The fertility of dairy heifers and cows is not influenced by the follicular wave of the ovulatory follicle.

Two studies were conducted to evaluate the effects of the follicular wave on ovarian function and fertility in dairy heifers and lactating cows. In study 1, the estrous cycle of the selected Holstein heifers was initially synchronized using two intra-muscular prostaglandin F2α (PGF2α) administrations 11 days apart. Heifers in group FFW (n = 14) received an intra-muscular 500 µg PGF2α administration on day 7 after detecting standing estrus, while Heifers in group SFW (n = 14) were administered PGF2α 13 days after detecting standing estrus. The pregnancy rates of FFW (n = 98) and SFW (n = 100) heifers were also determined 35-37 days after artificial insemination (AI). In Study 2, healthy Holstein lactating cows (n = 28) were randomly assigned to either the FFW (n = 14) or SFW (n = 14) groups. The estrous cycles of the cows were presynchronized using two intra-muscular administrations of PGF2α given 14 days apart. Then, the emergences of the follicular waves were induced using an Ovsynch protocol. The pregnancy rate of FFW (n = 99) versus SFW (n = 98) cows was also determined 35-37 days after AI. The ovulatory follicle and corpus luteum (CL) resulting from the ovulatory follicle of FFW were larger than those of the dominant follicle and the CL of SFW in dairy heifers and lactating cows. However, the pregnancy rate did not differ between the FFW and SFW groups in heifers and lactating cows 35-37 days after AI. In conclusion, although the characteristics of the ovulatory follicles in FFW versus SFW animals differed, the follicular wave in dairy heifers or lactating cows did not affect fertility.

CRET-based immunoassay on magnetic beads for selective and sensitive detection of Nanog antigen as a key cancer stem cell marker.

A method is presented for chemiluminescence resonance energy transfer (CRET) using APTES-Fe3O4 as a highly efficient energy acceptor with strong magnetic effectiveness over extended distances, while an Au@BSA-luminol composite acts as the donor. In order to boost the chemiluminescence reactions, CuO nanoparticles were successfully employed. The distance between the donor and acceptor is a crucial factor in the occurrence of the CRET phenomenon. A sensitive and high-throughput sandwich chemiluminescence immunosensor has been developed accordingly with a linear range of 1.0 × 10-7 g/L to 6.0 × 10-5 g/L and a limit of detection of 0.8 × 10-7 g/L. The CRET-based sandwich immunosensor has the potential to be implemented to early cancer diagnosis because of its high sensitivity in detecting Nanog, fast analysis (30 min), and simplicity. Furthermore, this approach has the potential to be adapted for the recognition of other antigen-antibody immune complexes by utilizing the corresponding antigens and their selective antibodies.

Fluorescence labeling of anchor-modified Mart-1 peptide for increasing its affinity for HLA-A*0201: Hit two targets with one arrow.

One of the most successful strategies in designing peptide-based cancer vaccines is modifying natural epitope peptides to increase their binding strength to human leukocyte antigens (HLAs). Anchor-modified Mart-1 peptide (ELAGIGILTV) is among the artificial epitope peptides with the highest binding affinity for HLA-A*0201. In this study, by fluorescence labeling of its either C- or N-terminus with Nε -(5-carboxyfluorescein)-l-lysine, we not only made it traceable but also drastically increased its binding strength to HLA-A*0201. HLA streptamer, for the first time, is introduced for measuring the binding constants (Ka ) of the labeled peptides. The affinity of the labeled peptides for the HLA-A*201 of the MCF-7 cells was extraordinarily high and co-incubating them with the highest possible amount of the unlabeled peptide, as a competitor, did not significantly prohibit them from binding to the HLA. The reproducibility of the obtained results was confirmed by using the T2 cell line. The HLA-deficient K562 cell line was used as the negative control. With in silico simulations, we found two hydrophobic pockets on both sides of HLA-A*0201 for anchoring the C- or N-terminal 5-carboxyfluorescein probe, which can explain the extraordinary affinity of the labeled peptides for the HLA-A*0201.

A novel co-culture assay to evaluate the effects of sympathetic innervation on vascular smooth muscle differentiation.

