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1.
Nat Commun ; 10(1): 5061, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699989

RESUMO

A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.

2.
Invest Ophthalmol Vis Sci ; 60(13): 4277-4284, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31618764

RESUMO

Purpose: Juvenile-onset open-angle glaucoma (JOAG), if left untreated, will lead to severe visual disability. The purpose of this study was to identify the disease-causing mutations in a Chinese JOAG family. Methods: We recruited a Chinese JOAG family and unrelated primary open-angle glaucoma (POAG) patients (270, Chinese), and performed whole-exome sequencing (WES) to screen the sequence variations. Variants identified by WES were validated by Sanger sequencing. Subsequently, qPCR and Western blotting were used to determine the expression of wild-type (WT) and its mutated-type (MT) of 2'-5'-oligoadenylate synthetase 3 (OAS3) genes. Results: Seventeen heterozygous candidate variants were revealed in the JOAG family based on the screening of WES data. Of those, the heterozygous variant exon11:c.2299C>T: p.Arg767Cys in OAS3, a gene used to synthesize 2'-5'-oligoadenylate (2-5A), co-segregates with the disease phenotype. One unrelated POAG patient also carried this variant, but this variant was absent in 200 nonglaucoma healthy controls. Analysis of the Arg767Cys mutation with PolyPhen2, CADD, and SIFT all suggest that it is pathogenic. This arginine residue is highly conserved in all selected OAS3 orthologs. On the other hand, in peripheral blood samples, the mRNA expression of OAS3 in patients significantly decreased compared with unaffected controls. Moreover, the expression level of recombinant OAS3 protein (mutated Arg767Cys) also observably reduced compared with level of WT protein in HEK293T cells. Conclusions: Our study revealed a heterozygous mutation in OAS3 from a Chinese JOAG family. And this mutation showed a deleterious effect to the expression of OAS3.

3.
Br J Ophthalmol ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604699

RESUMO

BACKGROUND/AIMS: To determine the association and interaction of genome-wide association study-reported variants for Asian populations with myopia and ocular biometric parameters in southern Chinese population. METHODS: Totally, 1462 unrelated Han Chinese subjects were recruited with complete ophthalmic examinations, including 1196 myopia and 266 control subjects. A total of nine variants were selected for TaqMan genotyping. The genetic association, joint additive effect and genotype-phenotype correlation were investigated. RESULTS: The 4q25 variant rs10034228 (p=0.002, OR=0.56) and MIPEP variant rs9318086 (p=0.004, OR=1.62) were found to be significantly associated with myopia as well as different severity of myopia. Moreover, 15q14 variant rs524952 (p=0.015, OR=1.49) also showed mild association with myopia and high myopia. However, there was no significant association of CTNND2, vasoactive intestinal peptide receptor 2 and syntrophin beta 1 variants with myopia. Joint additive analysis revealed that the subjects carrying 6 risk alleles of the 3 associated variants were 10-fold higher risk predisposed to high myopia. Genotype-phenotype correlation analysis revealed that high myopia subjects carrying 4q25 rs10034228 T allele showed thicker central corneal thickness, whereas high myopia subjects carrying 15q14 rs524952 A allele were associated with longer axial length and larger curvature ratio. CONCLUSION: This study revealed significant association of 4q25, 15q14 and MIPEP variants with myopia and different severity of myopia in southern Chinese population, joint additively enhancing 10-fold of risk predisposing to high myopia. The correlation of these associated variants with axial length and corneal parameters suggests their contribution to the refractive status in high myopia subjects.

