Development and Validation of a Model for Endotracheal Intubation and Mechanical Ventilation Prediction in PICU Patients.

OBJECTIVES: To develop and externally validate an intubation prediction model for children admitted to a PICU using objective and routinely available data from the electronic medical records (EMRs). DESIGN: Retrospective observational cohort study. SETTING: Two PICUs within the same healthcare system: an academic, quaternary care center (36 beds) and a community, tertiary care center (56 beds). PATIENTS: Children younger than 18 years old admitted to a PICU between 2010 and 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data was extracted from the EMR. PICU stays with at least one mechanical ventilation event (≥ 24 hr) occurring within a window of 1-7 days after hospital admission were included in the study. Of 13,208 PICU stays in the derivation PICU cohort, 1,175 (8.90%) had an intubation event. In the validation cohort, there were 1,165 of 17,841 stays (6.53%) with an intubation event. We trained a Categorical Boosting (CatBoost) model using vital signs, laboratory tests, demographic data, medications, organ dysfunction scores, and other patient characteristics to predict the need of intubation and mechanical ventilation using a 24-hour window of data within their hospital stay. We compared the CatBoost model to an extreme gradient boost, random forest, and a logistic regression model. The area under the receiving operating characteristic curve for the derivation cohort and the validation cohort was 0.88 (95% CI, 0.88-0.89) and 0.92 (95% CI, 0.91-0.92), respectively. CONCLUSIONS: We developed and externally validated an interpretable machine learning prediction model that improves on conventional clinical criteria to predict the need for intubation in children hospitalized in a PICU using information readily available in the EMR. Implementation of our model may help clinicians optimize the timing of endotracheal intubation and better allocate respiratory and nursing staff to care for mechanically ventilated children.

The 2024 Pediatric Sepsis Challenge: Predicting In-Hospital Mortality in Children With Suspected Sepsis in Uganda.

The aim of this "Technical Note" is to inform the pediatric critical care data research community about the "2024 Pediatric Sepsis Data Challenge." This competition aims to facilitate the development of open-source algorithms to predict in-hospital mortality in Ugandan children with sepsis. The challenge is to first develop an algorithm using a synthetic training dataset, which will then be scored according to standard diagnostic testing criteria, and then be evaluated against a nonsynthetic test dataset. The datasets originate from admissions to six hospitals in Uganda (2017-2020) and include 3837 children, 6 to 60 months old, who were confirmed or suspected to have a diagnosis of sepsis. The synthetic dataset was created from a random subset of the original data. The test validation dataset closely resembles the synthetic dataset. The challenge should generate an optimal model for predicting in-hospital mortality. Following external validation, this model could be used to improve the outcomes for children with proven or suspected sepsis in low- and middle-income settings.

Effect of cold atmospheric plasma on changing of biomolecular structures involved in apoptosis pathways of melanoma cancer.

BACKGROUND: Cold atmospheric plasma (CAP), is a technology based on non-thermal ionized gas that is used for cancer therapy in research. We evaluated the effect of CAP on malignant melanoma cancer cell line (B16) in comparison with normal cells (L929). METHODS: The effect of CAP on the cytotoxicity of B16 and L929 cell lines was assayed by the MTT method and inverted microscopy. The induction of apoptosis in cells was evaluated using a fluorescence microscope. FTIR monitored the CAP effect in biomacromolecules changes in these cell lines. QPCR assayed gene expression of BAX, BCL-2, and Caspase-3 (CASP-3). RESULTS: The results of the MTT test showed CAP has a cytotoxic effect on the B16 cancer cell line more than L929 normal cells (p < 0.0001). The results of invert and fluorescence microscopy showed CAP-induced apoptotic morphology on cancerous cells. FTIR spectroscopy indicated CAP changes biomacromolecules structure. Evaluation of gene expression showed CAP increased BAX and CASP-3 gene expression. Also, it decreased BCL-2 gene expression. CONCLUSIONS: Taken together, CAP may change biomacromolecule structures involved in apoptosis pathways, decrease proliferation and induce apoptosis in cancer cells.

Association between angiotensin-converting enzyme-2 gene polymorphism (rs2106809) with severity and outcome of COVID-19 infection.

