Clinical heterogeneity in families with multiple cases of inborn errors of immunity.

BACKGROUND: Inborn errors of immunity (IEI) are a diverse range of genetic immune system illnesses affecting the innate and/or adaptive immune systems. Variable expressivity and incomplete penetrance have been reported in IEI patients with similar clinical diagnoses or even the same genetic mutation. METHODS: Among all recorded patients in the national IEI registry, 193 families with multiple cases have been recognized. Clinical, laboratory and genetic variability were compared between 451 patients with different IEI entities. RESULTS: The diagnosis of the first children led to the earlier diagnosis, lower diagnostic delay, timely treatment and improved survival in the second children in the majority of IEI. The highest discordance in familial lymphoproliferation, autoimmunity and malignancy were respectively observed in STK4 deficiency, DNMT3B deficiency and ATM deficiency. Regarding immunological heterogeneity within a unique family with multiple cases of IEI, the highest discordance in CD3+, CD4+, CD19+, IgM and IgA levels was observed in syndromic combined immunodeficiencies (CID), while non-syndromic CID particularly severe combined immunodeficiency (SCID) manifested the highest discordance in IgG levels. Identification of the first ATM-deficient patient can lead to improved care and better survival in the next IEI children from the same family. CONCLUSION: Intrafamilial heterogeneity in immunological and/or clinical features could be observed in families with multiple cases of IEI indicating the indisputable role of appropriate treatment and preventive environmental factors besides specific gene mutations in the variable observed penetrance or expressivity of the disease. This also emphasizes the importance of implementing genetic evaluation in all members of a family with a history of IEI even if there is no suspicion of an underlying IEI as other factors besides the underlying genetic defects might cause a milder phenotype or delay in presentation of clinical features. Thus, affected patients could be timely diagnosed and treated, and their quality of life and survival would improve.

Clinical, Immunological, and Genetic Features in Patients with NFKB1 and NFKB2 Mutations: a Systematic Review.

BACKGROUND: Inborn errors of immunity (IEIs) encompass various diseases with diverse clinical and immunological symptoms. Determining the genotype-phenotype of different variants in IEI entity precisely is challenging, as manifestations can be heterogeneous even in patients with the same mutated gene. OBJECTIVE: In the present study, we conducted a systematic review of patients recorded with NFKB1 and NFKB2 mutations, two of the most frequent monogenic IEIs. METHODS: The search for relevant literature was conducted in databases including Web of Science, PubMed, and Scopus. Information encompassing demographic, clinical, immunological, and genetic data was extracted from cases reported with mutations in NFKB1 and NFKB2. The comprehensive features of manifestations in patients were described, and a comparative analysis of primary characteristics was conducted between individuals with NFKB1 loss of function (LOF) and NFKB2 (p52-LOF/IκBδ-gain of function (GOF)) variants. RESULTS: A total of 397 patients were included in this study, 257 had NFKB1 mutations and 140 had NFKB2 mutations. There were 175 LOF cases in NFKB1 and 122 p52LOF/IκBδGOF cases in NFKB2 pivotal groups with confirmed functional implications. NFKB1LOF and p52LOF/IκBδGOF predominant cases (81.8% and 62.5% respectively) initially presented with a CVID-like phenotype. Patients with NFKB1LOF variants often experienced hematologic autoimmune disorders, whereas p52LOF/IκBδGOF patients were more susceptible to other autoimmune diseases. Viral infections were markedly higher in p52LOF/IκBδGOF cases compared to NFKB1LOF (P-value < 0.001). NFKB2 (p52LOF/IκBδGOF) patients exhibited a greater prevalence of ectodermal dysplasia and pituitary gland involvement than NFKB1LOF patients. Most NFKB1LOF and p52LOF/IκBδGOF cases showed low CD19 + B cells, with p52LOF/IκBδGOF having more cases of this type. Low memory B cells were more common in p52LOF/IκBδGOF patients. CONCLUSIONS: Patients with NFKB2 mutations, particularly p52LOF/IκBδGOF, are at higher risk of viral infections, pituitary gland involvement, and ectodermal dysplasia compared to patients with NFKB1LOF mutations. Genetic testing is essential to resolve the initial complexity and confusion surrounding clinical and immunological features. Emphasizing the significance of functional assays in determining the probability of correlations between mutations and immunological and clinical characteristics of patients is crucial.

