Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease.

There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self-limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis-related proteins like caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), proinflammatory cytokines like IL-1 and IL-18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well-defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.

The potential roles of Th17 cells in the pathogenesis of oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a T cell-mediated chronic autoimmune disease, whose pathogenesis and etiology are not entirely understood. OLP is characterized by subepithelial lymphocyte infiltration and elevated intra-epithelial lymphocytes. The majority of lamina propria lymphocytes are CD4+ T cells. CD4+ helper T (Th) cells play a crucial role in activating CD8+ cytotoxic T cells (CTLs) through interactions and cytokine production. Th1 and Th2 cells are well-accepted to be associated with OLP pathogenesis. However, OLP treatment is challenging yet, the more information we have about the pathology of OLP, the easier it will be treated. With the discovery of Th17 cells in recent years and the demonstration of their role in autoimmune disease, many researchers started to investigate the role of Th17 in the pathogenesis of OLP. METHODS: To make up this review, studies covering the role of TH17 in different types of lichen planus were selected from major databases. RESULTS: As we review in this article, Th17 cells and their signature cytokines play an important role in OLP pathogenesis. As well, utilizing some anti-IL-17 antibodies showed promising results in improving the disease; however, more studies are still needed to better understand and treat OLP.

Individual genetic variability mainly of Proinflammatory cytokines, cytokine receptors, and toll-like receptors dictates pathophysiology of COVID-19 disease.

Innate and acquired immunity responses are crucial for viral infection elimination. However, genetic variations in coding genes may exacerbate the inflammation or initiate devastating cytokine storms which poses severe respiratory conditions in coronavirus disease-19 (COVID-19). Host genetic variations in particular those related to the immune responses determine the patients' susceptibility and COVID-19 severity and pathophysiology. Gene polymorphisms such as single nucleotide polymorphisms (SNPs) of interferons, TNF, IL1, IL4, IL6, IL7, IL10, and IL17 predispose patients to the severe form of COVID-19 or severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). These variations mainly alter the gene expression and cause a severe response by B cells, T cells, monocytes, neutrophils, and natural killer cells participating in a cytokine storm. Moreover, cytokines and chemokines SNPs are associated with the severity of COVID-19 and clinical outcomes depending on the corresponding effect. Additionally, genetic variations in genes encoding toll-like receptors (TLRs) mainly TLR3, TLR7, and TLR9 have been related to the COVID-19 severe respiratory symptoms. The specific relation of these mutations with the novel variants of concern (VOCs) infection remains to be elucidated. Genetic variations mainly within genes encoding proinflammatory cytokines, cytokine receptors, and TLRs predispose patients to COVID-19 disease severity. Understanding host immune gene variations associated with the SARS-COV-2 infection opens insights to control the pathophysiology of emerging viral infections.

Anticancer traits of chimeric antigen receptors (CARs)-Natural Killer (NK) cells as novel approaches for melanoma treatment.

Owing to non-responsiveness of a high number of patients to the common melanoma therapies, seeking novel approaches seem as an unmet requirement. Chimeric antigen receptor (CAR) T cells were initially employed against recurrent or refractory B cell malignancies. However, advanced stages or pretreated patients have insufficient T cells (lymphopenia) amount for collection and clinical application. Additionally, this process is time-consuming and logistically cumbersome. Another limitation of this approach is toxicity and cytokine release syndrome (CRS) progress and neurotoxicity syndrome (NS). Natural killer (NK) cells are a versatile component of the innate immunity and have several advantages over T cells in the application for therapies such as availability, unique biological features, safety profile, cost effectiveness and higher tissue residence. Additionally, CAR NK cells do not develop Graft-versus-host disease (GvHD) and are independent of host HLA genotype. Notably, the NK cells number and activity is affected in the tumor microenvironment (TME), paving the way for developing novel approaches by enhancing their maturation and functionality. The CAR NK cells short lifespan is a double edge sword declining toxicity and reducing their persistence. Bispecific and Trispecific Killer Cell Engagers (BiKE and Trike, respectively) are emerging and promising immunotherapies for efficient antibody dependent cell cytotoxicity (ADCC). CAR NK cells have some limitations in terms of expanding and transducing NK cells from donors to achieve clinical response. Clinical trials are in scarcity regarding the CAR NK cell-based cancer therapies. The CAR NK cells short life span following irradiation before infusion limits their efficiency inhibiting their in vivo expansion. The CAR NK cells efficacy enhancement in terms of lifespan TME preparation and stability is a goal for melanoma treatment. Combination therapies using CAR NK cells and chemotherapy can also overcome therapy limitations.

