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1.
Clin Cardiol ; 2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34964140

RESUMO

BACKGROUND: Anemia is a common comorbidity in patients with atrial fibrillation (AF). Reports on the association of anemia and adverse events in patients with AF, especially from Asia, are limited. METHODS AND RESULTS: Based on data from the Chinese Atrial Fibrillation Registry Study (CAFR), a total of 18,106 AF patients enrolled between August 2011 and December 2018 had hemoglobin (Hb) values recorded at baseline. Patients were classified into three groups according to Hb levels: 15,606 patients (86.2%) into the no anemia group (male Hb≥130 g/L; female Hb≥120 g/L), 1800 (9.9%) with mild anemia (male 110≤Hb<129 g/L; female 110≤Hb<119 g/L), and 700 (3.9%) with moderate to severe anemia (Hb≤109 g/L). Multivariable Cox regression models were used to determine if anemia was independently associated with all-cause death, cardiovascular death, or major bleeding, after adjusting for confounders. Anemia was present in 13.8% of the population at baseline. During a median follow-up of 4.01 years, the incidences of all-cause death (1.8, 4.9, and 8.9 per 100 person-years), cardiovascular death (1.0, 2.9, and 4.5 per 100 person-years), and major bleeding (0.5, 0.6, and 0.7 per 100 person-years) were gradually accentuated in patients with no anemia, mild anemia, and moderate to severe anemia, respectively. Compared with patients with no anemia, those with anemia had higher risks for all-cause death (mild anemia; adjusted hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.08-1.38; moderate to severe anemia; adjusted HR: 1.53, 95% CI: 1.31-1.77); and cardiovascular death (mild anemia; adjusted HR: 1.29, 95% CI: 1.10-1.52; moderate to severe anemia; adjusted HR: 1.27, 95% CI: 1.03-1.57), but not for major bleeding. The association between anemia and all-cause death was similar among subgroups stratified by sex, kidney function, anticoagulant, or ablation therapy. CONCLUSIONS: Anemia was associated with increased risks of all-cause death, cardiovascular death, but no major bleeding in AF patients. The effect of anemia correction on the prognosis of patients with AF requires further study.

2.
J Geriatr Cardiol ; 18(11): 867-876, 2021 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-34908924

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in patients with atrial fibrillation (AF). However, the association between CKD and clinical consequences in AF patients is still under debate. METHODS: We included 19,079 nonvalvular AF patients with available estimated glomerular filtration rate (eGFR) values in the Chinese Atrial Fibrillation Registry from 2011 to 2018. Patients were classified into no CKD (eGFR ≥ 90 mL/min per 1.73 m2), mild CKD (60 ≤ eGFR < 90 mL/min per 1.73 m 2), moderate CKD (30 ≤ eGFR < 60 mL/min per 1.73 m 2), and severe CKD (eGFR < 30 mL/min per 1.73 m 2) groups. The risks of thromboembolism, major bleeding, and cardiovascular mortality were estimated with Fine-Gray regression analysis according to CKD status. Cox regression was performed to assess the risk of all-cause mortality associated with CKD. RESULTS: Over a mean follow-up of 4.1 ± 1.9 years, there were 985 thromboembolic events, 414 major bleeding events, 956 cardiovascular deaths, and 1,786 all-cause deaths. After multivariate adjustment, CKD was not an independent risk factor of thromboembolic events. As compared to patients with no CKD, those with mild CKD, moderate CKD, and severe CKD had a 45%, 47%, and 133% higher risk of major bleeding, respectively. There was a graded increased risk of cardiovascular mortality associated with CKD status compared with no CKD group: adjusted hazard ratio [HR] was 1.34 (95% CI: 1.07-1.68,P = 0.011) for mild CKD group, 2.17 (95% CI: 1.67-2.81,P < 0.0001) for moderate CKD group, and 2.95 (95% CI: 1.97-4.41, P < 0.0001) for severe CKD group, respectively. Risk of all-cause mortality also increased among patients with moderate or severe CKD. CONCLUSIONS: CKD status was independently associated with progressively higher risks of major bleeding and mortality, but didn't seem to be an independent predictor of thromboembolism in AF patients.