Methanol poisoning during COVID-19 pandemic; A systematic scoping review.

OBJECTIVE: In this systematic scoping review, it was aimed to assess the epidemiology of methanol poisoning, clinical findings and patients' management, causes, and recommendations regarding prevention or reduction of methanol poisoning during COVID-19 pandemic. METHODS: Three Electronic databases [Medline (accessed from PubMed), Scopus, and Science Direct] were searched systematically from December 01, 2019 to September 10, 2020, using MESH terms and the related keywords in English language. Considering the titles and abstracts, unrelated studies were excluded. The full texts of the remained studies were evaluated by authors, independently. Then, the studies' findings were assessed and reported. RESULTS: Total of 86 articles were obtained within the first step of searching, and 64 ones remained after removing the duplications. Through the title and abstract screening, 35 were removed. Finally, after reading the full text of the remained articles, 15 ones included in data extraction. Most of the previous reported evidence (13/15) were letter to editor, commentary and short reports. None of them were interventional, and none of them followed the patients. Findings were summarized in four categories: 1) epidemiology; 2) clinical findings and patients' management; 3) causes; and 4) recommendation regarding prevention or reduction of methanol poisoning during COVID-19 pandemic. CONCLUSION: The recent outbreak is the largest methanol mass poisoning outbreak throughout Iran and the world in recent decades. The causes of methanol poisoning during the COVID-19 pandemic are intertwined, and most of them are modifiable by health policy makers. Building trust, educating and warning, as well as controlling and monitoring are three main recommendation for prevention or reduction of methanol poisoning.

Chemical binding of pyrrolidinyl peptide nucleic acid (acpcPNA-T9) probe with AuNPs toward label-free monitoring of miRNA-21: A novel biosensing platform for biomedical analysis and POC diagnostics.

miRNAs are attractive factors in cancer research studies due to their important roles for regulating of gene expression. Because of miRNA-21 expression surplus in many types of cancers, so accurate identification is important. Increasing efforts have caused different methods to improve the sensitivity and specificity of detection. Present study is an attempt to report a new electrochemical label-free PNA-based bioassay for detection of miRNA-21. In this study, gold electrode was modified by gold nanoparticles to improve a functional PNA-based biosensor. The EDS and field emission scanning electron microscope (FE-SEM) were used to detect fabrication of biosensor. The electrochemical behavior of sensor was evaluated after inserting of acpcPNA probes and miRNA-21 on the stucture of electrode and analyzed essential parameters such as various concentration of target miRNA, hybridization time, reproducibility, stability, and applicability. The results of study demonstrated that engineered biosensor was successfully fabricated. The findings showed the highest amount of current in 5 minutes hybridization time, with suitable reproducibility and stability. This innovative miRNA-based biosensor presents a sensitive and specific method in fast and may be lab-on chip assay in future.

Lymphopenia in COVID-19: Therapeutic opportunities.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS-CoV-2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper.

Anti-microbial activity of curcumin nanoformulations: New trends and future perspectives.

