Aim: To determine the etiology of a Chinese family with thrombocytopenia by analyzing the clinical features and genetic variation.Methods: Clinical profiles and genomic DNA extracts of the family members were collected for the study. Whole exome sequencing and Sanger sequencing was used to detect the associated genetic variation and verify the family co-segregation respectively. Bioinformatics analysis assessed the pathogenicity of missense mutations.Results: The study reported a 3-generation pedigree including eight family members with thrombocytopenia. The platelet counts of the patients were varied, ranging from 38 to 110 × 109/L (reference range: 150–450 x 109/L). The mean volumes and morphology of the sampled platelet were both normal. The bleeding abnormality and mitochondriopathy were not observed in all the patients. Clinical signs of thrombocytopenia were mild. A novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified in CYCS gene associated with autosomal dominant thrombocytopenia.Conclusion: We report the first large family with autosomal dominant non-syndromic thrombocytopenia 4 in a Chinese family, a novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified. The whole exome sequencing is an efficient tool for screening the variants specifically associated with the disease. The finding enriches the mutation spectrum of CYCS gene and laid a foundation for future studies on the correlation between genotype and phenotype.
Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.
Background: Ubiquitin and ubiquitin-like (UB/UBL) conjugations are one of the most important post-translational modifications and involve in the occurrence of cancers. However, the biological function and clinical significance of ubiquitin related genes (URGs) in prostate cancer (PCa) are still unclear.Methods: The transcriptome data and clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA), which was served as training cohort. The GSE21034 dataset was used to validate. The two datasets were removed batch effects and normalized using the “sva” R package. Univariate Cox, LASSO Cox, and multivariate Cox regression were performed to identify a URGs prognostic signature. Then Kaplan-Meier curve and receiver operating characteristic (ROC) curve analyses were used to evaluate the performance of the URGs signature. Thereafter, a nomogram was constructed and evaluated.Results: A six-URGs signature was established to predict biochemical recurrence (BCR) of PCa, which included ARIH2, FBXO6, GNB4, HECW2, LZTR1 and RNF185. Kaplan-Meier curve and ROC curve analyses revealed good performance of the prognostic signature in both training cohort and validation cohort. Univariate and multivariate Cox analyses showed the signature was an independent prognostic factor for BCR of PCa in training cohort. Then a nomogram based on the URGs signature and clinicopathological factors was established and showed an accurate prediction for prognosis in PCa.Conclusion: Our study established a URGs prognostic signature and constructed a nomogram to predict the BCR of PCa. This study could help with individualized treatment and identify PCa patients with high BCR risks.
Xeroderma pigmentosum (XP) is a rare genetic condition in which exposure to sunlight leads to a high tumor incidence due to defective DNA repair machinery. Herein, we investigated seven patients clinically diagnosed with XP living in a small city, Montanhas (Rio Grande do Norte), in the Northeast region of Brazil. We performed high-throughput sequencing and, surprisingly, identified two different mutated genes. Six patients carry a novel homozygote mutation in the POLH/XPV gene, c.672_673insT (p.Leu225Serfs*33), while one patient carries a homozygote mutation in the XPC gene, c.2251-1G>C. This latter mutation was previously described in Southeastern Africa (Comoro Island and Mozambique), Pakistan, and in a high incidence in Brazil. The XP-C patient had the first symptoms before the first year of life with aggressive ophthalmologic tumor progression and a melanoma onset at 7 years of age. The XP-V patients presented a milder phenotype with later onset of the disorder (mean age of 16 years old), and one of the six XP-V patients developed melanoma at 72 years. The photoprotection is minimal among them, mainly for the XP-V patients. The differences in the disease severity between XP-C (more aggressive) and XP-V (milder) patients are obvious and point to the major role of photoprotection in the XPs. We estimate that the incidence of XP patients at Montanhas can be higher, but with no diagnosis, due to poor health assistance. Patients still suffer from the stigmatization of the condition, impairing diagnosis, education for sun protection, and medical care.