Dedifferentiation of vascular smooth muscle cells (VSMCs) from a functional phenotype to an inverse synthetic phenotype is a symptom of cardiovascular disorders, such as atherosclerosis and hypertension. The sympathetic nervous system (SNS) is an essential regulator of the differentiation of vascular smooth muscle cells (VSMCs). In addition, numerous studies suggest that SNS also stimulates VSMCs to retain their contractile phenotype. However, the molecular mechanisms for this stimulation have not been thoroughly studied. In this study, we used a novel in vitro co-culture method to evaluate the effective cellular interactions and stimulatory effects of sympathetic neurons on the differentiation of VSMCs. We co-cultured rat neural-like pheochromocytoma cells (PC12) and rat aortic VSMCs with this method. Expression of VSMCs contractile genes, including smooth muscle actin (acta2), myosin heavy chain (myh11), elastin (eln), and smoothelin (smtn), were determined by quantitative real-time-PCR analysis as an indicator of VSMCs differentiation. Fold changes for specific contractile genes in VSMCs grown in vitro for seven days in the presence (innervated) and absence (non-innervated) of sympathetic neurons were 3.5 for acta2, 6.5 for myh11, 4.19 for eln, and 4 for smtn (normalized to Tata Binding Protein (TBP)). As a result, these data suggest that sympathetic innervation promotes VSMCs' contractile gene expression and also maintains VSMCs' functional phenotype.

Fabrication and multiscale modeling of polycaprolactone/amniotic membrane electrospun nanofiber scaffolds for wound healing.

BACKGROUND: Enhancing the efficiency of cell-based skin tissue engineering (TE) approaches is possible via designing electrospun scaffolds possessing natural materials like amniotic membrane (AM) with wound healing characteristics. Concentrating on this aim, we fabricated innovative polycaprolactone (PCL)/AM scaffolds through the electrospinning process. METHODS: The manufactured structures were characterized by employing scanning electron microscope (SEM), attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, tensile testing, Bradford protein assay, etc. In addition, the mechanical properties of scaffolds were simulated by the multiscale modeling method. RESULTS: As a result of conducting various tests, it was concluded that the uniformity and distribution of fibers decreased with an increase in the amniotic content. Furthermore, PCL-AM scaffolds contained amniotic and PCL characteristic bands. In the case of protein release, greater content of AM led to the release of higher amounts of collagen. Tensile testing revealed that scaffolds' ultimate strength increased when the AM content augmented. The multiscale modeling demonstrated that the scaffold had elastoplastic behavior. In order to assess cellular attachment, viability, and differentiation, human adipose-derived stem cells (ASCs) were seeded on the scaffolds. In this regard, SEM and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays showed significant cellular proliferation and viability on the proposed scaffolds, and these analyses illustrated that higher cell survival and adhesion could be achieved when scaffolds possessed a larger amount of AM. After 21 days of cultivation, particular keratinocyte markers, such as keratin I and involucrin, were identified through utilizing immunofluorescence and real-time polymerase chain reaction (PCR) tests. The markers' expressions were higher in the PCL-AM scaffold with a ratio of 90:10 v v-1 compared with the PCL-epidermal growth factor (EGF) structure. Moreover, the presence of AM in the scaffolds resulted in the keratinogenic differentiation of ASCs even without employing EGF. Consequently, this state-of-the-art experiment suggests that the PCL-AM scaffold can be a promising candidate in skin bioengineering. CONCLUSION: This study showed that mixing AM with PCL, a widely used polymer, in different concentrations can overcome PCL disadvantages such as high hydrophobicity and low cellular compatibility.

The effect of Nano-liposomal sodium nitrite on smooth muscle cell growth in a tissue-engineered small-diameter vascular graft.

