Singleton pregnancy losses before gestational week 22 among patients with autoimmune disorders and Methylenetetrahydrofolate reductase polymorphisms

BACKGROUND: The rates of pregnancy losses (PLs) are increased by maternal risk factors such as autoimmune disorders (AD) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. OBJECTIVE: To evaluate singleton PLs before gestational week (gw) 22 among patients with AD and MTHFR polymorphisms. METHODS: Totally, 1108 singleton pregnancies in 243 women were categorized as: 1) 148 pregnancies in 33 patients with AD, 2) 316 pregnancies in 66 patients with MTHFR polymorphisms, 3) 644 pregnancies in 144 patients with AD +MTHFR polymorphisms. PLs were classified into subgroups: a) Chemical Pregnancy(CP), b) Blighted Ovum(BO), c) gw ⩽ 10, d) gw11–14 e) gw15–22, f) Ectopic Pregnancy(EP), g) Trophoblastic Disease(TD). Obstetric histories were compared using Beksac Obstetrics Index (BOI): [number of living child + (π/10)]/gravida. RESULTS: PL rates before gw22 were 39.2% (58/148), 33.2% (105/316), and 36.3% (234/644) in AD, MTHFR, and AD +MTHFR groups, respectively (p= 0.421). The rate of Pre-Prenatal Screening Period fetal losses (CP + BO + gw ⩽ 10 fetal losses + EP + TD) were 84.8%, 75.9%, and 77.8% in AD, MTHFR, and AD +MTHFR, respectively (p= 0.264). Gravidity ⩽ 4 versus those with gravidity ⩾ 5 had statistically significant differences in BOI (p< 0.001). CONCLUSIONS: PL rate before gw22 among singleton pregnancies with AD and/or MTHFR polymorphisms was 35.8%. The clinical findings seem to be more complicated in patients with gravidity ⩾ 5.

Mini-review: The market growth of diagnostic and therapeutic monoclonal antibodies; SARS CoV-2 an example

BACKGROUND: The emergence of novel viruses poses severe challenges to global public health highlighting the crucial necessity for new antivirals. MAIN BODY: Monoclonal antibodies (mAbs) are immunoglobulins that bind with a single epitope. Mouse mAbs are generated by classic hybridoma technology and are mainly used for immunodiagnostics. For immunotherapy, it is critical to use monoclonal antibodies in the human form to minimize adverse reactions. They have been successfully used to treat numerous illnesses, accordingly, an increasing number of mAbs, with high potency against emerging viruses is the target of every biopharmaceutical company. The diagnostic and therapeutic mAbs market grows rapidly into a multi-billion-dollar business. Biopharmaceuticals are innovative resolutions which revolutionized the treatment of significant chronic diseases and malignancies. Currently, a variety of therapeutic options that include antiviral medications, monoclonal antibodies, and immunomodulatory agents are available in the management of COVID-19. SHORT CONCLUSION: The invasion of mAbs in new medical sectors will increase the market magnitude as it is expected to generate revenue of about 300 billion $ by 2025. In the current mini-review, the applications of monoclonal antibodies in immune-diagnosis and immunotherapy will be demonstrated, particularly for COVID-19 infection and will focus mainly on monoclonal antibodies in the market.

Transcript levels of cytokine coding genes in peripheral blood and tissues of patients with periodontitis

Periodontal diseases are common conditions in almost all age groups and a public health problem. Numerous risk factors have been demonstrated for this condition. The main mechanism of tissue destruction in the periodontitis is the functional interactions between microbial pathogens and host immune responses, thus cytokines have crucial roles in the pathogenesis periodontitis. Our previous study has demonstrated the susceptibility role of HLA-DRB1*04 allele in development of this disease. So, the individuals who were positive for HLA-DRB1*04 allele were excluded. We aimed to appraise the function of cytokines in the pathogenesis of periodontitis via assessment of tissue and blood levels of a number of cytokine coding genes, namely IL-1B, CXCL8, IL-17, IFNG, TGFB and TNFA1. Expressions of IFNG, IL-17, TGFB and TNFA1 were significantly higher in the peripheral blood of individuals with periodontitis compared with unaffected persons (Posterior beta = 1.91, P value = 0.043; Posterior beta = 1.84, P value = 0.033; Posterior beta = 0.713, P value = 0.009 and Posterior beta = 2.85, P value = 0.001, respectively). Moreover, expression of IL-17 was higher in females compared with males (Posterior beta = 1.47, P value = 0.036). As the interaction effect between gender and group was remarkable for IL-17 expression, we further conducted subgroup analysis within gender group. Expression of IL-17 was higher in male patients compared with unaffected males (Posterior beta = 1.9, P value = 0.048). We did not detect any significant difference in the expression of these cytokines in tissues obtained from affected individuals and unaffected controls. Therefore, our results imply dysregulation of cytokine coding genes in patients with periodontitis and warrant further mechanistical studies.

