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1.
J Am Heart Assoc ; 10(20): e021587, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34632785

RESUMO

Background The long-term impact of newly discovered, asymptomatic abnormal ankle-brachial index (ABI) in patients with significant coronary artery disease is limited. Methods and Results Between January 2006 and December 2009, ABI was evaluated in 2424 consecutive patients with no history of claudication or peripheral artery disease who had significant coronary artery disease. We previously reported a 3-year result; therefore, the follow-up period was extended. The primary end point was a composite of all-cause death, myocardial infarction (MI), and stroke over 7 years. Of the 2424 patients with significant coronary artery disease, 385 had an abnormal ABI (ABI ≤0.9 or ≥1.4). During the follow-up period, the rate of the primary outcome was significantly higher in the abnormal ABI group than in the normal ABI group (P<0.001). The abnormal ABI group had a significantly higher risk of composite of all-cause death/MI/stroke than the normal ABI group, after adjustment with multivariable Cox proportional hazards regression analysis (hazard ratio [HR], 2.07; 95% CI, 1.67-2.57; P<0.001) and propensity score-matched analysis (HR, 1.97; 95% CI, 1.49-2.60; P<0.001). In addition, an abnormal ABI was associated with a higher risk of all-cause death, MI, and stroke, but not repeat revascularization. Conclusions Among patients with significant coronary artery disease, asymptomatic abnormal ABI was associated with sustained and increased incidence of composite of all-cause death/MI/stroke, all-cause death, MI, and stroke during extended follow-up over 7 years.

2.
Sci Rep ; 11(1): 18832, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552150

RESUMO

We investigated the clinical relevance of urinary cytokines/chemokines reflecting intrarenal immunologic micromilieu as prognostic markers and the optimal measurement timing after living donor kidney transplantation (LDKT). This prospective cohort study included 77 LDKT patients who were followed for ≥ 5 years. Patients were divided into control (n = 42) or acute rejection (AR, n = 35) group. Early AR was defined as AR occurring within 3 months. Serum and urine cytokines/chemokines were measured serially as follows: intraoperative, 8/24/72 h, 1 week, 3 months, and 1 year after LDKT. Intrarenal total leukocytes, T cells, and B cells were analyzed with immunohistochemistry followed by tissueFAXS. Urinary MCP-1 and fractalkine were also analyzed in a validation cohort. Urinary MCP-1 after one week was higher in the AR group. Urinary MCP-1, fractalkine, TNF-α, RANTES, and IL-6 after one week were significantly higher in the early AR group. Intrarenal total leukocytes and T cells were elevated in the AR group compared with the control group. Urinary fractalkine, MCP-1, and IL-10 showed positive correlation with intrarenal leukocyte infiltration. Post-KT 1 week urinary MCP-1 showed predictive value in the validation cohort. One-week post-KT urinary MCP-1 may be used as a noninvasive diagnostic marker for predicting AR after LDKT.

4.
J Hematol Oncol ; 14(1): 148, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530889

RESUMO

BACKGROUND: Little is known about endogenous inhibitors of angiogenic growth factors. In this study, we identified a novel endogenous anti-angiogenic factor expressed in pericytes and clarified its underlying mechanism and clinical significance. METHODS: Herein, we found Kai1 knockout mice showed significantly enhanced angiogenesis. Then, we investigated the anti-angiogenic roll of Kai1 in vitro and in vivo. RESULTS: KAI1 was mainly expressed in pericytes rather than in endothelial cells. It localized at the membrane surface after palmitoylation by zDHHC4 enzyme and induced LIF through the Src/p53 pathway. LIF released from pericytes in turn suppressed angiogenic factors in endothelial cells as well as in pericytes themselves, leading to inhibition of angiogenesis. Interestingly, KAI1 had another mechanism to inhibit angiogenesis: It directly bound to VEGF and PDGF and inhibited activation of their receptors. In the two different in vivo cancer models, KAI1 supplementation significantly inhibited tumor angiogenesis and growth. A peptide derived from the large extracellular loop of KAI1 has been shown to have anti-angiogenic effects to block the progression of breast cancer and retinal neovascularization in vivo. CONCLUSIONS: KAI1 from PC is a novel molecular regulator that counterbalances the effect of angiogenic factors.

