumatoid Arthritis, Osteoarthritis, and Psoriasis.

Alarmins are immune-activating factors released after cellular injury or death. By secreting alarmins, cells can interact with immune cells and induce a variety of inflammatory responses. The broad family of alarmins involves several members, such as high-mobility group box 1, S100 proteins, interleukin-33, and heat shock proteins, among others. Studies have found that the concentrations and expression profiles of alarmins are altered in immune-mediated diseases. Furthermore, they are involved in the pathogenesis of inflammatory conditions. The aim of this narrative review is to present the current evidence on the role of alarmins in rheumatoid arthritis, osteoarthritis, and psoriasis. We discuss their potential involvement in mechanisms underlying the progression of these diseases and whether they could become therapeutic targets. Moreover, we summarize the impact of pharmacological agents used in the treatment of these diseases on the expression of alarmins.

Immunolocalization of Matrix Metalloproteinases 2 and 9 and Their Inhibitors in the Hearts of Rats Treated with Immunosuppressive Drugs-An Artificial Intelligence-Based Digital Analysis.

BACKGROUND: Immunosuppressive agents represent a broad group of drugs, such as calcineurin inhibitors, mTOR inhibitors, and glucocorticosteroids, among others. These drugs are widely used in a number of conditions, but lifelong therapy is crucial in the case of organ recipients to prevent rejection. To further increase the safety and efficacy of these agents, their off-target mechanisms of action, as well as processes underlying the pathogenesis of adverse effects, need to be thoroughly investigated. The aim of this study was to examine the impact of various combinations of cyclosporine/tacrolimus/mycophenolate with rapamycin and steroids (CRG, TRG, MRG), on the morphology and morphometry of rats' cardiomyocytes, together with the presence of cardiac collagen and the immunoexpression of MMPs and TIMPs. METHODS: Twenty-four rats were divided into four groups receiving different immunosuppressive regiments. After six months of treatment, the hearts were collected and analyzed. RESULTS: Cardiomyocytes from the CRG cohorts demonstrated the most pronounced morphological alterations. In addition, chronic immunosuppression reduced the width and length of cardiac cells. However, immunosuppressive therapy did not alter the presence of cardiac collagen fibers. Nevertheless, we observed significant alterations regarding MMP/TIMP homeostasis. CONCLUSIONS: Chronic immunosuppression seems to disturb the MMP/TIMP balance in aspects of immunolocalization in the hearts of rats. Further studies are required to analyze other mechanisms and pathways affected by the use of immunosuppressants.

The effect of plasma cytokines on the expression of adiponectin and its receptors in the synovial membrane of joints and the infrapatellar fat pad in patients with rheumatoid arthritis and osteoarthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to joint destruction. Numerous pro-inflammatory mediators, including adipokines, play an important role in the pathogenesis of RA. OBJECTIVE: The aim of the study was to investigate the relationships between selected plasma cytokines and expression of adiponectin and its receptors in the synovium and the infrapatellar fat pad in patients with RA and osteoarthritis (OA). METHODS: Blood, synovium and fat pad samples from 18 patients with RA and 18 with OA were collected during joint replacement surgery. Spearman rank correlations between plasma concentrations of selected cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 p40, IL-13, IL-17, G-CSF and GM-CSF) and the expression of adiponectin and its receptors were determined. Plasma levels of cytokines were determined using a magnetic bead-based multiplex assay, mRNA expression of adiponectin and its receptors were determined by real-time PCR. RESULTS: In OA patients, there were significant positive correlations between adiponectin expression in the synovial membrane and plasma levels of IL-1ß, IL-4, G-CSF and GM-CSF, as well as a significant positive correlation between adiponectin expression in the fat pad and plasma levels of GM-CSF. In addition, OA patients showed significant negative correlations between AdipoR1 and AdipoR2 expression in the synovial membrane and plasma IL-6 levels, as well as between AdipoR2 expression in the synovial membrane and plasma MCP-1 and TNF-α levels. In patients with RA, there were no significant correlations between adiponectin expression in the synovial membrane and infrapatellar fat pad and plasma levels of the cytokines studied. In addition, RA patients showed a statistically significant negative correlation between AdipoR1 expression in the synovial membrane and plasma levels of TNF-α, IL-7, IL-12 and IL-13, and a significant negative correlation between AdipoR1 expression in the infrapatellar fat pad and plasma levels of IL-1ß. CONCLUSIONS: Adiponectin and its receptors showed the correlations with several plasma cytokines, however, a thorough understanding of the role of adiponectin in RA and OA requires further investigation.

How can we optimize the use of methotrexate to treat pediatric patients with inflammatory skin diseases?

INTRODUCTION: Methotrexate (MTX) is a folic acid antagonist used in clinical practice in oncology and rheumatology, as well as in the treatment of inflammatory skin conditions in children. The low-doses of MTX are commonly used in children for the treatment of many inflammatory and autoimmune conditions, including inflammatory skin diseases, due to its anti-inflammatory and immunomodulatory effects. AREAS COVERED: This review discusses the possibilities for optimizing the use of methotrexate in the treatment of pediatric patients with inflammatory skin diseases. A thorough search through PubMed and Embase databases was performed to identify relevant literature. EXPERT OPINION: Clinical observations confirm the high efficacy and safety of low-dose MTX in children with inflammatory skin diseases. Unfortunately, to date there are few studies providing guidelines on the optimal dosage of MTX in children with inflammatory skin diseases; routes of administration; principles of monitoring; and the safety of long-term use of this medication in children. There is still a need for specific recommendations on the safest and most effective dosing and monitoring regimen for children treated with methotrexate for inflammatory skin diseases.