3.
Exp Neurol ; 348: 113923, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34780773

RESUMO

Arginase 1 (A1) is the enzyme that hydrolyzes the amino acid, L-arginine, to ornithine and urea. We have previously shown that A1 deletion worsens retinal ischemic injury, suggesting a protective role of A1. In this translational study, we aimed to study the utility of systemic pegylated A1 (PEG-A1, recombinant human arginase linked to polyethylene glycol) treatment in mouse models of acute retinal and brain injury. Cohorts of WT mice were subjected to retinal ischemia-reperfusion (IR) injury, traumatic optic neuropathy (TON) or brain cerebral ischemia via middle cerebral artery occlusion (MCAO) and treated with intraperitoneal injections of PEG-A1 or vehicle (PEG only). Drug penetration into retina and brain tissues was measured by western blotting and immunolabeling for PEG. Neuroprotection was measured in a blinded fashion by quantitation of NeuN (neuronal marker) immunolabeling of retina flat-mounts and brain infarct area using triphenyl tetrazolium chloride (TTC) staining. Furthermore, ex vivo retina explants and in vitro retina neuron cultures were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (R) and treated with PEG-A1. PEG-A1 given systemically did not cross the intact blood-retina/brain barriers in sham controls but reached the retina and brain after injury. PEG-A1 provided neuroprotection after retinal IR injury, TON and cerebral ischemia. PEG-A1 treatment was also neuroprotective in retina explants subjected to OGD/R but did not improve survival in retinal neuronal cultures exposed to OGD/R. In summary, systemic PEG-A1 administration is neuroprotective and provides an excellent route to deliver the drug to the retina and the brain after acute injury.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34677727

RESUMO

This study aimed to explore antithrombotic strategy and its relationship with outcomes in patients with atrial fibrillation (AF) at high risk for stroke and chronic coronary syndrome (CCS) in real-world clinical practice. Patients with AF at high risk for stroke complicated with CCS from China Atrial Fibrillation Registry (CAFR) were enrolled. The patients were divided into non-antithrombotic (Non-AT) group, oral anticoagulants (OAC) group, antiplatelet therapy (APT) group (aspirin or clopidogrel), and dual antiplatelet therapy (DAPT) group (aspirin + clopidogrel) according to their antithrombotic strategies at baseline. The patients with OAC + single antiplatelet drug (14 cases) and OAC + dual antiplatelet therapy (7 cases) were excluded for the small sample size. The primary effectiveness outcome was the composite outcome of coronary events, thromboembolism, and all-cause mortality. The primary safety outcome was major bleeding events. From 2011 to 2018, 25,512 patients were included in the CARF study, 769 patients with AF at high risk for stroke and CCS were enrolled in this study. After a follow-up of 47.4 ± 25.3 months, the incidences of primary effectiveness outcome were 44.6%, 25.7%, 43.6%, and 29.1% in the four groups, respectively (P < 0.001). The incidences of primary effectiveness and all-cause mortality were both significantly lower in the OAC group than in the Non-AT group, (25.7% vs. 44.6%, HR 0.53, 95% CI 0.39-0.73, P < 0.001) and (14.6% vs. 38.5%, HR 0.36, 95%CI 0.25-0.52, P < 0.001). In multivariate analysis, age (HR 1.03, 95%CI 1.01-1.05, P = 0.015), heart failure (HR 1.67, 95%CI 1.20-2.33, P = 0.002) and OAC (HR 0.66, 95%CI 0.47-0.91, P = 0.012) were independent factors for the composite outcome. There was no significant difference in major bleeding events between the four groups. OAC monotherapy significantly reduced the primary effectiveness composite outcome and all-cause mortality in the patients with AF at high risk for stroke complicated with CCS. However, there was no significant difference in major bleeding among the different antithrombotic strategies.Trial Registration www.chictr.org.cn (No. ChiCTR-OCH-13003729).

5.
Clin Cardiol ; 44(10): 1422-1431, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34318505

RESUMO

BACKGROUND: Atrial fibrillation (AF) and stable coronary artery disease (SCAD) frequently coexist. HYPOTHESIS: To investigate the prognosis of catheter ablation versus drug therapy in patients with AF and SCAD. METHODS: In total, 25 512 patients with AF in the Chinese AF Registry between 2011 and 2019 were screened for SCAD. 815 patients with AF and SCAD underwent catheter ablation therapy were matched with patients by drug therapy in a 1:1 ratio. Primary end point was composite of thromboembolism, coronary events, major bleeding, and all-cause death. The secondary endpoints were each component of the primary endpoint and AF recurrence. RESULTS: Over a median follow-up of 45 ± 23 months, the patients in the catheter ablation group had a higher AF recurrence-free rate (53.50% vs. 18.41%, p < .01). In multivariate analysis, there was no significant difference between the strategy of catheter ablation and drug therapy in primary composite end point (adjusted HR 074, 95%CI 0.54-1.002, p = .0519). However, catheter ablation was associated with fewer all-cause death independently (adjusted HR 0.36, 95%CI 0.22-0.59, p < .01). In subgroup analysis, catheter ablation was an independent risk factor for all-cause death in the high-stroke risk group (adjusted HR 0.39, 95%CI 0.23-0.64, p < .01), not in the low-medium risk group (adjusted HR 0.17, 95%CI 0.01-2.04, p = .17). CONCLUSIONS: In the patients with AF and SCAD, catheter ablation was not independently associated with the primary composite endpoint compared with drug therapy. However, catheter ablation was an independent protective factor of all-cause death.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Doença da Artéria Coronariana , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/terapia , Estudos de Coortes , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Humanos , Prognóstico , Estudos Prospectivos , Recidiva , Fatores de Risco , Resultado do Tratamento
6.
Oxid Med Cell Longev ; 2021: 5510663, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791071