5.
JACC Cardiovasc Interv ; 14(18): 2059-2068, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34556280

RESUMO

OBJECTIVES: This study evaluated the association between elevated levels of lipoprotein(a) [Lp(a)] and risk of recurrent ischemic events in patients who underwent percutaneous coronary intervention (PCI). BACKGROUND: Elevated levels of Lp(a) have been identified as an independent, possibly causal, risk factor for atherosclerotic cardiovascular disease in a general population study. METHODS: A prospective single-center registry was used to identify 12,064 patients with baseline Lp(a) measurements who underwent PCI between 2003 and 2013. The primary outcomes were a composite of cardiovascular death, spontaneous myocardial infarction, and ischemic stroke. RESULTS: From the registry, 3,747 (31.1%) patients had high Lp(a) (>30 mg/dL) and 8,317 (68.9%) patients had low Lp(a) (≤30 mg/dL). During a median follow-up of 7.4 years, primary outcomes occurred in 1,490 patients, and the incidence rates of primary outcomes were 2.0 per 100 person-years in the high-Lp(a) group and 1.6 per 100 person-years in the low-Lp(a) group (adjusted hazard ratio [aHR]: 1.17; 95% confidence interval [CI]: 1.05-1.30; P = 0.004). Increased risk of recurrent ischemic cardiovascular events in the high-Lp(a) group was consistent in various subgroups including patients receiving statin treatment at discharge (aHR: 1.18; 95% CI: 1.03-1.34; P = 0.011). In addition, the risk of repeated revascularization was significantly higher in the high-Lp(a) group (aHR: 1.13; 95% CI: 1.02-1.25; P = 0.022). CONCLUSIONS: Elevated levels of Lp(a) were significantly associated with the recurrent ischemic events in patients who underwent PCI. This study provides a rationale for outcome trials to test Lp(a)-lowering therapy for secondary prevention in patients undergoing PCI.

6.
Nanotechnology ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587601

RESUMO

Nanostructural modification of two-dimensional (2D) materials has attracted significant attention for enhancing hydrogen evolution reaction (HER) activity. In this study, the nanostructure of TaS2 films was controlled by controlling the Ar/H2S gas ratio used in plasma-enhanced chemical vapor deposition (PECVD). At a high Ar/H2S gas ratio, vertically aligned TaS2 (V-TaS2) films were formed over a large area (4 in) at a temperature of 250 °C, which, to the best of our knowledge, is the lowest temperature reported for PECVD. Furthermore, the plasma species formed in the injected gas at various Ar/H2S gas ratios were analyzed using optical emission spectroscopy to determine the synthesis mechanism. In addition, the 4 in wafer-scale V-TaS2 was analyzed by X-ray photoelectron spectroscopy, transmission electron microscopy, and atomic force microscopy, and the HER performance of the as-synthesized TaS2 fabricated with various Ar/H2S ratios was measured. The results revealed that, depending on the film structure of TaS2, the HER performance can be enhanced owing to its structural advantage. Furthermore, the excellent stability and robustness of V-TaS2 was confirmed by conducting 1,000 HER cycles and post-HER material characterization. This study provides important insights into the plasma-assisted nanostructural modification of 2D materials for application as enhanced electrocatalysts.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34574725

RESUMO

The formation and pollution of particulate matter (PM), a side effect of rapid industrialization and urbanization, is considered a global issue. However, various plant species are able to effectively capture and reduce atmospheric PM concentrations. We investigated the indoor growth and morphology of 21 indigenous Korean evergreen species at low light intensities to ascertain their ability to reduce PM of aerosol particles in a closed acrylic chamber. The decrease in PM mass concentration differed significantly across species, with a significant correlation (8 h; p < 0.001). The reduction in the mass concentration of PM differed with particle size and across species. The highest reduction of PM2.5 occurred after 8 h with Dryopteris lacera (86.8%), Ilex × wandoensis (84.9%), Machilus thunbergii (84.3%), and Rhododendron brachycarpum (84.0%). Reduction of PM10 after 8 h was highest with Cephalotaxus harringtonii (98.3%), I. × wandoensis (98.5%), M. thunbergii (98.5%), and R. brachycarpum (98.3%). Plant morphological characteristics (category, plant height, leaf shape, leaf area) and relative humidity were closely related to the decrease in PM mass concentration. In conclusion, our findings can be used to identify Korean plant species that can reduce PM concentration and are suitable for indoor use.