BACKGROUND: Nitric oxide is a chemical agent produced by endothelial cells in a healthy blood vessel, inhibiting the overgrowth of vascular smooth muscle cells and regulating vessel tone. Liposomes are biocompatible and biodegradable drug carriers with a similar structure to cell bilayer phospholipid membrane that can be used as useful nitric oxide carriers in vascular grafts. METHOD: Using a custom-designed apparatus, the sheep carotid arteries were decellularized while still maintaining important components of the vascular extracellular matrix (ECM), allowing them to be used as small-diameter vascular grafts. A chemical signal of sodium nitrite was applied to control smooth muscle cells' behavior under static and dynamic cell culture conditions. The thin film hydration approach was used to create nano-liposomes, which were then used as sodium nitrite carriers to control the drug release rate and enhance the amount of drug loaded into the liposomes. RESULTS: The ratio of 80:20:2 for DPPC: Cholesterol: PEG was determined as the optimum formulation of the liposome structure with high drug encapsulation efficiency (98%) and optimum drug release rate (the drug release rate was 40%, 65%, and 83% after 24, 48, and 72 h, respectively). MTT assay results showed an improvement in endothelial cell proliferation in the presence of nano-liposomal sodium nitrite (LNS) at the concentration of 0.5 µg/mL. Using a suitable concentration of liposomal sodium nitrite (0.5 µg/mL) put onto the constructed scaffold resulted in the controllable development of smooth muscle cells in the experiment. The culture of smooth muscle cells in a pulsatile perfusion bioreactor indicated that in the presence of synthesized liposomal sodium nitrite, the overgrowth of smooth muscle cells was inhibited in dynamic cell culture conditions. The mechanical properties of ECM graft were measured, and a multi-scale model with an accuracy of 83% was proposed to predict mechanical properties successfully. CONCLUSION: The liposomal drug-loaded small-diameter vascular graft can prevent the overgrowth of SMCs and the formation of intimal hyperplasia in the graft. Aside from that, the effect of LNS on endothelial has the potential to stimulate endothelial cell proliferation and re-endothelialization.

Biomimetic vascular tissue engineering by decellularized scaffold and concurrent cyclic tensile and shear stresses.

Decellularization by chemical approaches has harmful effects on extracellular matrix (ECM) proteins, and damages lots of functional peptides and biomolecules present in the ultrastructure. In this study, we employed a combination of chemical and physical decellularization methods to overcome these disadvantages. The induced osmotic pressure by hypertonic/hypotonic solutions dissociated and removed most of cellular membranes significantly without any detergent or chemical agent. In total, 0.025% trypsin solution was found adequate to remove the remaining debrides, and ultimately 1% Triton X-100 was utilized for final cleansing. In addition, conducting all the decellularization processes at 4 °C yielded an ECM with least damages in the ultrastructure which could be inferred by close mechanical strength and swelling ratio to the native vessel, and high quality and quantity of cell attachment, migration and proliferation which were examined by optical microscopy and scanning electron microscopy (SEM) of the histology samples. Moreover, the obtained biological scaffold (BS) had no cytotoxicity according to the MTT assay, and this scaffold is storable at -20 °C. Employing bioreactor for concurrent cyclic tensile and shear stresses improved the cell migration into pores of the BS and made the cells and the scaffold compact in analogous to native tissue. As opening angle test showed by decellularizing of the blood vessel, the residual stress dropped significantly which revealed the role of cells in the amount of induced stress in the structure. However, intact and healthy ECM explicitly recovered upon recellularization and beat the initial residual stress of the native tissue. The tensile test of the blood vessels in longitudinal and radial directions revealed orthotropic behavior which can be explained by collagen fibers direction in the ECM. Furthermore, by the three regions of the stress-strain curve can be elucidated the roles of cells, elastin and collagen fibers in mechanical behavior of the vascular tissues.

Clinical and laboratory findings following transplantation of allogeneic adipose-derived mesenchymal stromal cells in knee osteoarthritis, a brief report.