Curcumin has been used in numerous anti-microbial research because of its low side effects and extensive traditional applications. Despite having a wide range of effects, the intrinsic physicochemical characteristics such as low bioavailability, poor water solubility, photodegradation, chemical instability, short half-life and fast metabolism of curcumin derivatives limit their pharmaceutical importance. To overcome these drawbacks and improve the therapeutic ability of curcuminoids, novel approaches have been attempted recently. Nanoparticulate drug delivery systems can increase the efficiency of curcumin in several diseases, especially infectious diseases. These innovative strategies include polymeric nanoparticles, hydrogels, nanoemulsion, nanocomposite, nanofibers, liposome, nanostructured lipid carriers (NLCs), polymeric micelles, quantum dots, polymeric blend films and nanomaterial-based combination of curcumin with other anti-bacterial agents. Integration of curcumin in these delivery systems has displayed to improve their solubility, bioavailability, transmembrane permeability, prolong plasma half-life, long-term stability, target-specific delivery and upgraded the therapeutic effects. In this review paper, a range of in vitro and in vivo studies have been critically discussed to explore the therapeutic viability and pharmaceutical significance of the nano-formulated delivery systems to elevate the anti-bacterial activities of curcumin and its derivatives.

How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?

INTRODUCTION: Genetic defects affect the manner of the immune system's development, activation, and function. Nuclear factor-kappa B subunit 1 (NF-κB1) and NF-κB2 are involved in different biological processes, and deficiency in these transcription factors may reveal clinical and immunological difficulties. AREAS COVERED: This review article gathers the most frequent clinical and immunological remarkable characteristics of NF-κB1 and NF-κB2 deficiencies. Afterward, an effort is made to describe the biological mechanism, which is likely to be the cause of these clinical and immunological abnormalities. EXPERT OPINION: The present review article has explained the mechanism of contributions of the NF-κB1 and NF-κB2 deficiency in revealing immunodeficiency symptoms, specifically immunological and clinical manifestations. These mechanisms demonstrate the importance of NF-κB1 and NF-κB2 signaling pathways for B and T cell development, activation, antibody production, and immunotolerance. The manifestation of a mutation can range from no symptoms to severe complications in a family.

NF-κB1 and NF-κB2 are the transcription factors that have an essential role in the development and function of the immune system. Several mutations in the NF-κBs could lead to inborn errors of immune manifestations.There are different reports of NF-κB mutations with various clinical and immunological manifestations, whereas the mechanisms behind the appearance of these have been less discussed. We collected frequent clinical and immunological manifestations from the literature and discussed the likely biological cause of their occurrence. Here we clarify the potential mechanism that defects in NF-κB1 and NF-κB2 signaling lead to inadequate B and T cells function, specifically, insufficient switched memory B cells and class-switched antibodies and autoimmunity. We also focused on the straight correlation between deficiencies in immune system responses caused by defects in NF-κB and susceptibility to recurrent infections and other clinical problems.Since our understanding of the mechanisms of signaling pathways such as NF-κB deficiencies from genetic mutations to clinical manifestations in PIDs is limited, further in vitro and animal model studies are necessary to assess these pathways' comprehensive roles in immunodeficiency more accurately. [Figure: see text].

Flexible paper-based label-free electrochemical biosensor for the monitoring of miRNA-21 using core-shell Ag@Au/GQD nano-ink: a new platform for the accurate and rapid analysis by low cost lab-on-paper technology.

miRNA-21 is one of the most famous and prominent microRNAs that is important in the development and emergence of cancers. So, the sensitive and selective monitoring of miRNA-21 as a very common biomarker in cancer treatment is necessary. In this work, a novel paper-based electrochemical peptide nucleic acid (PNA) sensor was developed for the detection of miRNA-21 in human plasma samples by using Ag@Au core-shell nanoparticles electrodeposited on graphene quantum dots (GQD) conductive nano-ink (Ag@Au core-shell/GQD nano-ink), which was designed directly by writing pen-on paper technology on the surface of photographic paper. This nano-ink has a great surface area for biomarker immobilization. The prepared paper-based biosensor is very small and cheap, and also has high stability and sensitivity. Hybridization of PNA was measured using various electrochemical techniques, such as cyclic voltammetry (CV), square wave voltammetry (SWV) and chronoamperometry (ChA). FE-SEM (Field Scanning Electron Microscope), TEM (Transmission Electron Microscope), EDS and DLS (Dynamic Light Scattering) tests were performed to identify the engineering safety sensor. Under optimal conditions, the linear range for the calibration curve was from 5 pM to 5 µM, and the achieved LLOQ was 5 pM. The obtained results recommended that the proposed bioassay might be suitable for an early diagnosis of cancer based on the inhibition of the expression of miRNA-21, which activates the enzyme caspase and accelerates apoptotic proteins and death in tumor cells.