PURPOSE: Genetic factors play important role in the severity of the COVID-19 infection since SARS-CoV-2 binds to the ACE2 receptor on the surface of host cells. ACE2 polymorphisms that may influence the expression of ACE2 can alter patients' susceptibility to COVID-19 infection or increase the severity of the disease. This study aimed to investigate the association between ACE2 rs2106809 polymorphism and the severity of the COVID-19 infection. METHODS: In this cross-sectional study, ACE2 rs2106809 polymorphism was assessed in 142 COVID-19 patients. The disease was confirmed according to clinical symptoms, imaging, and laboratory findings. The severity of the disease was graded as severe versus non-severe based on the CDC. Genomic DNA was extracted from the whole blood and PCR- RFLP was performed to genotype the ACE2-rs2106809 with specific primers and Taq1 restriction enzyme. RESULTS: G/G genotype was significantly associated with COVID-19 severity (44.4% in severe vs. 17.5% in non-severe, OR: 4.1; 95%CI: 1.8-9.5, p = 0.0007). Patients with the G/G genotype need more mechanical ventilation (p = 0.021). ACE2 expression in patients carrying the A/G genotype was higher in the severe compared to the non-severe form of the disease (2.99 ± 0.99 vs. 2.21 ± 1.1), but it was not statistically significant (p = 0.9). CONCLUSION: The G allele and G/G genotype of ACE2 rs2106809 is associated with more severe COVID-19 and adverse disease outcomes.

Pharmacophenotype identification of intensive care unit medications using unsupervised cluster analysis of the ICURx common data model.

BACKGROUND: Identifying patterns within ICU medication regimens may help artificial intelligence algorithms to better predict patient outcomes; however, machine learning methods incorporating medications require further development, including standardized terminology. The Common Data Model for Intensive Care Unit (ICU) Medications (CDM-ICURx) may provide important infrastructure to clinicians and researchers to support artificial intelligence analysis of medication-related outcomes and healthcare costs. Using an unsupervised cluster analysis approach in combination with this common data model, the objective of this evaluation was to identify novel patterns of medication clusters (termed 'pharmacophenotypes') correlated with ICU adverse events (e.g., fluid overload) and patient-centered outcomes (e.g., mortality). METHODS: This was a retrospective, observational cohort study of 991 critically ill adults. To identify pharmacophenotypes, unsupervised machine learning analysis with automated feature learning using restricted Boltzmann machine and hierarchical clustering was performed on the medication administration records of each patient during the first 24 h of their ICU stay. Hierarchical agglomerative clustering was applied to identify unique patient clusters. Distributions of medications across pharmacophenotypes were described, and differences among patient clusters were compared using signed rank tests and Fisher's exact tests, as appropriate. RESULTS: A total of 30,550 medication orders for the 991 patients were analyzed; five unique patient clusters and six unique pharmacophenotypes were identified. For patient outcomes, compared to patients in Clusters 1 and 3, patients in Cluster 5 had a significantly shorter duration of mechanical ventilation and ICU length of stay (p < 0.05); for medications, Cluster 5 had a higher distribution of Pharmacophenotype 1 and a smaller distribution of Pharmacophenotype 2, compared to Clusters 1 and 3. For outcomes, patients in Cluster 2, despite having the highest severity of illness and greatest medication regimen complexity, had the lowest overall mortality; for medications, Cluster 2 also had a comparably higher distribution of Pharmacophenotype 6. CONCLUSION: The results of this evaluation suggest that patterns among patient clusters and medication regimens may be observed using empiric methods of unsupervised machine learning in combination with a common data model. These results have potential because while phenotyping approaches have been used to classify heterogenous syndromes in critical illness to better define treatment response, the entire medication administration record has not been incorporated in those analyses. Applying knowledge of these patterns at the bedside requires further algorithm development and clinical application but may have the future potential to be leveraged in guiding medication-related decision making to improve treatment outcomes.

Cold atmospheric pressure plasma treatment combined with starvation increases autophagy and apoptosis in melanoma in vitro and in vivo.