RESUMO

Bladder cancer is one of the most commonly diagnosed cancers worldwide, especially in males. Current therapeutic interventions, including surgery, radiation therapy, chemotherapy, and immunotherapy, have not been able to improve the clinical outcome of bladder cancer patients with satisfaction. Recombinant human arginase (rhArg, BCT-100) is a novel agent with great anticancer effects on arginine-auxotrophic tumors. However, the effects of BCT-100 on bladder cancer remain unclear. In this study, the in vitro anticancer effects of BCT-100 were assessed using four bladder cancer cell lines (J82, SCaBER, T24, and 5637), while the in vivo effects were evaluated by establishing T24 nude mice xenograft models. Intracellular arginine level was observed to be sharply decreased followed by the onset of apoptotic events. Furthermore, BCT-100 was found to induce H2O2 production and mitochondrial membrane depolarization, leading to the release of mitochondrial cytochrome c and Smac to the cytosol. Treatment with BCT was observed to upregulate the expression of LC3B and Becllin-1, but downregulate the expression of p62 in a time-dependent manner. Autophagic flux was also observed upon BCT-100 treatment. Besides, the phosphorylation of the AKT/mTOR pathway was suppressed in a time-dependent fashion in BCT-100-treated T24 cells. While N-acetyl-L-cysteine was shown to alleviate BCT-100-induced apoptosis and autophagy, chloroquine, MK-2206, and rapamycin were found to potentiate BCT-100-triggered apoptosis. Finally, BCT-100 was demonstrated to induce autophagy and apoptosis via the ROS-mediated AKT/mTOR signaling pathway in bladder cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Arginase/farmacologia , Autofagia/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/patologia , Animais , Arginina/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Ecotoxicol Environ Saf ; 216: 112216, 2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33853024

RESUMO

Understanding picophytoplankton variations that play important roles in the material circulation and energy flow are critical to assessing overall status of waterbody, especially for clean reservoirs which remain a relatively stable community structure and high species diversity due to lower nitrogen and phosphorus nutrients. However, their response to key environmental factors and tightly acting microbial remains poorly understood. Traditional quantification methods are limited, such as chlorophyll-a, turbidity and microscope. There are still many defects with present molecular analysis. In this study, a flow cytometric analysis and high-throughput sequencing combination methodology was developed and tested on clean water from a reservoir, by a monthly dynamic for a vegetative period April-September in 2019 to improve the accuracy of dynamic monitoring for the picophytoplankton system. More species of Pico-Cyanobacteria and Pico-Eukaryotes were discovered. The increased percentage of pigment compounds from 8.2% to 76.3% proves the effective reduce of heterotrophic disturbing and enrichment of target populations. Picophytoplankton that was previously neglected due to their low relative abundance has once again entered the scope of our eyes. Phytoplankton were divided into three categories. The first one was the highly abundant and frequently present taxa, the second one was the low-abundance but highly-transient population, and the third one was the low abundance and stable group. Synechococcus, Emiliania, Tetraselmis and Thalassiosira were dominant picophytoplankton and displayed obvious temporal and spatial distribution characteristics. Pico-PE rich Cyanobacteria and Nano-Eukaryotes with high transience abnormally increased in summer. Temperature, ammonia-N, nitrate-N, turbidity and total nitrogen were most influencing factors, while some picophytoplankton with special physiological structure showed distinct competitive advantages in the microbial community. As for the off-flavor compounds, the concentration of 2-methylisoborneol and geosmin were high even 66.7% and 20.8% of the samples exceeded their olfactory threshold. Chrysochromuina, Planktothrix and Microcystis might be the potential producers.