BACKGROUND: Mesenchymal stromal cells (MSCs) injection has been proposed as an innovative treatment for knee osteoarthritis (KOA). Since, allogeneic MSCs can be available as off-the-shelf products, they are preferable in regenerative medicine. Among different sources for MSCs, adipose-derived MSCs (AD-MSCs) appear to be more available. METHODS: Three patients with KOA were enrolled in this study. A total number of 100 × 106 AD-MSCs was injected intra-articularly, per affected knee. They were followed up for 6 months by the assessment of clinical outcomes, magnetic resonance imaging (MRI), and serum inflammatory biomarkers. RESULTS: The primary outcome of this study was safety and feasibility of allogeneic AD-MSCs injection during the 6 months follow-up. Fortunately, no serious adverse events (SAEs) were reported. Assessment of secondary outcomes of visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and knee osteoarthritis outcome score (KOOS) indicated improvement in all patients. Comparison between baseline and endpoint findings of MRI demonstrated a slight improvement in two patients. In addition, decrease in serum cartilage oligomeric matrix protein (COMP) and hyaluronic acid (HA) indicated the possibility of reduced cartilage degeneration. Moreover, quantification of serum interleukin-10 (IL-10) and interleukin-6 (IL-6) levels indicated that the host immune system immunomodulated after infusion of AD-MSCs. CONCLUSION: Intra-articular injection of AD-MSCs is safe and could be effective in cartilage regeneration in KOA. Preliminary assessment after six-month follow-up suggests the potential efficacy of this intervention which would need to be confirmed in randomized controlled trials on a larger population. TRIAL REGISTRATION: This study was registered in the Iranian registry of clinical trials (https://en.irct.ir/trial/46) in 24 April 2018 with identifier IRCT20080728001031N23.

The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS).

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in PIK3CD and loss-of-function of PIK3R1 genes lead to APDS1 and APDS2, respectively. METHODS: Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method. RESULTS: Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of PIK3CD was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of PIK3R1 (66.7%). Mortality rate was significantly higher in APDS2 group (P = .02) mainly due to chronic lung infections. CONCLUSION: Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients' survival.

Cabbage-derived three-dimensional cellulose scaffold-induced osteogenic differentiation of stem cells.

Herbal-derived three-dimensional scaffolds have a unique structure that represents the natural cellular microenvironment and can be potentially used for tissue engineering applications. In the present study, cabbage (Cb) leaves were decellularized and then their characteristics, such as surface roughness, wettability, porosity, mechanical properties, and specific surface area, were investigated. After that, scaffold osteoinductivity was studied by bone-marrow-derived mesenchymal stem cells (BM-MSCs) osteogenic differentiation while growing on the decellularized Cb leaves. Cells mineralization, calcium secretion, alkaline phosphatase (ALP) activity, and expression levels of bone-related genes were determined during the differentiation process. Our results from the structural characterization of the scaffolds demonstrated that decellularized Cb leaves are good candidates for bone differentiation in terms of surface roughness, mechanical properties, and interconnected pores. Osteogenic differentiation evaluation of the BM-MSCs determined that the cell's ALP activity and mineralization were increased significantly while cultured on the decellularized Cb leaves compared to the cells cultured on the culture plate as a control. Besides, Runx2, ALP, collagen-1 (Col-I), and osteocalcin genes were expressed in cells cultured on decellularized Cb leaves significantly higher than cells cultured on the culture plate. Based on these results, it can be concluded that the decellularized Cb scaffold has great potential for promoting BM-MSCs proliferation and osteogenic differentiation.

Autoimmune manifestations among 461 patients with monogenic inborn errors of immunity.

BACKGROUND: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunologic, and molecular data of monogenic IEI patients with and without autoimmune manifestations. METHODS: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data. RESULTS: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1%) were born to consanguineous parents. At the time of the study, 330 individuals (75.7%) were alive and 106 (24.3%) were deceased. Autoimmunity was reported in 92 (20.0%) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5%) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4%). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0%), ATM (in 13 patients, 14.0%), and BTK (in 9 patients, 10.0%) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100%), 3 of 3 AIRE (100%), and 21 of 30 LRBA (70.0%) mutated genes had the highest prevalence of autoimmunity. CONCLUSIONS: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders, especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next-generation sequencing to discover responsible genes for the immune dysregulation at an early stage of the disease.

Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity.

BACKGROUND: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis. METHODS: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children's Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data. RESULTS: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity. CONCLUSION: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.

The Heterogeneous Pathogenesis of Selective Immunoglobulin A Deficiency.

