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1.
Otolaryngol Head Neck Surg ; : 194599820926137, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32484727

RESUMO

OBJECTIVE: To investigate the changes of blood pressure (BP) on patients with obstructive sleep apnea/hypopnea syndrome (OSA) before and after upper airway surgery. DESIGN: Case series with chart review. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: Patients with OSA who underwent upper airway surgery were enrolled. We retrospectively investigated the nighttime and daytime BP before and at least 3 months after OSA surgery. Paired t test was used to compare the changes of BP before and after surgery. Generalized estimating equation was used to examine the prognostic significance of the variables in predicting the changes of postoperative BP. RESULTS: In total, 176 patients with OSA (149 men, 27 women; mean age, 42.9 years; mean apnea/hypopnea index, 43.1/h) were enrolled in this study. The overall nighttime and daytime BP decreased significantly before and after OSA surgery (daytime systolic BP was reduced from 137.3 ± 14.0 mm Hg to 132.7 ± 17.0 mm Hg, P < .01; nighttime systolic BP was reduced from 138.7 ± 16.0 mm Hg to 133.7 ± 15.3 mm Hg, P < .01; daytime diastolic BP was reduced from 87.7 ± 14.7 mm Hg to 84.9 ± 10.6 mm Hg, P = .01; nighttime diastolic BP was reduced from 85.4 ± 12.9 mm Hg to 83.1 ± 11.1 mm Hg, P = .02). The changes of nighttime systolic and diastolic BP were significantly associated with the improvement of percentage of O2 saturation <90% during polysomnography. CONCLUSION: Surgical modifications of the upper airways for patients with OSA could benefit blood pressure.

2.
Int J Mol Sci ; 21(10)2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32414036

RESUMO

Zinc oxide nanoparticles (ZnONPs) are frequently encountered nanomaterials in our daily lives. Despite the benefits of ZnONPs in a variety of applications, many studies have shown potential health hazards of exposure to ZnONPs. We have shown that oropharyngeal aspiration of ZnONPs in mice increases lung inflammation. However, the detailed mechanisms underlying pulmonary inflammatory cell infiltration remain to be elucidated. Endothelium functions as a barrier between the blood stream and the blood vessel wall. Endothelial barrier dysfunction may increase infiltration of immune cells into the vessel wall and underlying tissues. This current study examined the effects of ZnONPs exposure on endothelial barriers. ZnONPs exposure increased leukocyte infiltration in the mouse lungs. In endothelial cells, ZnONPs reduced the continuity of tight junction proteins claudin-5 and zonula occludens-1 (ZO-1) at the cell junctions. ZnONPs induced adherens junction protein VE-cadherin internalization from membrane to cytosol and dissociation with ß-catenin, leading to reduced and diffused staining of VE-cadherin and ß-catenin at cell junctions. Our results demonstrated that ZnONPs disrupted both tight and adherens junctions, compromising the integrity and stability of the junction network, leading to inflammatory cell infiltration. Thus, ZnONPs exposure in many different settings should be carefully evaluated for vascular effects and subsequent health impacts.

3.
Radiat Oncol ; 15(1): 84, 2020 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-32307024

RESUMO

BACKGROUND: To evaluate the longitudinal changes of quality of life (QoL) and survival in patients with nasopharyngeal carcinoma (NPC) treated by volumetric-modulated arc therapy (VMAT) versus intensity-modulated radiotherapy (IMRT). METHODS: One hundred and forty non-distant metastatic NPC patients treated by VMAT (n = 66) or IMRT (n = 74) with simultaneously integrated boost between March 2013 and December 2015 at a single institute were analyzed. QoL was prospectively assessed by the EORTC QLQ-C30 and HN35 questionnaires at the four time points: before RT, RT 42.4 Gy (20 fractions), and 3, 12 months after RT. RESULTS: The 3-year locoregional relapse-free survival, distant metastasis-free survival, failure-free survival, and overall survival rates were 96.6, 89.4, 86.1%, and 87.4 for the VMAT group, respectively, compared with 91.4, 90.0, 79.8, and 91.3% for the IMRT group (p value > 0.05). The pattern of QoL changes was similar between the VMAT and IMRT group. No statistically or clinically significant difference in all the QoL scales was observed between VMAT and IMRT group at each time point. Compared to before RT, we observed statistically (p<0.05) and clinically (difference of mean scores≧10) better outcome in global QoL and social functioning, but worse head and neck symptomatic outcome in swallowing, taste/smell, opening mouth, dry mouth, and sticky saliva at the time point of 1 year after RT for both groups. CONCLUSION: The study provides the evidence that the tumor control, survival and changes of QoL is compatible for NPC patients treated by VMAT versus IMRT.