Despite advances in therapy, malignant melanoma remains a fatal disease. Among several emerging approaches to combat cancer, cold atmospheric pressure plasma (CAP) has shown promising results as a novel antitumor agent in preclinical models so far. The technology mainly relies on the emittance of various reactive oxygen and nitrogen species (ROS/RNS) that are tumor-toxic at high concentrations. Moreover, malignant melanoma has a metabolic dimension that can be targeted by mild starvation. To this end, we investigated the combined effect of starvation and CAP treatment on melanoma in vitro and in vivo. In vitro, starvation+CAP led to cell morphology changes, decreased metabolic activity and increased lipid peroxidation accompanied by apoptosis and DNA fragmentation in murine B16 melanoma cells but not murine non-malignant L929 fibroblasts. This was paralleled by increased apoptosis (Bax, Bcl-2 and Caspase-3) and autophagy (Lc3 and Atg5)-related gene expression. In vivo, starvation reduced tumor burden. Combination with CAP treatment augmented this effect significantly, albeit there was no difference of combination treatment to CAP exposure alone. Interestingly, there was an overall greater increase of Lc3 and Atg5 in the tumor tissue compared to CAP exposure alone, while starvation-induced autophagy-related gene expression was similar to in the combination group. These data collectively suggest that CAP-derived ROS/RNS treatment and autophagy-induction augment antitumor effects in malignant melanoma in vitro and in vivo.

The effect of immunomodulatory properties of naringenin on the inhibition of inflammation and oxidative stress in autoimmune disease models: a systematic review and meta-analysis of preclinical evidence.

BACKGROUND/OBJECTIVE: Naringenin is a member of the flavonoid family that can perform many biological processes to treat a wide range of inflammatory diseases and pathological conditions related to oxidative stress (OS). Naringenin immunomodulatory activities have been the subject of recent research as an effective alternative treatment for autoimmune disorders. The effects of naringenin on the levels of inflammatory biomarkers and OS factors in animal models of autoimmune disorders (ADs) were studied in this meta-analysis. METHODS: Up until January 2022, electronic databases such as Cochrane Library and EMBASE, PubMed, Web of Science, and Scopus were used to conduct a comprehensive literature search in English language. To evaluate the effect of naringenin on inflammatory mediators, such as TNF-α, IL-6, IL-ß, IFN-γ, NF-κB, and nitric oxide, and OS biomarkers, such as CAT, SOD, GPx, GSH and MDA, in AD models, we measured the quality assessment and heterogeneity test using the PRISMA checklist protocol and I2 statistic, respectively. A random-effects model was employed based on the heterogeneity test, and then pooled data were standardized as mean difference (SMD) with a 95% confident interval (CI). RESULTS: We excluded all clinical trials, cell experiment studies, animal studies with different parameters, non-autoimmune disease models, and an inadequate series of studies for quantitative synthesis. Finally, from 627 potentially reports, 12 eligible studies were included in the meta-analysis. Data were collected from several groups. Of these, 153 were in the naringenin group and 149 were in the control group. Our meta-analysis of the pooled data for the parameters of inflammation and OS indicated that naringenin significantly reduced the levels of NF-κB (SMD - 3.77, 95% CI [- 6.03 to - 1.51]; I2 = 80.1%, p = 0.002), IFN-γ (SMD - 6.18, 95% CI [- 8.73 to - 3.62]; I2 = 53.7%, p = 0.115), and NO (SMD - 3.97, 95% CI [- 5.50 to - 2.45]; I2 = 73.4%, p = 0.005), IL-1ß (SMD - 4.23, 95% CI [- 5.09 to - 3.37]; I2 = 0.0%, p = 0.462), IL-6 (SMD - 5.84, 95% CI [- 7.83 to - 3.85]; I2 = 86.5%, p < 0.001), and TNF-α (SMD - 5.10, 95% CI [- 6.34 to - 3.86]; I2 = 74.7%, p < 0.001). These findings also demonstrated the efficacy of naringenin on increasing the levels of CAT (SMD 4.19, 95% CI [1.33 to 7.06]; I2 = 79.9%, p = 0.007), GSH (SMD 4.58, 95% CI [1.64 to 7.51]; I2 = 90.5%, p < 0.001), and GPx (SMD 9.65, 95% CI [2.56 to 16.74]; I2 = 86.6%, p = 0.001) and decreasing the levels of MDA (SMD - 3.65, 95% CI [- 4.80 to - 2.51]; I2 = 69.4%, p = 0.001) than control groups. However, treatment with naringenin showed no statistically difference in SOD activity (SMD 1.89, 95% CI [- 1.11 to 4.89]; I2 = 93.6%, p < 0.001). CONCLUSION: Overall, our findings revealed the immunomodulatory potential of naringenin as an alternative treatment on inhibition of inflammation and OS in several autoimmune-related diseases. Nevertheless, regarding the limitation of clinical trials, strong preclinical models and clinical settings in the future are needed that address the effects of naringenin on ADs. Before large-scale clinical studies, precise human pharmacokinetic investigations are required to determine the dosage ranges and evaluate the initial safety profile of naringenin.