Opportunities and obstacles for the melanoma immunotherapy using T cell and chimeric antigen receptor T (CAR-T) applications: a literature review.

Chimeric antigen receptor T (CAR-T) cell therapy procedure includes taking personal T cells and processing or genetic engineering using specific antigens and in vitro expanding and eventually infusing into the patient's body to unleash immune responses. Adoptive cell therapy (ACT) includes lymphocytes taking, in vitro selection and expansion and processing for stimulation or activation and infusion into the patient's body. Immune checkpoint inhibitors (ICIs), ACT and CAR-T cell therapies have demonstrated acceptable results. However, rare CAR-T cells tissue infiltration, off-target toxicity and resistance development include main disadvantages of CAR-T cell based therapy. Selection of suitable target antigens and novel engineered immune cells are warranted in future studies using "surfaceome" analysis. Employment of cytokines (IL-2, IL-7) for T cells activation has been also associated with specific anti-melanoma function which overcome telomeres shortening and further T cells differentiation. In resistant cases, rapidly accelerated fibrosarcoma B-type and mitogen-activated extracellular signal-regulated kinase inhibitors have been mostly applied. The aim of this study was evaluation of CAR-T cell and adoptive cell therapies efficiency for the treatment of melanoma.

Percutaneous endoscopic gastrostomy in children: a single center study at Tertiary hospital Iran.

INTRODUCTION: The aim of this study was to evaluate complications after percutaneous endoscopic gastrostomy among children who underwent percutaneous endoscopic gastrostomy in Nemazee hospital. MATERIALS AND METHODS: All children who underwent percutaneous endoscopic gastrostomy were included in the current study. Place of the study was department of pediatric gastroenterology of Nemazee children hospital of Shiraz university of medical sciences. Duration of the study was 5 year starting from 2008. All drugs such as aspirin, NSAIDS, and heparin were discontinued 1-7 days before procedures. All patients were kept NPO 6-8 hours before procedure according to the age. Single dose antibiotic was prescribed for all cases before procedure. During procedure, all patients were sedated using propofol and or midazolam. Some patients required intubation. RESULTS: Of 39 cases who underwent PEG, 4 (10.2%) patients showed complication. The most common indication for PEG insertion were neurologic problem (84.6%) and metabolic disease (10.2%). Of our patients, 84.6% of the cases had the weight below third percentile. CONCLUSION: The most common indication for percutaneous endoscopic gastrostomy was cerebral palsy. The complication rate in our study was 10.2%. Celulitis was the most common complication.

Soft Palate Ulcer: An Unusual Presentation of a Posttransplant Lymphoproliferative Disorder.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. It has several clinical manifestations, including infectious mononucleosis-like syndrome, lymphadenopathy, and other organ involvement. Soft palate ulcer is a rare manifestation of PTLD. The aim of this study is to present a 17-year-old girl with liver transplantation due to metastatic liver disease. After transplantation, she presented with a painful whitish ulcerative lesion accompanied by central necrosis in the right soft palate area measuring about 3 cm×3.5 cm. Histopathologic evaluation of the lesion showed monomorphic B-cell-type PTLD. She received 6 courses of CHOP chemotherapy plus rituximab. In the follow-up, the lesion disappeared with scar formation. Therefore, PTLD has different clinical presentations and may involve any part of the body. Therefore, when an unusual oral lesion after solid organ transplantation is observed, PTLD should be considered in addition to other differential diagnoses.

Incidence of testicular microlithiasis in patients with ß-thalassemia major.

