RESUMO
NADP+-dependent malic enzyme 1 (ME1) decarboxylates malate to form pyruvate and NADPH in the cytoplasm, where it mediates diverse biological functions related to the generation of lipids and other cellular building blocks. As such, ME1 has been implicated in the progression of cancers and has received attention as a promising drug target. Here we report the identification of a novel small-molecule inhibitor of ME1, designated AS1134900. AS1134900 is highly selective for ME1 compared with ME2 and uncompetitively inhibits ME1 activity in the presence of its substrates NADP+ and malate. In addition, X-ray crystal structure analysis of the enzyme-inhibitor complex revealed that AS1134900 binds outside the ME1 active site in a novel allosteric site. Structural comparison of the ME1 quaternary complex with AS1134900, NADPH, and Mn2+, alongside known crystal structures of malic enzymes, indicated the determined crystal ME1-inhibitor complex is in the open form conformation. These results provide insights and a starting point for further discovery of drugs that inhibit ME1 activity in cancer cells.
Assuntos
Malato Desidrogenase , Malatos , Sítio Alostérico , Malato Desidrogenase/metabolismo , Malatos/metabolismo , NADP/metabolismoRESUMO
OBJECTIVES: To analyse the protective effect of different doses of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for early severe infections in antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV), considering time-varying changes. METHODS: In this retrospective observational study, we assessed the protective effect of TMP/SMX within the first 6 months of diagnosis among Japanese patients with AAV. We included 250 consecutive patients with AAV who were admitted to our hospital. The protective effect of TMP/SMX against early severe infections was verified using Cox regression analysis along with potential confounding factors. Cox regression with inverse probability treatment weights for early severe infections was also performed as a sensitivity analysis. RESULTS: Cox regression analysis showed that the reduced TMP/SMX exposure group had a significant protective effect against early severe infections (standard-dose group versus no TMP/SMX group: hazard ratio [HR] 0.393, 95% confidence interval [CI]: 0.139-1.11, p=0.077; reduced-dose group versus no TMP/SMX group: HR 0.418, 95%CI: 0.216-0.807, p=0.009), even when considering time-dependent changes. In the sensitivity analysis, the reduced-dose group still had a significantly lower risk of early severe infections than the no TMP/SMX group (HR = 0.393, 95%CI: 0.177-0.873, p=0.022). During follow-up, 18.0% of the patients discontinued TMP/SMX due to side effects. CONCLUSIONS: TMP/SMX is highly effective in preventing severe infections among patients with AAV despite the high incidence of side effects. Further studies are needed to determine the optimal dose of TMP/SMX for preventing severe infections, especially considering renal impairment.
Assuntos
Doenças Transmissíveis , Vasculite , Humanos , Incidência , Estudos Retrospectivos , Combinação Trimetoprima e Sulfametoxazol/efeitos adversosRESUMO
Metabolic programs are rewired in cancer cells to support survival and tumor growth. Among these, recent studies have demonstrated that glutamate-oxaloacetate transaminase 1 (GOT1) plays key roles in maintaining redox homeostasis and proliferation of pancreatic ductal adenocarcinomas (PDA). This suggests that small molecule inhibitors of GOT1 could have utility for the treatment of PDA. However, the development of GOT1 inhibitors has been challenging, and no compound has yet demonstrated selectivity for GOT1-dependent cell metabolism or selective growth inhibition of PDA cell lines. In contrast, potent inhibitors that covalently bind to the transaminase cofactor pyridoxal-5'-phosphate (PLP), within the active site of the enzyme, have been reported for kynurenine aminotransferase (KAT) and gamma-aminobutyric acid aminotransferase (GABA-AT). Given the drug discovery successes with these transaminases, we aimed to identify PLP-dependent suicide substrate-type GOT1 inhibitors. Here, we demonstrate that PF-04859989, a known KAT2 inhibitor, has PLP-dependent inhibitory activity against GOT1 and shows selective growth inhibition of PDA cell lines.
