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1.
Blood Purif ; 51(2): 171-181, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34175850

RESUMO

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) constitute an important treatment option for anemia in hemodialysis (HD) patients. We investigated the relationships among the dosage of ESA, erythropoietin resistance index (ERI) scores, and mortality in Chinese MHD patients. METHODS: This multicenter observational retrospective study included MHD patients from 16 blood purification centers (n = 824) who underwent HD in 2011-2015 and were followed up until December 31, 2016. We collected demographic variables, HD parameters, laboratory values, and ESA dosages. Patients were grouped into quartiles according to ESA dosage to study the effect of ESA dosage on all-cause mortality. The ERI was calculated as follows: ESA (IU/week)/weight (kg)/hemoglobin levels (g/dL). We also compared outcomes among the patients stratified into quartiles according to ERI scores. We used the Cox proportional hazards model to measure the relationships between the ESA dosage, ERI scores, and all-cause mortality. Using propensity score matching, we compared mortality between groups according to ERI scores, classified as either > or ≤12.80. RESULTS: In total, 824 patients were enrolled in the study; 200 (24.3%) all-cause deaths occurred within the observation period. Kaplan-Meier analyses showed that patients administered high dosages of ESAs had significantly worse survival than those administered low dosages of ESAs. A multivariate Cox regression identified that high dosages of ESAs could significantly predict mortality (ESA dosage >10,000.0 IU/week, HR = 1.59, 95% confidence intervals (CIs) (1.04, 2.42), and p = 0.031). Our analysis also indicated a significant increase in the risk of mortality in patients with high ERI scores. Propensity score matching-analyses confirmed that ERI > 12.80 could significantly predict mortality (HR = 1.56, 95% CI [1.11, 2.18], and p = 0.010). CONCLUSIONS: Our data suggested that ESA dosages >10,000.0 IU/week in the first 3 months constitute an independent predictor of all-cause mortality among Chinese MHD patients. A higher degree of resistance to ESA was related to a higher risk of all-cause mortality.


Assuntos
Eritropoetina , Hematínicos , Eritropoese , Eritropoetina/uso terapêutico , Hematínicos/uso terapêutico , Humanos , Diálise Renal , Estudos Retrospectivos
2.
Signal Transduct Target Ther ; 6(1): 414, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873151

RESUMO

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.


Assuntos
Antivirais/administração & dosagem , Azidas/administração & dosagem , COVID-19/tratamento farmacológico , Desoxicitidina/análogos & derivados , SARS-CoV-2/metabolismo , Timo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Coronavirus Humano OC43/metabolismo , Desoxicitidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Timo/metabolismo , Timo/virologia
3.
Theranostics ; 11(19): 9605-9622, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646389

RESUMO

Rationale: Recurrent and metastatic cancers often undergo a period of dormancy, which is closely associated with cellular quiescence, a state whereby cells exit the cell cycle and are reversibly arrested in G0 phase. Curative cancer treatment thus requires therapies that either sustain the dormant state of quiescent cancer cells, or preferentially, eliminate them. However, the mechanisms responsible for the survival of quiescent cancer cells remain obscure. Methods: Dual genome-editing was carried out using a CRISPR/Cas9-based system to label endogenous p27 and Ki67 with the green and red fluorescent proteins EGFP and mCherry, respectively, in melanoma cells. Analysis of transcriptomes of isolated EGFP-p27highmCherry-Ki67low quiescent cells was conducted at bulk and single cell levels using RNA-sequencing. The extracellular acidification rate and oxygen consumption rate were measured to define metabolic phenotypes. SiRNA and inducible shRNA knockdown, chromatin immunoprecipitation and luciferase reporter assays were employed to elucidate mechanisms of the metabolic switch in quiescent cells. Results: Dual labelling of endogenous p27 and Ki67 with differentiable fluorescent probes allowed for visualization, isolation, and analysis of viable p27highKi67low quiescent cells. Paradoxically, the proto-oncoprotein c-Myc, which commonly drives malignant cell cycle progression, was expressed at relatively high levels in p27highKi67low quiescent cells and supported their survival through promoting mitochondrial oxidative phosphorylation (OXPHOS). In this context, c-Myc selectively transactivated genes encoding OXPHOS enzymes, including subunits of isocitric dehydrogenase 3 (IDH3), whereas its binding to cell cycle progression gene promoters was decreased in quiescent cells. Silencing of c-Myc or the catalytic subunit of IDH3, IDH3α, preferentially killed quiescent cells, recapitulating the effect of treatment with OXPHOS inhibitors. Conclusion: These results establish a rigorous experimental system for investigating cellular quiescence, uncover the high selectivity of c-Myc in activating OXPHOS genes in quiescent cells, and propose OXPHOS targeting as a potential therapeutic avenue to counter cancer cells in quiescence.