4.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 433-437, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631614

RESUMO

Objective: To identify risk factors associated with thyroid nodular lesions in patients with acromegaly. Methods: Clinical and thyroid ultrasonography data of patients with acromegaly diagnosed in the West China Hospital of Sichuan University from May 2009 to January 2018 were reviewed and analyzed. Multivariate linear regression models were established to identify factors associated with thyroid volumes and size of thyroid nodules. Multivariate binary logistic regression models were established to determine risk factors associated with thyroid nodules in patients with acromegaly. Results: Of the 240 acromegaly patients, 70 received thyroid ultrasonography and 56 had thyroid nodules (56/70, 80%). The patients with thyroid nodules had a longer median duration of acromegaly than 14 patients who without thyroid nodules (8.0 years vs. 3.0 years, P<0.05), but had a similar mean age and female to male ratio with the latter. The risk of thyroid nodules increased with the duration of acromegaly (odds ratio=1.306, 95% confidence interval (1.010, 1.688), P=0.042). The level of random growth hormone was linearly correlated with thyroid volumes. Gender, age, and serum growth hormone were not predictors of thyroid nodules in patients with acromegaly. Conclusion: Duration of acromegaly is an independent predictor of thyroid nodules.


Assuntos
Acromegalia/complicações , Nódulo da Glândula Tireoide/complicações , China , Feminino , Humanos , Masculino , Fatores de Risco , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia
5.
J Diabetes ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31642603

RESUMO

BACKGROUND: Evidence for the association between environmental tobacco smoke (ETS) exposure and the risk of type 2 diabetes mellitus (T2DM) is limited. The aim of this study was to investigate this association in female never-smokers. METHODS: We analyzed 28 177 female participants of the China Kadoorie Biobank (CKB) in Suzhou area, who were never-smokers without diabetes. ETS exposure was defined as exposing to other people's tobacco smoke either at home, workplace or in public places at least 1 day/week. Cox proportional hazard regression models were used to assess the association between ETS exposure and incident T2DM, according to the frequency and duration of ETS exposure, respectively. RESULTS: A total of 774 incident cases of T2DM were identified during a median 7.3 years follow-up. Compared with the no ETS exposure, hazard ratios (95% confidence intervals) for all ETS exposure, the daily and ≥14h/week ETS exposure were 1.17 (1.00-1.37), 1.23 (1.04-1.46) and 1.25 (1.03-1.53), respectively. Moreover, a positive dose-response relationship was observed between ETS exposure level and T2DM (all P<0.05 for trend). CONCLUSIONS: This prospective study suggested that ETS exposure increased the risk of T2DM incidence with dose-response relationship in female never-smokers. Thus, reducing ETS exposure may benefit in decreasing the burden of T2DM in Chinese females. This article is protected by copyright. All rights reserved.

6.
Nat Commun ; 10(1): 4209, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527657

RESUMO

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.

7.
Indian J Ophthalmol ; 67(10): 1629-1633, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31546497

RESUMO

Purpose: This study evaluated bimanual intracapsular irrigation-aspiration for ectopia lentis with use of a small incision for 4-point scleral fixation of a foldable posterior-chamber intraocular lens (IOL) and anterior vitrectomy in patients with Marfan syndrome. Methods: We performed a retrospective study of 18 eyes from 10 patients with Marfan syndrome who underwent surgical intervention for ectopia lentis at our clinic between July 2012 and September 2018. In this study, intraoperative and postoperative complications, uncorrected visual acuity, best-corrected visual acuity, spherical equivalent, intraocular pressure, and endothelial cell density were evaluated. Results: No intraoperative complications were reported. In all cases, early postoperative evaluation revealed a clear cornea, round pupil, and well-centered IOL. Mean logMAR uncorrected visual acuity improved from 1.09 preoperatively to 0.56 postoperatively (P < 0.05). Mean logMAR best-corrected visual acuity improved from 0.45 preoperatively to 0.17 postoperatively (P < 0.05). Aside from transient ocular hypertension, no postoperative complications were reported. Conclusion: The combined surgical technique presented above yields excellent visual outcomes with an extremely low incidence of complications. This approach is simple, safe, and effective in the treatment of ectopia lentis in patients with Marfan syndrome.