Assuntos
Aspartato Aminotransferase Citoplasmática/antagonistas & inibidores , Carcinoma Ductal Pancreático/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/farmacologia , Aspartato Aminotransferase Citoplasmática/metabolismo , Carcinoma Ductal Pancreático/enzimologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Humanos , Neoplasias Pancreáticas/enzimologiaRESUMO
BACKGROUND: Patients with clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) frequently develop rapidly progressive interstitial pneumonia (RPIP), often with fatal outcomes. Therapeutic plasma exchange (TPE) has been reported as effective against CADM-RPIP refractory to conventional immunosuppressive therapy. However, the detailed mechanisms by which TPE improves disease activity of CADM-RPIP remain unclear. AIM: To elucidate the clinical and demographic characteristics of patients with anti-MDA5 Ab-positive CADM-RPIP treated with TPE and to analyze changes in laboratory findings before, during, and after TPE. MATERIALS & METHODS: Patients hospitalized for CADM-RPIP and treated with TPE in 2017 and 2018 were analyzed retrospectively. RESULTS: Three patients were successfully treated with TPE, with good tolerance. Anti-MDA5 Ab titers decreased significantly over the course of TPE. CONCLUSION: We emphasize that TPE could represent an effective treatment option for CADM-RPIP refractory to traditional therapy. Removal of anti-MDA5 Ab and other pathogenic factors may facilitate favorable outcomes.
Assuntos
Dermatomiosite/complicações , Doenças Pulmonares Intersticiais/terapia , Troca Plasmática/métodos , Autoanticorpos/sangue , Feminino , Hemoperfusão , Humanos , Helicase IFIH1 Induzida por Interferon/imunologia , Masculino , Pessoa de Meia-Idade , Polimixina B/administração & dosagem , Estudos RetrospectivosRESUMO
BACKGROUND: Streptococcus pyogenes (group A Streptococcus [GAS]) is a major human pathogen that causes a wide spectrum of clinical manifestations. Although invasive GAS (iGAS) infections are relatively uncommon, emm3/ST15 GAS is a highly virulent, invasive, and pathogenic strain. Global molecular epidemiology analysis has suggested that the frequency of emm3 GAS has been recently increasing. CASE PRESENTATION: A 14-year-old patient was diagnosed with streptococcal toxic shock syndrome and severe pneumonia, impaired renal function, and rhabdomyolysis. GAS was isolated from a culture of endotracheal aspirates and designated as KS030. Comparative genome analysis suggested that KS030 is classified as emm3 (emm-type) and ST15 (multilocus sequencing typing [MLST]), which is similar to iGAS isolates identified in the UK (2013) and Switzerland (2015). CONCLUSIONS: We conclude that the global dissemination of emm3/ST15 GAS strain has the potential to cause invasive disease.
Assuntos
Choque Séptico/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/isolamento & purificação , Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/genética , Humanos , Epidemiologia Molecular , Tipagem de Sequências Multilocus , Choque Séptico/epidemiologia , Infecções Estreptocócicas/epidemiologia , Streptococcus pyogenes/classificação , Streptococcus pyogenes/genética , Suíça/epidemiologiaRESUMO
Prasugrel, a thienopyridine anti-platelet agent, is pharmacologically activated by hydrolysis and hydroxylation. It is efficiently hydrolyzed in the intestine after oral administration, and the enzyme responsible for the hydrolysis in humans was demonstrated to be carboxylesterase (CES)2. Prasugrel hydrolase activity is detected in dog intestines, where CES enzymes are absent; therefore, this prompted us to investigate the involvement of an enzyme(s) other than CES. Human arylacetamide deacetylase (AADAC) is highly expressed in the small intestine, catalyzing the hydrolysis of several clinical drugs containing small acyl moieties. In the present study, we investigated whether AADAC catalyzes prasugrel hydrolysis. Recombinant human AADAC was shown to catalyze prasugrel hydrolysis with a CLint value of 50.0 ± 1.2 ml/min/mg protein with a similar Km value to human intestinal and liver microsomes, whereas the CLint values of human CES1 and CES2 were 4.6 ± 0.1 and 6.6 ± 0.3 ml/min/mg protein, respectively. Inhibition studies using various chemical inhibitors and the relative activity factor approach suggested that the contribution of AADAC to prasugrel hydrolysis in human intestine is comparable to that of CES2. In dog intestine, the expression of AADAC, but not CES1 and CES2, was confirmed by measuring the marker hydrolase activities of each human esterase. The similar Km values and inhibition profiles between recombinant dog AADAC and small intestinal microsomes suggest that AADAC is a major enzyme responsible for prasugrel hydrolysis in dog intestine. Collectively, we found that AADAC largely contributes to prasugrel hydrolysis in both human and dog intestine.
Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Cloridrato de Prasugrel/metabolismo , Animais , Carboxilesterase/metabolismo , Linhagem Celular , Cães , Humanos , Hidrolases/metabolismo , Hidrólise , Mucosa Intestinal/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/metabolismo , Células Sf9 , SpodopteraRESUMO
The dynamic properties of phospholipid (PL) membranes (phase state and phase transition) play crucial roles in biological systems. However, highly sensitive, direct analytical methods that shed light on the nature of lipids and their assemblies have not been developed to date. Here, we describe the analysis of PL-modified Au nanoparticles (Au@PL) using membrane surface-enhanced Raman spectroscopy (MSERS) and report the properties of the self-assembled PL membranes on the Au nanoparticle. The Raman intensity per PL concentration increased by 50-170 times with Au@PL, as compared to large unilamellar vesicles (LUVs) at the same PL concentration. The phase state and phase transition temperature of the PL membrane of Au@PL were investigated by analyzing the Raman peak ratio (R = I2882/I2930). The enhancement at 714 cm(-1) (EF(714)) varied with the hydrocarbon chain length of the PLs and the assembled degree of Au@PLs. In calculation, the EF(714),assembled was estimated to be 111-142 when the distance between AuNPs was 7.0-7.5 nm, which was correlated to the speculative enhancement factor, suggesting that the assembly of the Au@PLs contributed to the MSERS.
Assuntos
Fosfolipídeos/análise , Fosfolipídeos/química , Análise Espectral Raman , Ouro/química , Nanopartículas Metálicas/química , Propriedades de SuperfícieRESUMO
Topological crystalline superconductivity in locally noncentrosymmetric multilayer superconductors (SCs) is proposed. We study the odd-parity pair-density wave (PDW) state induced by the spin-singlet pairing interaction through the spin-orbit coupling. It is shown that the PDW state is a topological crystalline SC protected by a mirror symmetry, although it is topologically trivial according to the classification based on the standard topological periodic table. The topological property of the mirror subsectors is intuitively explained by adiabatically changing the Bogoliubov-de Gennes Hamiltonian. A subsector of the bilayer PDW state reduces to the two-dimensional noncentrosymmetric SC, while a subsector of the trilayer PDW state is topologically equivalent to the spinless p-wave SC. Chiral Majorana edge modes in trilayers can be realized without Cooper pairs in the spin-triplet channel and chemical potential tuning.
RESUMO
We sought to determine the morphologic predictors of major adverse cardiac events (MACEs) after successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES), using integrated backscatter intravascular ultrasound (IB-IVUS). Conventional IVUS and IB-IVUS were performed in 260 consecutive patients who underwent PCI with DES. Three-dimensional analyses were performed to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcification). Patients were divided into two groups according to the median lipid volume (LV) in the target lesion. MACEs were defined as death, nonfatal myocardial infarction, and any repeat revascularization. The median follow-up interval was 1285 days. MACEs were observed in 64 patients (24.6 %). Patients having a larger LV compared with their counterparts had worse long-term clinical outcomes regarding mortality (3.8 vs. 0 %, P = 0.02) and MACEs (31.5 vs. 17.7 %, P = 0.008) by log-rank test. After adjustment for confounders, large LV (odds ratio 1.95, 95 % confidence interval 1.14-3.33, P = 0.02) was significantly and independently associated with MACEs. The assessment of coronary plaque characteristics in the target lesion may be useful to predict long-term outcome following successful coronary intervention.
Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Doença da Artéria Coronariana , Lipídeos/análise , Placa Aterosclerótica , Complicações Pós-Operatórias , Idoso , Angioplastia Coronária com Balão/métodos , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/terapia , Stents Farmacológicos , Seguimentos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/patologia , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Sirolimo , Resultado do Tratamento , Ultrassonografia de Intervenção/métodosRESUMO
Thermal shielding materials that can block near-infrared (NIR) light from the sunlight while maintaining visible transparency have become increasingly important from an energy-saving perspective. Here, we demonstrate a gigantic NIR shielding by an engineered plasmonic material based on a two-dimensional (2D) polytungstate (Cs4-xW11O35-d). Starting from a charge-neutral polytungstate (Cs4W11O35), we synthesize charge-imbalanced 2D nanosheets (Cs4-xW11O35-d) that undergo an unusual structural change with the semiconductor-to-metal transition in a reduced atmosphere. Layer-by-layer engineering of the 2D nanosheets enables a plasmon-induced enhancement of the NIR reflectance (>53%) with a high visible transparency (>71%), realizing high-performance thermal shielding. Our approach offers a solution for future thermal management technology.
RESUMO
BACKGROUND: It is well known that chronic kidney disease is a strong independent predictor of adverse outcomes after percutaneous coronary intervention in patients with ischemic heart disease. Recently, peri-procedural myocardial injury has been associated with adverse cardiac events. The aim of this study was to investigate the relationship between renal function and peri-procedural myocardial injury in patients undergoing elective stent implantation. METHODS: This study comprised 273 consecutive patients who underwent elective stent implantation. They were divided into two groups: estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m(2) and eGFR ≥60 mL/min/1.73m(2). Peri-procedural TnT levels higher than three times the normal limit were defined as peri-procedural myocardial injury. RESULTS: Patients with eGFR <60 mL/min/1.73m(2) showed a higher incidence of peri-procedural myocardial injury compared to patients with eGFR ≥60 mL/min/1.73m(2) (4.3 versus 20.9%, P < 0.0001). Even after a multivariate adjustment, the eGFR level predicted peri-procedural myocardial injury [odds ratio 0.92, 95% confidence interval (CI): 0.89-0.95, P < 0.0001]. Total stent length was also an independent predictor of peri-procedural myocardial injury (odds ratio 1.09, 95% CI: 1.02-1.16, P = 0.009). Using a receiver-operating curve analysis, eGFR level of 62.1 mL/min/1.73m(2) (sensitivity 93.3%, specificity 57.2%) was the best value (area under the curve = 0.803) to maximize the power of eGFR levels in predicting peri-procedural myocardial injury. CONCLUSIONS: Patients with eGFR <60 mL/min/1.73m(2) were strongly associated with peri-procedural myocardial injury after elective stent implantation. Therefore, eGFR may be a simple and convenient predictor of peri-procedural myocardial injury.
Assuntos
Falência Renal Crônica/complicações , Falência Renal Crônica/cirurgia , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Stents/efeitos adversos , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Japão/epidemiologia , Masculino , Infarto do Miocárdio/epidemiologia , Curva ROC , Fatores de Risco , Resultado do TratamentoRESUMO
Hypoglycemic agents with a mechanism of depeptidyl peptidase IV (DPP-4) inhibition are suitable for once daily oral dosing. It is difficult to strike a balance between inhibitory activity and duration of action in plasma for inhibitors bearing an electrophilic nitrile group. We explored fused bicyclic heteroarylpiperazine substituted at the γ-position of the proline structure in the investigation of L-prolylthiazolidines lacking the electrophilic nitrile. Among them, 2-trifluoroquinolyl compound 8g is the most potent, long-lasting DPP-4 inhibitor (IC(50) = 0.37 nmol/L) with high selectivity against other related peptidases. X-ray crystal structure determination of 8g indicates that CH-π interactions generated between the quinolyl ring and the guanidinyl group of Arg358 enhances the DPP-4 inhibitory activity and selectivity.