The effects of apigenin administration on the inhibition of inflammatory responses and oxidative stress in the lung injury models: a systematic review and meta-analysis of preclinical evidence.

BACKGROUND/OBJECTIVE: Apigenin is a member of the flavonoid family that can regulate various biological processes, which is characterized as a treatment of different inflammatory disorders and pathological problems associated with oxidative stress (OS). Recent research has focused on apigenin immunomodulatory properties as a potential treatment for different types of lung injuries. This meta-analysis was designed to determine the impact of apigenin treatment on inflammatory markers and OS parameters in animal models of lung injuries. METHODS: The comprehensive literature search was conducted using electronic databases such as Google Scholar, PubMed, Web of Science, Scopus, and Embase up to August 2021. To assess apigenin's effect on inflammatory mediators and OS biomarkers in lung injury animal models, we used the I2 statistic to determine the heterogeneity. We then pooled data as standardized mean difference (SMD) with a 95% confidence interval (CI). RESULTS: Our meta-analysis of the pooled data for inflammatory biomarkers demonstrated that the apigenin administration significantly decreased the NF-κB expression (SMD - 1.60, 95% CI [- 2.93 to - 0.26]; I2 = 89.0%, p < 0.001), IL-1ß (SMD - 4.30, 95% CI [- 6.24 to - 2.37]; I2 = 67.3%, p = 0.047), IL-6 (SMD - 4.10, 95% CI [- 5.04 to - 3.16]; I2 = 72.6%, p < 0.001), TNF-α (SMD - 3.74, 95% CI [- 4.67 to - 2.82]; I2 = 84.1%, p < 0.001), and TNF-α gene expression (SMD - 3.44, 95% CI [- 4.44 to - 2.43]; I2 = 0.0%, p = 0.622). This study also indicated the efficacy of apigenin in increasing the level of CAT (SMD 4.56, 95% CI [3.57 to 5.55]; I2 = 15.3%, p = 3.15), GSH (SMD 5.12, 95% CI [3.53 to 6.70]; I2 = 77.6%, p < 0.001), and SOD (SMD 3.45, 95% CI [2.50 to 4.40]; I2 = 79.2%, p < 0.001), and decreasing the level of MDA (SMD - 3.87, 95% CI [- 5.25 to - 2.49]; I2 = 80.3%, p < 0.001) and MPO (SMD - 4.02, 95% CI [- 5.64 to - 2.40]; I2 = 88.9%, p < 0.001), TGF- ß (SMD - 3.81, 95% CI [- 4.91 to - 2.70]; I2 = 73.4%, p = 0.001) and W/D level (SMD - 3.22, 95% CI [- 4.47 to - 1.97]; I2 = 82.1%, p < 0.001) than control groups. CONCLUSION: Overall, our findings showed the immunomodulatory potential of apigenin as an alternative treatment for the suppression of inflammatory responses and OS in different types of lung injury diseases. Nevertheless, due to the paucity of clinical studies, reliable preclinical models, and clinical settings, evaluating the influence of apigenin on lung injury is required in the future. Before conducting large-scale clinical trials, detailed human pharmacokinetic studies are also needed to establish dosage ranges and determine the initial safety and tolerability of apigenin.

Tuberculosis comorbidity with rheumatoid arthritis: Gene signatures, associated biomarkers, and screening.