8.
Pacing Clin Electrophysiol ; 44(5): 773-781, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32856303

RESUMO

BACKGROUND: Catheter ablation of perimitral atrial tachycardia (PMAT) is challenging. Epicardial conduction of the Marshall bundle (MB) across the mitral isthmus (MI) remains an important cause of recurrent tachycardia. The role of ethanol infusion into the vein of Marshall (EI-VOM) for PMAT has not been fully elucidated. METHODS: The study enrolled 28 consecutive patients with recurrent PMAT after atrial fibrillation (AF) ablation. Conventional PMAT (group 1, n = 15) and MB-related PMAT (group 2, n = 13) were diagnosed by detailed activation mapping and entrainment mapping. VOM venography and EI-VOM were first performed, and additional ablation was performed if necessary. RESULTS: The VOM was accessible in 24 (85.7%) patients (12 [80%] in group 1 and 12 [92.3%] in group 2). Patients with MB-related PMAT were more responsive to EI-VOM (as shown by PMAT termination or tachycardia cycle length prolongation) (92.4% vs 53.3%, P = .038). In the 16 patients requiring additional ablation after EI-VOM, all residual MI conduction gaps were located on the annular side of the MI. At the end of the procedure, MI bidirectional block was achieved in 14 (93.3%) patients in group 1 and in 12 (92.3%) patients in group 2 (P = 1.000). After a mean follow-up of 7.5 ± 3.1 months, three (10.7%) patients had recurrent AT. CONCLUSIONS: EI-VOM is feasible and effective in the treatment of PMAT after AF ablation, especially in patients with MB-related PMAT.

9.
Semin Thromb Hemost ; 46(8): 887-894, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33368110

RESUMO

Atrial fibrillation (AF) can be secondary to acute pulmonary embolism (PE). This study aimed to investigate the prognostic impact of new-onset AF on patients with acute PE. In this study, 4,288 consecutive patients who were diagnosed with acute PE were retrospectively screened. In total, 77 patients with acute PE and new-onset AF were analyzed. Another 154 acute PE patients without AF were selected as the age- and sex-matched control group. Adverse in-hospital outcome comprised one of the following conditions: all-cause death, endotracheal intubation, cardiopulmonary resuscitation, and intravenous catecholamine therapy. The patients with new-onset AF had higher prevalence of congestive heart failure, higher simplified PE severity index (sPESI), higher creatinine, and larger left atrium diameter. The incidences of adverse in-hospital outcomes were 10.4 and 2.6% in patients with new-onset AF and no AF, respectively (p = 0.02). Patients with sPESI ≥ 1 had higher incidence of adverse in-hospital outcomes than those with sPESI = 0 (9.4 vs. 0.9%, p < 0.01). The area under the receiver operating characteristic curve of sPESI and sPESI + AF (adding 1 point for new-onset AF) scores in assessing the adverse in-hospital outcome were 0.80 (95% confidence interval [CI]: 0.68-0.93) and 0.84 (95% CI: 0.72-0.96), respectively. In multivariable analysis, sPESI ≥ 1 (odds ratio, 8.88; 95% CI: 1.10-72.07; p = 0.04) was an independent predictor of adverse in-hospital outcome. However, new-onset AF was not an independent predictor. In the population studied, sPESI is an independent predictor of adverse in-hospital outcomes, whereas new-onset AF following acute PE is not, but it may add predictive value to sPESI.


Assuntos
Fibrilação Atrial/diagnóstico , Embolia Pulmonar/complicações , Idoso , Feminino , Humanos , Pacientes Internados , Masculino , Prognóstico , Embolia Pulmonar/patologia , Fatores de Risco , Resultado do Tratamento
10.
Plant Divers ; 42(5): 343-350, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33134617

RESUMO

Camellia huana is an endangered species with a narrow distribution in limestone hills of northern Guangxi and southern Guizhou provinces, China. We used one chloroplast DNA (cpDNA) fragment and 12 pairs of microsatellite (simple sequence repeat; SSR) markers to assess the genetic diversity and structure of 12 C. huana populations. A total of 99 alleles were detected for 12 polymorphic loci, and eight haplotypes and nine polymorphic sites were detected within 5200 bp of cpDNA. C. huana populations showed a low level of genetic diversity (n = 8, Hd = 0.759, Pi = 0.00042 for cpDNA, N A  = 3.931, H E  = 0.466 for SSRs), but high genetic differentiation between populations (F ST  = 0.2159 for SSRs, F ST  = 0.9318 for cpDNA). This can be attributed to the narrow distribution and limestone habitat of C. huana. STRUCTURE analysis divided natural C. huana populations into two groups, consistent with their geographical distribution. Thus, we suggest that five natural C. huana populations should be split into two units to be managed effectively.