4.
Aging Cell ; 19(1): e13075, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31755176

RESUMO

Aging, cancer, and longevity have been linked to intracellular Ca2+ signaling and nociceptive transient receptor potential (TRP) channels. We found that TRP canonical 7 (TRPC7) is a nociceptive mechanoreceptor and that TRPC7 channels specifically mediate the initiation of ultraviolet B (UVB)-induced skin aging and tumor development due to p53 gene family mutations. Within 30 min after UVB irradiation, TRPC7 mediated UVB-induced Ca2+ influx and the subsequent production of reactive oxygen species in skin cells. Notably, this function was unique to TRPC7 and was not observed for other TRP channels. In TRPC7 knockout mice, we did not observe the significant UVB-associated pathology seen in wild-type mice, including epidermal thickening, abnormal keratinocyte differentiation, and DNA damage response activation. TRPC7 knockout mice also had significantly fewer UVB-induced cancerous tumors than did wild-type mice, and UVB-induced p53 gene family mutations were prevented in TRPC7 knockout mice. These results indicate that TRPC7 activity is pivotal in the initiation of UVB-induced skin aging and tumorigenesis and that the reduction in TRPC7 activity suppresses the UVB-induced aging process and tumor development. Our findings support that TRPC7 is a potential tumor initiator gene and that it causes cell aging and genomic instability, followed by a change in the activity of proto-oncogenes and tumor suppressor genes to promote tumorigenesis.

5.
BMC Endocr Disord ; 19(1): 80, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349821

RESUMO

BACKGROUND: Myasthenia gravis (MG) is the most common disorder of neuromuscular transmission, and it is typified by fluctuating degrees and variable combinations of weakness in the ocular, bulbar, limb, and respiratory muscles. Under rare circumstances, MG can be accompanied by Addison's disease. CASE PRESENTATION: Here, we reported the case of a 57-year-old Chinese woman with MG. She experienced progressive muscle weakness for 1 week. MG with acute exacerbation was initially suspected. However, further biochemistry tests found mild hyperkalemia (5.6 mEq/L) and a lower renal potassium excretion rate. Consequently, low aldosterone action was highly suspected. Further findings included a suppressed cortisol level, a higher adrenocorticotropic hormone concentration, and 21-hydroxylase antibody positivity, supporting a diagnosis of primary adrenal insufficiency due to autoimmune adrenalitis. CONCLUSION: We successfully demonstrated that adrenal insufficiency could be diagnosed, due to the presence of hyperkalemia. This case suggested a need for clinicians to consider the possible coincidence of adrenal insufficiency in a patient with MG and hyperkalemia. Early hormone supplementation should be begun.


Assuntos
Hiperpotassemia/patologia , Miastenia Gravis/complicações , Feminino , Humanos , Hiperpotassemia/etiologia , Pessoa de Meia-Idade , Prognóstico
6.
Cell Death Dis ; 10(6): 420, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142735

RESUMO

Accelerated glucose metabolism is critical in hepatocarcinogenesis, but the utilities of different glucose transporter inhibitors in treating hepatocellular carcinoma (HCC) remain largely uncharacterized. In this study, we examined a collection of glucose transporter inhibitors and found differential anti-HCC effects among these compounds. Canagliflozin (CANA), phloretin, and WZB117 decreased cellular glucose influx, but only CANA showed potent growth inhibition in HCC, which indicated a glucose-independent anti-HCC mechanism. Notably, we found that CANA treatment significantly downregulated the expression of ß-catenin in HCC cells in. By co-treating cells with cycloheximide and MG-132, we proved that CANA promoted proteasomal degradation of ß-catenin protein by increasing phosphorylation of ß-catenin, and CANA-induced inactivation of protein phosphatase 2A was identified being responsible for this effect. Moreover, using Huh7 xenografted tumor model, CANA treatment was shown to delay tumor growth and improved the survival of HCC bearing mice. Our study highlights the unique dual ß-catenin-inhibition mechanisms of CANA, which may provide new thoughts on treating HCC patient with concurrent diabetes, and, furthermore, on developing novel treatment targeting metabolic reprogram and/or WNT/ß-catenin signaling in HCC.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31018505