Rheumatoid arthritis (RA) is known to be related to an elevated risk of infections because of its pathobiology and the use of immunosuppressive therapies. Reactivation of latent tuberculosis (TB) infection is a serious issue in patients with RA, especially after receiving anti-TNFs therapy. TNF blocking reinforces the TB granuloma formation and maintenance and the growth of Mycobacterium tuberculosis (Mtb). After intercurrent of TB infection, the standard recommendation is that the treatment with TNF inhibitors to be withheld despite its impressive effect on suppression of inflammation until the infection has resolved. Knowing pathways and mechanisms that are common between two diseases might help to find the mechanistic basis of this comorbidity, as well as provide us a new approach to apply them as therapeutic targets or diagnostic biomarkers. Also, screening for latent TB before initiation of an anti-TNF therapy can minimize complications. This review summarizes the shared gene signature between TB and RA and discusses the biomarkers for early detection of this infection, and screening procedures as well.

Overexpression of chemokine receptor CXCR4 predicts lymph node metastatic risk in patients with melanoma: A systematic review and meta-analysis.

CXCR4 is a member of CXC-type and G protein-coupled receptors that can conduce many biological processes, including hemostasis, migration, and adhesion of different types of immune cells. Also, the contribution of CXCR4 in metastasis cascade and development of various malignancies has been addressed in previous reports. This meta-analysis was performed to explore whether the CXCR4 expression affects prognosis and clinicopathologic features in melanoma cancer. Our study involved 656 melanoma patients from 13 reports by detailed literature search from PubMed, Embase, Web of Science, and Google Scholar up to April 2021. To evaluate the association between CXCR4 expression and clinicopathological features of melanoma, we calculated odds ratios (ORs) with its 95% confidence intervals (CIs). We indicated that the CXCR4 overexpression was obviously correlated with ulceration (OR = 0.56, 95% CI: 0.38 to 0.74; I2 = 0.0%, P = 0.999), tumor thickness (OR = 0.56, 95% CI: 0.38 to 0.74; I2 = 0.0%, P = 0.999) and lymph node metastasis (OR = 8.54, 95% CI: 1.04 to 16.04; I2 = 98.9, P < 0.0001). In conclusion, our results reveal that CXCR4 is involved in enhancing the progression and metastasis of melanoma, and further clinical studies are necessary to investigate the role of CXCR4 as a diagnostic and therapeutic biomarker through the progress of melanoma cancer.

A novel recombinant protein vaccine containing the different E7 proteins of the HPV16, 18, 6, 11 E7 linked to the HIV-1 Tat (47-57) improve cytotoxic immune responses.

OBJECTIVES: Human papillomavirus infection (HPV) is the most common viral infection which is causes of cervical, penal, vulvar, anal and, oropharyngeal cancer. E7 protein of HPV is a suitable target for induction of T cell responses and controlling HPV-related cancer. The aim of the current study was to designed and evaluated a novel fusion protein containing the different E7 proteins of the HPV 16, 18, 6 and 11, linked to the cell-penetrating peptide HIV-1 Tat 49-57, in order to improve cytotoxic immune responses in in-vitro and in-vivo. RESULTS: In this study whole sequence of HPV16,18,6,11 E7-Tat (47-57) and HPV16,18,6,11 E7 cloned into the vector and expressed in E. coli (BL21). The purified protein was confirmed by SDS page and western blotting and then injected into the C57BL/6 mice. The efficiency of the fusion protein vaccine was assessed by antibody response assay, cytokine assay (IL-4 and IFN-γ), CD + 8 cytotoxicity assay and tumor challenge experiment. Result showed that fusion proteins containing Adjuvant (IFA,CFA) could express higher titer of antibody. Also, we showed that vaccination with E7-Tat and, E7-Tat-ADJ induced high frequencies of E7-specific CD8 + T cells and CD107a expression as well as IFN-γ level and enhanced long-term survival in the therapeutic animal models. CONCLUSION: Our finding suggested that this novel fusion protein vaccine was able to induce therapeutic efficacy and immunogenicity by improving CD8 + T cell in TC-1 tumor bearing mice; so this vaccine may be appreciated for research against HPV and tumor immunotherapies.

Effects of coenzyme Q10 supplementation on inflammation, angiogenesis, and oxidative stress in breast cancer patients: a systematic review and meta-analysis of randomized controlled- trials.