Selective immunoglobulin A deficiency (SIgAD) is the most prevalent type of primary immunodeficiency disorder. The phenotypic feature of SIgAD is related to a defect in B lymphocyte differentiation into plasma cell-producing immunoglobulin A (IgA). In this review, we summarize the recent advances in this regard. Genetic (including major histocompatibility complex [MHC] and non-MHC genes), immunologic (including B and T lymphocyte subsets abnormality), cytokines/chemokines and their related receptors, apoptosis and microbiota defects are reviewed. The mechanisms leading to SIgAD are most likely multifactorial and it can be speculated that several pathways controlling B cells functions or regulating epigenetic of the IGHA gene encoding constant region of IgA heavy chain and long-term survival of IgA switched memory B cells and plasma cells may be defective in different SIgAD patients.

Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency.

BACKGROUND: Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited. OBJECTIVES: This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically. METHODS: Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients. RESULTS: The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome (P < .001), onset of disease at greater than 5 years (P = .02), and absence of multiple affected family members (P = .04) were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ataxia-telangiectasia mutated (ATM), autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3), and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs. CONCLUSIONS: This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.

Clinical, immunologic, molecular analyses and outcomes of iranian patients with LRBA deficiency: A longitudinal study.

BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency caused by mutation in LRBA gene. The patients have a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, autoimmunity, and enteropathy. METHODS: A total of 17 LRBA-deficient patients were enrolled in this longitudinal study. For all patients, demographic information, clinical records, laboratory, and molecular data were collected. RESULT: Hypogammaglobulinemia was reported in 14 (82.4%), CD4+ T-cell deficiency in five (29.4%), NK cell deficiency in three (21.4%), and CD19+ B-cell deficiency in 11 (64.7%) patients. All patients had history of infectious complications; pneumonia was the most common (76.5%) occurring infection. A history of lymphoproliferative disorders was observed in 14 (82.3%), enteropathy in 13 (76.5%), allergic symptoms in six (35.5%), neurologic problems in four (23.5), and autoimmunity (mostly autoimmune cytopenia) in 13 (76.5%) patients. Sirolimus treatment improved enteropathy of patients with remarkable success. The 20-year overall survival rate declined to 70.6%. CONCLUSION: LRBA deficiency has a very broad and variable phenotype and should be considered, especially in children with early-onset hypogammaglobulinemia, severe autoimmune manifestations, enteropathy, lymphoproliferation, and recurrent respiratory tract infections.

Measurement of Health-Related Quality of Life in Primary Antibody-Deficient Patients.

BACKGROUND: Primary immunodeficiency diseases are a group of disorders that result from a variety of defects of the immune system. Primary antibody deficiencies (PADs) are the most common forms of these disorders. Occurrence of recurrent infections, autoimmune diseases, cancers, and lymphoproliferative disorders is higher in PAD patients. Chronicity of these diseases, delayed diagnosis, inadequate treatment, and treatment side effects may affect the quality of life (QoL) of PAD patients. Evaluating QoL is important for patient care, understanding the burden of these diseases, and finding the patients' major health problems. We investigated the QoL in a group of PAD patients undergoing regular follow-up and treatment at the Children's Medical Center Hospital in Tehran, Iran. METHODS: Seventy patients with a diagnosis of PAD in two age groups (younger and older than 18 years) were included. QoL was measured using PedsQL and SF-36 questionnaires. Correlation of demographic, clinical, and immunological parameters with QoL scores was assessed and patients' scores were compared with the normal population, using nonparametric tests of SPSS software. RESULTS: Patients expressed significantly reduced scores in some mental and physical components. Patients with longer follow-up periods had higher scores in mental components but physical component scores were still low. There was no significant correlation between sex, age, and disease types with scores. CONCLUSIONS: PAD patients had significantly lower scores in mental and physical components compared to normal population. By early diagnosis and long-term follow-up periods, we may be able to prevent complications and help patients to have a better QoL.

Cellular and molecular mechanisms of immune dysregulation and autoimmunity.

Primary immunodeficiencies (PIDs) constitute a large group of rare disorders that affect the function of the immune system. A specific group of PIDs entitled "diseases of immune dysregulation" are developed due to mutation in the genes which have critical roles in the regulation of immune responses and immunological tolerance. This group of PID patients develop autoimmune and inflammatory disorders as a result of their impaired immunity, therefore they could be considered as a model for analyzing the link between immune dysregulation and autoimmunity. In this article, our aim is to describe the function of the mutated gene, the molecular and cellular mechanisms underlying the immune dysregulation and review the literature in regard with the reported autoimmune disorders in the main types of immunodysregulatory diseases including genetic defects of regulatory T cells, familial hemophagocytic lymphohistiocytosis syndromes, autoimmunity without lymphoproliferation, autoimmune lymphoproliferative syndrome, immune dysregulation with colitis, and type 1 interferonopathies.