Assuntos
Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Antígeno Ki-67/metabolismo , Melanoma/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Senescência Celular , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Isocitrato Desidrogenase/metabolismo , Neoplasias/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fase de Repouso do Ciclo Celular , Transcriptoma/genética
4.
Cell Death Dis ; 12(8): 724, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290231

RESUMO

Glioblastomas (GBM) is the most common primary malignant brain tumor, and radiotherapy plays a critical role in its therapeutic management. Unfortunately, the development of radioresistance is universal. Here, we identified calcium-regulated heat-stable protein 1 (CARHSP1) as a critical driver for radioresistance utilizing genome-wide CRISPR activation screening. This is a protein with a cold-shock domain (CSD)-containing that is highly similar to cold-shock proteins. CARHSP1 mRNA level was upregulated in irradiation-resistant GBM cells and knockdown of CARHSP1 sensitized GBM cells to radiotherapy. The high expression of CARHSP1 upon radiation might mediate radioresistance by activating the inflammatory signaling pathway. More importantly, patients with high levels of CARHSP1 had poorer survival when treated with radiotherapy. Collectively, our findings suggested that targeting the CARHSP1/TNF-α inflammatory signaling activation induced by radiotherapy might directly affect radioresistance and present an attractive therapeutic target for GBM, particularly for patients with high levels of CARHSP1.


Assuntos
Neoplasias Encefálicas/genética , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Proteínas de Ligação a DNA/metabolismo , Genoma Humano , Glioblastoma/genética , Fosfoproteínas/metabolismo , Tolerância a Radiação/genética , Fatores de Transcrição/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Fosfoproteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/genética
5.
Nat Commun ; 12(1): 3734, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145290

RESUMO

Genomic amplification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy. Here we functionally characterise a non-protein product of the 3q region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in diverse cancer types through copy number gain as well as E2F1-mediated transcriptional activation. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, thus leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. This is, at least in part, responsible for PLANE-mediated promotion of cancer cell proliferation and tumorigenicity. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.


Assuntos
Processamento Alternativo/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Células A549 , Linhagem Celular Tumoral , Proliferação de Células/genética , Cromossomos Humanos Par 3/genética , Variações do Número de Cópias de DNA/genética , Fator de Transcrição E2F1/metabolismo , Células HCT116 , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Humanos , Células MCF-7 , Neoplasias/patologia , Correpressor 2 de Receptor Nuclear/genética , Interferência de RNA , RNA Interferente Pequeno/genética
6.
Medicine (Baltimore) ; 98(6): e14376, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732173

RESUMO

There are few studies on the correlation between red blood cell distribution width (RDW) and cardiovascular events in the patients receiving peritoneal dialysis (PD). We explored the correlation between RDW and cardiovascular events in PD patients and possible mechanism.A total of 138 PD patients were divided into RDW < 15% group (n = 104) and RDW ≥ 15% group (n = 34).The levels of serum C-reactive protein (CRP) [3.05 (0.79, 15.30) mg/L vs 2.15 (1.00, 6.50) mg/L] and parathyroid hormone (PTH) [260.0 (192.7, 352.6) ng/L vs 200.7 (118.0, 319.7) ng/L] were significantly higher, but the levels of serum albumin [30.65 (27.4,32.8) g/L vs 32.3 (29.25,34.95) g/L], prealbumin [(299 ±â€Š96) g/L vs (346 ±â€Š86) g/L], triglyceride [1.24 (0.72, 1.50) mmol/L vs 1.42 (1.12,1.84) mmol/L], and transferrin saturation [27.9 (16.4, 43.6)% vs 37.8 (23.3, 57.2)%] were significantly lower in the RDW ≥ 15% group than in the RDW < 15% group (all P < 0.05). The RDW was negatively correlated with albumin (r = - 0.258, P = 0.002), prealbumin (r = -0.236, P = 0.005), and triglyceride (r = -0.194, P = 0.023), but was positively correlated with CRP level (r = 0.174, P = 0.041). The incidence of cardiovascular events was significantly higher in the RDW ≥ 15% group (6 patients, 17.6%) than in the RDW < 15% group (6.7%) (7 patients, P < 0.01). Cox proportional hazard model showed that elevated RDW level was an independent risk factor for cardiovascular events in PD patients (HR = 1.622, 95% CI: 1.063-2.475, P = 0.025).The elevated RDW may be served as a risk factor to predict the cardiovascular events in PD patients.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Eritrócitos/metabolismo , Diálise Peritoneal/estatística & dados numéricos , Adulto , Proteína C-Reativa , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Pré-Albumina/análise , Albumina Sérica
7.
Chin Med J (Engl) ; 130(8): 885-891, 2017 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-28397716