BACKGROUND/OBJECTIVE: Systemic inflammation and oxidative stress (OS) are associated with breast cancer. CoQ10 as an adjuvant treatment with conventional anti-cancer chemotherapy has been demonstrated to help in the inflammatory process and OS. This systematic review and meta-analysis of randomized clinical trials (RCTs) aimed to evaluate the efficacy of CoQ10 supplementation on levels of inflammatory markers, OS parameters, and matrix metalloproteinases/tissue inhibitor of metalloproteinases (MMPs/TIMPs) in patients with breast cancer. METHODS: A systematic literature search was carried out using electronic databases, including PubMed, Web of Science, Scopus, Google Scholar, and Embase, up to December 2020 to identify eligible RCTs evaluating the effect of CoQ10 supplementation on OS biomarkers, inflammatory cytokines, and MMPs/TIMPs. From 827 potential reports, 5 eligible studies consisting of 9 trials were finally included in the current meta-analysis. Quality assessment and heterogeneity tests of the selected trials were performed using the PRISMA checklist protocol and the I2 statistic, respectively. Fixed and random-effects models were assessed based on the heterogeneity tests, and pooled data were determined as the standardized mean difference (SMD) with a 95% confidence interval (CI). RESULTS: Our meta-analysis of the pooled findings for inflammatory biomarkers of OS and MMPs showed that CoQ10 supplementation (100 mg/day for 45-90 days) significantly decreased the levels of VEGF [SMD: - 1.88, 95% CI: (- 2. 62 to - 1.13); I2 = 93.1%, p < 0.001], IL-8 [SMD: - 2.24, 95% CI: (- 2.68 to - 1.8); I2 = 79.6%, p = 0.001], MMP-2 [SMD: - 1.49, 95% CI: (- 1.85 to - 1.14); I2 = 76.3%, p = 0.005] and MMP-9 [SMD: - 1.58, 95% CI: (- 1.97 to - 1.19); I2 = 79.6%, p = 0.002], but no significant difference was observed between CoQ10 supplementation and control group on TNF-α [SMD: - 2.30, 95% CI: (- 2.50 to - 2.11); I2 = 21.8%, p = 0.280], IL-6 [SMD: - 1.56, 95% CI: (- 1.73 to - 1.39); I2 = 0.0%, p = 0.683], IL-1ß [SMD: - 3.34, 95% CI: (- 3.58 to - 3.11); I2 = 0.0%, p = 0.561], catalase (CAT) [SMD: 1.40, 95% CI: (1.15 to 1.65); I2 = 0.0%, p = 0.598], superoxide dismutase (SOD) [SMD: 2.42, 95% CI: (2.12 to 2.71); I2 = 0.0%, p = 0.986], glutathione peroxidase (GPx) [SMD: 2.80, 95% CI: (2.49 to 3.11); I2 = 0.0%, p = 0.543]], glutathione (GSH) [SMD: 4.71, 95% CI: (4.26 to 5.16); I2 = 6.1%, p = 0.302] and thiobarbituric acid reactive substances (TBARS) [SMD: - 3.20, 95% CI: (- 3.53 to - 2.86); I2 = 29.7%, p = 0.233]. CONCLUSION: Overall, the findings showed that CoQ10 supplementation reduced some of the important markers of inflammation and MMPs in patients with breast cancer. However, further studies with controlled trials for other types of cancer are needed to better understand and confirm the effect of CoQ10 on tumor therapy.

IL-35, a double-edged sword in cancer.

Interleukin 35 (IL-35), a cytokine mainly produced by regulatory T cells (Treg cells), is composed of an Epstein-Barr virus-induced gene 3 ß-chain and an IL-12 p35 α-chain. IL-35 causes tumorigenicity in cancer, protects cancer cells against apoptosis, and facilitates cancer progression. However, a few reports have referred to its contradictory roles in cancer prevention. Therefore, the exact purpose of this cytokine in cancer development has become a fundamental question that needs to be answered. In this review, we explain the structure of IL-35 and its receptors and their different signaling pathways. Finally, the function of IL-35 in some cancers and the possible application of this cytokine in approaches for cancer therapy have been discussed.

Association between polymorphisms of cytokine genes and brucellosis: A comprehensive systematic review and meta-analysis.