RESUMO

Previous studies have demonstrated that organochlorine pesticide (OCP) exposure has a negative impact on the neurological function of infants. Only a few reports have investigated the thyroid and growth hormones and their relationship to neurodevelopment after human exposure to OCPs, especially in the case of infants. Our goal was to determine whether breastmilk OCP residues were associated with negative impacts and/or alterations in the neurodevelopment of infants among specific southern Taiwanese mother-breastfed infant pairs. Our subjects (n = 55 pairs) were recruited from southern Taiwan between 2007 and 2010. The thyroid and growth hormone levels in the cord blood samples collected after childbirth were determined. The breastmilk was gathered within one month after childbirth for the determination of OCP levels using a high-resolution gas chromatograph with mass spectrometry, and the neurodevelopment of 10-12-month-old infants was examined using the Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III). It was observed that 4,4'-dichlorodiphenyl-dichloroethylene (4,4'-DDE) (mean = 10.3 ng/g lipid) was the most predominant OCP compound in the breastmilk samples. At higher concentrations (>75th percentile), specific OCPs were associated with significantly lower levels of thyroid and growth hormones than at lower concentrations (<75th percentile). Significantly higher odds ratios (ORs) were observed for binary cognitive (OR = 8.09, p = 0.025 for 4,4'-DDT), language (OR = 11.9, p = 0.013 for 4,4'-DDT) and social-emotional (OR = 6.06, p = 0.01 for trans-CHL) composite scores for specific OCPs belonging to the lower exposure group as compared to the higher OCP exposure group. The five domain Bayley-III infant neurodevelopment outcomes were negatively associated with specific OCPs in the breast milk samples based on the redundancy analysis (RDA) test. Bayley-III scales, which include cognitive, language, motor, social-emotional, and adaptive behavior scales, could be predicted by 4,4'-DDT, endrin, endosulfan I, heptachlor, or heptachlor epoxide using multivariate linear regression models with adjustment for maternal age, pre-pregnant BMI, parity, and infant gender. In conclusion, although our study showed that postnatal exposure to breast milk OCPs may be associated with infant neurodevelopmental outcomes and that prenatal exposure, if extrapolated from breastmilk levels, is associated with changes in thyroid and growth hormones that may have effects on neurodevelopment, these associations are only suggestive; thus, further studies are recommended for confirmation.


Assuntos
Sistema Nervoso Central/crescimento & desenvolvimento , Sangue Fetal/química , Hidrocarbonetos Clorados/análise , Exposição Materna , Leite Humano/química , Resíduos de Praguicidas/análise , Hormônios Tireóideos/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lactente , Paridade , Parto , Gravidez , Taiwan
8.
PLoS One ; 14(3): e0213400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870448

RESUMO

Transforming growth factor-ß (TGF-ß) is an important target for treating systemic sclerosis (SSc). However, our study revealed three levels of TGF-ß1 expression in SSc patients, indicating that inhibiting TGF-ß is not sufficient to treat SSc. A previous clinical trial also displayed disappointing results. Thus, our study attempted to search for a potential novel approach. Ingenuity Pathway Analysis (IPA) indicated that the SSc pathological pathways were closely associated with store-operated Ca2+ entry (SOCE)-regulated signals, and SOCE activity was found to be increased in SSc fibroblasts. Further treatment of SSc fibroblasts with SOCE inhibitors, 2APB, and associated calcium channel inhibitors SKF96365, and indomethacin, showed that the SOCE inhibitors selectively decreased fibrosis markers and altered the cell morphology. Consequently, SOCE inhibitors, especially 2APB and indomethacin, caused the dedifferentiation of SSc fibroblasts via cytoskeleton remodeling and altered collagen secretion and restored the cell mobility. We further explained SSc pathogenesis as fibroblast differentiation with SOCE. Treatment with exogenous factors, gelatin-1, FAM20A and human albumin, which were identified from the conditioned medium of SSc fibroblasts, was important for regulating the differentiation of fibroblasts with higher levels of SOCE and α-SMA. Conclusively, to treat SSc, blockage of the increased SOCE activity in SSc induces the dedifferentiation of SSc fibroblasts and simultaneously changes the extracellular matrix (ECM) structure to limit SSc pathogenesis.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Compostos de Boro/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Desdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Microambiente Celular/efeitos dos fármacos , Colágeno/metabolismo , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Imidazóis/farmacologia , Indometacina/farmacologia , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta1/metabolismo
9.
Environ Toxicol ; 34(7): 814-824, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30919559