RESUMO

BACKGROUND: Patients on hemodialysis have a high-mortality risk. This study analyzed factors associated with death in patients on maintenance hemodialysis (MHD). While some studies used baseline data of MHD patients, this study used the most recent data obtained from patients just prior to either a primary endpoint or the end of the study period to find the characteristics of patients preceding death. METHODS: Participants were selected from 16 blood purification centers in China from January 2012 to December 2014. Patients' data were collected retrospectively. Based on survival status, the participants were divided into two groups: survival group and the death group. Logistic regression analysis was performed to determine factors associated with all-cause mortality. RESULTS: In total, 4104 patients (57.58% male, median age 59 years) were included. Compared with the survival group, the death group had more men and more patients with diabetic nephropathy (DN) and hypertensive nephropathy. The patients preceding death also had lower levels of diastolic blood pressure, hemoglobin, serum albumin, serum calcium, serum phosphate, Kt/V, and higher age. Multivariate analysis revealed that male sex (odd ratio [OR]: 1.437, 95% confidence interval [CI]: 1.094-1.886), age (OR: 1.046, 95% CI: 1.036-1.057), and presence of DN (OR: 1.837, 95% CI: 1.322-2.552) were the risk factors associated with mortality. High serum calcium (OR: 0.585, 95% CI: 0.346-0.989), hemoglobin (OR: 0.974, 95% CI: 0.967-0.981), albumin (OR: 0.939, 95% CI: 0.915-0.963) levels, and dialysis with noncuffed catheter (OR: 0.165, 95% CI: 0.070-0.386) were protective factors based on a multivariate analysis. CONCLUSIONS: Hemodialysis patients preceding death had lower hemoglobin, albumin, and serum calcium levels. Multivariate analysis showed that male sex, age, DN, low hemoglobin, low albumin, and low serum calcium were associated with death in hemodialysis patients.


Assuntos
Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Adulto , Idoso , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco
8.
Int J Clin Exp Med ; 7(12): 5772-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25664105

RESUMO

Polymorphisms in the Xba I and Pvu II restriction enzyme recognition sites in the estrogen receptor-alpha gene (ESR1) have been associated with multiple diseases, including osteoarthritis. To determine whether such polymorphisms are associated with osteoarthritis in a Han Chinese population, 98 women with osteoarthritis and 196 healthy women were genotyped by PCR-RFLP of ESR1 with Xba I and Pvu II. Absence of a restriction polymorphism is indicated as an X or P allele; presence of the restriction polymorphism is indicated as an x or p allele. Clinical information was collected on each participant, including body weight, body mass index (BMI), knee radiograms, and bone mineral density (BMD). Body weight and BMI were higher for each Xba I genotype (all P < 0.05) in individuals with osteoarthritis compared to controls (p < 0.05). Femoral BMD was also significantly higher in the osteoarthritis group (p < 0.05). Additionally, the xx genotype for ESR1 was a significant risk factor for osteoarthritis (OR=1.98, 95% CI: 1.13~4.20, p=0.036). Thus, consistent with findings in other populations, the estrogen receptor genotype xx appears to be associated with susceptibility to osteoarthritis among Han Chinese women.