8.
Pathol Res Pract ; 215(11): 152638, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31551175

RESUMO

AIM: Long non-coding RNA (lncRNA) is currently considered to play an important regulatory role in various diseases, including tumors, at present a hot topic in research. As a non-coding transcription product of imprinted gene, LncRNA H19 is expressed as a parent imprinted maternal allele without protein-coding ability. Increasing evidence indicates that LncH19 may be a new tumor marker for early clinical diagnosis and prognosis judgment. In this study, LncH19 expression was investigated by RNA in situ hybridization for further exploring the clinicopathological role of its expression in esophageal squamous cell cancer (ESCC). METHODS: 121 tumor samples and seven cases of adjacent non-tumor tissues from esophageal cancer patients were detected by RNA in situ hybridization (ISH) and the ISH staining was graded with modified Allred scoring. RESULTS: While no LncH19 expression in the tumor adjacent to normal epithelia was disclosed with the technology, significantly higher levels of LncH19 expression were detected in the tumors obtained from the patients who died within one year after surgery, compared to the expression in those tumors from the patients who survived longer than five years after the same treatment regimen (P = 0.001). In addition, LncH19 expression was verified to correlate with a larger tumor size (P = 0.002) and a higher UICC stage (P = 0.001). CONCLUSION: Our LncH19 ISH data verify the involvement of LncH19 in ESCC. Higher levels of LncH19 expression were not only detected in tumors with larger size and in clinical late stage, but also significantly associated with shorter survival, strongly indicating its clinical significance in the malignant progression of ESCC and useful value as a poor prognostic factor for the patients.

10.
J Am Soc Nephrol ; 30(9): 1605-1624, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383731

RESUMO

BACKGROUND: The discoidin domain receptor 1 (DDR1) is activated by collagens, upregulated in injured and fibrotic kidneys, and contributes to fibrosis by regulating extracellular matrix production, but how DDR1 controls fibrosis is poorly understood. DDR1 is a receptor tyrosine kinase (RTK). RTKs can translocate to the nucleus via a nuclear localization sequence (NLS) present on the receptor itself or a ligand it is bound to. In the nucleus, RTKs regulate gene expression by binding chromatin directly or by interacting with transcription factors. METHODS: To determine whether DDR1 translocates to the nucleus and whether this event is mediated by collagen-induced DDR1 activation, we generated renal cells expressing wild-type or mutant forms of DDR1 no longer able to bind collagen. Then, we determined the location of the DDR1 upon collagen stimulation. Using both biochemical assays and immunofluorescence, we analyzed the steps involved in DDR1 nuclear translocation. RESULTS: We show that although DDR1 and its natural ligand, collagen, lack an NLS, DDR1 is present in the nucleus of injured human and mouse kidney proximal tubules. We show that DDR1 nuclear translocation requires collagen-mediated receptor activation and interaction of DDR1 with SEC61B, a component of the Sec61 translocon, and nonmuscle myosin IIA and ß-actin. Once in the nucleus, DDR1 binds to chromatin to increase the transcription of collagen IV, a major collagen upregulated in fibrosis. CONCLUSIONS: These findings reveal a novel mechanism whereby activated DDR1 translates to the nucleus to regulate synthesis of profibrotic molecules.