We assessed the prevalence of testicular microlithiasis by scrotal ultrasonography in ß-thalassemia major patients older than 10 years and evaluated the association with serum ferritin levels, calcium (Ca), phosphate (Ph), and parathyroid hormone levels (PTH). In this cross-sectional study, 132 male ß-thalassemia major patients from 300 male patients older than 10 years old were randomly evaluated by scrotal ultrasonography. Parathyroid hormone, calcium, phosphate, and serum ferritin levels were also evaluated. All of the patients were urologically asymptomatic. One hundred healthy age-matched subjects were selected as control group. Testicular microlithiasis was found in 16 patients and 1 individual in control group (12.1 vs 1 %; p = 0.003). Testicular microlithiasis was associated with age and high serum ferritin levels, but there was no association between Ca, Ph, and PTH levels; blood transfusion; and oral or subcutaneous iron chelation therapy. Also, there was no significant correlation between hyperparathyroidism, history of viral hepatitis, and splenectomy with testicular microlithiasis. The frequency of testicular microlithiasis in ß-thalassemia major patients was higher than previously reported. A correlation was found between testicular microlithiasis with age and serum ferritin levels, so regular and adequate iron chelator therapy (at least 10-12 h per day for 5-6 days a week) is recommended. We suggest a close observation and treatment with iron-chelating agents of these patients. Since testicular microlithiasis is occasionally associated with germ cell tumors, clinical and sonographic follow-up is recommended.

CircRNA-associated ceRNA networks (circCeNETs) in chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD), a chronic airway disorder, which is mostly brought on by cigarette smoke extract (CSE), is a leading cause of death which has a high frequency. In COPD patients, smoking cigarette could also trigger the epithelial-mesenchymal transition (EMT) of airway remodeling. One of the most significant elements of environmental contaminants that is linked to pulmonary damage is fine particulate matter (PM2.5). However, the basic processes of lung injury brought on by environmental contaminants and cigarette smoke are poorly understood, particularly the molecular pathways involved in inflammation. For the clinical management of COPD, investigating the molecular process and identifying workable biomarkers will be important. According to newly available research, circular RNAs (circRNAs) are aberrantly produced and serve as important regulators in the pathological processes of COPD. This class of non-coding RNAs (ncRNAs) functions as microRNA (miRNA) sponges to control the levels of gene expression, changing cellular phenotypes and advancing disease. These findings led us to concentrate our attention in this review on new studies about the regulatory mechanism and potential roles of circRNA-associated ceRNA networks (circCeNETs) in COPD.

Paxlovid: Mechanism of Action, Synthesis, and In Silico Study.

In this work, the discovery and description of PF-07321332, a major bioavailable oral SARS-CoV-2 protease inhibitor with in vitro human coronavirus antiviral activity, and excellent selection of off-target and in vivo immune profiles are reported. Various drugs and novel compound candidates for the treatment of the COVID-19 pandemic have been developed. PF-07321332 (or nirmatrelvir) is a new oral antiviral drug developed by Pfizer. In response to the pandemic, Pfizer has developed the COVID vaccine and in 2022 will launch its new major anti-SARS-Cov-2 protease inhibitor (PI). The combination of ritonavir and nirmatrelvir is under study in phase III of the clinical trial with a brand name Paxlovid. Paxlovid is an active 3Cl protease inhibitor. Paxlovid exerts its antiviral efficacy by inhibiting a necessary protease in the viral replication procedure. Proteases of coronavirus cleave several sites in the viral polyprotein where pyrrolidone was replaced by flexible glutamine. Due to the coronavirus pandemic, there is high demand for synthesis and development of this novel drug. Herein, we report the synthetic route and the mechanism of action was recently published on nirmatrelvir. Also, a comparison of the performance of two new oral antiviruses (molnupiravir and nirmatrelvir) for the treatment of COVID-19 is described. This review will be helpful for different disciplines such as biochemistry, organic chemistry, medicinal chemistry, and pharmacology.

Purinergic receptors are a key bottleneck in tumor metabolic reprogramming: The prime suspect in cancer therapeutic resistance.

