A comprehensive bioinformatics analysis to identify potential prognostic biomarkers among CC and CXC chemokines in breast cancer.

Breast cancer (BC) is a major human health problem due to its increasing incidence and mortality rate. CC and CXC chemokines are associated with tumorigenesis and the progression of many cancers. Since the prognostic values of CC and CXC families' expression in various types of cancers are becoming increasingly evident, we aimed to conduct a comprehensive bioinformatics analysis elucidating the prognostic values of the CC and CXC families in BC. Therefore, TCGA, UALCAN, Kaplan-Meier plotter, bc-GenExMiner, cBioPortal, STRING, Enrichr, and TIMER were utilized for analysis. We found that high levels of CCL4/5/14/19/21/22 were associated with better OS and RFS, while elevated expression of CCL24 was correlated with shorter OS in BC patients. Also, high levels of CXCL9/13 indicated longer OS, and enhanced expression of CXCL12/14 was linked with better OS and RFS in BC patients. Meanwhile, increased transcription levels of CXCL8 were associated with worse OS and RFS in BC patients. In addition, our results showed that CCL5, CCL8, CCL14, CCL20, CCL27, CXCL4, and CXCL14 were notably correlated with the clinical outcomes of BC patients. Our findings provide a new point of view that may help the clinical application of CC and CXC chemokines as prognostic biomarkers in BC.

Comparative analysis of protein-protein interaction networks in metastatic breast cancer.

Metastatic lesions leading causes of the majority of deaths in patients with the breast cancer. The present study aimed to provide a comprehensive analysis of the differentially expressed genes (DEGs) in the brain (MDA-MB-231 BrM2) and lung (MDA-MB-231 LM2) metastatic cell lines obtained from breast cancer patients compared with those who have primary breast cancer. We identified 981 and 662 DEGs for brain and lung metastasis, respectively. Protein-protein interaction (PPI) analysis revealed seven shared (PLCB1, FPR1, FPR2, CX3CL1, GABBR2, GPR37, and CXCR4) hub genes between brain and lung metastasis in breast cancer. Moreover, GNG2 and CXCL8, C3, and PTPN6 in the brain and SAA1 and CCR5 in lung metastasis were found as unique hub genes. Besides, five co-regulation of clusters via seven important co-expression genes (COL1A2, LUM, SPARC, THBS2, IL1B, CXCL8, THY1) were identified in the brain PPI network. Clusters screening followed by biological process (BP) function and pathway enrichment analysis for both metastatic cell lines showed that complement receptor signalling, acetylcholine receptor signalling, and gastric acid secretion pathways were common between these metastases, whereas other pathways were site-specific. According to our findings, there are a set of genes and functional pathways that mark and mediate breast cancer metastasis to the brain and lungs, which may enable us understand the molecular basis of breast cancer development in a deeper levele to the brain and lungs, which may help us gain a more complete understanding of the molecular underpinnings of breast cancer development.

Novel variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability in Iranian consanguineous families.

BACKGROUND: Intellectual disability (ID) is a heterogeneous group of neurodevelopmental disorders that is characterized by significant impairment in intellectual and adaptive functioning with onset during the developmental period. Whole-exome sequencing (WES)-based studies in the consanguineous families with individuals affected with ID have shown a high burden of relevant variants. So far, over 700 genes have been reported in syndromic and non-syndromic ID. However, genetic causes in more than 50% of ID patients still remain unclear. METHODS: Whole-exome sequencing was applied for investigation of various variants of ID, then Sanger sequencing and in silico analysis in ten patients from five Iranian consanguineous families diagnosed with autosomal recessive neurodevelopmental disorders, intellectual disability, performed for confirming the causative mutation within the probands. The most patients presented moderate-to-severe intellectual disability, developmental delay, seizure, speech problem, high level of lactate, and onset before 10 years. RESULTS: Filtering the data identified by WES, two novel homozygous missense variants in FBXO31 and TIMM50 genes and one previously reported mutation in the CEP290 gene in the probands were found. Sanger sequencing confirmed the homozygote variant's presence of TIMM50 and FBXO31 genes in six patients and two affected siblings in their respective families. Our computational results predicted that the variants are located in the conserved regions across different species and have the impacts on the protein stability. CONCLUSION: Hence, we provide evidence for the pathogenicity of two novel variants in the patients which will expand our knowledge about potential mutation involved in the heterogeneous disease.

