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1.
Nano Lett ; 24(6): 2003-2010, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38306120

RESUMO

Heat-assisted magnetic anisotropy engineering has been successfully used in selective magnetic writing and microwave amplification due to a large interfacial thermal resistance between the MgO barrier and the adjacent ferromagnetic layers. However, in spin-orbit torque devices, the writing current does not flow through the tunnel barrier, resulting in a negligible heating effect due to efficient heat dissipation. Here, we report a dramatically reduced switching current density of ∼2.59 MA/cm2 in flexible spin-orbit torque heterostructures, indicating a 98% decrease in writing energy consumption compared with that on a silicon substrate. The reduced driving current density is enabled by the dramatically decreased magnetic anisotropy due to Joule dissipation and the lower thermal conductivity of the flexible substrate. The large magnetic anisotropy could be fully recovered after the impulse, indicating retained high stability. These results pave the way for flexible spintronics with the otherwise incompatible advantages of low power consumption and high stability.

2.
J Transl Med ; 22(1): 83, 2024 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-38245759

RESUMO

BACKGROUND: Observational studies have suggested an association between multiple sclerosis (MS) and cortical structure, but the results have been inconsistent. OBJECTIVE: We used two-sample Mendelian randomization (MR) to assess the causal relationship between MS and cortical structure. METHODS: MS data as the exposure trait, including 14,498 cases and 24,091 controls, were obtained from the International Multiple Sclerosis Genetics Consortium. Genome-wide association study (GWAS) data for cortical surface area (SAw/nw) and thickness (THw/nw) in 51,665 individuals of European ancestry were obtained from the ENIGMA Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Enrichment analysis was performed on MR analyses filtered by sensitivity analysis. RESULTS: After IVW and sensitivity analysis filtering, only six surviving MR results provided suggestive evidence supporting a causal relationship between MS and cortical structure, including lingual SAw (p = .0342, beta (se) = 5.7127 (2.6969)), parahippocampal SAw (p = .0224, beta (se) = 1.5577 (0.6822)), rostral middle frontal SAw (p = .0154, beta (se) = - 9.0301 (3.7281)), cuneus THw (p = .0418, beta (se) = - 0.0020 (0.0010)), lateral orbitofrontal THw (p = .0281, beta (se) = 0.0025 (0.0010)), and lateral orbitofrontal THnw (p = .0417, beta (se) = 0.0029 (0.0014)). Enrichment analysis suggested that leukocyte cell-related pathways, JAK-STAT signaling pathway, NF-kappa B signaling pathway, cytokine-cytokine receptor interaction, and prolactin signaling pathway may be involved in the effect of MS on cortical morphology. CONCLUSION: Our results provide evidence supporting a causal relationship between MS and cortical structure. Enrichment analysis suggests that the pathways mediating brain morphology abnormalities in MS patients are mainly related to immune and inflammation-driven pathways.


Assuntos
Encefalopatias , Esclerose Múltipla , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Esclerose Múltipla/genética , Causalidade , Receptores de Citocinas , Polimorfismo de Nucleotídeo Único/genética
3.
Diabetes Obes Metab ; 26(4): 1197-1206, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38172083

RESUMO

AIM: To evaluate the effect of age and disease duration on the efficacy and safety of iGlarLixi versus insulin glargine 100 units/ml (iGlar) or lixisenatide (Lixi) alone in Asian people with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (LixiLan-O-AP) or basal insulin ± oral antidiabetic drugs (LixiLan-L-CN). MATERIALS AND METHODS: In this post hoc analysis, the glycated haemoglobin (HbA1c) changes were assessed from baseline to week 24 (LixiLan-O-AP) or 30 (LixiLan-L-CN) in subgroups defined by baseline age (<65, ≥65 years) and duration of T2D. The proportion who achieved the composite of HbA1c <7% (<53.0 mmol/mol) without weight gain and without symptomatic hypoglycaemia (plasma glucose ≤3.9 mmol/L) and the incidences of hypoglycaemia and gastrointestinal disorders were also analysed. RESULTS: HbA1c reductions were consistently greater with iGlarLixi versus iGlar or Lixi across all subgroups, including participants aged ≥65 years and those with T2D for ≥15 or ≥20 years. Greater proportions of participants achieved HbA1c <7% (<53.0 mmol/mol) without weight gain or hypoglycaemia with iGlarLixi versus iGlar or Lixi, regardless of age or T2D duration. Hypoglycaemia incidence was similar with iGlarLixi versus iGlar across most subgroups; the incidence of gastrointestinal disorders was lower with iGlarLixi versus Lixi in all subgroups. CONCLUSIONS: iGlarLixi showed consistent efficacy and safety across all age and disease duration subgroups in Asian people with uncontrolled T2D, including older individuals and those with longstanding disease.


