3M syndrome patient with a novel mutation: A case report.

BACKGROUND: A rare autosomal recessive genetic disorder, 3M syndrome, is characterized by severe intrauterine and postnatal growth retardation. Children with 3M syndrome typically exhibit short stature, facial deformities, long tubular bones, and high vertebral bodies but generally lack mental abnormalities or other organ damage. Pathogenic genes associated with 3M syndrome include CUL7, OBSL1 and CCDC8. The clinical and molecular characteristics of patient with 3M syndrome are unique and serve as important diagnostic indicators. CASE SUMMARY: In this case, the patient displayed square shoulders, scoliosis, long slender tubular bones, and normal neurological development. Notably, the patient did not exhibit the typical dysmorphic facial features, relative macrocephaly, or growth retardation commonly observed in individuals with 3M syndrome. Whole exon sequencing revealed a novel heterozygous c.56681+1G>C (Splice-3) variant and a previously reported nonsense heterozygous c.3341G>A (p.Trp1114Ter) variant of OBSL1. Therefore, it is important to note that the clinical features of 3M syndrome may not always be observable, and genetic confirmation is often required. Additionally, the identification of the c.5683+1G>C variant in OBSL1 is noteworthy because it has not been previously reported in public databases. CONCLUSION: Our study identified a new variant (c.5683+1G>C) of OBSL1 that contributes to expanding the molecular profile of 3M syndrome.

Bioinformatic analysis of the molecular mechanisms underlying the progression of bone defects.

Background: The pathophysiology of bone defects (BDs) is complex, and the treatment for bone defects, in particular massive bone defects, remains a major clinical challenge. Our study was conducted to explore the molecular events related to the progression of bone defects a common clinical condition. Methods: First, microarray data of GSE20980 were obtained from the Gene Expression Omnibus (GEO) database, where 33 samples in total were used to analyze the molecular biological processes related to bone defects. Next, the original data were normalized and differentially expressed genes (DEGs) were identified. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Finally, a protein-protein interaction (PPI) network was constructed and the trends of the different genes were confirmed. Results: Compared with the samples of non-critical size defects (NCSD), the samples of critical size defects (CSD) had 2057, 827, and 1,024 DEGs at 7, 14, and 21 days post injury, respectively. At day 7, the DEGs were significantly enriched in metabolic pathways, at day 14 the DEGs were predominantly enriched in G-protein coupled signaling pathways and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, and at day 21 the DEGs were mainly enriched in circadian entrainment and synaptic-related functions. The PPI network showed similar results. Quantitative real-time PCR (qRT-PCR) and western blot (WB) were performed to validate the partial results of sequencing. Conclusion: This study provides some clues about the molecular mechanism behind bone defects, which should contribute to scientific research and clinical treatment of this condition.

A prospective marker for the prediction of postoperative deep venous thrombosis: Neutrophil extracellular traps.

Deep venous thrombosis (DVT) is a common medical complication in patients with lumbar fractures. The current study aimed to investigate the predictive value of neutrophil extracellular traps (NETs) in postoperative DVT formation in patients with lumbar fractures and to develop a nomogram relating clinical admission information for prediction. Patients who underwent open reduction and pedicle screw internal fixation in the treatment of single-segment lumbar fracture in the Department of Spine Surgery, the First Affiliated Hospital of Nanjing Medical University, from December 2020 to June 2022 were enrolled in this study. Baseline data and laboratory results were collected from enrollees, and the primary study endpoint event was the occurrence of DVT in patients after surgery. Multivariable logistic regression analysis was used to identify risk factors associated with higher odds of DVT after surgery. A nomogram was constructed using the results of the multivariable model. The calibration plot and receiver operating characteristics (ROC) curve were used to show the satisfactory predictive capacity of the model. Of these 393 patients who did not have DVT preoperatively, 79 patients developed it postoperatively, and 314 did not, respectively. Multivariate analysis showed that higher body mass index (BMI) (BMI between 24 and 28: RR = 1.661, 95% CI = 0.891-3.094; BMI ≤28: RR = 5.625, 95% CI = 2.590-12.217; reference: BMI <24), neutrophils (RR = 1.157, 95% CI 1.042-1.285), D-dimer (RR = 1.098, 95% CI 1.000-1.206), and citrullinated histone H3 (CitH3) (RR = 1.043, 95% CI 1.026-1.060) were independent risk factors for postoperative DVT. Using the multivariable analysis, we then constructed a nomogram to predict DVT, which was found to have an area under the curve of 0.757 (95% CI = 0.693-0.820). Calibration plots also showed the satisfied discrimination and calibration of the nomogram. In conclusion, patients with lumbar fractures with postoperative DVT had higher levels of NETs in the circulation preoperatively compared to those without postoperative DVT. Furthermore, based on BMI, D-dimer, neutrophils, and CitH3, we developed a predictive model to predict postoperative DVT incidence in these patients.

Potential predictive and therapeutic applications of small extracellular vesicles-derived circPARD3B in osteoarthritis.