RESUMO

Exposure to ambient particulate matter (PM) is associated with hypertension and cardiovascular diseases. Recently, we reported that exposure to fine and coarse PM caused pulmonary inflammation and pulmonary small arterial remodeling in mice, and osteopontin (OPN) level was elevated following PM exposure. However, in the present study, cotreatment with 5-methoxytryptophan for 4 weeks partially reduced coarse PM-induced pulmonary inflammation without reducing pulmonary OPN secretion or recovery from pulmonary arterial remodeling in mice. Persistent vascular dysfunction may lead to vascular remodeling. Therefore, we further compared the relationship between coarse PM-induced inflammation and vascular dysfunction by exposing mice to PM before and after cessation of PM exposure. Oropharyngeal aspiration of PM for 8 weeks induced pulmonary inflammation and pulmonary small artery remodeling in mice, as well as increased serum C-reactive protein and OPN concentrations and systolic blood pressure (SBP). After the cessation of PM exposure for another 8 weeks, lung inflammation had recovered and vascular remodeling had partially recovered. Elevation of OPN, metalloproteinases (MMPs), and cytokines in bronchioalveolar lavage were significantly reduced. However, PM-induced systemic responses did not recover after the cessation of PM exposure. Notably, not only serum OPN and SBP remained significantly elevated; also, serum endothelin-1, MMP-9, and keratinocyte-derived chemokine concentrations were significantly increased after cessation of PM exposure for another 8 weeks. These data suggested that systemic inflammation and systemic vascular dysfunction might be important in PM-induced elevation of SBP. Furthermore, SBP elevation was persistent after cessation of PM exposure for 8 weeks.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Material Particulado/efeitos adversos , Pneumonia/fisiopatologia , Pneumonia/reabilitação , Poluentes Atmosféricos/efeitos adversos , Animais , Hipertensão/complicações , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Pneumonia/complicações , Pneumonia/patologia , Recuperação de Função Fisiológica , Testes de Toxicidade
10.
Medicine (Baltimore) ; 98(13): e14986, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30921209

RESUMO

RATIONALE: The chronic complications caused by the tunneled cuffed catheter in chronic dialysis patients are infection and catheter dysfunction. While bleeding due to this access can occur occasionally. PATIENT CONCERNS: We present a 92-year-old woman with a 6-year history of regular hemodialysis (HD). For the past 2 years, she has been receiving HD via a tunneled cuffed catheter placed in the right internal jugular vein. She suffered from a right chest subcutaneous hematoma near the catheter without recent trauma. The increasing size of hematoma after dialysis, and the oozing from the outlet of the catheter were also observed. DIAGNOSIS: Computed tomography of chest and angiography were done and showed that the hematoma was caused by thoracoacromial artery bleeding, which was near the puncture site of the tunneled cuffed catheter. INTERVENTIONS: Fluid resuscitation, blood transfusion, surgical drainage, and parenteral antibiotics were prescribed. OUTCOMES: Patient recovered fully without any further sequelae. LESSONS: Spontaneous bleeding of thoracoacromial artery is rare and clinicians should keep in mind as a differential diagnosis in patient with new-onset hematoma over anterior chest wall. Early diagnosis and treatment are important in such cases.