Astaxanthin Induces the Expression of CatSper1 Gene and Protects Sperms in Toxicity Induced by Cadmium in Mice.

Cadmium (Cd) as a heavy metal damages testis and decreases fertility, however, antioxidants can improve sperm parameters and decrease male infertility. In this study we investigated the effect of astaxanthin (AST) on sperm parameters, expression levels of CatSper1 and CatSper2 genes in presence of Cd in mice. Thirty adults' mice were divided into 4 groups, sham group received olive oil and saline (olive oil is the solvent of AST and saline is the solvent of Cd), Cd group received 1 mg/kg Cdcl2, a group received 10 mg/kg AST and 1 mg/kg Cdcl2 and a group received 10 mg/kg AST. The treatments were done intraperitoneally for 14 days. After 14 days sperm parameters were analyzed. Malondialdehyde level, catalase enzyme activity, the alteration of CatSper1 and CatSper2 genes expression were measured in testis. Results showed that Sperm count, viability, CatSper1 gene expression and catalase activity significantly decreased by Cd compared to sham group. Cd significantly increased sperm DNA fragmentation (SDF), abnormal sperm morphology and malondialdehyd level compared to sham group. AST significantly increased sperm count, viability and CatSper1 gene expression and decreased SDF and abnormal sperm in comparison with Cd group. AST protected testis and decreased oxidative stress induced by Cd. Our findings indicated that AST could protect sperm DNA, enhanced CatSper1 gene expression and sperm quality in presence of Cd. No significant differences were found in CatSper2 expression among treatments. Therefore, AST as a strong antioxidant can help to protect the potential of fertility against Cd toxicity.

Minimal invasive percutaneous nephrolithotomy (Mini-PCNL) in children: Ultrasound versus fluoroscopic guidance.

BACKGROUND: Miniaturization of endoscopic instruments in percutaneous nephrolithotomy (PCNL) allowed less invasive procedures with low complication rates, especially in children. This study was conducted to evaluate the safety and efficacy of ultrasonography-guided (USG) versus fluoroscopy-guided (FG) mini-PCNL in children. MATERIALS AND METHODS: This is a retrospective comparative study conducted from June 2015 to June 2020. The sample included 70 children (35 pateints underwent USG mini-PCNL and 35 pateints underwent FG mini-PCNL). They were compared mainly by the patients' demographic characteristics, procedural information, and post-treatment outcomes. In the USG mini-PCNL group, puncturing was performed using a 3.5 MHz US probe, whereas fluoroscopy was utilized in the FG mini- PCNL group. RESULTS: Both groups were comparable in terms of gender, previous history of failed ESWL, and hydronephrosis grade. The mean stone burden was 15.94 ± 3.69 mm and 19.20 ± 7.41 mm in USG and FG groups, respectively (p = 0.024). The stonefree rate (SFR) was 97.1% in the USG group and 94.3% in the FG group, which was not statistically significant (p = 0.16). Mean operative time in the USG group and FG group was 69.00 ± 13.33 minutes and 63.48 ± 16.90 minutes, respectively. Four (11.4%) patients in the FG group required blood transfusions to restore the hemodynamic state (p = 0.039). Fever was detected in 4 (11.4%) patients in the USG group and 15 (31.4%) patients in the FG group (p = 0.041). CONCLUSIONS: In children, mini PCNL under USG is safe and as effective as fluoroscopy.

Antimicrobial Activity of Nanostructured Lipid Carriers Loaded Punica granatum Seed Oil against Staphylococcus epidermidis.