Background: Heterogeneous phenotypes that display distinct common characteristics of osteoarthritis (OA) are not well defined and will be helpful in identifying more customized therapeutic options for OA. Circular RNAs (circRNAs) have attracted more and more attention due to their role in the progression of OA. Investigating the role of circRNAs in the pathogenesis of OA will contribute to the phenotyping of OA and to individualized treatment. Methods: Small extracellular vesicles (sEV) were isolated from serum samples from patients with OA of different stages and sEV-derived circPARD3B was determined using RT-qPCR analysis. CircPARD3B expression in a stimulated coculture that included OA fibroblast-like synoviocytes (OA-FLS) as well as human dermal microvascular endothelial cells (HDMECs), plus the effects of circPARD3B on the expression of vascular endothelial growth factor (VEGF) long with angiogenic activity, were evaluated in vitro. Based on bioinformatics analysis and luciferase reporter assay (LRA), MiR-326 and sirtuin 1 (SIRT1) were found to be interactive partners of circPARD3B. Mesenchymal stem cells (SMSCs) overexpressing circPARD3B were constructed and SMSCs-derived sEV with overexpressed circPARD3B (OE-circPARD3B-SMSCs-sEV) were obtained to explore the effect of the intervention of circPARD3B combined with SMSCs-sEV-based therapy in vitro and in a OA model induced by collagenase in vivo. Results: Serum sEV-linked circPARD3B was indentified to be significantly decreased in the inflammatory phenotype of OA. Overexpression of circPARD3B was found to inhibit the expression of VEGF, as well as the angiogenesis induced by VEGF in a IL-1ß stimulated the co-culture of OA-FLS as well as HDMECs. CircPARD3B is directly bound to miR-326. SIRT1 was considered a novel miR-326 target gene. OE-circPARD3B-SMSCs-sEV significantly reduced VEGF expression in coculture of OA-FLS and HDMECs. Injection of OE-circPARD3B-SMSCs-sEV could also reduce synovial VEGF; additionally, it could further ameliorate OA in the mouse model of OA in vivo. Conclusion: Serum sEV circPARD3B is a potential biomarker that enables the identification of the inflammatory phenotype of patients with OA. Correspondingly, intracellular transfer of circPARD3B through OE-circPARD3B-SMSCs-sEV could postpone disease progression through a functional module regulated angiogenesis of circPARD3B-miR-326-SIRT1, providing a novel therapeutic strategy for OA.

Comparative transcriptomics and network pharmacology analysis to identify the potential mechanism of celastrol against osteoarthritis.

INTRODUCTION: Celastrol is a promising therapeutic agent for the treatment of osteoarthritis (OA). However, the mechanism of action of celastrol is unclear. This study was aiming to identify the potential function of celastrol on OA and determine its underlying mechanism. METHOD: Celastrol targets were collected from web database searches and literature review, while pathogenic OA targets were obtained from Online Mendelian Inheritance in Man (OMIM) and GeneCards databases. Transcriptomics data was sequenced using an Illumina HiSeq 4000 platform. Celastrol-OA overlapping genes were then identified followed by prediction of the potential function and signaling pathways associated with celastrol using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A celastrol-target network was constructed to identify the candidate core targets of celastrol. The predictions were then validated by performing molecular docking and molecular dynamics simulation studies. RESULTS: In total, 96 genes were identified as the putative celastrol targets for treatment of OA. These genes were possibly involved in cell phenotype changes including response to lipopolysaccharide and oxidative stress as well as in cell apoptosis and aging. The genes also induced the mTOR pathway and AGE-RAGE signaling pathway at the intracellular level. Additionally, results indicated that 13 core targets including mTOR, TP53, MMP9, EGFR, CCND1, MAPK1, STAT3, VEGFA, CASP3, TNF, MYC, ESR1, and PTEN were likely direct targets of celastrol in OA. Finally, mTOR was determined as the most likely therapeutic target of celastrol in OA. CONCLUSION: This study provides a basic understanding and novel insight into the potential mechanism of celastrol against OA. Key Points • Our study provides a strong indication that further study of celastrol therapy in OA is required. • mTOR is the most likely therapeutic target of celastrol in OA.

Investigating the safety and compliance of using csDMARDs in rheumatoid arthritis treatment through face-to-face interviews: a cross-sectional study in China.

Rheumatoid arthritis (RA) significantly impacts the health of Chinese patients. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are used as the standard treatment for patients with RA. However, Chinese patients with RA have reported poor compliance with csDMARDs. This study aims to better understand the safety and compliance of using csDMARDs in RA treatment. Face-to-face interviews were conducted by questionnaires on safety and compliance of csDMARDs in 400 patients with RA and 100 rheumatologists from 13 cities in China. Rheumatologists were from Tier 3 Class A hospitals with independent rheumatology departments, who admitted more than 30 patients with RA per week. All patients were diagnosed for > 3 months before the survey and had been treated with csDMARDs for > 3 months. The incidence of adverse events (AEs) that attributed to csDMARDs estimated by rheumatologists was lower than that reported by patients for all four prescribed csDMARDs. Also, types of common AEs in rheumatologist's perception differed from those in the patient's report. Only 86% (116/135) of patients claimed they notified their rheumatologist about AEs, and 40.8% (150/368) of patients did not strictly adhere to their prescribed treatment. Reasons why patients were not compliant with their treatment, other than AEs, included symptoms being less severe, travel, and busy working life/business trips. This study revealed gaps in perceptions of csDMARDs-related AEs and medication adherence between rheumatologists and patients. These findings suggested adequate doctor-patient communications, and considerations of multiple real-world situations may improve adherence in the treatment of RA patients. Key Points • This study identified gaps in rheumatologists' perception of the prevalence and type of AEs experienced by their patients, which could potentially help them improve their patients' compliance with treatment.