8.
Blood Adv ; 5(20): 3919-3930, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34535012

RESUMO

Recent studies identified germline mutations in HAVCR2 (encoding T-cell immunoglobulin mucin 3) as a genetic factor that predisposes to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, the differences between HAVCR2-mutated (HAVCR2MUT) and HAVCR2 wild-type (HAVCR2WT) SPTCLs remain unclear. A nationwide cohort of 53 patients with SPTCL diagnosed at 8 Korean institutions was established. Whole-exome sequencing and RNA-sequencing were performed on 8 patients in the discovery set. In the validation set, targeted gene sequencing or direct sequencing of HAVCR2 was performed. Of 49 patients with available HAVCR2 status, 25 (51.0%) were HAVCR2Y82C. HAVCR2Y82C was associated with younger age (P = .001), development of hemophagocytic lymphohistiocytosis or hemophagocytic lymphohistiocytosis-like systemic illness (P < .001), and short relapse-free survival (RFS) (P = .023). Most mutated genes in SPTCLs were involved in immune responses, epigenetic modifications, and cell signaling. Mutations in UNC13D, PIAS3, and KMT2D were more frequent in HAVCR2WT SPTCLs. At the gene expression level, HAVCR2Y82C SPTCLs were enriched in genes involved in IL6-JAK-STAT3 signaling and in tumor necrosis factor-α signaling via NF-κB. CCR4 was significantly upregulated in HAVCR2WT SPTCLs both at the messenger RNA level and at the protein level. We established a risk stratification system for SPTCL by integrating clinical and histopathological features, including age and HAVCR2 mutation status. This risk stratification system was strongly associated with RFS (P = .031). In conclusion, the HAVCR2Y82C mutation was common in Korean patients with SPTCL and was associated with unique clinicopathological and genetic features. Combining clinicopathological parameters could aid in predicting prognosis for patients with SPTCL.

9.
Artigo em Inglês | MEDLINE | ID: mdl-34414491

RESUMO

BACKGROUND: We hypothesized that the outcomes of articular reduction with elimination of irreducible articular intercalary fragments for Mayo type IIB fractures fixed using olecranon locking plates would be as satisfactory as those of noncomminuted fractures. METHODS: A total of 65 patients were enrolled from among 92 who had undergone operative treatment for olecranon fractures between March 2008 and February 2015. Patients with fragments that were eliminated because they were too comminuted to be fixed during surgery (type IIB) were included in group 1. Patients without intraarticular comminuted fragments (type IIA) or with very few fragments were assigned to group 2. In group 1, articular congruency and reduction status were confirmed by direct visualization. The fracture was then fixed with a locking plate and irreducible intercalary fragments were eliminated. RESULTS: There were no significant differences in demographic characteristics, such as age and gender, between the two groups. Both groups achieved bony union within the approximately 6-year follow-up period and there were no serious complications in either group. The grades of heterotrophic ossification and ulnohumeral arthritis were not significantly different between the groups. The mean flexion-extension and pronation-supination arcs were similarly satisfactory in both groups (127.35° and 134.39° vs. 129.69° and 133.75° in groups 1 and 2°, respectively). Clinical outcomes including visual analog scale pain scores, as well as the Mayo Elbow Performance scores (87.73 vs. 88.28 in groups 1 and 2, respectively), were also similarly satisfactory in both groups. CONCLUSIONS: Locking plate fixation under direct visualization (to reduce the articular surface in Mayo type IIB fractures) and elimination of articular intercalary fragments resulted in satisfactory radiologic and clinical outcomes, similar to those of noncomminuted fractures also treated using a locking plate. LEVEL OF EVIDENCE: Level IV, Retrospective therapeutic study.

