Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age‐related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) ...regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y‐box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis‐splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age‐related osteoporosis.
Synopsis
Alternative splicing has been shown to regulate cellular senescence and differentiation. This study links the reduced expression of the splicing regulator YBX1 in aging bone marrow stromal cells to senescence and aging‐related bone loss.
The expression level of YBX1 in BMSCs decreases during aging.
Ybx1 overexpression in BMSCs stimulates bone formation, while its deletion accelerates bone loss.
YBX1 suppresses BMSC senescence and modulates BMSC differentiation by controlling RNA splicing.
The small compound sciadopitysin attenuates YBX1 degradation and bone loss in old mice.
Reduced expression of YBX1 in aging bone marrow stromal cells induces their senescence and bone loss due to mRNA mis‐splicing.
Biochemical analysis revealed the IDS enzyme activity in the proband was 2.10 nmol·mg−1·4h−1 (reference range >30 nmol·mg−1·4h−1). ...the urinary polysaccharide toluene blue staining test of the boy ...was positive. ...enzyme activity of IDS was significantly affected. The IDS gene is the only pathogenic gene of MPS II. ...the identification of IDS mutations is significant and helpful for genetic counseling, pre-natal diagnosis, and treatment of the disease.
According to the American College of Medical Genetics and Genomics guidelines (2015), this mutation is predicted to be pathogenic (PVS1 + PM2 + PP1 + PP3). Funding This work was supported by grants ...from the National Natural Science Foundation of China (Nos. 81770875 and 81572639), the Science and Technology Department of Sichuan Province (No. 2018SZ0142), Sichuan University (No. 2018SCUH0093), and the National Clinical Research Center for Geriatrics of West China Hospital (No. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.cmj.org).Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind ...of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity
and
. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid-derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer.
RNA-binding proteins (RBPs) interact with RNA and ubiquitously regulate RNA transcripts during their life cycle, playing a fundamental role in the progression of angiogenesis-related diseases. In the ...skeletal system, endothelium-dependent angiogenesis is indispensable for bone formation. However, the role of RBPs in endothelium-dependent bone formation is unclear. Here, we show that RBP-Y-box-binding protein 1 (YBX1) was strongly reduced in the bone vasculature of ovariectomy (OVX) mice. Endothelial cell-specific deletion of Ybx1 impaired CD31-high, endomucin-high (CD31hiEMCNhi) endothelium morphology and resulted in low bone mass whereas Ybx1 overexpression promoted angiogenesis-dependent osteogenesis and ameliorated bone loss. Mechanistically, YBX1 deletion disrupted CD31, EMCN, and bone morphogenetic protein 4 (BMP4) stability in an m5C-dependent manner and blocked endothelium-derived BMP4 release, thereby inhibiting osteogenic differentiation of bone mesenchymal stromal cells. Administration of recombinant BMP4 protein restored impaired bone formation in Ybx1 deletion mice. Tail vein injection of CD31-modified polyethylene glycol-poly (lactic-co-glycolic acid) carrying sciadopitysin, a natural YBX1 agonist, pharmacologically partially reversed CD31hiEMCNhi vessels' decline and improved bone mass in both OVX and aging animals. These findings demonstrated the role of RBP-YBX1 in angiogenesis-dependent bone formation and provided a therapeutic approach for ameliorating osteoporosis.
To determine the effect of fibroblast growth factor-21(FGF-21)on the osteogenic differention of human bone mesenchymal stem cells (hBMSCs) exposed to a hyperglycemia condition
.
hBMSCs were isolated ...from adult bone marrows, and identified by Alizarin red and oil red O staining. The expressions of immunophenotype were analysed using flow cytometry (CD105, CD90, CD73, CD44).HBMSCs were divided into control groupglucose (Glu) concentration of 5.5 mmol/L, Glu A, B, C groups(Glu 16.5, 25, 40 mmol/L), FGF-21 group (Glu 5.5mmol/ L+ FGF-21 ),Glu B+ FGF-21 group, and Glu B +FGF-21+cell mitogen activated protein kinase (MAPK) blocker (PD98059, SP600125 ,and SB203580) groups. The effect of FGF-21 on the differentiation of hBMSCs was detected using indicators as follows: alkaline phosphatase(ALP)on day 14, mRNA expressions of
, osteocalcin(
)and
, protein expressions and phosphorylation of extracellular signal regulated kinase (ERK), mitogen-activated protein kinase(P38) and c-Jun N-terminal kinases(JNK) on day 21.