11.
Thorac Cancer ; 10(10): 1962-1972, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31441580

RESUMO

BACKGROUND: Previous studies have reported that soluble fms-like tyrosine kinase-1 (sFlt-1) possesses anti-tumor effects by inhibiting angiogenesis in many cancers. Exosomes can be engineered as delivery vehicles for transferring functional biomolecules, such as proteins, lipids, and nucleic acids (DNA, mRNA, and miRNA) to target cells to affect inflammation, apoptosis, and angiogenesis. The purpose of this study was to investigate whether exosomes can function as efficient carriers of sFlt-1 in vitro and in vivo, to play a role in SCLC therapy. METHODS: We adopted three different methods: TEM, NTA and western blot analysis to characterize the cell-derived exosomes from NCI-H69 SCLC cell line and normal bronchial epithelial BEAS-2B cell line. we next explored the effects of these exosomes on HUVE cell proliferation and migration in vitro.To verify sFlt-1-loaded exosomes suppress the tumor growth in vivo,we established subcutaneous xenografts in nude mice using the NCI-H69 cell line. RESULTS: We observed that NCI-H69-exo significantly increased human umbilical vein endothelial cells (HUVEC) migration compared to BEAS-2B-exo in vitro and in vivo. sFlt-1 protein expression was statistically higher in BEAS-2B-exo than NCI-H69-exo. sFlt-1 protein or sFlt-1-enriched exosomes can inhibit the migration of HUVECs. Furthermore, sFlt-1-enriched exosomes exhibited higher inhibition efficacy on pro-angiogenesis of NCI-H69-exo in comparison with the same concentration of sFlt-1 protein. Intriguingly, sFlt-1-loaded exosomes showed marked anti-tumor activity by inhibiting the growth of NCI-H69 tumor xenografts. CD31 staining revealed that sFlt-1-loaded exosomes significantly reduced the vascular density of experimental mice. sFlt-1-loaded exosomes markedly induced tumor apoptosis and inhibited tumor cell proliferation in mice. CONCLUSION: Exosomes from a SCLC cell line contain low levels of sFlt-1 and significantly increased the migration of HUVECs. SFlt-1-enriched exosomes can inhibit NCI-H69-exo-induced HUVEC migration. Exosomes enriched in sFlt-1 have the potential to be effective therapeutic agents for SCLC.

12.
J Am Chem Soc ; 141(32): 12738-12743, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31328519

RESUMO

The ability to accurately identify and isolate cells is the cornerstone of precise disease diagnosis and therapies. A single-step cell identification method based on logic analysis of multiple surface markers will have unique advantages because of its accuracy and efficacy. Herein, using multiple DNA aptamers for cancer biomarker recognition and associative toehold activation for signal integration and amplification as two molecular keys, we have successfully operated a cell-surface device that can perform AND Boolean logic analysis of multiple biomarkers and precisely label the target cell subtype in large populations of similar cells via the presence or absence of different biomarkers. Our approach can achieve single-step cancer cell identification and isolation with excellent sensitivity and accuracy and thus will have broad applications in biological science, biomedical engineering, and personalized medicine.

13.
J Am Soc Nephrol ; 30(9): 1659-1673, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292196

RESUMO

BACKGROUND: Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. METHODS: To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. RESULTS: In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. CONCLUSIONS: These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.

14.
Thyroid ; 29(8): 1147-1157, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31298631

RESUMO

Background: Particulate matter (PM) air pollution is an environmental risk to public health. The prevalence of thyroid disease during pregnancy has increased rapidly in recent decades, but the available data on the relationships among air pollution, thyroid function, and birth outcomes in pregnant women, particularly in China, are scarce. We aimed to evaluate the association between maternal exposure to PM2.5 and its components and maternal and neonatal thyroid function and to investigate whether thyroid function acts as a mediator between air pollution and birth weight. Methods: In this prospective birth cohort study, the levels of maternal exposure to PM2.5 and its components during the first trimester were assessed in 433 pregnant women in Nanjing, China, enrolled during 2014-2015. We evaluated the levels of maternal exposure to PM2.5 and its six main constituents-organic matter (OM), black carbon (BC), sulfate (SO42-), nitrate (NO3-), ammonium (NH4+), and soil dust-using the V4.CH.02 product of the Dalhousie University Atmospheric Composition Analysis Group. The maternal serum-free thyroxine (fT4), thyrotropin (TSH), and thyroid peroxidase antibody (TPOAb) levels during the second trimester were measured through electrochemiluminescent microparticle immunoassays. The neonatal TSH levels were detected using an AutoDELFIA Neonatal TSH kit within 72 hours after birth, and the birth weight Z-score of each newborn was estimated. Results: Higher exposure to maternal PM2.5 and some components (BC and NH4+) decreased the maternal fT4 level (p < 0.05), and the birth weight Z-score was decreased (p < 0.05) by higher exposure to maternal PM2.5 and some components (OM, BC, NO3-, and NH4+). A mediation analysis clarified that the maternal fT4 levels explained 15.9%, 18.4%, and 20.9% of the associations of maternal PM2.5, BC, and NH4+ exposure with the birth weight Z-score, respectively (p < 0.05). After additional sensitivity analyses including only nonpreterm participants (n = 418) and non-TPOAb-positive participants (n = 415), the models remained stable. Conclusions: Our results suggest an inverse association between maternal exposure to PM2.5 and its components and the maternal fT4 levels. Maternal fT4 might act as a mediator between exposure to PM2.5 and its components and birth weight.