MADS-box gene family members play multifarious roles in regulating the growth and development of crop plants and hold enormous promise for bolstering grain yield potential under changing global environments. Bread wheat (Triticum aestivum L.) is a key stable food crop around the globe. Until now, the available information concerning MADS-box genes in the wheat genome has been insufficient. Here, a comprehensive genome-wide analysis identified 300 high confidence MADS-box genes from the publicly available reference genome of wheat. Comparative phylogenetic analyses with Arabidopsis and rice MADS-box genes classified the wheat genes into 16 distinct subfamilies. Gene duplications were mainly identified in subfamilies containing unbalanced homeologs, pointing towards a potential mechanism for gene family expansion. Moreover, a more rapid evolution was inferred for M-type genes, as compared with MIKC-type genes, indicating their significance in understanding the evolutionary history of the wheat genome. We speculate that subfamily-specific distal telomeric duplications in unbalanced homeologs facilitate the rapid adaptation of wheat to changing environments. Furthermore, our in-silico expression data strongly proposed MADS-box genes as active guardians of plants against pathogen insurgency and harsh environmental conditions. In conclusion, we provide an entire complement of MADS-box genes identified in the wheat genome that could accelerate functional genomics efforts and possibly facilitate bridging gaps between genotype-to-phenotype relationships through fine-tuning of agronomically important traits.
Neoplasic transformation is a continuous process that occurs in the body. Even before clinical signs, the immune system is capable of recognizing these aberrant cells and reacting to suppress them. However, transformed cells acquire the ability to evade innate and adaptive immune defenses through the secretion of molecules that inhibit immune effector functions, resulting in tumor progression. Hormones have the ability to modulate the immune system and are involved in the pathogenesis of autoimmune diseases, and cancer. Hormones can control both the innate and adaptive immune systems in men and women. For example androgens reduce immunity through modulating the production of pro-inflammatory and anti-inflammatory mediators. Women are more prone than men to suffer from autoimmune diseases such as systemic lupus erythematosus, psoriasis and others. This is linked to female hormones modulating the immune system. Patients with autoimmune diseases consistently have an increased risk of cancer, either as a result of underlying immune system dysregulation or as a side effect of pharmaceutical treatments. Epidemiological data on cancer incidence emphasize the link between the immune system and cancer. We outline and illustrate the occurrence of hormone-related cancer and its relationship to the immune system or autoimmune diseases in this review. It is obvious that some observations are contentious and require explanation of molecular mechanisms and validation. As a result, future research should clarify the molecular pathways involved, including any causal relationships, in order to eventually allocate information that will aid in the treatment of hormone-sensitive cancer and autoimmune illness.
During spaceflight, astronauts are exposed to multiple unique environmental factors, particularly microgravity and ionizing radiation, that can cause a range of harmful health consequences. Over the past decades, increasing evidence demonstrates that the space environment can induce changes in gene expression and RNA processing. Long non-coding RNA (lncRNA) represent an emerging area of focus in molecular biology as they modulate chromatin structure and function, the transcription of neighboring genes, and affect RNA splicing, stability, and translation. They have been implicated in cancer development and associated with diverse cardiovascular conditions and associated risk factors. However, their role on astronauts’ health after spaceflight remains poorly understood. In this perspective article, we provide new insights into the potential role of exosomal lncRNA after spaceflight. We analyzed the transcriptional profile of exosomes isolated from peripheral blood plasma of three astronauts who flew on various Shuttle missions between 1998–2001 by RNA-sequencing. Computational analysis of the transcriptome of these exosomes identified 27 differentially expressed lncRNAs with a Log2 fold change, with molecular, cellular, and clinical implications.
Effective treatment of glioblastoma (GBM) remains an open challenge. Given the critical role of the immune microenvironment in the progression of cancers, we aimed to develop an immune-related gene (IRG) signature for predicting prognosis and improving the current treatment paradigm of GBM. Multi-omics data were collected, and various bioinformatics methods, as well as machine learning algorithms, were employed to construct and validate the IRG-based signature and to explore the characteristics of the immune microenvironment of GBM. A five-gene signature (ARPC1B, FCGR2B, NCF2, PLAUR, and S100A11) was identified based on the expression of IRGs, and an effective prognostic risk model was developed. The IRG-based risk model had superior time-dependent prognostic performance compared to well-studied molecular pathology markers. Besides, we found prominent inflamed features in the microenvironment of the high-risk group, including neutrophil infiltration, immune checkpoint expression, and activation of the adaptive immune response, which may be associated with increased hypoxia, epidermal growth factor receptor (EGFR) wild type, and necrosis. Notably, the IRG-based risk model had the potential to predict the effectiveness of radiotherapy. Together, our study offers insights into the immune microenvironment of GBM and provides useful information for clinical management of this desperate disease.