OBJECTIVE: Owing to involvement of host genetic factors in susceptibility to brucellosis infection and its outcome, this study aimed to carry out a comprehensive systematic review and meta-analysis to derive a precise evaluation of the association between the risk of brucellosis and its focal complication and all cytokines examined in case-control studies, including Interferon gamma (IFN-γ), Tumor Necrosis Factor (TNF)-α, TNF-ß, Transforming Growth Factor(TGF)-ß, IL-2, IL-4, IL-6, IL-10, IL-12B, IL-15, and IL-18 polymorphisms. METHODS: A systematic literature search in PubMed, Web of Science, Google Scholar, and Scopus was performed to identify the relevant studies, and related information was extracted. The effect size (ES) and corresponding 95% confidence intervals (CIs) were calculated to estimate the association. RESULTS: From 158 initial results, twenty-five eligible studies were included in the meta-analysis. Overall, the pooled results showed that the dominant models of IFN-γ UTR5644, TGF-ß rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 were significantly less frequent in brucellosis patients than the controls. Also, the pooled analysis of the mutant allele vs. wild allele of TGF-ß rs1800471 and IL-10 rs1800872 showed negative association with brucellosis risk. On the other hand, our pooled analysis demonstrated that the mutant allele of IL-4 rs2243250 and IL-18 rs1946519 were associated with increased susceptibility to brucellosis. In addition, the IFN-γ UTR5644 and TGF-ß rs1800470 were more frequent in the patients without focal forms. CONCLUSIONS: IL-4 rs2243250 and IL-18 rs1946519 have a positive correlation with brucellosis whereas the IFN-γ UTR5644, TGF-ß rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 showed a negative association with this disease. The association between the other single nucleotide polymorphisms (SNP) and brucellosis risk was not confirmed in the current meta-analysis. PROSPERO Registration: CRD42018117203.

Different types of adjuvants in prophylactic and therapeutic human papillomavirus vaccines in laboratory animals: a systematic review.

Human papillomavirus (HPV) causes cervical carcinoma, which and is the third most common cancer, accounting for 275,000 deaths annually worldwide. Adjuvants have a key role in promotion of vaccine efficacy; therefore, using prophylactic and therapeutic vaccines combined with adjuvant could be of great benefit in prevention and treatment of cervical cancer. There are different types of adjuvants, including MF59TM adjuvants, RNA-based, JY (interleukin2/chitosan), cholera toxin (CT), heat-labile enterotoxin (LT), Freund's adjuvant, alum, SA-4-1BBL, λ-carrageenan (λ-CGN), heat shock proteins (HSPs), juzen-taiho-to (JTT) and hochu-ekki-to (HET), ISCOM and ISCOMATRIX™, very small size proteoliposomes (VSSPs), granulocyte macrophage colony-stimulating factor (GM-CSF), and Toll-like receptors (TLRs). Adjuvants have various functions, especially in therapeutic vaccines, and they lead to an increase in cytotoxic T lymphocytes (CTLs), so they are important in the design of vaccines. Here, we review the currently used adjuvants and their combinations with HPV protein vaccines in order to introduce an appropriate adjuvant for HPV vaccines.

Innate immune response in systemic autoimmune diseases: a potential target of therapy.

Innate immunity refers to defense mechanisms that are always present, ready to combat microbes and other offending agents. Innate immunity acts as a first-line defense and activates the conventional immune responses; however, it has been speculated that the importance of innate immunity in initiation and development of some disorders is more than just the "first line of defense". Autoimmune diseases, caused by immune system overactivation, are among the most challenging scientific and clinical problems, and there is still much to be learned about their pathogenesis. We aimed to provide a comprehensive overview of available documents about the role of innate immunity in systemic autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, polymyositis, and systemic sclerosis. This study highlights the innate immunity pathways or molecules that are under investigation for therapy of these diseases.