hBM
In order to systematically analyze the key causes of miners’ unsafe behavior, based on the complexity of behavioral causes, this paper studies the distribution characteristics of unsafe behavior from ...the dimensions of time, place, behavior classification, department, position and degree of violation. Adopting the Apriori algorithm, strong association rules from many association rules of unsafe behavior of miners are found. The results show that during the early shift, the number of unsafe behavior is the largest among the three ones and the highest rate of unsafe behavior is that in the yard; among the 26 types of unsafe behavior, the incorrect wearing of safety operating equipment is the most likely unsafe behavior; the fully mechanized excavation teams account for the largest number of unsafe behavior among the 9 responsible departments; the common miners produce the most unsafe behavior; and the majority of unsafe behavior violations are at the general level. In addition, focus on preventing and controllin
To identify risk factors for HIV infection among men who have sex with men （MSM） and to provide a theoretical basis for prevention interventions. Between December 2011 and August 2012, a case-control ...study was conducted among MSM who underwent voluntary counselling and testing for HIV. Confirmed HIV-positive MSM were included in the case group, and HIV-negative MSM were included in the control group. Information on possible risk factors was collected by a survey questionnaire and a qualitative interview. The results of a conditional logistic regression showed that the following were influencing factors for HIV infection： average monthly income between 2001 and 3000 Yuan （odds ratio （0R）=6.341, 95% Ch 1.714-12.544）, only sometimes using condoms when having anal sex with men in the last 6 months （0R=7.601, 95% Ch 1.359-23.083）, having HIV-positive sex partners （0R=5.273, 95% Ch 1.572- 17.691）, rectal trauma with bleeding in the last 6 months （0R=2.947, 95% Ch 1.308-6.638）, not using condoms at last sexual encounter （OR-- 1.278, 95% Ch 1.012-5.595）, engaging in commercial sex （0R=5.925, 95% Ch 1.923-13.890） and having more than 16 sex partners in the last 6 months （0R=1.175, 95% Ch 1.021-1.353）. These seven factors were the risk factors of HIV infection （OR〉l）. However, having anal sex less than 10 times in the previous 1 month （OR=O.O02, 95% CI： 0.000-0.287） was a protective factor against HIV infection among MSM （OR〈l）, and insertive （0R=0.116, 95% Ch 0.000-0.236） （OR〈l） anal intercourse influenced HIV infection. Interventions should be targeted at MSM whose average monthly income is between 2001 and 3000 Yuan, and who engage in commercial sex. In addition, the importance of using condoms at every sexual encounter should be emphasised in health education, as should the treatment of rectal trauma with bleeding. Finally, MSM should decrease the number of sex partners and frequency of anal sex to decrease the rate of HIV infection.
The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic ...characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy.
We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions.
IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038).
Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC.
Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC.
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•Immunogenomic discrepancies among multifocal HCC vary within patients and shape tumor evolutionary trajectories.•Immune escape involves HLA alterations, M2 macrophage infiltration, inhibitory ligands and immunoediting.•Immune context imprinted by genetics can exert selective pressures.•Immune evasion correlates with tumor regression and can predict postoperative recurrence.•Personalized immunotherapy strategies should be adopted for multifocal HCC to maximize efficacy.
Recently, long noncoding RNA SNHG12 has been reported to be dysregulated in various types of cancer. This study investigated its biological function and the underlying molecular mechanism in cervical ...squamous cell carcinoma (CSCC). We found that SNHG12 was significantly overexpressed in CSCC tissues. Further evidence showed that human papillomavirus (HPV) type 16 E6 and E7 might regulate the expression level of SNHG12 by modulating transcription factor c‐Myc. Functional experiments suggested that SNHG12 knockdown dramatically repressed CSCC cells proliferation, migration, and invasion while induced apoptosis in vitro as well as suppressed tumor growth in vivo. In addition, SNHG12 could facilitate epithelial–mesenchymal transition through ERK/Slug/E‐cadherin pathway at least in part. Our findings highlight SNHG12 functions as an oncogenic long noncoding RNA in malignant phenotype and tumorigenesis of CSCC, which implicate it may be a potential target for CSCC treatment.
SNHG12 expression may be driven by the HPV16 E6 and E7 oncogene, through a mechanism that is dependent on c‐Myc activation. SNHG12 contributes to cervical squamous cell carcinoma (CSCC) cells malignant behavior at least partly through activating ERK/Slug signaling pathway, accordingly influences the downstream proteins, for example, E‐cadherin, hence promoting migration, invasion, and epithelial–mesenchymal transition (EMT) in HPV‐infected cells.
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