Assuntos
Cateteres de Demora/efeitos adversos , Hematoma/patologia , Veias Jugulares , Diálise Renal/métodos , Idoso de 80 Anos ou mais , Artérias/patologia , Feminino , Hematoma/terapia , Humanos
11.
Environ Pollut ; 245: 975-985, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30682754

RESUMO

Ambient particulate matter (PM) exposure is associated with pulmonary and cardiovascular diseases; however, there is scant research linking data on animal and human cells. The objective of this study was to investigate these associations. Vascular remodeling plays a crucial role in both pulmonary and cardiovascular diseases. Therefore, we conducted a transcriptomic analysis using vascular smooth muscle cells (VSMCs) to identify potential regulators or markers of PM exposure. We demonstrated that fine and coarse PM increased VSMC proliferation in mice. We conducted a genome-wide cDNA microarray analysis, followed by a pathway analysis of VSMCs treated with coarse PM for durations of 24, 48, and 72 h. Sixteen genes were discovered to be time-dependently upregulated and involved in VSMC proliferation. Osteopontin (OPN) is indicated as one of the regulators of these upregulated genes. Both fine and coarse PM from industrial and urban areas significantly increased OPN expression in VSMCs and macrophages. Moreover, oropharyngeal instillation of fine and coarse PM for 8 weeks increased the VSMCs in the pulmonary arteries of mice. OPN level was consistently increased in the lung tissues, bronchoalveolar lavage fluid, and serum of mice. Moreover, we analyzed the plasma OPN levels of 72 healthy participants recruited from the studied metropolitan area. Each participant wore a personal PM2.5 sampler to assess their PM2.5 exposure over a 24 h period. Our results indicate that personal exposure to fine PM is positively correlated with plasma OPN level in young adults. The data obtained in this study suggest that exposure to fine and coarse PM may cause pulmonary vascular lesions in humans and that OPN level may be a biomarker of PM exposure in humans.


Assuntos
Poluentes Atmosféricos/análise , Exposição Ambiental/análise , Macrófagos/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Osteopontina/metabolismo , Material Particulado/análise , Adulto , Poluentes Atmosféricos/toxicidade , Animais , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Miócitos de Músculo Liso/metabolismo , Osteopontina/genética , Tamanho da Partícula , Material Particulado/toxicidade , Células RAW 264.7 , Adulto Jovem
12.
Cancers (Basel) ; 11(1)2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634502

RESUMO

Meta-analysis revealed that Leucine Zipper Down-Regulated In Cancer 1 (LDOC1) increased methylation more in people with lung tumors than in those who were healthy and never smoked. Quantitative methylation-specific PCR revealed that cigarette smoke condensate (CSC) exposure drives LDOC1 promoter hypermethylation and silence in human bronchial cells. Immunohistochemistry studies showed that LDOC1 downregulation is associated with poor survival of patients with lung cancer. Loss and gain of LDOC1 functions enhanced and attenuated aggressive phenotypes in lung adenocarcinoma A549 and non⁻small cell lung carcinoma H1299 cell lines, respectively. We found that LDOC1 deficiency led to reinforcing a reciprocal loop of IL-6/JAK2/STAT3, through which LDOC1 mediates the cancer progression. LDOC1 knockdown considerably augmented tumorigenesis and the phosphorylation of JAK2 and STAT3 in vivo. Results from immunoprecipitation and immunofluorescent confocal microscopy indicated that LDOC1 negatively regulates JAK2 activity by forming multiple protein complexes with pJAK2 and E3 ubiquitin-protein ligase LNX1, and in turn, LDOC1 targets pJAK2 to cause ubiquitin-dependent proteasomal degradation. LDOC1 deficiency attenuates the interactions between LNX1 and pJAK2, leading to ineffective ubiquitination of pJAK2, which activates STAT3. Overall, our results elucidated a crucial role of LDOC1 in lung cancer and revealed how LDOC1 acts as a bridge between tobacco exposure and the IL-6/JAK2/STAT3 loop in this human malignancy.