Survivin a pivotal antiapoptotic protein in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease, pathologically characterized by lymphocyte infiltration of the synovial membrane that leads to chronic inflammation and progressive joint damage. RA develops as a result of increased cell infiltration and cell proliferation as well as impaired cell death. Activated cells in joints including lymphocytes and fibroblast-like synoviocytes (FLS) survive for a long time as a consequence of compromised apoptosis, but the mechanism underlying cell survival in synovium remains to be firmly established. Inhibition of apoptosis by survivin, as a critical antiapoptotic protein, contributes to both the persistence of autoreactive T lymphocytes and tumor-like phenotype of FLS in RA. In addition to the antiapoptotic role, survivin also has prognostic relevance in RA prodromal phase. Hence, this review provides an overview of the current knowledge regarding the involvement of survivin protein in the pathogenesis of RA.

1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design, synthesis and biological evaluation.

A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3-triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (IC50s = 0.06-6.80 µM), being superior to reference drug, kojic acid. In particular, the naphthyloxy analogs 6o and 6p were found to be 31-155 times more potent than kojic acid. The metal-binding study of selected compound 6o revealed that the prototype compound possesses metal-chelating ability, particularly with Cu2+ ions. The promising compounds 6o and 6p had acceptable safety profile as demonstrated by cytotoxicity assay against melanoma (B16) cell line and Human Foreskin Fibroblast (HFF) cells.

The comparison of MAMA PCR and SSCP PCR to study chromosomal resistance against Ciprofloxacin and Nalidixic acid in Escherichia coli and Klebsiella pneumoniae.

The mutation in gyrA and parC genes alters amino acids. Also, it causes resistance against Fluoroquinolones in E. coli and K. pneumoniae. The purpose of this study was to diagnose the significant mutation of gyrA (ser83-asp87) and parC (ser80-glu84) genes through using MAMA PCR and SSCP PCR methods. In so doing, the isolated samples were collected. Then, utilizing agar disc diffusion method, the researchers performed antibiotic sensitivity test. Moreover, Fluoroquinolones resistance was confirmed by E-test method (MIC experiment). Furthermore, the obtained data from MAMA PCR method were sequenced accidentally. According to the findings, among 103 isolated samples, 65 samples (63/2%) were belonged to E. coli and 38 samples (36/8%) to K. pneumoniae. In all E. coli that resisted to Ciprofloxacin, at least one mutation were observed. Also, at least one mutation was observed in all K. pneumoniae samples that resisted to Ciprofloxacin. However, four mutation points were detected for each of seven samples and, interestingly, there was no mutation in five sensitive samples to Ciprofloxacin. In addition, the results revealed that the mutation in gyrA and parC genes was closely related to Quinolones resistance. Based on the findings, preparing an infection control program in Iran is highly required.

Molecular Modeling and Structural Stability of Wild-Type and Mutant CYP51 from Leishmania major: In Vitro and In Silico Analysis of a Laboratory Strain.

Cutaneous leishmaniasis is a neglected tropical disease and a major public health in the most countries. Leishmania major is the most common cause of cutaneous leishmaniasis. In the Leishmania parasites, sterol 14α-demethylase (CYP51), which is involved in the biosynthesis of sterols, has been identified as an attractive target for development of new therapeutic agents. In this study, the sequence and structure of CYP51 in a laboratory strain (MRHO/IR/75/ER) of L. major were determined and compared to the wild-type strain. The results showed 19 mutations including seven non-synonymous and 12 synonymous ones in the CYP51 sequence of strain MRHO/IR/75/ER. Importantly, an arginine to lysine substitution at position of 474 resulted in destabilization of CYP51 (ΔΔG = 1.17 kcal/mol) in the laboratory strain; however, when the overall effects of all substitutions were evaluated by 100 ns molecular dynamics simulation, the final structure did not show any significant changes (p-value < 0.05) in stability parameter of the strain MRHO/IR/75/ER compared to the wild-type protein. The energy level for the CYP51 of wild-type and MRHO/IR/75/ER strain were -40,027.1 and -39,706.48 Kcal/mol respectively. The overall Root-mean-square deviation (RMSD) deviation between two proteins was less than 1 Å throughout the simulation and Root-mean-square fluctuation (RMSF) plot also showed no substantial differences between amino acids fluctuation of the both protein. The results also showed that, these mutations were located on the protein periphery that neither interferes with protein folding nor with substrate/inhibitor binding. Therefore, L. major strain MRHO/IR/75/ER is suggested as a suitable laboratory model for studying biological role of CYP51 and inhibitory effects of sterol 14α-demethylase inhibitors.