Assuntos
Diabetes Mellitus Tipo 2 , Gastroenteropatias , Hipoglicemia , Humanos , Povo Asiático , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Combinação de Medicamentos , Hemoglobinas Glicadas , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Insulina Glargina , Aumento de Peso , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso
4.
Diabetes Obes Metab ; 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38922731

RESUMO

AIM: To compare the efficacy and safety of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs). METHODS: In Soli-D, a 24-week, multicentre, open-label, study, insulin-naïve adults were randomized 1:1 to once-daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium-glucose co-transporter-2 inhibitors. The primary endpoint was non-inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed. RESULTS: At week 24, iGlarLixi showed non-inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: -0.20 [95% confidence interval {CI}: -0.33, -0.07]; P < .001 for non-inferiority; [97.5% CI: -0.35, -0.05]; P = .003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of -1.49 kg in favour of iGlarLixi (97.5% CI: -2.32, -0.66; P < .001). Event rates (per person-year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported. CONCLUSIONS: In Chinese people with T2D suboptimally controlled with OADs, once-daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp.

5.
Exp Cell Res ; 433(1): 113795, 2023 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-37797799

RESUMO

It was reported that lowly expressed RING1 indicates poor prognosis in breast cancer (BC) patients, while the mechanism by which RING1 is involved in BC progression is not fully understood. Here, we found that RING1 was lowly expressed in BC tissues and cells than in normal mammary tissues and epithelial cells. Overexpression of RING1 suppressed the cell proliferative and colony formation abilities, and facilitated cell cycle arrest and cell apoptosis in BC cells (T47D and MCF-7 cells). Mechanistically, as an ubiquitin ligase, RING1 bound to HSF1 and induced its proteasome-dependent degradation. HSF1 could bind to the promoter region of MT2A to promote the transcriptional level of MT2A. While RING1 overexpression hindered the transcriptional activation of MT2A induced by HSF1. Moreover, ectopic expression of MT2A reversed the inhibitory effect of RING1 on cell proliferation and clonogenesis, and antagonized the promotion effect of RING1 on cell cycle arrest and apoptosis in BC cells. Additionally, T47D cells infected with or without lentivirus-mediated RING1 overexpression vector (LV-RING1) were injected subcutaneously into the right back of nude mice to evaluate tumorigenicity. And overexpression of RING1 impeded the growth of BC xenografts in mice. In conclusion, RING1 suppressed the transcriptional activation of MT2A induced by HSF1 by facilitating the ubiquitination degradation of HSF1, resulting in cell cycle arrest and apoptosis in BC cells.

6.
Crit Rev Eukaryot Gene Expr ; 33(6): 43-53, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37522544

RESUMO

As an autophagy inhibitor, chloroquine (CQ) showed anti-tumor effect on several types of cancer and paclitaxel (PTX) is widely used in the treatment of esophageal carcinoma patients, but chemoresistance remains a major hurdle for PTX application due to the cytoprotective autophagy. Therefore, the aim of this study was to investigate whether CQ could elevate the anti-tumor effect of PTX on esophageal carcinoma cell line EC109 and explore the potential molecular mechanisms. We confirmed the suppressive effect of PTX on EC109 by MTT, scratch test, transwell and soft agar assay. And, we detected the key proteins in Akt/mTOR pathway, as well as the autophagy marker LC3 and p62 through Western Blot. In addition, GFP-LC3 plasmid was transfected into EC109 cells to monitor the autophagosome after CQ and PTX treatment. Ultimately, we observed the alterations in the proliferation and colony formation abilities of EC109 after knocking down mTOR by shRNA. We confirmed PTX could suppress the proliferation, migration and colony formation (all P < 0.05) abilities of EC109, and CQ could sensitize the inhibition effect of PTX by inhibiting autophagy through Akt/mTOR pathway. Furthermore, inhibiting Akt/mTOR pathway initiated autophagy and enhanced the sensitivity of EC109 to CQ and PTX. In summary, we suggest CQ could be used as a potential chemosensitizer for PTX in esophageal carcinoma treatment.