15.
BMC Plant Biol ; 19(1): 331, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357955

RESUMO

BACKGROUND: Salt stress is one of the environmental factors that greatly limits crop production worldwide because high salt concentrations in the soil affect morphological responses and physiological and metabolic processes, including root morphology and photosynthetic characteristics. Soil aeration has been reported to accelerate the growth of plants and increase crop yield. The objective of this study was to examine the effects of 3 NaCl salinity levels (28, 74 and 120 mM) and 3 aeration volume levels (2.3, 4.6 and 7.0 L/pot) versus non-aeration and salinity treatments on the root morphology, photosynthetic characteristics and chlorophyll content of potted tomato plants. RESULTS: The results showed that both aeration volume and salinity level affected the root parameters, photosynthetic characteristics and chlorophyll content of potted tomato plants. The total length, surface area and volume of roots increased with the increase in aeration volume under each NaCl stress level. The effect was more marked in the fine roots (especially in ≤1 mm diameter roots). Under each NaCl stress level, the photosynthetic rate and chlorophyll content of tomato significantly increased in response to the aeration treatments. The net photosynthetic rate and chlorophyll a and t content increased by 39.6, 26.9, and 17.9%, respectively, at 7.0 L/pot aeration volume compared with no aeration in the 28 mM NaCl treatment. We also found that aeration could reduce the death rate of potted tomato plants under high salinity stress conditions (120 mM NaCl). CONCLUSIONS: The results suggest that the negative effect of NaCl stress can be offset by soil aeration. Soil aeration can promote root growth and increase the photosynthetic rate and chlorophyll content, thus promoting plant growth and reducing the plant death rate under NaCl stress conditions.


Assuntos
Lycopersicon esculentum/fisiologia , Fotossíntese , Raízes de Plantas/anatomia & histologia , Clorofila/metabolismo , Lycopersicon esculentum/anatomia & histologia , Lycopersicon esculentum/crescimento & desenvolvimento , Lycopersicon esculentum/metabolismo , Raízes de Plantas/fisiologia , Salinidade , Estresse Salino , Solo
16.
NMR Biomed ; 32(11): e4128, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31355979

RESUMO

Excessive tissue scarring, or fibrosis, is a critical contributor to end stage renal disease, but current clinical tests are not sufficient for assessing renal fibrosis. Quantitative magnetization transfer (qMT) MRI provides indirect information about the macromolecular composition of tissues. We evaluated measurements of the pool size ratio (PSR, the ratio of immobilized macromolecular to free water protons) obtained by qMT as a biomarker of tubulointerstitial fibrosis in a well-established murine model with progressive renal disease. MR images were acquired from 16-week-old fibrotic hHB-EGFTg/Tg mice and normal wild-type (WT) mice (N = 12) at 7 T. QMT parameters were derived using a two-pool five-parameter fitting model. A normal range of PSR values in the cortex and outer stripe of outer medulla (CR + OSOM) was determined by averaging across voxels within WT kidneys (mean ± 2SD). Regions in diseased mice whose PSR values exceeded the normal range above a threshold value (tPSR) were identified and measured. The spatial distribution of fibrosis was confirmed using picrosirius red stains. Compared with normal WT mice, scattered clusters of high PSR regions were observed in the OSOM of hHB-EGFTg/Tg mouse kidneys. Moderate increases in mean PSR (mPSR) of CR + OSOM regions were observed across fibrotic kidneys. The abnormally high PSR regions (% area) detected by the tPSR were significantly increased in hHB-EGFTg/Tg mice, and were highly correlated with regions of fibrosis detected by histological fibrosis indices measured from picrosirius red staining. Renal tubulointerstitial fibrosis in OSOM can thus be assessed by qMT MRI using an appropriate analysis of PSR. This technique may be used as an imaging biomarker for chronic kidney diseases.