BACKGROUND: Nanostructured lipid carriers (NLCs), due to their impressive benefits, have recently been considered in different areas. Besides, NLC loaded with essential oils is attractive for finding more effective antimicrobial products, especially against common bacteria such as Staphylococcus epidermidis (S. epidermidis). OBJECTIVE: This study aims to prepare and characterize NLCs encapsulated with Punica granatum (P. granatum) seed oil (PGS oil-loaded NLCs) and examine the antimicrobial effect of this combination against S. epidermidis. METHODS: PGS oil-loaded NLCs were prepared using a hot melt homogenization method. Later, they were characterized by determining particle size distribution (particle size analyzer), morphology (scanning electron microscopy (SEM)), and zeta potential (surface charge of NLCs). Minimum inhibitory concentrations (MIC) of PGS oil-loaded NLCs were assessed and compared with seed oil emulsion of P. granatum against S. epidermidis. RESULTS: PGS oil-loaded NLCs were spherical shaped nanoparticles, with a mean size of 102.10 nm and narrow size distribution (PDI = 0.26). The antibacterial assay showed PGS oil-loaded NLCs to have a higher in vitro antimicrobial activity than seed oil emulsion of P. granatum. CONCLUSION: To conclude, NLCs may be a favorable carrier to develop new antimicrobial agents. Lay Summary: The lipid nanoparticles such as nanostructured lipid carriers (NLCs) appeared as products first on the cosmetic market. Their advantages help them to be used in different healthcare and cosmetic products. With regard to previous studies, Punica granatum (P. granatum) extract shows antimicrobial and antioxidant properties that could be a valuable natural source against the wide ranges of bacteria. Then, P. granatum seed oil (PGS oil-loaded NLCs) prepared in this study can be used in dental and skin-related materials as a new natural antimicrobial product.

Effect of IL-36γ expression on chronic periodontitis with an increase in NF-KB signaling pathway.

Background: An inappropriate inflammatory response is the cause of many common diseases, especially periodontitis. Considering that no studies have been carried out to investigate the effect of IL-36γ on chronic periodontitis, this study aimed to investigate the inflammatory mechanism of IL-36γ by stimulating macrophage cells using NF-KB pathway. Methods: This experimental study was performed on 50 healthy individuals and 50 subjects with chronic periodontitis. In this study, macrophage cells were extracted first, and then RNA was isolated from all the samples using TRIzol method. Subsequently, the rate of IL-36γ gene expression was analyzed and compared using real-time PCR technique. Additionally, immunofluorescence (IF) technique was used to investigate the rate of inflammation. The rate of NF-Kb expression was also measured via western blot technique. Finally, statistical analysis of the samples was carried out using appropriate statistical methods with SPSS 17. Results: The results showed that the rate of IL-36γ expression in subjects with periodontitis was higher compared to healthy subjects (P<0.05). Moreover, the results showed that following treatment of cells with TLR4, the rate of IL36γ expression increased significantly, especially during the 12-hour period after treatment. Conclusion: This indicates that after stimulating the TLR pathways, the rate of IL-36γ expression will probably increase.

Targeted cancer drug delivery with aptamer-functionalized polymeric nanoparticles.

Based on exceptional advantages of aptamers, increasing attention has been presented in the utilise of them as targeted ligands for cancer drug delivery. Recently, the progress of aptamer-targeted nanoparticles has presented new therapeutic systems for several types of cancer with decreased toxicity and improved efficacy. We highlight some of the promising formulations of aptamer-conjugated polymeric nanoparticles for specific targeted drug delivery to cancer cells. This review paper focuses on the current progresses in the use of the novel strategies to aptamer-targeted drug delivery for chemotherapy. An extensive literature review was performed using internet database, mainly PubMed based on MeSH keywords. The searches included full-text publications written in English without any limitation in date. The abstracts, reviews, books as well as studies without obvious relating of aptamers as targeted ligands for cancer drug delivery were excluded from the study. The reviewed literature revealed that aptamers with ability to modify and conjugate to various molecules can be used as targeted cancer therapy agents. However, development of aptamers unique to each individual's tumour to the development of personalised medicine seems to be needed.