Assuntos
Carcinoma , Neoplasias Esofágicas , Humanos , Paclitaxel/farmacologia , Cloroquina/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Apoptose , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Serina-Treonina Quinases TOR/genética , Autofagia , Proliferação de Células
7.
J Neuroinflammation ; 20(1): 138, 2023 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-37268957

RESUMO

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico , Granzimas , Esclerose Múltipla Crônica Progressiva/diagnóstico , Linfócitos T CD8-Positivos , Subpopulações de Linfócitos T , Esclerose Múltipla Recidivante-Remitente/diagnóstico
8.
Helicobacter ; 28(3): e12964, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36880502

RESUMO

Gastric cancer (GC) is a globally important disease. The discovery of Helicobacter pylori (H. pylori) demonstrated that the human stomach is not a sterile environment, and recent advances in molecular biology have led to the detection of large populations of microorganisms in the stomach. A growing number of studies have elucidated differences in the microbiota of patients at various stages of GC development. Evidence from insulin-gastrin transgenic (INS-GAS) and human gastric microbiota-transplanted mouse models have further demonstrated the potential causality of microbiota in the development of GC. To date, H. pylori is still thought to be the strongest risk factor for GC. H. pylori interacts with non-H. pylori commensals and affects the composition of the gastric microbiota. This review provides an overview of the relationship between the gastric microbiota and GC, including the mechanisms of microbe-associated carcinogenesis, the clinical value of the microbiota as a GC biomarker, and the potential of modulating the microbiota for GC prevention or therapy.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Microbiota , Lesões Pré-Cancerosas , Neoplasias Gástricas , Camundongos , Animais , Humanos , Neoplasias Gástricas/etiologia , Helicobacter pylori/genética , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Carcinogênese , Mucosa Gástrica
9.
Helicobacter ; 28(1): e12940, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36458325

RESUMO

BACKGROUND: Although vonoprazan has been proven to be a highly potent drug for Helicobacter pylori eradication, there have been no randomized trials comparing the effectiveness of regimens containing vonoprazan 20 mg daily with alternative standard strategies. We aimed to assess the efficacy, tolerance, and cost-effectiveness of quadruple therapy with vonoprazan 20 mg daily as a first-line therapy for H. pylori eradication. MATERIALS AND METHODS: We conducted a single-center, open-label, noninferiority, randomized controlled study in Zhejiang, China. Treatment-naive H. pylori-positive participants (n = 234) were randomly assigned to three groups in a 1:1:1 ratio: vonoprazan 20 mg daily with amoxicillin 1000 mg, furazolidone 100 mg and colloidal bismuth 200 mg each given twice a day for 10 days (V10) or 14 days (V14), or esomeprazole 20 mg with amoxicillin 1000 mg, furazolidone 100 mg and colloidal bismuth 200 mg each given twice a day for 14 days (E14). The primary endpoint was the eradication rates in each group. The secondary endpoints were the incidence of adverse events (AEs) and compliance. RESULTS: The eradication rates in the V10, V14 and E14 groups were 96.2% (89.2-99.2%), 94.9% (87.4-98.6%), and 93.6% (85.7-97.9%) in the intention-to-treat analysis, and 98.6% (92.7-100.0%), 97.4% (90.8-99.7%), and 94.8% (87.2-98.6%) in the per-protocol analysis, respectively. Quadruple therapy with vonoprazan 20 mg daily was noninferior to the esomeprazole-based regimen (Farrington and Manning test: margin 10%, significance level 2.5%). The adverse event rates were 12.8% versus 3.8% versus 6.4% in the V10, V14, and E14 groups, respectively. All regimens were well tolerated without significant differences (p = 0.096). The cost-effectiveness ratio was 1.32, 1.88, and 3.06 for the V10, V14, and E14 groups in the intention-to-treat analysis, respectively. (NCT04907747). CONCLUSIONS: Vonoprazan (20 mg daily) was as effective as esomeprazole (20 mg twice a day) in quadruple therapies for the eradication of H. pylori, was more economical, and was well tolerated. In addition, the 10-day regimen of vonoprazan (20 mg daily) was comparable to the 14-day regimen.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Humanos , Infecções por Helicobacter/tratamento farmacológico , Esomeprazol , Antibacterianos/efeitos adversos , Bismuto/uso terapêutico , Furazolidona , Quimioterapia Combinada , Amoxicilina/uso terapêutico , Resultado do Tratamento , Inibidores da Bomba de Prótons/uso terapêutico
10.
Clin Oral Investig ; 27(3): 1289-1299, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36318336