10.
Clin Ther ; 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34429197

RESUMO

PURPOSE: We investigated whether the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy in patients requiring cholesterol-lowering therapy. METHODS: This was a multicenter randomized, double-blind study to investigate the safety and efficacy of a fixed-dose combination of rosuvastatin 2.5 mg and ezetimibe 10 mg (R2.5+E10) compared to those of ezetimibe 10 mg monotherapy (E10), rosuvastatin 2.5 mg (R2.5), and rosuvastatin 5 mg monotherapy (R5) in patients with hypercholesterolemia. A total of 348 patients at 15 centers in Korea were screened, and 279 patients were randomized to different groups in the study. Clinical and laboratory examinations were performed at baseline and 4 and 8 weeks after intervention. The primary endpoint was the percentage change of low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. FINDINGS: Baseline characteristics were similar among the four groups. There were significant changes in lipid profiles at the 8-week follow-up. A greater decrease in the LDL cholesterol levels (primary endpoint) were found in the R2.5+E10 group (-45.7±18.6%) than in the E10 group (-16.7±14.7%, p<0.0001), R2.5 group (-32.6±15.1%, p<0.0001), and R5 group (-38.9±13.9%, p=0.0003). Similar outcomes were observed regarding the decrease in total cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B protein. In addition, changes in the triglyceride and HDL levels in the R2.5+E10 group were significantly different compared with those in the E10 group; however, the changes were similar to those in the other treatment groups. In patients with low and moderate risk, all patients achieved the target LDL cholesterol levels in the R2.5+E10 group (100%) compared to 13.0% in the E10 group, 47.6% in the R2.5 group, and 65.2% in the R5 group. Adverse effects were rare and similar in the four groups. IMPLICATIONS: Fixed-dose combination of low-intensity rosuvastatin and ezetimibe was more effective in lowering LDL cholesterol and achieving LDL cholesterol goals than moderate-intensity rosuvastatin monotherapy. These findings suggest that the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy for cholesterol management, particularly in patients with low and moderate risk. ClinicalTrials.gov identifier: NCT04652349.

11.
Eur Heart J ; 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34431997

RESUMO

AIMS: The aim of this study was to assess the association of smoking cessation and reduction with risk of cardiovascular disease (CVD). METHODS AND RESULTS: A total of 897 975 current smokers aged ≥40 years who had undergone two consecutive national health examinations (in 2009 and 2011) were included. Participants were classified as quitters (20.6%), reducers I (≥50% reduction, 7.3%), reducers II (20-50% reduction, 11.6%), sustainers (45.7%), and increasers (≥20% increase, 14.5%). During 5 575 556 person-years (PY) of follow-up, 17 748 stroke (3.2/1000 PY) and 11 271 myocardial infarction (MI) (2.0/1000 PY) events were identified. Quitters had significantly decreased risk of stroke [adjusted hazard ratio (aHR) 0.77 95% confidence interval (CI) 0.74-0.81; absolute risk reduction (ARR) -0.37, 95% CI -0.43 to -0.31] and MI (aHR 0.74, 95% CI 0.70-0.78; ARR -0.27, 95% CI -0.31 to -0.22) compared to sustainers after adjustment for demographic factors, comorbidities, and smoking status. The risk of stroke and MI incidence in reducers I (aHR 1.02, 95% CI 0.97-1.08 and aHR 0.99, 95% CI 0.92-1.06, respectively) and reducers II (aHR 1.00, 95% CI 0.95-1.05 and aHR 0.97, 95% CI 0.92-1.04, respectively) was not significantly different from the risk in sustainers. Further analysis with a subgroup who underwent a third examination (in 2013) showed that those who quit at the second examination but had starting smoking again by the third examination had 42-69% increased risk of CVD compared to sustained quitters. CONCLUSIONS: Smoking cessation, but not reduction, was associated with reduced CVD risk. Our study emphasizes the importance of sustained quitting in terms of CVD risk reduction.

12.
Medicine (Baltimore) ; 100(31): e26702, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397805

RESUMO

INTRODUCTION: Pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) catheter ablation. However, a PVI alone has been considered insufficient for persistent AF. This study aimed to evaluate the efficacy of persistent AF ablation targeting complex fractionated atrial electrogram (CFAE) areas within low voltage zones identified by high-resolution mapping in addition to the PVI. METHODS: We randomized 50 patients (mean age 58.4 ±â€Š9.5 years old, 86.0% males) with persistent AF to a PVI + CFAE group and PVI only group in a 1:1 ratio. CFAE and voltage mapping was performed simultaneously using a Pentaray Catheter with the CARTO3 CONFIDENSE module (Biosense Webster, CA, USA). The PVI + CFAE group, in addition to the PVI, underwent ablation targeting low voltage areas (<0.5 mV during AF) containing CFAEs. RESULTS: The mean persistent AF duration was 24.0 ±â€Š23.1 months and mean left atrial dimension 4.9 ±â€Š0.5 cm. In the PVI + CFAE group, AF converted to atrial tachycardia (AT) or sinus rhythm in 15 patients (60%) during the procedure. The PVI + CFAE group had a higher 1-year AF free survival (84.0% PVI + CFAE vs 44.0 PVI only, P = .006) without antiarrhythmic drugs. However, there was no difference in the AF/AT free survival (60.0% PVI + CFAE vs 40.0% PVI only, P = .329). CONCLUSION: Persistent AF ablation targeting CFAE areas within low voltage zones using high-density voltage mapping had a higher AF free survival than a PVI only. Although recurrence with AT was frequent in the PVI+CFAE group, the sinus rhythm maintenance rate after redo procedures was 76%.