Assuntos
Compostos Bicíclicos com Pontes/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Nitrilas/química , Piperazinas/química , Prolina/análogos & derivados , Prolina/síntese química , Prolina/farmacologia , Tiazolidinas/síntese química , Tiazolidinas/farmacologia , Animais , Cristalografia por Raios X , Dipeptidil Peptidase 4/sangue , Inibidores da Dipeptidil Peptidase IV/síntese química , Relação Dose-Resposta a Droga , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Prolina/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazolidinas/químicaRESUMO
Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the γ-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine (8 g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8 g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8 g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8 g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Pirazóis/química , Pirazóis/uso terapêutico , Tiazolidinas/química , Tiazolidinas/uso terapêutico , Animais , Glicemia/metabolismo , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Teste de Tolerância a Glucose , Haplorrinos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Simulação de Acoplamento Molecular , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Ratos Wistar , Ratos Zucker , Tiazolidinas/farmacocinética , Tiazolidinas/farmacologiaRESUMO
We measured serum TARC (Thymus and activation-regulated chemokine, CCL-17) levels in three patients of gastrointestinal food allergies in neonates and infants. Patient 1: 14-day-old girl. The chief complaints were poor feeding and weight loss. She tested peripheral eosinophilia (5820 /µL), high serum TARC levels (4730 pg/mL) and positive milk-specific IgE (1.53 UA/mL) at the time of onset. After change from cow' milk formula to hydrolyzed infant formulas and breast milk ahead of dairy products intake, the symptoms resolved. One month and a half later, she re-tested negative milk-specific IgE and normal serum TARC levels (198 pg/mL). Patient 2: 3-month-old girl. The chief complaint was vomiting after intake of cow' milk formula. She tested negative milk-specific IgE and very high serum TARC levels (25200 pg/mL) at the time of onset. After changing to hydrolyzed infant formulas and breast milk ahead of dairy products intake, the symptom resolved. Three months later, she re-tested positive milk-specific IgE (0.42 UA/mL) and normal serum TARC levels (1250 pg/mL). Patient 3: 21-day-old boy. The chief complaint was vomiting after intake of cow' milk formula. He tested peripheral eosinophilia (2923 /µL), very high serum TARC levels (49100 pg/mL) and positive milk-specific IgE (0.47 UA/mL) at the time of onset. After changing to hydrolyzed infant formulas and breast milk ahead of dairy products intake, the symptom resolved. Two weeks later, he re-tested negative milk-specific IgE and serum TARC levels (2210 pg/mL). Serum TARC may be related to the part of gastrointestinal food allergies in neonates and infants.