RESUMO

OBJECTIVES: To investigate the variant of an amelogenesis imperfecta (AI) family and to explore the function of the FAM83H (family with sequence similarity 83 member H) in the enamel formation. MATERIALS AND METHODS: We investigated a five-generation Chinese family diagnosed with AI; clinical data was collected, whole-exome sequencing (WES) was conducted to explore the pathogenic gene and variants and Sanger sequencing was used to verify the variants. The three-dimensional protein structures of wild-type and mutant FAM83H were predicted using alpha fold 2. To study the possible regulatory function of Fam83h on amelogenesis, immunolocalization was performed to observe the expression of Fam83h protein in Sprague-Dawley rat postnatal incisors. The mRNA and protein level of amelogenin, enamelin, kallikrein-related peptidase-4 and ameloblastin were also detected after the Fam83h was knocked down by small interfering RNA (siRNA) in HAT-7 cells. RESULTS: A known nonsense variant (c.973 C > T) in exon 5 of FAM83H gene was found in this family, causing a truncated protein (p.R325X). Immunolocalization of Fam83h in Sprague-Dawley rat postnatal incisors showed that Fam83h protein expression was detected in presecretory and secretory stages. When Fam83h expression was reduced by siRNA, the expression of amelogenin, enamelin, kallikrein-related peptidase-4 decreased. However, the expression of ameloblastin increased. CONCLUSIONS: FAM83H gene variant (c.973 C > T) causes AI. FAM83H regulates the secretion of enamel matrix proteins and affects ameloblast differentiation. CLINICAL RELEVANCE: This study provided that FAM83H variants could influence enamel formation and provided new insights into the pathogenesis of AI.


Assuntos
Amelogênese Imperfeita , Proteínas do Esmalte Dentário , Humanos , Ratos , Animais , Amelogênese Imperfeita/genética , Amelogenina/genética , Ratos Sprague-Dawley , População do Leste Asiático , Proteínas do Esmalte Dentário/genética , Proteínas/genética , Calicreínas
11.
Clin Oral Investig ; 27(7): 3885-3894, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37017752

RESUMO

OBJECTIVES: To investigate the genetic causes and teeth characteristics of dentin dysplasia Shields type II(DD-II) in three Chinese families. MATERIALS AND METHODS: Data from three Chinese families affected with DD-II were collected. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were conducted to screen for variations, and Sanger sequencing was used to verify mutation sites. The physical and chemical characteristics of the affected teeth including tooth structure, hardness, mineral content, and ultrastructure were investigated. RESULTS: A novel frameshift deletion mutation c.1871_1874del(p.Ser624fs) in DSPP was found in families A and B, while no pathogenic mutation was found in family C. The affected teeth's pulp cavities were obliterated, and the root canals were smaller than normal teeth and irregularly distributed comprising a network. The patients' teeth also had reduced dentin hardness and highly irregular dentinal tubules. The Mg content of the teeth was significantly lower than that of the controls, but the Na content was obviously higher than that of the controls. CONCLUSIONS: A novel frameshift deletion mutation, c.1871_1874del (p.Ser624fs), in the DPP region of the DSPP gene causes DD-II. The DD-II teeth demonstrated compromised mechanical properties and changed ultrastructure, suggesting an impaired function of DPP. Our findings expand the mutational spectrum of the DSPP gene and strengthen the understanding of clinical phenotypes related to the frameshift deletion in the DPP region of the DSPP gene. CLINICAL RELEVANCE: A DSPP mutation can alter the characteristics of the affected teeth, including tooth structure, hardness, mineral content, and ultrastructure.