Evaluation of molecular apoptosis signaling pathways and its correlation with EBV viral load in SLE patients using systems biology approach

BACKGROUND: Considerable evidence supports that SLE could be related to apoptotic cells and EBV infection. OBJECTIVE: The aim of this study was to identify the transcriptional signature of EBV infection in SLE patients for survey of the molecular apoptosis signaling pathways. METHODS: The PBMCs gene expression profiles of healthy control and SLE patients were obtained from GEO. Functional annotation and signaling pathway enrichment were carried out using DAVID, KEGG. To validate bioinformatics analysis the changes in genes expression of some of obtained genes, Real time PCR was performed on PBMCs from 28 SLE patients and 18 controls. RESULTS: We found that mean viral load was 6013 ± 390.1 copy/μg DNA from PBMCs in all patients. QRT-PCR results showed that the expression of the DUSP1 and LAMP3 genes which had most changes in the logFC among 4 candidate genes, increased significantly in comparison with control. The consistent expression of LMP2 as viral latency gene involve in apoptosis signaling pathways was detected in SLE patients with EBV viral load and some controls. CONCLUSIONS: The study indicated that some cellular genes may have an important role in pathogenesis of SLE through apoptosis signaling pathways. Beside, EBV infection as an environmental risk factor for SLE may affect the dysfunction of apoptosis.

COVID-19 pandemic: Insights into genetic susceptibility to SARS-CoV-2 and host genes implications on virus spread, disease severity and outcomes

The outbreak of the newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) all over the world has caused global public health emergencies, international concern and economic crises. The systemic SARS-CoV-2 disease (COVID-19) can lead to death through causing unrestrained cytokines-storm and subsequent pulmonary shutdown among the elderly and patients with pre-existing comorbidities. Additionally, in comparison with poor nations without primary health care services, in developed countries with advanced healthcare system we can witness higher number of infections per one million people. In this review, we summarize the latest studies on genes associated with SARS-CoV-2 pathogenesis and propose possible mechanisms of the virus replication cycle and its triggered signaling pathways to encourage researchers to investigate genetic and immune profiles of the disease and try strategies for its treatment. Our review shows that immune response in people with different genetic background might vary as African and then Asian populations have lowest number of affected cases compared with European and American nations. Considering SARS-CoV-2 pathogenesis, we put forward some potentially important genetic gateways to COVID-19 infection including genes involved in the entry and replication of SARS-CoV-2 and the regulation of host immune response which might represent explanation for its spread, severity, and morality. Finally, we suggest that genetic alterations within these gateways could be critical factors in influencing geographical discrepancies of the virus, so it is essential to fully study them and design appropriated and reliable therapeutic agents against COVID-19.

Circulating macrophage inflammatory protein-1β/IL-12p40 ratio predicts sofosbuvir-based treatment outcome in HCV- genotype 4 patients

This study aimed to evaluate the prognostic value of baseline macrophage inflammatory protein (MIP)-1β/IL12p40 ratio for antiviral treatment outcome in HCV genotype 4 patients. METHODS: Sera of 450 treatment-naïve chronic HCV patients and 50 healthy individuals were collected. Liver transaminases, total bilirubin and albumin were biochemically tested, viral RNA was quantified, and circulating MIP-1β and IL-12p40 were estimated using human anti-MIP-1β and IL-12p40 antibodies in Sandwich ELISA. RESULTS : No difference was observed in the baseline chemokines levels between responders and relapsers, but the later had a significantly higher MIP-1β/IL-12p40 ratio (P< 0.0001). Multivariate regression analysis of baseline characteristics showed that gender, age, viral load, albumin level and chemokine ratios can significantly predict treatment outcome (P= 0.0114, 0.0095, 0.042, 0.0004 and < 0.0001; respectively). Accordingly, a predictive threshold of baseline chemokine ratio was calculated and it showed an AUC of 0.6917 (P= 0.0108; 95% CI: 0.5566 to 0.8268). The calculated threshold for predicting virologic response was 8.245, with positive and negative predictive values of 92.98% and 100%; respectively. The chemokine ratios had significant correlations with liver transaminases in treated groups whether pre or post-treatment. CONCLUSION: Baseline MIP-1β/IL-12p40 ratio represents a non-invasive prognostic biomarker that would provide shorter treatment duration and minimizes the emergence of drug-resistant variants in HCV genotype 4-patients.