Identification and Analysis of Genes Underlying Bone Mineral Density by Integrating Microarray Data of Osteoporosis.

Osteoporosis is a kind of brittle bone disease, which is characterized by a reduction in bone mineral density (BMD). In recent years, a number of genes and pathophysiological mechanisms have been identified for osteoporosis. However, the genes associated with BMD remain to be explored. Toward this end, we integrated multiple osteoporosis microarray datasets to identify and systematically characterize BMD-related genes. By integrating the differentially expressed genes from three osteoporosis microarray datasets, 152 genes show differentially expressed between high and low BMD osteoporosis samples in at least two of the three datasets. Among them, 88 were up-regulated in high BMD samples and 64 were up-regulated in low BMD samples. The expression of ZFP36, JUNB and TMEM8A were increased at high BMD samples in all three datasets. Hub genes were further identified by co-expression network analysis. Functional enrichment analysis showed that the gene up-regulated in high BMD were enriched in immune-related functions, suggesting that the immune system plays an important role in osteoporosis. Our study explored BMD-related genes based on the integration of osteoporosis microarray data, providing guidance to other researchers from a new perspective.

Long noncoding RNA FER1L4 regulates rheumatoid arthritis via targeting NLRC5.

OBJECTIVES: Rheumatoid arthritis (RA) is a systematic autoimmune disease that cardinally affects the joints and other organs. Many people all over the world are suffering from the disease and no effective treatment has been established. Fibroblast-like synoviocytes (FLSs) play a critical role in the occurrence and development of RA. Long non-coding RNA Fer-1-like protein 4 (FER1L4) has been reported to participate in various cancers as a tumour suppressor. However, its clinical significance and biological role in RA is completely unknown. METHODS: RT-qPCR or FISH were used to examine the expression of FER1L4 NLRC5, FER1L4 and inflammatory cytokine levels in synovial tissues (STs) from patients with RA or RA FLSs. Western blot was applied to examine the expression of NLRC5 and inflammatory cytokine levels in synovial tissues (STs) from patients with RA or RA FLSs. BrdU staining and MTT assay were used to examine the cell proliferation ability. The methylation-specific PCR was performed to analyse the methylation levels. RESULTS: The level of FER1L4 significantly reduced in STs and FLSs, whereas the nucleotide oligomerisation domain-like receptors 5 (NLRC5) levels were increased. Overexpression of FER1L4 can decreased the level of NLRC5 and inflammatory cytokine level. The FER1L4 gene promoter was significantly methylated in RA STs and FLSs. More importantly, treatment with methylation inhibitor 5-aza-2-deoxycytidine (5-azadC) inhibited hypermethylation of FER1L4 promoter and the expression of NLRC5. CONCLUSIONS: These results indicated that FER1L4 regulates RA via targeting NLRC5 potentially. Therefore, this study may provide a candidate therapeutic target for RA.

[Prognostic significance of serial determinations of lactate dehydrogenase in follow-up for patients with myelodysplastic syndrome].

This study was aimed to dynamically observe the expression level of lactate dehydrogenase (LDH) in MDS patients and to explore the significance of LDH level for prognostic judgement of MDS patients. The expression level of LDH in 163 confirmedly diagnosed patients from 2001 to 2009 years in our hospital, the changes of LDH level in follow-up patients and relation of the LDH changes to prognosis, survival time and MDS progression, as well as the relation of LDH level to blood cell count, ratio and karyotype of blast cells in bone marrow were analyzed retrospectively. The results showed that the median LDH level in 163 MDS patients at diagnosis was 214 U/L (range 102 - 865 U/L), the median survival time of patients with increased LDH (> 240 U/L) was 25.6 months which was significantly shorter than that of patients with normal LDH level (56.8 months)(p < 0.05). When MDS patients were classified according to IPSS, the increased LDH level in MDS patients was observed in high risk and intermediate II groups (337.20 ± 298.00 U/L and 234.07 ± 216.00 U/L, respectively) which was significantly higher than that in low risk group (154.94 ± 46.08 U/L) (p < 0.05). The LDH level in patients with MDS progression was obviously enhanced while LDH level in patients without progression was not enhanced, mainly maintained in stable level as compared with LDH level at diagnosis and before progression (p < 0.005). By multivariate analysis, the increase of LDH level was found to be an independent prognostic factor. It is concluded that the LDH level may be used as indicator for judging prognosis of MDS patients, which is helpful to early recognition of MDS progression and risk stratification of disease, as well as selection of rational therapy.