Copy number variation analysis implicates novel pathways in patients with oculo-auriculo-vertebral-spectrum and congenital heart defects.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder of craniofacial morphogenesis. Its etiology is unclear, but assumed to be complex and heterogeneous, with contribution of both genetic and environmental factors. We assessed the occurrence of copy number variants (CNVs) in a cohort of 19 unrelated OAVS individuals with congenital heart defect. Chromosomal microarray analysis identified pathogenic CNVs in 2/19 (10.5%) individuals, and CNVs classified as variants of uncertain significance in 7/19 (36.9%) individuals. Remarkably, two subjects had small intragenic CNVs involving DACH1 and DACH2, two paralogs coding for key components of the PAX-SIX-EYA-DACH network, a transcriptional regulatory pathway controlling developmental processes relevant to OAVS and causally associated with syndromes characterized by craniofacial involvement. Moreover, a third patient showed a large duplication encompassing DMBX1/OTX3, encoding a transcriptional repressor of OTX2, another transcription factor functionally connected to the DACH-EYA-PAX network. Among the other relevant CNVs, a deletion encompassing HSD17B6, a gene connected with the retinoic acid signaling pathway, whose dysregulation has been implicated in craniofacial malformations, was also identified. Our findings suggest that CNVs affecting gene dosage likely contribute to the genetic heterogeneity of OAVS, and implicate the PAX-SIX-EYA-DACH network as novel pathway involved in the etiology of this developmental trait.

Integration of gene expression data identifies key genes and pathways in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant tumor and prevalent cause of cancer-related death worldwide. In this study, we analyzed the gene expression profiles of patients with CRC with the aim of better understanding the molecular mechanism and key genes in CRC. Four gene expression profiles including, GSE9348, GSE41328, GSE41657, and GSE113513 were downloaded from GEO database. The data were processed using R programming language, in which 319 common differentially expressed genes including 94 up-regulated and 225 down-regulated were identified. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were conducted to find the most significant enriched pathways in CRC. Based on the GO and KEGG pathway analysis, the most important dysregulated pathways were regulation of cell proliferation, biocarbonate transport, Wnt, and IL-17 signaling pathways, and nitrogen metabolism. The protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape software and hub genes including MYC, CXCL1, CD44, MMP1, and CXCL12 were identified as the most critical hub genes. The present study enhances our understanding of the molecular mechanisms of the CRC, which might potentially be applied in the treatment strategies of CRC as molecular targets and diagnostic biomarkers.

The Global Emergency of Novel Coronavirus (SARS-CoV-2): An Update of the Current Status and Forecasting.

Over the past two decades, there have been two major outbreaks where the crossover of animal Betacoronaviruses to humans has resulted in severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). In December 2019, a global public health concern started with the emergence of a new strain of coronavirus (SARS-CoV-2 or 2019 novel coronavirus, 2019-nCoV) which has rapidly spread all over the world from its origin in Wuhan, China. SARS-CoV-2 belongs to the Betacoronavirus genus, which includes human SARS-CoV, MERS and two other human coronaviruses (HCoVs), HCoV-OC43 and HCoV-HKU1. The fatality rate of SARS-CoV-2 is lower than the two previous coronavirus epidemics, but it is faster spreading and the large number of infected people with severe viral pneumonia and respiratory illness, showed SARS-CoV-2 to be highly contagious. Based on the current published evidence, herein we summarize the origin, genetics, epidemiology, clinical manifestations, preventions, diagnosis and up to date treatments of SARS-CoV-2 infections in comparison with those caused by SARS-CoV and MERS-CoV. Moreover, the possible impact of weather conditions on the transmission of SARS-CoV-2 is also discussed. Therefore, the aim of the present review is to reconsider the two previous pandemics and provide a reference for future studies as well as therapeutic approaches.

A Novel PCNT Frame Shift Variant (c.7511delA) Causing Osteodysplastic Primordial Dwarfism of Majewski Type 2 (MOPD II).

Background: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is an autosomal recessive and skeletal disorder included wide spectrum of clinical abnormalities such as fetal growth restriction, disproportionate face, microcephaly, post-natal growth retardation, adult height under 100 cm, abnormal skin pigmentation, insulin resistance, and susceptibility to cerebrovascular and hematologic abnormalities. Due to heterogeneous feature of MOPDs diseases and common clinical features among the different subtypes, mutation analysis can be considered as fundamental in the accurate diagnosis and confirmation of the MOPD II disease. Some studies revealed that, variants of gene encoding Pericentrin protein, PCNT, were associated with MOPD II. Methods: We performed whole exome sequencing based on the next generation sequencing (Illumina platform), to perform correct diagnosis in a 17-year-old girl with an unknown disease who was referred to the Diabetes Research Center in Yazd, Iran. The clinical features of the patient were short stature, generalized brachydactyly, gradual deterioration of brain functioning, menstrual irregularity, clitoromegaly, acanthosis nigricans, diabetes mellitus, hyperinsulinemia, insulin resistance, and dyslipidemia. Accordingly, her parents were also first cousin with no background disease. After identifying the novel variant, it was confirmed in the proband and her family using bi-directional Sanger sequencing, and its pathogenicity was also checked by different online tools. Results: Our study revealed a novel frame-shift variant in PCNT gene (c.7511delA, p.K2504Sfs*27), which causes premature termination of Pericentrin protein. The result disclosed that, the proband was affected by MOPD II disease. In addition, the Sanger sequencing confirmed the novel homozygote variant in the proband and heterozygote one in her parents, and the extended family perfectly segregated among them. Online tools such as Varsome and MutationTaster also showed a high level of pathogenicity for the variant identified. Conclusion: A novel variant was identified in the proband and her extended family, which emphasized the importance of PCNT gene mutations analysis in the screening and accurate identification of MOPD II disease, especially in prenatal diagnosis.