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.

The Genetic Aspects of Periodontitis Pathogenesis and the Regenerative Properties of Stem Cells.

Periodontitis (PD) is a prevalent and chronic inflammatory disease with a complex pathogenesis, and it is associated with the presence of specific pathogens, such as Porphyromonas gingivalis. Dysbiosis and dysregulated immune responses ultimately lead to chronic inflammation as well as tooth and alveolar bone loss. Multiple studies have demonstrated that genetic polymorphisms may increase the susceptibility to PD. Furthermore, gene expression is modulated by various epigenetic mechanisms, such as DNA methylation, histone modifications, or the activity of non-coding RNA. These processes can also be induced by PD-associated pathogens. In this review, we try to summarize the genetic processes that are implicated in the pathogenesis of PD. Furthermore, we discuss the use of these mechanisms in diagnosis and therapeutic purposes. Importantly, novel treatment methods that could promote tissue regeneration are greatly needed in PD. In this paper, we also demonstrate current evidence on the potential use of stem cells and extracellular vesicles to stimulate tissue regeneration and suppress inflammation. The understanding of the molecular mechanisms involved in the pathogenesis of PD, as well as the impact of PD-associated bacteria and stem cells in these processes, may enhance future research and ultimately improve long-term treatment outcomes.

The Role of Extracellular Vesicles in the Pathogenesis and Treatment of Rheumatoid Arthritis and Osteoarthritis.

Cells can communicate with each other through extracellular vesicles (EVs), which are membrane-bound structures that transport proteins, lipids and nucleic acids. These structures have been found to mediate cellular differentiation and proliferation apoptosis, as well as inflammatory responses and senescence, among others. The cargo of these vesicles may include immunomodulatory molecules, which can then contribute to the pathogenesis of various diseases. By contrast, EVs secreted by mesenchymal stem cells (MSCs) have shown important immunosuppressive and regenerative properties. Moreover, EVs can be modified and used as drug carriers to precisely deliver therapeutic agents. In this review, we aim to summarize the current evidence on the roles of EVs in the progression and treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), which are important and prevalent joint diseases with a significant global burden.

Anaplastic lymphoma kinase inhibitors-a review of anticancer properties, clinical efficacy, and resistance mechanisms.

Fusions and mutations of anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, have been identified in several neoplastic diseases. Rearranged ALK is a driver of tumorigenesis, which activates various signaling pathway associated with proliferation and survival. To date, several agents that target and inhibit ALK have been developed. The most studied ALK-positive disease is non-small cell lung cancer, and three generations of ALK tyrosine kinase inhibitors (TKIs) have been approved for the treatment of metastatic disease. Nevertheless, the use of ALK-TKIs is associated with acquired resistance (resistance mutations, bypass signaling), which leads to disease progression and may require a substitution or introduction of other treatment agents. Understanding of the complex nature and network of resistance mutations may allow to introduce sequential and targeted therapies. In this review, we aim to summarize the efficacy and safety profile of ALK inhibitors, describe off-target anticancer effects, and discuss resistance mechanisms in the context of personalized oncology.

Targeting cyclin-dependent kinases in rheumatoid arthritis and psoriasis - a review of current evidence.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with synovial proliferation and bone erosion, which leads to the structural and functional impairment of the joints. Immune cells, together with synoviocytes, induce a pro-inflammatory environment and novel treatment agents target inflammatory cytokines. Psoriasis is a chronic immune-mediated skin disease, and several cytokines are considered as typical mediators in the progression of the disease, including IL-23, IL-22, and IL-17, among others. AREA COVERED: In this review, we try to evaluate whether cyclin-dependent kinases (CDK), enzymes that regulate cell cycle and transcription of various genes, could become novel therapeutic targets in RA and psoriasis. We present the main results of in vitro and in vivo studies, as well as scarce clinical reports. EXPERT OPINION: CDK inhibitors seem promising for treating RA and psoriasis because of their multidirectional effects. CDK inhibitors may affect not only the process of osteoclastogenesis, thereby reducing joint destruction in RA, but also the process of apoptosis of neutrophils and macrophages responsible for the development of inflammation in both RA and psoriasis. However, assessing the efficacy of these drugs in clinical practice requires multi-center, long-term clinical trials evaluating the effectiveness and safety of CDK-blocking therapy in RA and psoriasis.

The use of glucarpidase as a rescue therapy for high dose methotrexate toxicity - a review of pharmacological and clinical data.

INTRODUCTION: This review aims to summarize recent data on the pharmacodynamic, pharmacokinetic, and safety of glucarpidase. This is an enzymatic agent that catalyzes the conversion of methotrexate (MTX) into inactive metabolites. Glucarpidase is used to manage high-dose MTX (HDMTX) toxic plasma concentration, especially in patients with impaired renal function. AREAS COVERED: In this review, studies on glucarpidase clinical efficacy as a therapeutic option for patients suffering from MTX kidney toxicity were presented. Pharmacodynamic and pharmacokinetic properties of glucarpidase were included. Moreover, potential interactions and safety issues were discussed. EXPERT OPINION: The use of glucarpidase is an effective therapeutic strategy in both adults and children treated with high doses of MTX for various types of cancer who have developed acute renal failure. Glucarpidase causes MTX to be converted to nontoxic metabolites and accelerates the time for its complete elimination. After administration of glucarpidase, it is possible to resume HDMTX.