ATP and other nucleoside phosphates have specific receptors named purinergic receptors. Purinergic receptors and ectonucleotidases regulate various signaling pathways that play a role in physiological and pathological processes. Extracellular ATP in the tumor microenvironment (TME) has a higher level than in normal tissues and plays a role in cancer cell growth, survival, angiogenesis, metastasis, and drug resistance. In this review, we investigated the role of purinergic receptors in the development of resistance to therapy through changes in tumor cell metabolism. When a cell transforms to neoplasia, its metabolic processes change. The metabolic reprogramming modified metabolic feature of the TME, that can cause impeding immune surveillance and promote cancer growth. The purinergic receptors contribute to therapy resistance by modifying cancer cells' glucose, lipid, and amino acid metabolism. Limiting the energy supply of cancer cells is one approach to overcoming resistance. Glycolysis inhibitors which reduce intracellular ATP levels may make cancer cells more susceptible to anti-cancer therapies. The loss of the P2X7R through glucose intolerance and decreased fatty acid metabolism reduces therapeutic resistance. Potential metabolic blockers that can be employed in combination with other therapies will aid in the discovery of new anti-cancer immunotherapy to overcome therapy resistance. Therefore, therapeutic interventions that are considered to inhibit cancer cell metabolism and purinergic receptors simultaneously can potentially reduce resistance to treatment.

Association between dietary patterns with insulin resistance in an Iranian population.

AIM: To assess the association between dietary patterns no single food or group, and risk of insulin resistance (Fasting blood sugar (FBS), Fasting insulin, 2h-glucose, 2h-insulin and HOMA-IR). METHODS: In a cross-sectional, population-based study in Tehran, Iran, 2016-2017. Adults (n = 1500, 38% men) mean age 43.72 ± 14.9 years. Dietary intake was collected by semi-quantitative food frequency questionnaire and insulin resistance was evaluated by Fasting blood sugar (FBS), Fasting insulin, 2h glucose, 2h insulin and HOMA-IR. Associations were assessed by using correlation and multivariable linear regression. RESULTS: After controlling of the confounding factor or possible underlying such as gender, age, menopausal, BMI, physical activity and the amount of daily energy intake, unhealthy dietary pattern had a positive relationship with all indexes of insulin resistance except 2h glucose and HOMA-IR, healthy dietary pattern had negative and significant relationship with indexes of insulin resistance but apart from 2h glucose. CONCLUSIONS: It can be figured out that receiving diet rich in healthy foods might reduce the risk of creating insulin resistance.

Caustic Ingestion in Children in South of Iran: A Two-Year Single Center Study.

BACKGROUND Caustic ingestion is one of the most important injuries during childhood, which leads to serious sequel. In this study, we evaluated the clinical manifestations, endoscopic appearance, complications, and treatment results in patients with caustic ingestion in our hospital. METHODS Hospital chart of patients with caustic ingestion who admitted to Nemazee Teaching Hospital affiliated to Shiraz University of Medical Sciences during a 2-year period (2015-2016) were reviewed retrospectively. The age, sex, nature of the caustic agent, clinical presentations, grade of injury in endoscopy, degree of parents' education, site of ingestion, accidental or intentional attempts, complications, and outcomes were reviewed. RESULTS In this study the charts of 41 patients (26 boys and 15 girls) with caustic ingestion over the 2-year period were reviewed. The mean age of the patients was 4.4 year. Of them, 95.1% had ingested the materials accidentally, and 2 (4.9%) patients had ingested unknown substances for suicidal attempt. Of all cases, 68.3% of caustic ingestion occurred in the kitchen. 19 (46.3%) agents were acidic substances and 17 (41.5%) were alkali agents. 5 (12.1%) patients ingested unknown substances. 24.3% of the patients were asymptomatic and the most common presentation was drooling (34.14%). 26.8% of the patients had dysphagia, and 24.3% presented with oral ulcer. 7.3% had abdominal pain, 4.8% had fever, and 2.4% had hematemesis. 14 (34.1%) patients had normal feature, 6 (14.6%) had grade I injury, 12 (29.3%) had grade II injury, and 8 (19.5%) had grade III injury in endoscopic evaluation. CONCLUSION Most of the caustic ingestion occurred in kitchen. Male was the dominant sex in the caustic injury.

Solitary rectal ulcer syndrome: Is it really a rare condition in children?