11.
Europace ; 22(11): 1712-1717, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830238

RESUMO

AIMS: Accessory pathways (APs) successfully ablated at the aortomitral continuity (AMC) were sporadically reported but relevant data are very limited. We aimed to describe the electrophysiological characteristics of AMC-AP and the related anatomy. METHODS AND RESULTS: This study involved eight (male/female = 3/5, mean age 42.6 ± 10.5 years) patients with left-sided AP successfully ablated in the AMC region. The retrograde atrial activation sequence was analysed and compared via recordings at the His-bundle (HB), coronary sinus (CS), and roving catheter during tachycardia, and the peak of QRS from the same cardiac circle used as time reference. Of the eight patients, two received prior ablations. During tachycardia, the activation time at the proximal CS (CSp), lateral CS (CSl), and HB region averaged 120 ± 26 ms, 124 ± 29 ms, and 117 ± 21 ms following the reference, respectively (P = 0.86). The latest atrial activation was recorded in the posterior CS which averaged 135 ± 25 ms following the reference. Placing the ablation catheter to AMC via retrograde approach was attempted in all cases but stable positioning achieved in none. Via transseptal approach, the ablation catheter could be easily placed at the AMC and recorded the earliest retrograde atrial activations with 60 ± 27 ms earlier than the relatively 'earliest' CS/HB recordings, and ablation at this site successfully eliminated AP conduction. No patients had recovered AP conduction after at least 12-month follow-up. CONCLUSION: AMC-AP is featured by recording comparable retrograde atrial activation times at CSp, CSl, and HB with the latest recordings at the posterior CS. Stable placement and successful ablation in the AMC via retrograde aortic approach was difficult but can be achieved via transseptal approach.


Assuntos
Feixe Acessório Atrioventricular , Ablação por Cateter , Feixe Acessório Atrioventricular/cirurgia , Adulto , Eletrocardiografia , Feminino , Átrios do Coração/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia
12.
J Cardiovasc Transl Res ; 13(6): 965-969, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32488597

RESUMO

This study aimed to verify the reliability of ablation index (AI) for ablation lesion estimating with different settings for radiofrequency (RF) parameters: power, impedance, contact angles, irrigation rate, temperature of irrigation saline, and irrigation solution. RF ablations (N = 66) were performed on ex vivo porcine left ventricle submerged in 37 °C saline. The aforementioned ablation parameters were changed to measure whether the size of the ablation lesion was consistent at a fixed AI value of 500. The maximum lesion diameter (r = - 0.631, P = 0.028), depth (r = - 0.896, P < 0.001), and volume (r = - 0.745, P < 0.005) were significantly reduced with an increase of the impedance. The lesion depth (P < 0.05) and the lesion volume (P < 0.05) were significantly larger with glucose irrigation than saline irrigation. In conclusion, at a fixed AI value, impedance and irrigation solution have impact on the ablation lesions, which could affect the accuracy of AI formula to estimate ablation lesion size. Graphical abstract.


Assuntos
Ablação por Cateter , Glucose/química , Ventrículos do Coração/cirurgia , Solução Salina/química , Irrigação Terapêutica , Animais , Impedância Elétrica , Ventrículos do Coração/patologia , Sus scrofa , Temperatura
13.
Sci Rep ; 9(1): 12030, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427725

RESUMO

Drug resistance is a major hurdle in the treatment of small cell lung cancer (SCLC). Previously we demonstrated the potential anticancer effect of pegylated arginase BCT-100 in SCLC cell lines and xenograft models. To facilitate future clinical application of BCT-100 in SCLC treatment, we elucidated the potential mechanisms that underlie acquired drug resistance to BCT-100. H446 and H526 SCLC cells were serially cultured in stepwise increasing concentrations of BCT-100 until stable BCT-100-resistant cell lines emerged (H446-BR and H526-BR). Compared with parent cells, H446-BR and H526-BR displayed stronger migration ability, anoikis resistance and EMT progression. Gene chip assay was employed to select three potential targets (CDH17, CNTN-1 and IGF2BP1). Silencing CNTN-1 rather than CDH17 or IGF2BP1 in H446-BR and H526-BR cells re-sensitized resistant cells to BCT-100 treatment and attenuated the epithelial-mesenchymal transition (EMT) phenotype. The AKT signaling pathway was activated in H446-BR and H526-BR cells accompanied by EMT progression, and AKT inhibitor LY294002 reversed the EMT progression in resistant cells.