Nitric oxide-releasing thiolated starch nanoparticles embedded in gelatin sponges for wound dressing applications.

This study introduces a novel wound dressing by combining nitric oxide-releasing thiolated starch nanoparticles (NO-TS NPs) with gelatin. First, starch was thiolated (TS), and then its nanoparticles were prepared (TS NPs). Subsequently, NPs were covalently bonded to sodium nitrite to obtain NO-releasing TS NPs (NO-TS-NPs) that were incorporated into gelatin sponges at various concentrations. The resulting spherical TS NPs had a mean size of 85.42 ± 5.23 nm, which rose to 100.73 ± 7.41 nm after bonding with sodium nitrite. FTIR spectroscopy confirmed S-nitrosation on the NO-TS NPs' surface, and morphology analysis showed well-interconnected pores in all sponges. With higher NO-TS NPs content, pore size, porosity, and water uptake increased, while compressive modulus and strength decreased. Composites exhibited antibacterial activity, particularly against E. coli, with enhanced efficacy at higher NPs' concentrations. In vitro release studies demonstrated Fickian diffusion, with faster NO release in sponges containing more NPs. The released NO amounts were non-toxic to fibroblasts, but samples with fewer NO-TS NPs exhibited superior cellular density, cell attachment, and collagen secretion. Considering the results, including favorable mechanical strength, release behavior, antibacterial and cellular properties, gelatin sponges loaded with 2 mg/mL of NO-TS NPs can be suitable for wound dressing applications.

Machine learning-assisted liquid crystal-based aptasensor for the specific detection of whole-cell Escherichia coli in water and food.

We have developed a rapid, facile liquid crystal (LC)-based aptasensor for E. coli detection in water and juice samples. A textile grid-anchored LC platform was used with specific aptamers adsorbed via a cationic surfactant, cetyltrimethylammonium bromide (CTAB), on the LC surface. The presence of E. coli dissociates the aptamers from CTAB and restores the dark signal induced by the surfactant. Using polarized microscopy, the images of the LCs in the presence of various concentrations of E. coli were captured and analyzed using image analysis and machine learning (ML). The artificial neural networks (ANN) and extreme gradient boosting (XGBoost) rendered the best results for water samples (R2 = 0.986 and RMSE = 0.209) and juice samples (R2 = 0.976 and RMSE = 0.262), respectively. The platform was able to detect E. coli with a detection limit (LOD) of 6 CFU mL-1.

Hepatocellular carcinoma (HCC) immunotherapy by anti-PD-1 monoclonal antibodies: A rapidly evolving strategy.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world, with a high relapse rate. Delayed symptom onset observed in 70-80% of patients leads to diagnosis in advanced stages commonly associated with chronic liver disease. Programmed cell death protein 1 (PD-1) blockade therapy has recently emerged as a promising therapeutic option in the clinical management of several advanced malignancies, including HCC, due to the activation of exhausted tumor-infiltrating lymphocytes and improved outcomes of T-cell function. However, many people with HCC do not respond to PD-1 blockade therapy, and the diversity of immune-related adverse events (irAEs) restricts their clinical utility. Therefore, numerous effective combinatory strategies, including combinations with anti-PD-1 antibodies and other therapeutic methods ranging from chemotherapy to targeted therapies, are evolving to improve therapeutic outcomes and evoke synergistic anti-tumor impressions in patients with advanced HCC. Unfortunately, combined therapy may have more side effects than single-agent treatment. Nonetheless, identifying appropriate predictive biomarkers can aid in managing potential immune-related adverse events by distinguishing patients who respond best to PD-1 inhibitors as single agents or in combination strategies. In the present review, we summarize the therapeutic potential of PD-1 blockade therapy for advanced HCC patients. Besides, a glimpse of the pivotal predictive biomarkers influencing a patient's response to anti-PD-1 antibodies will be provided.