Assuntos
Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Técnicas Eletrofisiológicas Cardíacas , Idoso , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Intervalo Livre de Doença , Técnicas Eletrofisiológicas Cardíacas/métodos , Feminino , Átrios do Coração , Humanos , Masculino , Pessoa de Meia-Idade , Veias Pulmonares/cirurgia , Recidiva , Cirurgia Assistida por Computador , Taquicardia/etiologia
13.
Heart Vessels ; 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34341876

RESUMO

The association of the soluble suppression of tumorigenicity 2 (sST2) and the prognosis of heart failure have been well evaluated. However, little is known about the prediction of sST2 for left ventricular (LV) remodeling in acute coronary syndrome (ACS). We investigated the ability of sST2 to predict LV remodeling following the revascularization of ACS. From May 2019 to December 2020, 95 patients with LV ejection fraction (EF) < 50% who underwent coronary revascularization for ACS (unstable angina, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction) were enrolled. Echocardiography and sST2 were performed at baseline and at a 3-month follow-up. The association between LV remodeling, using the end-diastolic volume index, and sST2 at baseline and at the 3-month follow-up, and the difference between each value was explored. During follow-up, 41 patients showed LV adverse remodeling. The baseline sST2 increased in patients without adverse remodeling (32.05 ng/mL vs. 23.5 ng/mL, p < 0.001), although clinical characteristics were similar between the two groups. During the mean follow-up of 3 months, a significant correlation was found in the changes between sST2 and LV end-diastolic/systolic volume index (r = 0.649; p < 0.001, r = 0.618; p < 0.001, respectively), but not in the changes of LVEF (r = - 0.132, p = 0.204). The use of angiotensin-converting enzyme 2 inhibitors/receptor blockers was higher (90.7% vs. 53.7%, p < 0.001) and sST2 decreased more predominantly in patients without adverse remodeling (23.18 ng/mL vs 26.40 ng/mL, p = 0.003). However, the changes in sST2 and LV volume were not different according to the ACS types (p > 0.05, for all). Estimates of the odds ratio (OR) for remodeling according to the sST2 difference increased substantially with a negative increase in the sST2 difference. Multivariable analysis found that, the difference between the baseline and 3-month sST2 was the most important determinant of LV remodeling following the revascularization of ACS (OR 1.24; 95% confidence interval: 1.09 to 1.41; p = 0.001). In conclusion, an increase in sST2 during follow-up was a useful predictor of LV remodeling.

14.
Coron Artery Dis ; 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34347637

RESUMO

BACKGROUND: Cholesterol control with statins has been shown to have beneficial effects in coronary artery disease. However, the relationship between initial very low low-density lipoprotein (LDL) cholesterol levels and long-term clinical outcomes in patients with acute myocardial infarction (AMI) remains unclear. METHODS: A total of 8741 (mean age: 64.6 ± 12.7 years, men) consecutive AMI patients treated with drug-eluting stents were entered into the Korea Acute Myocardial Infarction Registry from November 2011 to December 2015. Patients were divided into six groups according to whether they were taking statins (on-statin group) or not (statin naive group) and depending on their LDL cholesterol level at admission (<70, 70-99, 100-129, 130-159, >160 mg/dl). Clinical outcomes at 24 months in patients with AMI were examined. RESULTS: The incidence of risk factors including hypertension, diabetes, coronary artery disease and heart failure was lower as LDL cholesterol increased, except in the on-statin group. Clinical outcomes, including total mortality at 24 months, showed better outcomes in those with high LDL cholesterol than those with low LDL cholesterol, except in the statin group. In the statin-naïve group, the higher the LDL cholesterol level, the higher the rate of 24-month survival. In a Cox regression model, initial low LDL cholesterol was an independent predictor of mortality at 24 months after adjusting for baseline confounding factors. CONCLUSIONS: At admission, a very low LDL cholesterol level (<70 mg/dL) in statin-naïve AMI patients undergoing percutaneous coronary intervention was independently associated with higher mortality at 24 months.