Assessment of cancer prevention effect of exercise

There are many documents about benefits of exercise on human health. However, evidences indicate to positive effect of exercise on disease prevention, understanding of many aspects of this mechanism need more investigations. Determination of critical genes which effect human health. GSE156249 including 12 gene expression profiles of healthy individual biopsy from vastus lateralis muscle before and after 12-week combined exercise training intervention were extracted from gene expression omnibus (GEO) database. The significant DEGs were included in interactome unit by Cytoscape software and STRING database. The network was analyzed to find the central nodes subnetwork clusters. The nodes of prominent cluster were assessed via gene ontology by using ClueGO. Number of 8 significant DEGs and 100 first neighbors analyzed via network analysis. The network includes 2 clusters and COL3A1, BGN, and LOX were determined as central DEGs. The critical DEGs were involved in cancer prevention process.

Anti-drug antibodies to antibody-based therapeutics in multiple sclerosis

Multiple sclerosis is the major demyelinating autoimmune disease of the central nervous system. Relapsing MS can be treated by a number of approved monoclonal antibodies that currently target: CD20, CD25 (withdrawn), CD49d and CD52. These all target potentially pathogenic memory B cell subsets and perhaps functionally inhibit pathogenic T cell function. These consist of chimeric, humanized and fully human antibodies. However, despite humanization it is evident that all of these monoclonal antibodies can induce binding and neutralizing antibodies ranging from < 1% to over 80% within a year of treatment. Importantly, it is evident that monitoring these allow prediction of future treatment-failure in some individuals and treatment cessation and switching therefore potentially limiting disease breakthrough and disability accumulation. In response to the COVID-19 pandemic and the need to avoid hospitals, shortened infusion times and extended dose intervals have been implemented, importantly, subcutaneous delivery of alternative treatments or formulations have been developed to allow for home treatment. Therefore, hospital-based and remote monitoring of ADA could therefore be advantageous to optimize patient responses in the future.

Effect of KRAS and BRAF mutations in metastatic colorectal cancer patients: A systematic review and meta-analysis based on tumor sidedness and KRAS subtypes

INTRODUCTION: Metastatic or recurrent colorectal cancer (MRCRC) has a poor prognosis. The aim of the present meta-analysis was to assess the prevalence of different subtypes of KRAS mutation and BRAF mutation in metastatic CRC patients, and evaluate the relationship between the tumor sidedness and prevalence of KRAS and BRAF mutation. METHODS: We searched MEDLINE/PubMed, the Cochrane Library, and ClinicalTrials.gov from January 2010 to July 2020. The data were extracted independently according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The statistical analysis was done using STATA and Meta-Disk 1.4 applications. RESULTS: Overall, 6699 colorectal cancer patients were included. KRAS and BRAF mutation was reported in 28% and 6% of patients, respectively. The overall prevalence of right primary and left primary metastatic CRC patients with mutated KRAS was 40% and 60%. However, the prevalence BRAF mutated right primary and left primary metastatic CRC patients was 37% and 63%. The overall HR was 2.38 for patients with metastatic CRC who had a mutated type of KRAS. Our study showed a mean overall survival of 35.4 month for KRAS mutant and a 10.12 month survival for BRAF mutant patients with metastatic colorectal cancer patients. CONCLUSION: The prevalence of KRAS and BRAF mutations varied significantly according to the location of the tumor. BRAF mutations are more commonly found in metastatic colorectal cancers on the right side. Liver was the most common site of metastases in patients with mutant KRAS and the mortality of patients with mutant KRAS was 2.3 times higher than the patients with wild types. These results help to better describe the population of mCRC patients and can have implications for improving and organizing anti-EGFR therapies. Further research is needed to assess differences in survival through mutation status and primary tumor location.

Association of increased C-Reactive Protein and hypocomplementemia with risk factors for thrombosis in women who have susceptibility for poor gestational outcome; importance of preconceptional counseling

This study aimed to investigate the association of increased C-Reactive Protein (CRP) and hypocomplementemia with risk factors for thrombosis such as Factor V Leiden (FVLP) and Prothrombin G20210A polymorphisms (PP), increased Activated Protein C Resistance (APCR) and decreased anti-thrombin III (ATIII) activity in women who have metabolic (MTHFR polymorphisms) and immunological risk factors (autoimmune antibody positivity, autoimmune disorders, and chronic inflammatory diseases). All patients (n= 197) were evaluated in terms of risk factors for thrombosis including FVLP, PP, increased APCR, and decreased ATIII activity as well as CRP and complement (C) 3 and C4 levels within a framework of preconceptional care program. Patients with high CRP levels together with hypocomplementemia were included to the study group (n= 13), while women with normal levels of CRP, C3, and C4 were accepted as controls (n= 184). Decreased ATIII activity was found to be statistically more frequent in the study group compared to controls (p= 0.036). There were no significant differences between the study and control groups in terms of the presence of FVLP, PP and increased APCR (p= 0.386, p= 0.462, p= 0.625, respectively). Decreased ATIII activity should be the concern of preconceptional and antenatal care programs in risky patients with increased CRP levels and hypocomplementemia in order to prevent placental inflammation related gestational complications.