13.
Colloids Surf B Biointerfaces ; 173: 788-797, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30384276

RESUMO

Cancer is a complex and tenacious disease. Drug-delivery systems in combination with multimodal therapy strategies are very promising candidates for cancer theranostic applications. In this study, a new drug-delivery vehicle that combine human serum albumin (HSA)- and poly(sodium 4-styrenesulfonate) (PSS)-coated gold nanorod nanoparticles(GNR/PSS/HSA NPs) was developed for synergistic cancer therapy. Doxorubicin (DOX) was loaded onto GNR/PSS/HSA NPs, by electrostatic and hydrophobic forces, to create multimodal DOX@GNR/PSS/HSA NPs. DOX@GNR/PSS/HSA NPs were found to be highly biocompatible and stable in physiological solutions. Furthermore, GNR/PSS/HSA NPs with or without DOX were designed to exhibit strong absorbance in the near-infrared region and high photothermal conversion efficiency. Therefore, bimodal DOX release from DOX@GNR/PSS/HSA NPs could be triggered by an acidic pH and by near-infrared irradiation after NPs preferentially accumulated at tumor sites, leading to a significant chemotherapeutic effect. Moreover, DOX@GNR/PSS/HSA NPs were designed to be applied during chemo- and photo-thermal combination therapy and exhibited a synergistic anticancer effect that was superior to the effect of monotherapy, from both in vitro and in vivo results. These results suggest that DOX@GNR/PSS/HSA NPs are a strong candidate for a nanoplatform for future antitumor therapeutic strategies.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Preparações de Ação Retardada , Doxorrubicina/farmacologia , Terapia de Alvo Molecular/métodos , Nanotubos/química , Neoplasias/terapia , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Terapia Combinada/métodos , Doxorrubicina/química , Doxorrubicina/metabolismo , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Ouro/química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Injeções Subcutâneas , Terapia com Luz de Baixa Intensidade/métodos , Camundongos , Camundongos Nus , Polímeros/química , Albumina Sérica Humana/química , Ácidos Sulfônicos/química , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Sci Rep ; 8(1): 16729, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30425257

RESUMO

Despite reported evidence on the relationship between higher serum aluminum levels and poor outcomes in patients on chronic hemodialysis (CHD), the acceptable cutoff value of serum aluminum for mortality remains unclear. A retrospective observational cohort study with 636 Taiwanese patients on CHD was conducted to investigate the impact of serum aluminum levels on mortality. The predictors were bivariate serum aluminum level (<6 and ≥6 ng/mL) and the Outcomes were all-cause and cardiovascular (CV) mortality. During the mean follow-up of 5.3 ± 2.9 years, 253 all-cause and 173 CV deaths occurred. Crude analysis showed that a serum aluminum level of ≥6 ng/mL was a significant predictor of all-cause [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.40-2.23] and CV (HR, 1.84; 95% CI, 1.36-2.50) mortality. After multivariable adjustment, the serum aluminum level of ≥6 ng/mL remained a significant predictor of all-cause mortality (HR, 1.37, 95% CI, 1.05-1.81) but became insignificant for CV mortality (HR, 1.29; 95% CI, 0.92-1.81). Therefore, our study revealed that a serum aluminum level of ≥6 ng/mL was independently associated with all-cause death in patients on CHD, suggesting that early intervention for aluminum level in patients on CHD might be beneficial even in the absence of overt aluminum toxicity.


Assuntos
Alumínio/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Diálise Renal , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo
15.
Sci Rep ; 8(1): 11866, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089847

RESUMO

Electronegative L5 low-density lipoprotein (LDL) level may be a useful biomarker for predicting cardiovascular disease. We determined the range of plasma L5 levels in healthy adults (n = 35) and examined the power of L5 levels to differentiate patients with coronary artery disease (CAD; n = 40) or patients with hyperlipidemia (HLP) without evidence of CAD (n = 35) from healthy adults. The percent L5 in total LDL (L5%) was quantified by using fast-protein liquid chromatography with an anion-exchange column. Receiver operating characteristic curve analysis was performed to determine cut-off values for L5 levels. The mean L5% and plasma concentration of L5 (ie, [L5]) were significantly higher in patients with HLP or CAD than in healthy adults (P < 0.001). The ranges of L5% and [L5] in healthy adults were determined to be <1.6% and <1.7 mg/dL, respectively. In individuals with L5% >1.6%, the odds ratio was 9.636 for HLP or CAD. In individuals with [L5] >1.7 mg/dL, the odds ratio was 17.684 for HLP or CAD. The power of L5% or [L5] to differentiate patients with HLP or CAD from healthy adults was superior to that of the LDL/high-density lipoprotein ratio. The ranges of L5% and [L5] in healthy adults determined here may be clinically useful in preventing and treating cardiovascular disease.