9.
Chin Med J (Engl) ; 126(12): 2276-80, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23786938

RESUMO

BACKGROUND: Data on the epidemiology of hypertension in Chinese non-dialysis chronic kidney disease (CKD) patients are limited. The aim of the present study was to investigate the prevalence, awareness, treatment, and control of hypertension in the non-dialysis CKD patients through a nationwide, multicenter study in China. METHODS: The survey was performed in 61 tertiary hospitals in 31 provinces, municipalities, and autonomous regions in China (except Hong Kong, Macao, and Taiwan). Trained physicians collected demographic and clinical data and measured blood pressure (BP) using a standardized protocol. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, and/or use of antihypertensive medications. BP < 140/90 mmHg and < 130/80 mmHg were used as the 2 thresholds of hypertension control. In multivariate logistic regression with adjustment for sex and age, we analyzed the association between CKD stages and uncontrolled hypertension in non-dialysis CKD patients. RESULTS: The analysis included 8927 non-dialysis CKD patients. The prevalence, awareness, and treatment of hypertension in non-dialysis CKD patients were 67.3%, 85.8%, and 81.0%, respectively. Of hypertensive CKD patients, 33.1% and 14.1% had controlled BP to < 140/90 mmHg and < 130/80 mmHg, respectively. With successive CKD stages, the prevalence of hypertension in non-dialysis CKD patients increased, but the control of hypertension decreased (P < 0.001). When the threshold of BP < 130/80 mmHg was considered, the risk of uncontrolled hypertension in CKD 2, 3a, 3b, 4, and 5 stages increased 1.3, 1.4, 1.4, 2.5, and 4.0 times compared with CKD 1 stage, respectively (P < 0.05). Using the threshold of < 140/90 mmHg, the risk of uncontrolled hypertension increased in advanced stages (P < 0.05). CONCLUSIONS: The prevalence of hypertension Chinese non-dialysis CKD patients was high, and the hypertension control was suboptimal. With successive CKD stages, the risk of uncontrolled hypertension increased.


Assuntos
Hipertensão/epidemiologia , Insuficiência Renal Crônica/complicações , Adulto , Idoso , Conscientização , Feminino , Humanos , Hipertensão/complicações , Hipertensão/terapia , Masculino , Pessoa de Meia-Idade , Prevalência
10.
Nephrol Dial Transplant ; 24(1): 172-8, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18697800

RESUMO

UNLABELLED: Objective. Anti-C1q antibodies are common in sera from patients with lupus nephritis (LN) and are associated with disease activity. The current study aimed to further investigate the prevalence of serum IgG anti-C1q antibody, its subclass distribution and their clinical and pathological association in patients with LN. METHODS: Sera were collected from 150 patients with renal biopsy-proven LN, diagnosed from 2000 to 2006 in our hospital, 30 patients with systemic lupus erythematosus (SLE) without clinical evidence of renal involvement (non-renal SLE, NR-SLE) and 63 healthy donors. ELISA was used to detect serum IgG anti-C1q antibody and its subclass. Their clinical and pathological associations were further analysed. RESULTS: The prevalence of IgG anti-C1q antibody in LN (84/150, 56%) was significantly higher than that in NR-SLE (6/30, 20%) and healthy controls (3/63, 4.8%) (P < 0.005, P < 0.001, respectively). The prevalence of anti-C1q antibody in patients with diffuse proliferative renal lesions (class IV) (59/82, 71.95%) was significantly higher than that in those with non-diffuse proliferative renal lesions (class II + III) (12/26, 46.15%, P = 0.016) and class V (13/42, 30.95%, P < 0.001). The prevalence of IgG2 (60/135, 44.44%) was significantly higher than that of IgG1 (37/135, 27.41%) and IgG3 (25/135, 18.52%) (P < 0.005, P < 0.001, respectively). IgG2 was associated with the occurrence of arthritis (P < 0.05), higher serum creatinine (P < 0.05) and lower serum C3 (P < 0.05). Of the 38 LN patients with sera both in active phase and in remission, 17 were anti-C1q antibody-positive in active phase and the antibody levels decreased in all and turned to negative in 9 (52.94%) in remission. Meanwhile, the ratio of turning negative of IgG1, IgG2 and IgG3 anti-C1q was 33%(2/6), 53.85% (7/13) and 100% (7/7), respectively. CONCLUSIONS: Anti-C1q antibodies are prevalent in LN and are closely associated with diffuse proliferative lesions. IgG2 anti-C1q might be pathogenic and IgG3 anti-C1q might be a more specific biomarker for monitoring disease activity.


Assuntos
Autoanticorpos/sangue , Complemento C1q/imunologia , Imunoglobulina G/sangue , Nefrite Lúpica/imunologia , Adulto , Autoanticorpos/classificação , Estudos de Casos e Controles , China , Feminino , Humanos , Imunoglobulina G/classificação , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/etiologia , Nefrite Lúpica/patologia , Masculino , Adulto Jovem
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