15.
Nucl Med Commun ; 42(9): 972-978, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34397987

RESUMO

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors reduce the risk of cardiovascular events in type 2 diabetic patients with coronary artery disease (CAD); however, the underlying mechanisms remain unclear. OBJECTIVES: We compared the effects of empagliflozin vs. sitagliptin therapy on myocardial perfusion reserve (MPR) using dynamic single-photon emission computed tomography (SPECT) imaging. METHODS: In total, 100 patients with type 2 diabetes, CAD and an MPR <2.5 were randomized to receive either empagliflozin (10 mg once daily) or sitagliptin (100 mg once daily). Dynamic SPECT examinations were performed at baseline and at 6 months. The primary endpoint was the percent change of global MPR. Evaluable SPECT data were available for 98 patients. RESULTS: Baseline clinical characteristics and SPECT data were well balanced between the two groups. At a 6-month follow-up, the fasting glucose and glycated hemoglobin levels significantly decreased in both groups. Hematocrit and hemoglobin levels significantly increased in the empagliflozin group but not in the sitagliptin group. The global MPR significantly improved after treatment in both groups (34.5 ± 70.6%; P = 0.005 for empagliflozin vs. 22.4 ± 45.7%; P = 0.024 for sitagliptin). However, there was no significant difference in the global MPR between the two groups (P = 0.934). Similar findings were detected with regard to the regional MPR. CONCLUSION: Among patients with type 2 diabetes and CAD, both empagliflozin and sitagliptin significantly improved the global MPR with no significant difference between the groups.

16.
J Enzyme Inhib Med Chem ; 36(1): 1922-1930, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34425714

RESUMO

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.


Assuntos
Antiprotozoários/química , Leishmania donovani/efeitos dos fármacos , Fosforilcolina/química , Pirrolidinas/química , Amida Sintases/metabolismo , Antiprotozoários/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Palmitatos/química , Pirrolidinas/farmacologia , Esfingomielinas/química , Relação Estrutura-Atividade
17.
In Vivo ; 35(5): 2647-2653, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410952

RESUMO

BACKGROUND/AIM: To evaluate the role of serine protease inhibitor B11 (SERPINB11) expression as a prognostic biomarker in high-grade serous carcinoma (HGSC) and clear cell carcinoma of the ovary (CCC). MATERIALS AND METHODS: We obtained tumor tissues from patients with HGSC (n=145) and CCC (n=59). We evaluated immunohistochemically the expression of SERPINB11 and investigated whether SERPINB11 expression affects platinum-resistance and the prognosis of HGSC and CCC. RESULTS: High expression of SERPINB11 was more common in CCC than in HGSC (57.6% vs. 28.3%; p<0.01), and SEPRINB11 expression did not correlate with platinum-resistance of HGSC and CCC. High expression of SERPINB11 was associated with worse progression-free survival and overall survival with marginal significance in HGSC; no relation between SERPINB11 expression and the prognosis of CCC was found. CONCLUSION: SERPINB11 expression maybe a prognostic biomarker for HGSC.


Assuntos
Adenocarcinoma de Células Claras , Neoplasias Ovarianas , Serpinas , Adenocarcinoma de Células Claras/genética , Biomarcadores Tumorais/genética , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Prognóstico , Inibidores de Serino Proteinase , Serpinas/genética
18.
Sci Rep ; 11(1): 16563, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400711

RESUMO

The muscular discontinuities at the pulmonary vein (PV)-left atrial (LA) junction are known. The high-density mapping may help to find the muscular discontinuity. This study evaluated the efficacy of a partial antral ablation for a pulmonary vein (PV) isolation using high density (HD) mapping. A total of 60 drug-refractory atrial fibrillation (AF) patients undergoing catheter ablation were enrolled. The detailed activation mapping of each PV and LA junction was performed using an HD mapping system, and each PV segment's activation pattern was classified into a "directly-activated from the LA" or "passively-activated from an adjacent PV segment" pattern. The antral ablations were performed at the directly-activated PV segments only when the PV had "passively-activated segments". If the PV did not contain passively-activated segments, a circumferential antral ablation was performed on those PVs. A "successful partial antral ablation" was designated if the electrical isolation of targeted PV was achieved by ablation at the directly-activated segments only. If the isolation was not achieved even though all directly-activated segments were ablated, a "failed partial antral ablation" was designated, and then a circumferential ablation was performed. Among 240 PVs, passively-activated segments were observed in 140 (58.3%) PVs. Both inferior PVs had more passively-activated segments than superior PVs, and the posteroinferior segments had the highest proportion of passive activation. The overall rate of successful partial antral ablation was 85%. The atrial tachyarrhythmia recurrence was observed in 10 patients (16.7%) at 1-year. HD mapping allowed the evaluation of the detailed activation patterns of the PVs, and passively-activated segments may represent muscular discontinuity. Partial antral ablation of directly-activated antral segments only was feasible and effective for a PVI.