Assuntos
Dentinogênese Imperfeita , Dente , Humanos , Dentina/patologia , Dentinogênese , Dentinogênese Imperfeita/genética , Proteínas da Matriz Extracelular/genética , Mutação , Fenótipo
12.
Radiology ; 304(1): 106-113, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35412367

RESUMO

Background Deep learning (DL) algorithms could improve the classification of ovarian tumors assessed with multimodal US. Purpose To develop DL algorithms for the automated classification of benign versus malignant ovarian tumors assessed with US and to compare algorithm performance to Ovarian-Adnexal Reporting and Data System (O-RADS) and subjective expert assessment for malignancy. Materials and Methods This retrospective study included consecutive women with ovarian tumors undergoing gray scale and color Doppler US from January 2019 to November 2019. Histopathologic analysis was the reference standard. The data set was divided into training (70%), validation (10%), and test (20%) sets. Algorithms modified from residual network (ResNet) with two fusion strategies (feature fusion [hereafter, DLfeature] or decision fusion [hereafter, DLdecision]) were developed. DL prediction of malignancy was compared with O-RADS risk categorization and expert assessment by area under the receiver operating characteristic curve (AUC) analysis in the test set. Results A total of 422 women (mean age, 46.4 years ± 14.8 [SD]) with 304 benign and 118 malignant tumors were included; there were 337 women in the training and validation data set and 85 women in the test data set. DLfeature had an AUC of 0.93 (95% CI: 0.85, 0.97) for classifying malignant from benign ovarian tumors, comparable with O-RADS (AUC, 0.92; 95% CI: 0.85, 0.97; P = .88) and expert assessment (AUC, 0.97; 95% CI: 0.91, 0.99; P = .07), and similar to DLdecision (AUC, 0.90; 95% CI: 0.82, 0.96; P = .29). DLdecision, DLfeature, O-RADS, and expert assessment achieved sensitivities of 92%, 92%, 92%, and 96%, respectively, and specificities of 80%, 85%, 89%, and 87%, respectively, for malignancy. Conclusion Deep learning algorithms developed by using multimodal US images may distinguish malignant from benign ovarian tumors with diagnostic performance comparable to expert subjective and Ovarian-Adnexal Reporting and Data System assessment. © RSNA, 2022 Online supplemental material is available for this article.


Assuntos
Aprendizado Profundo , Neoplasias Ovarianas , Algoritmos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico por imagem , Curva ROC , Estudos Retrospectivos
13.
Anticancer Drugs ; 33(3): 286-299, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34924499

RESUMO

Circular RNAs (circRNAs) are implicated with the progression of multiple cancers, including breast cancer. Besides, circRNA dysregulation is involved in the chemoresistance of cancer development. This study aimed to investigate the role of circRNA-cyclin dependent kinase 1 (circCDK1) in breast cancer. Quantitative real-time PCR (qPCR) and western blot were applied for expression analysis. Cell viability was determined by the cell counting kit-8 (CCK-8). Cell proliferation was evaluated by CCK-8, colony formation and 5-ethynyl-2'-deoxyuridine assays. Cell apoptosis was assessed by flow cytometry and the activities of caspase3 and caspase9. The potential binding between miR-489-3p and circCDK1 or CDK1 was verified by RNA immunoprecipitation assay, dual-luciferase reporter assay and pull-down assay. Animal models were constructed to explore the role of circCDK1 in vivo. CircCDK1 was overexpressed in Tamoxifen-resistant breast cancer cells, LCC2 and LCC9. The expression of circCDK1 in tumor tissues with Tamoxifen resistance was higher than that in tissues without Tamoxifen resistance. CircCDK1 knockdown strengthened the sensitivity of Tamoxifen in LCC2 and LCC9 cells and reduced Tamoxifen IC50. The downregulation of circCDK1 inhibited LCC2 andLCC9 cell proliferation and promoted cell apoptosis. CDK1 was the parent gene of circCDK1 and circCDK1 positively regulated CDK1 expression by targeting miR- 489-3p. CDK1 overexpression reversed the effects of circCDK1 knockdown. MiR-489-3p inhibition also reversed the effects of circCDK1 knockdown. CircCDK1 knockdown was verified to enhance Tamoxifen sensitivity in animal models. CircCDK1 knockdown enhanced the sensitivity of Tamoxifen in breast cancer cells and suppressed cell growth and survival by depleting CDK1 expression via releasing miR- 489-3p.


