Global Medical Genetics最新文献

Cleft lip and/or cleft palate (CL/P) is one of the most common congenital anomalies of the human face with a complex etiology involving multiple genetic and environmental factors. Several studies have shown the association of the paired box 7 ( PAX7 ) gene with CL/P in different populations worldwide. However, the current literature reveals no reported case-parent trio studies to evaluate the association between the PAX7 gene and the risk of nonsyndromic cleft lip and/or palate (NSCL/P) in the Indian population. Hence, the purpose of this study was to assess the PAX7 gene single nucleotide polymorphisms (SNPs) in the etiology of NSCL/P among the Indian cleft trios. Forty Indian case-parent trios of NSCL/P were included. The cases and their parents' genomic DNA were extracted. The SNPs rs9439714, rs1339062, rs6695765, rs742071, and rs618941of the PAX7 gene were genotyped using the Agena Bio MassARRAY analysis. The allelic transmission disequilibrium test was performed using PLINK software while pair-wise linkage disequilibrium by the Haploview program. The SNP rs9439714 showed evidence of association ( p -value = 0.02, odds ratio = 3) with NSCL/P. Considering the parent-of-origin effects, the SNPs rs9439714 and rs618941 showed an excess maternal transmission of allele C at rs9439714 ( p -value = 0.05) and G allele at rs618941 ( p -value = 0.04). The results of the present study suggested that the SNPs rs9439714 and rs618941 showed an excess maternal transmission of alleles suggestive of the possible role of the PAX7 gene involvement in the etiology of NSCL/P in the Indian population.

Background  Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1 , MSH2 , MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods  The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results  The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion  Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.

Statement of Problem  MicroRNAs are small non-coding RNAs that regulate an array of functions by targeting crucial genes. A significant dysregulation in the TP53 profile has been observed in the head and neck squamous cell carcinoma (HNSCC) patients. Hence, the present in silico study was designed to identify those microRNAs which target TP53 gene and demonstrate their differential expression in HNSCC cases. Materials and Methods  The study was extended further to explore their exosomal location using database such as EVmiRNA and ExoCarta. The study follows an observational in silico design. Computational tool miRDB was used identify the microRNA targets of TP53 gene. The UALCAN server was used to ascertain the expression of microRNA in HNSCC cases derived from the Cancer Gene Atlas dataset. The survival of HNSCC patients based on the differential expression microRNA markers were recorded. Further, each of the microRNA was queried for their exosomal presence using EVmiRNA. Results  About 102 microRNA targets of TP53 gene with a target score in the range of 95-50 were identified. The differential expression data for 52 microRNAs was retrieved from the UALCAN database. The microRNAs hsa-miR-421, hsa-miR-548f-5p, and hsa-let-7c-5p were found to be differentially expressed with marked influence over the survival of HNSCC patients. Furthermore, hsa-miR-421 and hsa-let-7c-5p were found to have an exosomal origin especially in body fluids such as blood and saliva. Conclusion  The results accumulated from the present study identified three microRNAs which can affect the functions of TP53 gene and bring about serious outcomes in HNSCC patients. The microRNAs of exosomal origin targeting TP53 gene in HNSCC patients can be a promising prognostic marker, which can be further used as a therapeutic lead by designing inhibitors.

Organoids are powerful systems to facilitate the study of individuals' disorders and personalized treatments because they mimic the structural and functional characteristics of organs. However, the full potential of organoids in research has remained unrealized and the clinical applications have been limited. One of the reasons is organoids are most efficient grown in reconstituted extracellular matrix hydrogels from mouse-derived, whose poorly defined, batch-to-batch variability and immunogenicity. Another reason is that organoids lack host conditions. As a component of the tumor microenvironment, microbiota and metabolites can regulate the development and treatment in several human malignancies. Here, we introduce several engineering matrix materials and review recent advances in the coculture of organoids with microbiota and their metabolites. Finally, we discuss current trends and future possibilities to build more complex cocultures.

Dendritic cells (DCs) play a key role in initiating and regulating immune responses, and in addition to their roles in vivo, DCs are used as natural adjuvants for various tumor vaccines. In vitro, monocytes can be used to induce DCs, but in tumor patients, due to insufficient bone marrow hematopoiesis, extramedullary hematopoiesis and tumor-associated myeloid cells expand, and monocytes mainly exist in the form of myeloid-derived suppressor cells (MDSCs). The purpose of this experiment was to explore the differences in the differentiation and immune function of DCs induced by MDSCs in tumor patients. In a mouse model, we used normal mouse bone marrow cell-derived DCs as control cells, and in a tumor-bearing model, we induced MDSCs in the spleen to generate DCs (MDSC-DCs). Through flow cytometry, we found that the production of MDSC-DCs was significantly higher than that of control mice, and the secretion of interferon-γ of MDSC-DCs was significantly reduced. Through OVA antigen presentation experiments, we found that the antigen presentation ability of MDSC-DCs was significantly decreased. Through adoptive treatment of tumor-bearing mice cells, we found that the antitumor immune function of MDSC-DCs was significantly reduced. After that, we explored the mechanism of the decrease of immune function activity of MDSC-DCs. We determined that the surface markers of MDSC-DCs were changed by flow cytometry. Through flow sorting and RNA sequencing, we found that some pathways and key gene expression in MDSC-DCs were changed. In conclusion, this study found that the immune function of MDSC-DCs decreased and explored the mechanism of the decreased immune function activity.

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. A crucial process that initiates and progresses CRC is various epigenetic and genetic changes occurring in colon epithelial cells. Recently, huge progress has been made to understand cancer epigenetics, especially regarding DNA methylation changes, histone modifications, dysregulation of miRNAs and noncoding RNAs. In the "epigenome" of colon cancer, abnormal methylation of genes that cause gene alterations or expression of miRNA has been reported in nearly all CRC; these findings can be encountered in the average CRC methylome. Epigenetic changes, known as driving events, are assumed to play a dominant part in CRC. Furthermore, as epigenetic changes in CRC become properly understood, these changes are being established as clinical biomarkers for therapeutic and diagnostic purposes. Progression in this area indicates that epigenetic changes will often be utilized in the future to prevent and treat CRC.

Variants (Alfa, Gamma, Beta, and Delta) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are circulating worldwide. These variants of concerns share some common mutations but they also have distinguishing mutations. These mutations affect transmissibility of virus and cause evasion from neutralizing antibodies. Monitoring and identification of circulating variants is of great importance for public health. In this study, an in-house SARS-CoV-2 reverse transcription quantitative polymerase chain reaction (RT-qPCR) kit was designed to detect variants of concerns by the World Health Organization. Primer sets and probes were designed to target presence of virus along with mutations for identifying different variants (for N501Y, HV69-70del, K417N, and T478K). Reactions were set by using commercially available master mixes without a reference dye. The RT-qPCR conditions were optimized by using commercially available ribonucleic acid samples of wild-type, Alfa, Beta, Gamma, and Delta variants. Several samples were also analyzed by the in-house kit after optimization studies. All Alfa variant and wild-type samples were also double confirmed with a commercially available variant detection kit demonstrating a 100% consistence with the in-house kit. Beta, Gamma, and Delta variants could not be confirmed with any other commercially available kits as there is not any available one in the market. SARS-CoV-2 variants are gaining importance during the pandemic and shaping the fight against the virus. RT-qPCR kits detecting different variants would provide a significant advantage while screening the population.