18.
Int J Biol Sci ; 15(6): 1252-1260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223284

RESUMO

CD44 is one of biomarkers of liver cancer stem cells (CSCs). The investigation of mechanism of CD44 translocation helps to uncover new molecular pathways participated in the regulation of various cellular processes in CSCs. In the present study, we observed the translocation of CD44 from cytoplasm to nuclear in the reprogramming process of C3A cells, full-length CD44 presented in the nucleus of liver iCSCs. CD44 was bound with importin ß and transportin 1 in liver iCSCs. Inhibition of importin ß transport leads to reduction of CD44 in the nucleus. Translocation of CD44 is also influenced by importin α. Besides, overexpression of naïve pluripotent genes, KLF2, KLF5, DNMT3L, GBX2, ZFP42, ESRRB and DPPA4 were found in liver iCSCs. Inhibition of CD44 leads to the reduction of these naïve genes. Luciferase and chromatin immunoprecipitation (ChIP) assays further identified nuclear CD44 bound to the promoter regions of naïve genes, KLF2, KLF5, and ESRRB functioned as transcriptional activators in liver iCSCs. Our present work provides new insight into the dynamic states and functions of CD44 in iCSCs.

19.
Hypertens Res ; 42(11): 1808-1815, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31253944

RESUMO

The cardiovascular protective role of furin has been suggested by some animal-based studies but has not been well studied in humans. Therefore, the objective of this study was to examine the prospective association between serum furin and high blood pressure in a longitudinal cohort of Chinese adults. Leveraging a longitudinal prospective cohort with blood pressure examined twice on average 4 years apart, we systemically examined the cross-sectional, longitudinal, and prospective associations of baseline serum furin with blood pressure and incident hypertension. Conventional risk factors, including age, sex, education level, cigarette smoking, alcohol consumption, BMI, fasting glucose, and lipids, were controlled. All participants included were free of cardiovascular and kidney disease at baseline. The cross-sectional analysis of 2312 participants (mean age 53 years) revealed that individuals with the lowest quartile of serum furin had average systolic, diastolic, and mean arterial blood pressures that were 2.58, 1.38, and 1.61 mmHg higher, respectively, than the corresponding pressures in individuals with the highest quartile (all P < 0.001). These negative associations remained significant after controlling for the dynamic risk profiles during follow-up in the longitudinal analysis. The prospective analysis of 1088 participants free of prevalent hypertension at baseline revealed that compared with participants with the highest quartile of serum furin, those with the lowest quartile had a 46% increased risk of incident hypertension (HR = 1.46, P = 0.003). These results indicate that lower serum furin is significantly associated with higher blood pressure and predicts an increased future risk of developing hypertension in Chinese adults. Furin may be a protective factor or marker of hypertension.

20.
Aging (Albany NY) ; 11(12): 3939-3957, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31195368

RESUMO

The B7-CD28 gene family plays a key role in regulating cellular immunity and is closely related to tumorigenesis and immune evasion. Here, we explored associations between clinical and immune features and B7-CD28 gene family expression in Gene Expression Omnibus (GEO) datasets representing 1812 diffuse large B-cell lymphoma (DLBCL) patients. This included 414 in the GSE10846 training cohort and 470 and 928 patients in the GSE31312 and GSE117556 validation cohorts, respectively. Four survival-associated genes identified in the GSE10846 cohort by univariate Cox analysis were incorporated into a multivariate analysis, ultimately establishing a three-gene risk signature. Risk scores assigned based on expression of these genes were validated by Kaplan­Meier and multivariable Cox analyses in the remaining datasets and in important clinical subsets. High-risk patients had shorter overall survival and, in some cases, progression-free survival than low-risk patients. Additionally, expression of programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1), as well as several other important immune checkpoint genes, differed between high-risk and low-risk patients, as did the proportions of various immune-infiltrating cells. Finally, further analysis confirmed that these B7-CD28 genes play important roles in immune responses altered in DLBCL.

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