Assuntos
Neoplasias da Mama , MicroRNAs , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteína Quinase CDC2/genética , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular , Tamoxifeno/farmacologia
14.
Helicobacter ; 27(3): e12889, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35363917

RESUMO

BACKGROUND: To investigate the current state of knowledge and practice of Helicobacter pylori (H. pylori) infection management in China. MATERIALS AND METHODS: This nationwide, multicenter, cross-sectional questionnaire survey was conducted between March and April 2021 with respect to the diagnosis and treatment of H. pylori infection in 31 provinces, encompassing over 1000 hospitals in mainland China. General physician information, diagnostic and detection status, eradication treatment, reexamination and follow-up after treatment, and basic knowledge of physicians were collected and compared with the Fifth Chinese National Consensus Report on Management of H. pylori infection and the 2016 Maastricht V/Florence guidelines. The subgroup analysis was also performed. RESULTS: Of the 6873 questionnaire respondents, 48.8% were males, and 51.2% were females. Approximately, 26.5% of respondents indicated that their hospitals had dedicated clinics for managing H. pylori infection. Moreover, 88.0% of respondents prescribed a bismuth-containing quadruple regimen as the initial eradication treatment, and 92.7% deemed the gastric acid suppression critical. Furthermore, 91.0% of respondents routinely recommended a reexamination 1-2 months after eradication therapy, and 95.1% advised patients to stop PPI treatment at least 2 weeks before reexamination. The detail of following (the choice of target population/methods; the choice/availability of drugs/regimens, indications for eradication, factors influencing eradication efficacy/improvement methods and factors influencing adherence, management options/factors influencing relapse; the timing and methods, awareness of reinfection rates/prevention measures, and the approach to continuing education, awareness of guidelines, and acceptance of current core concepts of management) was also described. Subgroup analysis further revealed that significant differences were existed in being gastroenterologist or not, different education level, professional title, years of working, and provincial administrative regions. CONCLUSIONS: Chinese physicians' skills and knowledge about the diagnosis and treatment of H. pylori infection could be improved. More works on education are needed in future.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Médicos , Antibacterianos/uso terapêutico , China/epidemiologia , Estudos Transversais , Quimioterapia Combinada , Feminino , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Humanos , Masculino
15.
BMC Neurol ; 22(1): 235, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35761294

RESUMO

BACKGROUND: Many patients with neurological disorders experience chronic fatigue, but the neural mechanisms involved are unclear. OBJECTIVE: Here we investigated whether the brain structural and functional connectivity alterations were involved in fatigue related to neuromyelitis optica spectrum disorder (NMOSD). METHODS: This prospective pilot study used structural and resting-state functional brain magnetic resonance imaging to compare total cortical thickness, cortical surface area, deep gray matter volume and functional connectivity (FC) between 33 patients with NMOSD and 20 healthy controls (HCs). Patients were subgrouped as low fatigue (LF) and high fatigue (HF). RESULTS: HF patients scored higher on the Hamilton Anxiety Rating Scale and Hamilton Rating Scale for Depression than LF patients and HCs. The two patient subgroups and HC group did not differ significantly in cortical thickness, cortical surface area and volumes of the bilateral caudate nucleus, bilateral putamen, bilateral amygdala, bilateral hippocampus, bilateral thalamus proper or right nucleus accumbens (p > 0.05). However, after correcting for age, sex, years of education, anxiety and depression, HF patients showed larger left pallidum than HCs (0.1573 ± 0.0214 vs 0.1372 ± 0.0145, p = 0.009). Meanwhile, both LF patients (0.0377 ± 0.0052 vs 0.0417 ± 0.0052, p = 0.009) and HF patients (0.0361 ± 0.0071 vs 0.0417 ± 0.0052, p = 0.013) showed smaller left nucleus accumbens than HCs.. Compared with LF patients, HF patients showed significantly decreased FC between the left pallidum and bilateral cerebellar posterior lobes. CONCLUSIONS: This was the first evidence linking structural and functional alterations in the brain to fatigue in NMOSD, and in the future, long term follow-up was necessary.