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/etiologia , Hiperlipidemias/sangue , Hiperlipidemias/complicações , Lipoproteínas LDL/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
16.
Eur J Cancer ; 102: 10-22, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30103095

RESUMO

AIM: Palbociclib is an oral cyclin-dependent kinase 4/6 inhibitor, which is efficacious in treating breast cancer. Currently, there are numerous active clinical trials testing palbociclib alone or in combination with other medications for treating various types of malignancies. Here, we evaluated the anti-cancer effect of palbociclib in combination with radiation therapy (RT) for treating human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) and addressed the molecular mechanism behind the combination therapy. METHODS: Immunofluorescence staining of γH2AX or 53BP1 was used to determine the effect of palbociclib on double-strand break (DSB) repair. Clonogenic assays, sphere formation and cell death ELISA were performed to study the sensitising effect of palbociclib on radiation-induced cytotoxicity. Signal alteration in DSB repair pathways was examined by Western blot analysis. Finally, we evaluated the in vivo anti-cancer activity and the associated molecular events of the combination therapy in a preclinical HCC xenograft model. RESULTS: Palbociclib affected the kinetics of DNA repair and enhanced the radiation sensitivity of HCC and CCA cells. Importantly, we found that palbociclib inhibits ataxia telangiectasia-mutated (ATM) kinase, the key upstream kinase responding to RT-induced DSBs. Furthermore, we showed that the inhibitory effect of palbociclib on RT-induced ATM kinase activation is mediated by protein phosphatase 5 (PP5). Both in vitro and in vivo investigations revealed that the inhibition of the PP5-ATM axis by palbociclib after DNA damage is responsible for the synergism between palbociclib and RT. CONCLUSION: Our findings provide a novel combination strategy against liver cancer cells. Clinical trials using palbociclib as an adjuvant in RT are warranted.


Assuntos
Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Neoplasias dos Ductos Biliares/terapia , Carcinoma Hepatocelular/terapia , Quimiorradioterapia , Colangiocarcinoma/terapia , Quebras de DNA de Cadeia Dupla , Reparo do DNA/efeitos dos fármacos , Neoplasias Hepáticas/terapia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Radiossensibilizantes/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/enzimologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Histonas/metabolismo , Humanos , Cinética , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Nus , Tolerância a Radiação , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nephron ; 140(3): 175-184, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30138926

RESUMO

BACKGROUND/AIMS: Taiwan has the highest incidence of end-stage renal disease, which requires renal replacement therapy. Chronic kidney disease (CKD) contributes to this burden. However, the current data on the epidemiologic features of CKD in Taiwan are incomplete. Therefore, we aimed to investigate the prevalence and incidence of CKD in a population-based study and then estimate the average dwelling time (ADT) in the main clinical burden of CKD (stages 3-5). METHODS: A prospective cohort study was designed with an integrated community-based multiple screening program of 106,094 individuals aged ≥20 years in Keelung, Taiwan, in 1999-2009. Prevalence was estimated as the percentage of CKD stages among individuals attending the first screening, and incidence was expressed as the ratio of total desired events in the following period to the total observational time. Finally, ADT was estimated from the ratio of prevalence to incidence. RESULTS: The participants' mean age was 47.7 ± 15.4 years. The estimated prevalence was 15.46% for total CKD and 9.06% for CKD stages 3-5. The incidence was 27.21/1,000 person-years (PY) for total CKD and 16.89/1,000-PY for CKD stages 3-5. Older patients, males, and those patients with comorbidities of diabetes mellitus (DM), hypertension, and metabolic syndrome (MetS) exhibited higher prevalence and incidence rates than their opposing counterparts. Moreover, the ADT of CKD stages 3-5 was 5.37 years (95% CI 5.17-5.57). Males and those with comorbidities of DM or MetS had shorter ADTs in CKD stages 3-5 than their opposing counterparts. Interestingly, the ADT of participants with hypertension was longer than those without. CONCLUSIONS: The prevalence and incidence of CKD in Taiwan are high. Moreover, ADT in CKD stages 3-5 varied according to sex, age, and comorbidity. Further exploration of the factors associated with the shifting of this duration will shed light on effective CKD management.