AIM: To evaluate the clinicopathologic characteristics of the children with solitary rectal ulcer. METHODS: Fifty-five children with a confirmed diagnosis of solitary rectal ulcer were studied in a period of 11 years from March 2003 to March 2014. All data were collected from the patients, their parents and medical records in the hospital. RESULTS: From 55 studied patients, 41 were male (74.5%) and 14 female (25.5%). The mean age of the patients was 10.4 ± 3.7 years and the average time period from the beginning of symptoms to diagnosis of solitary rectal ulcer was 15.5 ± 11.2 mo. The most common clinical symptoms in our patients were rectal bleeding (n = 54, 98.2%) and straining during defecation or forceful defecation (n = 50, 90.9%). Other symptoms were as follows respectively: Sense of incomplete evacuation (n = 34, 61.8%), mucorrhea (n = 29, 52.7%), constipation (n = 14, 25.4%), tenesmus and cramping (n = 10, 18.2%), diarrhea (n = 9, 16.4%), and rectal pain (n = 5, 9.1%). The colonoscopic examination revealed 67.3% ulcer, 12.7% polypoid lesions, 10.9% erythema, 7.3% both polypoid lesions and ulcer, and 1.8% normal. Most of the lesions were in the rectosigmoid area at a distance of 4-6 cm from the anal margin. Finally, 69.8% of the patients recovered successfully with conservative, medical and surgical management. CONCLUSION: The study revealed that solitary rectal ulcer is not so uncommon despite what was seen in previous studies. As the most common symptom was rectal bleeding, clinicians and pathologists should be familiar with this disorder and common symptoms in order to prevent its complications with early diagnosis.

Percutaneous endoscopic gastrostomy in children: a single center study at Tertiary hospital Iran / Gastrostomía percutánea en niños: reporte de un hospital terciario de Iran

Introduction: The aim of this study was to evaluate complications after percutaneous endoscopic gastrostomy among children who underwent percutaneous endoscopic gastrostomy in Nemazee hospital. Materials and methods: All children who underwent percutaneous endoscopic gastrostomy were included in the current study. Place of the study was department of pediatric gastroenterology of Nemazee children hospital of Shiraz university of medical sciences. Duration of the study was 5 year starting from 2008. All drugs such as aspirin, NSAIDS, and heparin were discontinued 1-7 days before procedures. All patients were kept NPO 6-8 hours before procedure according to the age. Single dose antibiotic was prescribed for all cases before procedure. During procedure, all patients were sedated using propofol and or midazolam. Some patients required intubation. Results: Of 39 cases who underwent PEG, 4 (10.2%) patients showed complication. The most common indication for PEG insertion were neurologic problem (84.6%) and metabolic disease (10.2%). Of our patients, 84.6% of the cases had the weight below third percentile. Conclusion: The most common indication for percutaneous endoscopic gastrostomy was cerebral palsy. The complication rate in our study was 10.2%. Celulitis was the most common complication

Introducción: El objetivo de este estudio fue evaluar las complicaciones luego de una gastrostomía endoscópica percutánea (PEG) en niños realizada en el hospital Nemazee. Material y métodos: Se incluyeron al estudio todos los niños que se realizaron PEG en el hospital. El lugar del estudio fue el departamento de gastroenterología pediátrica del Hospital para niños Nemazee de la Universidad Shiraz de ciencias médicas. La duración del estudio fue cinco años, iniciando en el año 2008. Todas las drogas como aspirina, AINES y heparina fueron suspendidas entre 1 a 7 días previos al procedimiento. Todos los pacientes estuvieron entre 6 a 8 horas del examen en ayunas dependiendo de la edad. Se prescribió una dosis de antibioterapia profiláctica en todos los casos previo al procedimiento. Durante el procedimiento, todos los pacientes fueron sedados usando propofol y/o midazolam. Algunos pacientes necesitaron intubación. Resultados: De 39 casos que se sometieron a PEG, 4 (10,2%) tuvieron alguna complicación. La indicación más frecuente de PEG fueron los problemas neurológicos (84,6%) y luego las enfermedades metabólicas (10,2%). De nuestros pacientes, 84,6% de los casos estuvieron por debajo del tercer percentile. Conclusión: La indicación más común de gastrostomía endoscópica percutánea fue la parálisis cerebral. La tasa de complicación en nuestro estudio fue 10,2%. La celulitis fue la complicación más común