Assuntos
Neuromielite Óptica , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Neuromielite Óptica/complicações , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/patologia , Projetos Piloto , Estudos Prospectivos
16.
Neurol Sci ; 43(1): 411-417, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33948764

RESUMO

BACKGROUND: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant disorder with high penetrance characterized by progressive cognitive and motor dysfunction. The objective of the study was to describe a new variant of the colony stimulating factor-1 receptor (CSF1R) gene causing HDLS in a Chinese family. METHODS: Physical examinations, laboratory tests, structural neuroimaging studies, and whole-exome sequence analysis were carried out. RESULTS: Three patients in this family exhibited typical manifestations of HDLS, including progressive cognitive impairment, language and motor dysfunctions, and urinary and bowel incontinence. Genetic analysis identified a heterozygous missense mutation (c.2264T>C, p.L755P) in exon 17 of the CSF1R gene that cosegregated with the HDLS phenotype in an autosomal-dominant pattern. Brain MRI of the proband and her father showed diffuse white matter changes. The proband's 10-year-old son, a gene carrier, remains clinically asymptomatic at present. CONCLUSIONS: Our findings identify a novel missense mutation, p.L755P, in the CSF1R gene within a Chinese family with autosomal-dominant HDLS and broaden the genetic spectrum of CSF1R-associated HDLS.


Assuntos
Leucoencefalopatias , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Criança , Feminino , Heterozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Receptor de Fator Estimulador de Colônias de Macrófagos/genética
17.
Neurol Sci ; 43(2): 1295-1301, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34089417

RESUMO

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder characterized by café-au-lait macules (CALMs), skinfold freckling, Lisch nodules, and neurofibromas. It is associated with heterozygous mutations in the neurofibromatosis type 1 (NF1) gene. Whole NF1 deletion has been described in some cases, but most cases are sporadic, and familial forms are extremely rare. To date, only two-generation familial forms have been described. OBJECTIVE: To describe a whole NF1 gene deletion in a three-generation family with neurofibromatosis type 1. METHODS: Physical examinations, laboratory tests, structural neuroimaging studies, whole-exome sequencing, and multiplex ligation-dependent probe amplification analysis were carried out. RESULTS: All the affected individuals within this three-generation family, including the 14-year-old female proband, her 40-year-old father, and 63-year-old grandmother, exhibited such typical manifestations of NF1 as CALMs and cutaneous neurofibromas, CALMs increased in size with age. The affected subjects had more localized hyperpigmentation and CALMs within the lesion areas, mainly in the chest, abdomen, waist, and back. In addition, learning disorder was observed in the proband, and brain MRI revealed abnormal high signal lesions in the brainstem. All the affected subjects had normal birth history and had no significant past medical history. Whole-exome sequencing and subsequent multiplex ligation-dependent probe amplification analysis identified deletion of the whole NF1 gene, co-segregating with the NF1 phenotype in an autosomal dominant pattern. CONCLUSIONS: Our findings are the first to identify whole NF1 deletion in a three-generation family with autosomal dominant NF1 and broaden the understanding of the genetic spectrum of NF1-associated NF1.


Assuntos
Neurofibromatose 1 , Adolescente , Adulto , Manchas Café com Leite/genética , Feminino , Genes da Neurofibromatose 1 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/genética , Fenótipo
18.
PLoS Genet ; 15(10): e1008357, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31609978

RESUMO

Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10-8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/genética , Fator de Transcrição PAX9/genética , Alelos , Encéfalo/fisiopatologia , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Dosagem de Genes/genética , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
19.
J Sex Med ; 18(9): 1500-1510, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34348883