Assuntos
Arginase/farmacologia , Contactina 1/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Etoposídeo/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Proteínas Proto-Oncogênicas c-akt
14.
Oncogenesis ; 8(3): 18, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808864

RESUMO

Depletion of arginine induced by PEGylated arginase 1 (ARG1) (BCT-100) has shown anticancer effects in arginine auxotrophic cancers that lack argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC). High levels of endogenous arginase 2 (ARG2) have been previously reported in human lung cancers. Although a high-ARG2 level neither causes immunosuppression nor affects disease progression, it may theoretically affect the efficacy of PEGylated ARG1 treatment. ARG2 was shown to be highly expressed in H520 squamous cell lung carcinoma (lung SCC) xenografts but undetectable in SK-MES-1 and SW900 lung SCC xenografts. We propose that high-endogenous expression of ARG2 could impede the anti-tumor effect of PEGylated ARG1 in lung SCC. The in vivo effect of PEGylated ARG1 was investigated using three xenograft models of lung SCC. PEGylated ARG1 (60 mg/kg) suppressed tumor growth in SK-MES-1 and SW900 but not H520 xenografts. ASS1 was expressed in SK-MES-1 and SW900 xenografts while OTC expression remained low in all xenografts. A high-endogenous ARG2 level was detected only in H520 xenografts. Serum arginine level was decreased significantly by PEGylated ARG1 in all xenografts. Nonetheless intratumoral arginine level was decreased by PEGylated ARG1 in SK-MES-1 and SW900, not H520 xenografts. In SK-MES-1 xenografts, PEGylated ARG1 treatment induced G1 arrest, downregulation of Ki67 and Mcl-1 and activation of apoptosis. In SW900 xenografts, upregulation of Bim and activation of apoptosis were observed upon PEGylated ARG1 treatment. Silencing of ARG2 re-sensitized the H520 xenografts to PEGylated ARG1 treatment, partially mediated through arginine depletion via G1 arrest and apoptosis. PEGylated ARG1 treatment (BCT-100) was effective in lung SCC xenografts with low-endogenous levels of ASS1/OTC and ARG2. High-endogenous ARG2 expression may cause resistance to PEGylated ARG1 treatment in lung SCC xenografts. ARG2 may serve as a third predictive biomarker in PEGylated ARG1 treatment in lung SCC.

15.
Cancer Sci ; 109(11): 3471-3482, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30155941

RESUMO

Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer cases. Small cell lung cancer is characterized by frequent relapse, and current treatments lack tumor specificity. Arginine is a non-essential amino acid for human normal cells but critical to some tumor cells that cannot synthesize arginine. Therefore, arginine deprivation has become a potential therapeutic option for selected tumors. BCT-100 is a pegylated arginase that has documented anticancer activity in arginine auxotrophic tumors, such as melanoma, hepatocellular carcinoma, and acute myeloid leukemia. One of the resistance mechanisms to arginase treatment is overexpression of argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC), two important enzymes in the urea cycle. We selected 9 SCLC and 1 non-small cell lung carcinoma cell lines to determine the growth inhibition effects of BCT-100 and established that cell lines with low expression of ASS1 and OTC are relatively sensitive to BCT-100 treatment. Knocking down OTC in a H841 cell line could potentiate its sensitivity to BCT-100 treatment. Arginine concentration was sharply decreased, accompanied by apoptosis through oxidative stress as well as G1 cell cycle arrest. In addition, BCT-100 showed an anticancer effect on H446 and H510A xenograft models by lowering arginine levels and inducing apoptosis.


Assuntos
Antineoplásicos/administração & dosagem , Arginase/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Arginase/farmacologia , Arginina/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Estresse Oxidativo , Proteínas Recombinantes/farmacologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Oncol Rep ; 40(4): 1994-2004, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30066894

RESUMO

Arginine depletion has shown anticancer effects among arginine auxotrophic cancers. An anti­proliferative effect of pegylated arginase (BCT­100) has been shown in acute myeloid leukaemia, hepatocellular carcinoma and mesothelioma. The aim of the present study was to evaluate the effect of BCT­100 in lung adenocarcinoma. A panel of lung adenocarcinoma cell lines and xenograft models were used to investigate the effect of BCT­100. Protein expression, arginine level, putrescine level, spermidine level and apoptosis were analyzed by western blotting, ELISA, high performance liquid chromatography, dot blot and TUNEL assay, respectively. BCT­100 converts arginine to ornithine. BCT­100 reduced in vitro cell viability across different lung adenocarcinoma cell lines and suppressed tumour growth in an HCC4006 xenograft, while paradoxical growth stimulation was observed in H358, HCC827, H1650 and H1975 xenografts. Upon BCT­100 treatment, ornithine decarboxylase 1 (ODC1) was induced in two solid tumour xenografts (H1650 and H1975). It was postulated that the accumulated ornithine could be channeled via ODC1 to produce polyamines that promoted tumour growth. The action of an ODC1 inhibitor (α­difluoromethylornithine, DFMO) was studied in the restoration of the anticancer effects of BCT­100 in lung adenocarcinoma. In both H1650 and H1975 xenografts, a combination of DFMO and BCT­100 significantly suppressed tumour growth, resulting in doubled median survival compared with the control. Putrescine was decreased in almost all treatment arms in the H1650, H1975 and HCC4006 xenografts. Nonetheless spermidine was reduced only following DFMO/BCT­100 treatment in the H1650 and H1975 xenografts. Apoptosis was enhanced in the combined treatment arm in both H1650 and H1975 xenografts. In the HCC4006 xenograft, addition of DFMO did not alter the tumour suppressive effect of BCT­100. In conclusion, inhibition of ODC1 by DFMO was crucial in facilitating BCT­100 treatment in lung adenocarcinoma that was partially mediated by depleting arginine and polyamines with consequent apoptosis.