Assuntos
Serviços de Saúde Comunitária/organização & administração , Falência Renal Crônica/epidemiologia , Programas de Rastreamento/métodos , Adulto , Feminino , Humanos , Incidência , Falência Renal Crônica/classificação , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Taiwan/epidemiologia
18.
BMC Nephrol ; 19(1): 160, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973184

RESUMO

BACKGROUND: Hypokalemia is one of the most common clinical electrolyte imbalance problems, and thyrotoxic periodic paralysis (TPP) is a leading cause of presentation to the emergency department. Low renal potassium secretion rates, a normal acid-base balance in the blood, and hyperthyroidism are the hallmarks of suspected TPP. CASE PRESENTATION: Here we report the case of a 36-year-old man who presented to the emergency department with a sudden onset of acute muscle weakness at 5 h prior to admission. Biochemistry tests revealed hypokalemia with hyperthyroidism and renal potassium wasting. TPP was initially not favored due to the presence of renal potassium wasting. However, his serum potassium level rebounded rapidly within several hours after potassium supplementation, indicating that the intracellular shifting of potassium ions was the main etiology for his hypokalemia. The early stage of TPP development may have contributed to this paradox. CONCLUSION: Therefore, it is premature to rule out TPP based on the presentation of high renal potassium secretion rates alone. This finding may result in an incorrect impression being made in the early stage of TTP and may consequently lead to an inappropriate potassium supplementation policy.


Assuntos
Hipertireoidismo/sangue , Hipopotassemia/sangue , Debilidade Muscular/sangue , Paralisia/sangue , Potássio/sangue , Adulto , Diagnóstico Diferencial , Humanos , Hipertireoidismo/complicações , Hipertireoidismo/diagnóstico , Hipopotassemia/complicações , Hipopotassemia/diagnóstico , Masculino , Debilidade Muscular/complicações , Debilidade Muscular/diagnóstico , Paralisia/complicações , Paralisia/diagnóstico
19.
Aging Cell ; 17(4): e12792, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29923368

RESUMO

Dysregulation of plasma lipids is associated with age-related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low-density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg-1  day-1 ) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence-associated ß-galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5-treated but not L1-treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high-fat diet, nuclear γH2AX deposition and senescence-associated ß-galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N-acetyl-cysteine (free-radical scavenger) or caffeine (ATM blocker), as well as in lectin-like oxidized LDL receptor-1 (LOX-1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free-radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5-induced endothelial senescence. In conclusion, L5 may promote mitochondrial free-radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5-induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.


Assuntos
Senescência Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Mitocôndrias/efeitos dos fármacos , Animais , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Injeções Intravenosas , Lipoproteínas LDL/administração & dosagem , Lipoproteínas LDL/sangue , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo
20.
J Pharmacol Exp Ther ; 366(3): 410-421, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29914877

RESUMO

Increasing evidence suggests that SET functions as an oncoprotein and promotes cancer survival and therapeutic resistance. However, whether SET affects radiation therapy (RT)-mediated anticancer effects has not yet been explored. We investigated the impact of SET on RT sensitivity in hepatocellular carcinoma (HCC). Using colony and hepatosphere formation assays, we found that RT-induced proliferative inhibition was critically associated with SET expression. We next tested a novel SET antagonist, N4-(3-ethynylphenyl)-6,7-dimethoxy-N2-(4-phenoxyphenyl) quinazoline-2,4-diamine (EMQA), in combination with RT. We showed that additive use of EMQA significantly enhanced the effects of RT against HCC in vitro and in vivo. Notably, compared with mice receiving either RT or EMQA alone, the growth of PLC5 xenografted tumor in mice receiving RT plus EMQA was significantly reduced without compromising treatment tolerability. Furthermore, we proved that antagonizing SET to restore protein phosphatase 2A-mediated phospho-Akt (p-AKT) downregulation was responsible for the synergism between EMQA and RT. Our data demonstrate a new oncogenic property of SET and provide preclinical evidence that combining a SET antagonist and RT may be effective for treatment of HCC. Further investigation is warranted to validate the clinical relevance of this approach.


Assuntos
Carcinoma Hepatocelular/radioterapia , Regulação para Baixo/efeitos dos fármacos , Chaperonas de Histonas/antagonistas & inibidores , Neoplasias Hepáticas/radioterapia , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos da radiação , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
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