19.
Cancers (Basel) ; 13(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298618

RESUMO

In epithelial ovarian cancer (EOC), carboplatin/cisplatin-induced chemoresistance is a major hurdle to successful treatment. Aerobic glycolysis is a common characteristic of cancer. However, the role of glycolytic metabolism in chemoresistance and its impact on clinical outcomes in EOC are not clear. Here, we show a functional interaction between the key glycolytic enzyme hexokinase II (HKII) and activated P-p53 (Ser15) in the regulation of bioenergetics and chemosensitivity. Using translational approaches with proximity ligation assessment in cancer cells and human EOC tumor sections, we showed that nuclear HKII-P-p53 (Ser15) interaction is increased after chemotherapy, and functions as a determinant of chemoresponsiveness as a prognostic biomarker. We also demonstrated that p53 is required for the intracellular nuclear HKII trafficking in the control of glycolysis in EOC, associated with chemosensitivity. Mechanistically, cisplatin-induced P-p53 (Ser15) recruits HKII and apoptosis-inducing factor (AIF) in chemosensitive EOC cells, enabling their translocation from the mitochondria to the nucleus, eliciting AIF-induced apoptosis. Conversely, in p53-defective chemoresistant EOC cells, HKII and AIF are strongly bound in the mitochondria and, therefore, apoptosis is suppressed. Collectively, our findings implicate nuclear HKII-P-p53(Ser15) interaction in chemosensitivity and could provide an effective clinical strategy as a promising biomarker during platinum-based therapy.

20.
Anticancer Res ; 41(7): 3689-3698, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230168

RESUMO

BACKGROUND/AIM: SPARC-related modular calcium-binding protein 2 (SMOC2), a secreted matricellular protein, is reported to be involved in cancer progression such as cell cycle, angiogenesis, and invasion. In this study, we aimed to investigate the expression of SMOC2 in various gastric lesions and assessed its prognostic value in a large cohort of gastric cancer (GC) patients. PATIENTS AND METHODS: SMOC2 mRNA levels were measured by quantitative real-time PCR using 26 matched fresh-frozen GC samples. SMOC2 protein expression was determined by immunohistochemistry on tissue microarrays including 734 GC specimens and its correlations with clinicopathological features and survival were evaluated. RESULTS: The transcription level of SMOC2 was higher in GC samples compared to normal mucosa (p=0.006). Its expression levels were associated with the intestinal stem cell (ISC) marker, LGR5, but there were no correlations with EPHB2 and OLFM4 or the candidate cancer stem cell markers CD133 and CD44. SMOC2 expression was significantly increased in the intestinal metaplasia and was further increased in gastric adenomas and early gastric cancers (EGC). In total, 34% of GCs were positive for SMOC2, and SMOC2 positivity was higher in old (p=0.001) and male (p<0.001) patients, and in well-differentiated GC (p<0.001). SMOC2 expression had a negative association with perineural invasion (p<0.001) and tumor stage (p<0.001). In survival analysis, SMOC2-positive GC patients had much better clinical outcomes in overall survival rates (p<0.001) compared to SMOC2-negative GC patients. The prognostic impact of SMOC2 remained significant both in intestinal (p<0.001) and diffuse-type GC (p<0.001). Remarkably, a multivariate analysis demonstrated SMOC2 as an independent prognostic marker [hazard ratio (HR)=0.732, p=0.045] along with venous invasion (p=0.012), tumor stage (p<0.001) and CDX2 (p=0.028). CONCLUSION: Our results suggest that SMOC2 can be a prognostic marker for better clinical outcomes in GC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Feminino , Humanos , Mucosa Intestinal/patologia , Masculino , Estadiamento de Neoplasias/métodos , Células-Tronco Neoplásicas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
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