RESUMO

BACKGROUND: The correlation between long-term treatment outcomes with genotypes in congenital hypogonadotropic hypogonadism (CHH) males is rarely reported. AIM: To investigate the correlations among genotypes, phenotypes, and treatment outcomes for CHH male patients. METHODS: Whole exome sequencing was performed for 73 Chinese CHH males from one academic center. Patients self-selected one of the 4 treatments: pulsatile Gonadorelin pump (PGP), cyclical gonadotropins therapy (CGT), human menopausal gonadotropin monotherapy, or testosterone replacement treatment. Clinical assessments were performed every 3 months for 3 years. OUTCOMES: The pathogenicity of variants was determined. Baseline clinical features, spermatogenesis outcomes were analysed. RESULTS: 62 variants were identified in 51 patients (69.9%), 17 of which were novel. Among these mutations, variants on FGFR1, PROKR2, CHD7, ANOS1 and NSMF gene were 16.1%, 16.1%, 11.3%, 8.1% and 8.1% respectively. 11 patients followed the oligogenic pattern (21.6%). All CHD7 patients had hearing impairment or structural deformities of external/inner ear, and were diagnosed as CHARGE syndrome. 24.7% of CHH patients manifested with ear/hearing anomalies. KS patients had higher rates of cryptorchidism history and ear/hearing anomalies than normosmic CHH subjects. Male patients with PROKR2 mutations showed relatively better testicular development, less dental deformity when compared with FGFR1 mutations. About 30% normosmic patients defined by simple olfactory assessment showed olfactory nerve center (ONC) dysplasia under nasal sinus MRI examination. Among the CHH males treated with CGT or PGP, 70.2% reached spermatogenesis within 3 years of treatment. CLINICAL IMPLICATIONS: No direct correlation was observed between certain responsible genes and spermatogenic outcomes. When CHH patients were identified with CHD7 variants, ear/hearing evaluation should be carefully performed. The precise assessment of ONC development was advised for normosmic CHH subjects. STRENGTHS & LIMITATIONS: This study provided informative long-term treatment data of CHH male patients screened with whole exome sequencing. The limitations included small number of subgroups with multifaceted gene variants, clinical heterogeneity, and uncontrolled sperm-inducing treatment method. The seventeen novel mutations worth experimental validation in the future. CONCLUSION: The clinical severity is partially related with specific gene variants, and detailed individualized data and outcomes were provided. Ear/hearing anomalies were closely connected with CHD7 variants, and were common problems for CHH patients. Simple olfactory assessment underestimated the true olfactory deficit. L. Zhang, Y. Gao, Q. Du, et al. Genetic Profiles and Three-year Follow-up Study of Chinese Males With Congenital Hypogonadotropic Hypogonadism. J Sex Med 2021;18:1500-1510.


Assuntos
Perfil Genético , Hipogonadismo , China , Seguimentos , Humanos , Hipogonadismo/genética , Masculino , Mutação
20.
Hepatobiliary Pancreat Dis Int ; 20(5): 426-432, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34246549

RESUMO

BACKGROUND: This study aimed to assess the association between metabolic syndrome (MetS) and severity of nonalcoholic fatty liver disease (NAFLD), and to discuss the pathological relevance of the diagnostic criteria in metabolic (dysfunction) associated fatty liver disease (MAFLD). METHODS: This was a multicenter, cross-sectional study. Patients with NAFLD confirmed by liver biopsy were enrolled between July 2016 and December 2018 from 14 centers across the mainland of China. Anthropometric and metabolic parameters were collected to assess the pathological relevance. RESULTS: Of 246 enrolled patients with NAFLD, 150 (61.0%) had the comorbidity of MetS. With the increase of metabolic components, the proportions of nonalcoholic steatohepatitis (NASH) and significant fibrosis were notably increased. The comorbid three metabolic components significantly increased the proportion of NASH, and further increase of metabolic components did not increase the proportion of NASH. However, the increase of metabolic components was parallel to the increase of the proportion of liver fibrosis. Among the 246 patients, 239 (97.2%) met the diagnostic criteria of MAFLD. Although non-MAFLD patients had less NASH, they present with similar proportion of significant fibrosis and cirrhosis. In the diagnostic criteria of MAFLD, BMI ≥ 23 kg/m2 was related to NASH (Mantel-Haenszel Common Estimate OR: 2.975; 95% CI: 1.037-8.538; P = 0.043), and T2DM was related to significant fibrosis (Mantel-Haenszel Common Estimate OR: 2.531; 95% CI: 1.388-4.613; P = 0.002). The homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.5 was the most significant factor for NASH (OR: 4.100; 95% CI: 1.772-9.487; P = 0.001) and significant factor for liver fibrosis (OR: 2.947; 95% CI: 1.398-6.210; P = 0.004) after the adjustments of the BMI and diabetes. CONCLUSIONS: Metabolic dysregulations are important risk factors in NAFLD progression. The insulin resistance status may play a predominant role in the progression in MAFLD patients.


Assuntos
Resistência à Insulina , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Biópsia , China/epidemiologia , Estudos Transversais , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia
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