Martsolf syndrome with novel mutation in the TBC1D20 gene in a family from Iran.

Warburg Micro syndrome and Martsolf syndrome are phenotypically overlapping autosomal recessive conditions characterized by multiple organ abnormalities involving the ocular, nervous, and endocrine systems. Warburg Micro syndrome, the more severe of the two conditions, is caused by loss of function mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes, whereas Martsolf syndrome has been attributed to less damaging mutations in RAB3GAP1 and RAB3GAP2 genes. We report the clinical description and molecular characterization of a consanguineous Iranian family with two siblings, a male and a female, with dysmorphic features, bilateral congenital cataracts, optic nerve atrophy, congenital glaucoma, mild to moderate intellectual disability, seizures, hypogonadism, and mild osteoporosis. Spastic quadriplegia with contractures was observed in the male patient, while the female patient showed only mild hyperreflexia. Magnetic resonance imaging scans performed in the male patient showed a normal brain structure. Both siblings had neither microcephaly nor postnatal growth retardation. Whole exome sequencing identified a novel homozygous nonsense mutation [c.1060C>T; p.(Arg354Ter)] in the TBC1D20 gene in both siblings and confirmed the heterozygous carrier status of both parents. This report describes a novel mutation in the TBC1D20 gene in two Iranian patients with Martsolf syndrome, further extending the allelic heterogeneity and phenotypic spectrum of this rare condition. The genotype and phenotype of the patients are compared with those of Martsolf syndrome and Warburg Micro syndrome patients reported in the literature.

Prevalence, Type, and Molecular Spectrum of NF1 Mutations in Patients with Neurofibromatosis Type 1 and Congenital Heart Disease.

The aim of this study was to assess the prevalence and type of congenital heart disease (CHD) and the associated mutation spectrum in a large series of patients with neurofibromatosis type 1 (NF1), and correlate the mutation type with the presence and subgroups of cardiac defects. The study cohort included 493 individuals with molecularly confirmed diagnosis of NF1 for whom cardiac evaluation data were available. CHD was reported in 62/493 (12.6%) patients. Among these patients, 23/62 (37.1%) had pulmonary valve stenosis/dysplasia, 20/62 (32.3%) had mitral valve anomalies, and 10/62 (16.1%) had septal defects. Other defects occurred as rare events. In this NF1 subcohort, three subjects carried a whole-gene deletion, while 59 were heterozygous for an intragenic mutation. A significantly increased prevalence of non-truncating intragenic mutations was either observed in individuals with CHD (22/59, 37.3%) or with pulmonary valve stenosis (13/20, 65.0%), when compared to individuals without CHD (89/420, 21.2%) (p = 0.038) or pulmonary valve stenosis (98/459, 21.4%) (p = 0.002). Similarly, patients with non-truncating NF1 mutations displayed two- and six-fold higher risk of developing CHD (odds ratio = 1.9713, 95% confidence interval (CI): 1.1162-3.4814, p = 0.0193) and pulmonary valve stenosis (odds ratio = 6.8411, 95% CI: 2.6574-17.6114, p = 0.0001), respectively. Noteworthy, all but one patient (19/20, 95.0%) with pulmonary valve stenosis, and 18/35 (51.4%) patients with other CHDs displayed Noonan syndrome (NS)-like features. Present data confirm the significant frequency of CHD in patients with NF1, and provide further evidence for a higher than expected prevalence of NF1 in-frame variants and NS-like characteristics in NF1 patients with CHD, particularly with pulmonary valve stenosis.

Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect.

Atrioventricular septal defect (AVSD) may occur as part of a complex disorder (e.g., Down syndrome, heterotaxy), or as isolate cardiac defect. Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported in a small fraction of affected subjects. In this study, 22 patients with isolated AVSD and 38 with AVSD and heterotaxy were screened for NFATC1 gene mutations. Sequence analysis identified three missense variants in three individuals, including a subject with isolated AVSD [p.(Ala367Val)], an individual with AVSD and heterotaxy [p.(Val210Met)], and a subject with AVSD, heterotaxy, and oculo-auriculo-vertebral spectrum (OAVS) [p.(Ala696Thr)], respectively. The latter was also heterozygous for a missense change in TBX1 [p.(Pro86Leu)]. Targeted resequencing of genes associated with AVSD, heterotaxy, or OAVS excluded additional hits in the three mutation-positive subjects. Functional characterization of NFATC1 mutants documented defective nuclear translocation and decreased transcriptional transactivation activity. When expressed in zebrafish, the three NFATC1 mutants caused cardiac looping defects and altered atrioventricular canal patterning, providing evidence of their functional relevance in vivo. Our findings support a role of defective NFATC1 function in the etiology of isolated and heterotaxy-related AVSD.