Role of vitamin D and vitamin D receptor (VDR) in oral cancer.

Oral cancer is known as one of the most common cancers, with a poor prognosis, related to delayed clinical diagnosis, either due to the lack of particular biomarkers related to the disease or costly therapeutic alternatives. Vitamin D executes its functions by interacting with the vitamin D receptor (VDR), both in healthy and diseased individuals, including oral cancer. This review discusses the role of vitamin D and VDR on tumorigenesis, emphasizing on oral cancer. Furthermore, regulation of VDR expression, mechanisms of anticancer effects of calcitriol, oral cancer chemoresistance and its relation with VDR and polymorphisms of VDR gene will be discussed. The manuscript is prepared mainly using the information collected from PubMed and MEDLINE.

Apoptosis induced by luteolin in breast cancer: Mechanistic and therapeutic perspectives.

BACKGROUND: Breast cancer is worldwide commonly found malignancy in women and effective treatment is regarded as a huge clinical challenge even in the presence of several options. Extensive literature is available that demonstrating polyphenols, the richly introduce phytopharmaceuticals as anticancer agents. Among these polyphenols, resveratrol, silibinin, quercetin, genistein, curcumin reported to have an awesome potential against breast cancer. However, till now no comprehensive survey found about the anticarcinogenic properties of luteolin against breast cancer. SCOPE AND APPROACH: This review targeted the available literature on luteolin in the treatment of breast cancer, effects in combination with other anticancer drugs with possible mechanisms. KEY FINDINGS AND CONCLUSION: An outstanding therapeutic potential of luteolin in the treatment of breast cancer has been recorded not just as a chemopreventive and chemotherapeutic agent yet complemented by its synergistic effects with other anticancer therapies such as cyclophosphamide, doxorubicin, and NSAID such as celecoxib, and possible underlying mechanisms. Ideally, this review will open new dimensions for luteolin as an effective and safe therapeutic agent in diminishing breast cancer.

Polymerase chain reaction (PCR)-based methods: Promising molecular tools in dentistry.

Polymerase chain reaction (PCR) has become a popular diagnosis and research technique in dentistry. Several studies show that high sensitivity and specificity of PCR method allows it to be as a precise, efficient, and rapid method for detection, identification, and quantification of microorganisms. Several genetic polymorphisms along with immune and inflammatory markers can be determined; providing the most accurate perception into the mechanisms underlying the dental and periodontal disease. This review paper discusses the application of PCR as a diagnostic molecular technique in periodontology, endodontic infections, implant-related and peri-implantitis infection, identification of immune and inflammatory markers, and genetic polymorphisms. Moreover, it reviews the application of next generation sequencing and microarray technologies in dentistry. The manuscript was prepared mainly using PubMed and MEDLINE.

STAT3 and apoptosis challenges in cancer.

Several studies have processed conceivable evidence for the vital role of Signal Transducer and Activator of Transcription 3 (STAT3) in cancer transformation and carcinogenesis. Therefore, one of the important factors in formation of cancer is STAT3 and for design of novel anticancer drugs is a suitable target. On the other hand, apoptosis pathway has a critical role in the cancers pathogenesis. Generally, increasing developments have been existed to expression, production, phosphorylation or activation of STAT3 in the effective or responsible cells of most of the cancers. In return, apoptosis process in this cells have been suffered inhibition, decrease in expression, produce or activation in some related factors which lead to debilitation or inhibition of the process. Further understanding of the STAT3 related signaling and apoptosis pathway can lead to the invention of novel approaches for therapies in unstudied disease. In this manuscript, review and highlight recent knowledge of the STAT3 pathway and its connection with apoptosis process in cancers and discuss STAT3-targeting agents to therapeutic developments.