Assuntos
Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Arginase/administração & dosagem , Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/patologia , Ornitina Descarboxilase/química , Polietilenoglicóis/química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Animais , Arginina/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ornitina/metabolismo , Ornitina Descarboxilase/metabolismo , Inibidores da Ornitina Descarboxilase/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Cardiovasc Electrophysiol ; 29(7): 951-957, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29858872

RESUMO

INTRODUCTION: To assess the long-term outcome of catheter ablation in patients with hypertrophic cardiomyopathy (HCM), especially in patients with apical HCM (ApHCM). METHODS AND RESULTS: From 9,249 AF ablation cases, 97 patients (28 with ApHCM and 69 with non-ApHCM) were enrolled. Another 97 patients matched by age, AF type, AF duration, and left atrial diameter were selected as the control group. After a mean follow-up of (44.3 ± 29.6) months, success rate after a single procedure was 42.9% in the ApHCM patients (P  =  0.725), 36.2% in the non-ApHCM patients (P  =  0.136) versus 50.5% in the control group. After multiple procedures, success rate both in the ApHCM group (50%, P  =  0.047) and in the non-ApHCM group (50.4%, P  =  0.017) were lower than in the controls (68.0%). More patients in the ApHCM and in the non-ApHCM group suffered very late recurrence beyond 1 year after the index procedure. Left atrial diameter (hazard ratio [HR] 1.04, 95% confidential interval [CI] 1.01-1.08, P  =  0.018) and AF duration (HR 1.01, 95% CI 1.00-1.01, P  =  0.005) were independent predictors of recurrence after the index ablation. There was no difference in thromboembolic events between the HCM group and the control group (8.2% vs. 3.1%, P  =  0.082). CONCLUSIONS: Patients with ApHCM or non-ApHCM had similar success rate of AF ablation after single procedure and lower success rate after multiple procedure compared with the control group.


Assuntos
Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/cirurgia , Ablação por Cateter/tendências , Idoso , Ablação por Cateter/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
18.
BMC Geriatr ; 18(1): 39, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29394886

RESUMO

BACKGROUND: Nursing home residents are frail, have multiple medical comorbidities, and are at high risk for delirium. Most of the existing evidence base on delirium is derived from studies in the acute in-patient population. We examine the association between clinical characteristics and medication use with the incidence of delirium during the nursing home stay. METHODS: This is a retrospective cohort study of 1571 residents from 12 nursing homes operated by a single care provider in Ontario, Canada. Residents were over the age of 55 and admitted between February 2010 and December 2015 with no baseline delirium and a minimum stay of 180 days. Residents with moderate or worse cognitive impairment at baseline were excluded. The baseline and follow-up characteristics of residents were collected from the Resident Assessment Instrument-Minimal Data Set 2.0 completed at admission and repeated quarterly until death or discharge. Multivariate logistic regression was used to identify characteristics and medication use associated with the onset of delirium. RESULTS: The incidence of delirium was 40.4% over the nursing home stay (mean LOS: 32 months). A diagnosis of dementia (OR: 2.54, p < .001), the presence of pain (OR: 1.64, p < .001), and the use of antipsychotics (OR: 1.87, p < .001) were significantly associated with the onset of delirium. Compared to residents who did not develop delirium, residents who developed a delirium had a greater increase in the use of antipsychotics and antidepressants over the nursing home stay. CONCLUSIONS: Dementia, the presence of pain, and the use of antipsychotics were associated with the onset of delirium. Pain monitoring and treatment may be important to decrease delirium in nursing homes. Future studies are necessary to examine the prescribing patterns in nursing homes and their association with delirium.