Acute myeloid leukemia (AML) is a clonal malignant proliferative blood disorder with a poor prognosis. Ferroptosis, a novel form of programmed cell death, holds great promise for oncology treatment, and has been demonstrated to interfere with the development of various diseases. A range of genes are involved in regulating ferroptosis and can serve as markers of it. Nevertheless, the prognostic significance of these genes in AML remains poorly understood. Transcriptomic and clinical data for AML patients were acquired from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Univariate Cox analysis was performed to identify ferroptosis-related genes with prognostic value, and the least absolute shrinkage and selection operator (LASSO) algorithm and stepwise multivariate Cox regression analysis were utilized to optimize gene selection from the TCGA cohort (132 samples) for model construction. Tumor samples from the GEO database (136 samples and 104 samples) were used as validation groups to estimate the predictive performance of the risk model. Finally, an eight-gene prognostic signature (including CHAC1, CISD1, DPP4, GPX4, AIFM2, SQLE, PGD, and ACSF2) was identified for the prediction of survival probability and was used to stratify AML patients into high- and low-risk groups. Survival analysis illustrated significantly prolonged overall survival and lower mortality in the low-risk group. The area under the receiver operating characteristic curve demonstrated good results for the training set (1-year: 0.846, 2-years: 0.826, and 3-years: 0.837), which verified the accuracy of the model for predicting patient survival. Independent prognostic analysis indicated that the model could be used as a prognostic factor (p ≤ 0.001). Functional enrichment analyses revealed underlying mechanisms and notable differences in the immune status of the two risk groups. In brief, we conducted and validated a novel ferroptosis-related prognostic model for outcome prediction and risk stratification in AML, with great potential to guide individualized treatment strategies in the future.
Background: Recurrence is still a major obstacle to the successful treatment of gliomas. Understanding the underlying mechanisms of recurrence may help for developing new drugs to combat gliomas recurrence. This study provides a strategy to discover new drugs for recurrent gliomas based on drug perturbation induced gene expression changes.Methods: The RNA-seq data of 511 low grade gliomas primary tumor samples (LGG-P), 18 low grade gliomas recurrent tumor samples (LGG-R), 155 glioblastoma multiforme primary tumor samples (GBM-P), and 13 glioblastoma multiforme recurrent tumor samples (GBM-R) were downloaded from TCGA database. DESeq2, key driver analysis and weighted gene correlation network analysis (WGCNA) were conducted to identify differentially expressed genes (DEGs), key driver genes and coexpression networks between LGG-P vs LGG-R, GBM-P vs GBM-R pairs. Then, the CREEDS database was used to find potential drugs that could reverse the DEGs and key drivers.Results: We identified 75 upregulated and 130 downregulated genes between LGG-P and LGG-R samples, which were mainly enriched in human papillomavirus (HPV) infection, PI3K-Akt signaling pathway, Wnt signaling pathway, and ECM-receptor interaction. A total of 262 key driver genes were obtained with frizzled class receptor 8 (FZD8), guanine nucleotide-binding protein subunit gamma-12 (GNG12), and G protein subunit β2 (GNB2) as the top hub genes. By screening the CREEDS database, we got 4 drugs (Paclitaxel, 6-benzyladenine, Erlotinib, Cidofovir) that could downregulate the expression of up-regulated genes and 5 drugs (Fenofibrate, Oxaliplatin, Bilirubin, Nutlins, Valproic acid) that could upregulate the expression of down-regulated genes. These drugs may have a potential in combating recurrence of gliomas.Conclusion: We proposed a time-saving strategy based on drug perturbation induced gene expression changes to find new drugs that may have a potential to treat recurrent gliomas.