Assuntos
Delírio/diagnóstico , Delírio/psicologia , Instituição de Longa Permanência para Idosos/tendências , Casas de Saúde/tendências , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Estudos de Coortes , Comorbidade , Delírio/epidemiologia , Feminino , Humanos , Incidência , Assistência de Longa Duração/tendências , Masculino , Ontário/epidemiologia , Dor/diagnóstico , Dor/epidemiologia , Dor/psicologia , Estudos Retrospectivos
19.
Europace ; 20(7): 1093-1098, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28637244

RESUMO

Aims: To assess the association and the predictive value of plasma homocysteine (Hcy) levels with LA/LAA thrombus in non-valvular Atrial fibrillation (AF) patients with low CHA2DS2-VASc score. Methods and results: Eight hundred and eighty-eight consecutive patients in non-valvular AF with CHA2DS2-VASc score of 0 and 1 were enrolled. All patients routinely underwent transthoracic echocardiography and transoesophageal echocardiography. A total of thirty-two patients had LA/LAA thrombus. Compared with patients without LA/LAA thrombus, plasma Hcy levels were significantly higher in patients with LA/LAA thrombus (16.5 ± 4.8 mmol/L vs. 13.4 ± 4.1 mmol/L, P = 0.009). In multivariate analysis, Hcy was independently associated with LA/LAA thrombus (OR 1.048, 95% CI 1.007-1.090, P = 0.022). Hcy demonstrated a significant predictive value with area under the curve of 0.722 (95% CI 0.662-0.781, P < 0.001). The optimal cut-off point for Hcy predicting LA/LAA thrombus was 13.5 mmol/L (sensitivity 67%, specificity 65%). Patients with Hcy ≥13.5 mmol/L had higher prevalence of LA/LAA thrombus compared with those with Hcy <13.5 mmol/L (6.1% vs. 2.1%, P < 0.001). Elevated Hcy significantly increased the risk of LA/LAA thrombus in patients with CHA2DS2-VASc score of 0 and 1 (OR 11.789, 95% CI 1.437-96.746, P = 0.022; OR 2.256, 95% CI 1.007-5.155, P = 0.048, respectively). Conclusion: Elevated plasma Hcy increases the risk of LA/LAA thrombus in non-valvular AF patients with low CHA2DS2-VASc score, thus it should be taken into account in prediction of thromboembolism.


Assuntos
Apêndice Atrial , Fibrilação Atrial/complicações , Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Trombose/etiologia , Idoso , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/fisiopatologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Estudos Transversais , Ecocardiografia Transesofagiana , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Medição de Risco , Fatores de Risco , Trombose/diagnóstico por imagem , Regulação para Cima
20.
Europace ; 20(9): 1468-1474, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29106529

RESUMO

Aims: Catheter ablation is underutilized in atrial septal defect (ASD) patients who have undergone implantation of an atrial septal occluder (ASO). This study evaluates the feasibility and safety of catheter ablation of atrial fibrillation (AF) in this subset of patients. Methods and results: Sixteen patients (age 56 ± 12 years, 10 men) with drug-refractory AF (10 paroxysmal and 6 persistent) and previously implanted ASO were enrolled. Balloon dilatation of the closure device was performed if the native septum passage could not be achieved. For paroxysmal AF, the ablation strategy was circumferential pulmonary vein isolation (CPVI), and for persistent AF, additional linear ablation was performed. Transseptal access was achieved through the native septum in 11 patients (Group A) and through the ASO using balloon dilatation in 5 patients (Group B). Circumferential pulmonary vein isolation was achieved in all 16 patients, and linear block was achieved in all persistent patients except for 1 patient who did not achieve mitral isthmus block. The transseptal, total fluoroscopy, and procedural durations were 5 ± 3 vs. 38 ± 8 min, 31 ± 11 vs. 54 ± 15 min, and 165 ± 35 vs. 224 ± 36 min, respectively, in Group A vs. Group B, respectively (all P < 0.05). No shunt at atrial level was detected by transthoracic echocardiography at 3-month follow-up. During a follow-up of 16 ± 6 months, sinus rhythm was maintained in 12 of 16 patients. No severe complications were observed. Conclusion: In ASD patients with ASO, catheter ablation of AF is feasible, safe, and effective. The balloon dilatation technique can facilitate transseptal access through the ASO.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Comunicação Interatrial/cirurgia , Veias Pulmonares/cirurgia , Dispositivo para Oclusão Septal , Adulto , Idoso , Angiografia , Fibrilação Atrial/complicações , Estudos de Viabilidade , Feminino , Comunicação Interatrial/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Punções/métodos
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