Assuntos
Quimiocina CCL17/sangue , Hipersensibilidade a Leite/sangue , Biomarcadores/sangue , Feminino , Humanos , Hipersensibilidade Tardia/sangue , Hipersensibilidade Tardia/diagnóstico , Lactente , Recém-Nascido , Hipersensibilidade a Leite/diagnósticoRESUMO
CASE PRESENTATION: A 73-year-old man with fever and fatigue presented to his doctor. He had a history of smoking (52 pack-years) and COPD on home oxygen therapy. The patient had no significant family medical history, illicit drug-use history, or recent alcohol use. Chest CT scan showed a slight infiltrative shadow of the left lower lobe on a background of emphysema. Broad-spectrum antibiotics were administered for community-acquired pneumonia without any clinical or radiologic improvement after 2 weeks of therapy. Additional tests showed rapid deterioration of renal function (creatinine level, which was 0.68 mg/dL 2 years earlier, had worsened to 2.08 mg/dL), BUN level of 49.8 mg/dL (reference range, 8- to 20 mg/dL), myeloperoxidase-anti-neutrophil cytoplasmic antibodies 484.0 units/mL (range, 0.0 to 3.4 units/mL), C-reactive protein level of 11.1 mg/dL (range, 0.0 to 0.14 mg/dL), hemoglobin level of 9.0 g/dL (range, 13.7 to 16.8 g/dL), and urinalysis protein 1+ and occult blood 3+. On physical examination, multiple lesions of purpura were observed on the body surface, and hemoptysis was present. No sputum, urine, or blood cultures were done. Based on the examination, the previous doctors suspected microscopic polyangiitis (MPA) rather than an atypical/resistant infectious disease. The patient was treated with high-dose methylprednisolone (500 mg for 2 days and 125 mg for 13 days), but hemoptysis reappeared, and the patient was subsequently transported to our hospital.
Assuntos
Hemoptise , Drogas Ilícitas , Idoso , Antibacterianos/uso terapêutico , Anticorpos Anticitoplasma de Neutrófilos , Proteína C-Reativa , Creatinina , Hemoglobinas , Hemoptise/diagnóstico , Hemoptise/etiologia , Humanos , Masculino , Metilprednisolona/uso terapêutico , Oxigênio , PeroxidaseRESUMO
BACKGROUND: Patients with acute coronary syndrome (ACS) have multiple complex coronary plaques associated with plaque vulnerability. The present study assessed the tissue characteristics of coronary plaques between ACS and stable angina pectoris (SAP) of culprit and non-culprit lesions using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS AND RESULTS: IVUS was performed in 165 patients (40 patients with ACS) with 225 culprit (65 lesions in ACS) and 171 non-culprit lesions (42 lesions in ACS). The percentage of fibrous area (fibrous area/plaque area, %FIB) and the percentage of lipid area (lipid area/plaque area, %LIP) at the segment with minimal luminal area were calculated using IB-IVUS system. Culprit and non-culprit lesions with ACS showed a significant increase in %LIP (38±18 vs. 30±15%, P=0.002, and 38±21 vs. 32±17%, P=0.03, respectively) and a significant decrease in %FIB (59±15 vs. 63±12 %, P=0.04, and 57±18 vs. 62±14%, P=0.04, respectively) compared to those with SAP. On logistic regression analysis, not only culprit lesions but also non-culprit lesions with ACS patients were significantly associated with the lipid-rich plaque. CONCLUSIONS: Non-culprit coronary lesions with ACS patients are associated with the lipid-rich plaque, suggesting the extensive development of plaques instability in these patients.
Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Angina Pectoris/diagnóstico por imagem , Angina Instável/diagnóstico por imagem , Ultrassonografia de Intervenção/métodos , Síndrome Coronariana Aguda/patologia , Síndrome Coronariana Aguda/terapia , Idoso , Angina Pectoris/patologia , Angina Pectoris/terapia , Angina Instável/patologia , Angina Instável/terapia , Angioplastia Coronária com Balão , Calcinose/diagnóstico por imagem , Calcinose/patologia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Feminino , Fibrose , Humanos , Lipídeos/análise , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Ruptura Espontânea , Método Simples-CegoRESUMO
BACKGROUND: Despite growing interest in non-target lesion events in patients undergoing percutaneous coronary intervention (PCI), there has been little discussion of predictors. METHODS AND RESULTS: A total of 155 consecutive patients who underwent PCI were enrolled. Conventional and integrated backscatter intravascular ultrasound (IB-IVUS) parameters were measured in non-target lesions utilizing a 40-MHz intravascular catheter. Lipid-rich plaques (LRP) were defined as lesions with an increased lipid volume (> median) and greater lipid content. Non-target ischemic events were defined as death, non-fatal myocardial infarction, any repeat revascularization and rehospitalization for angina involving the non-target vessel or the target vessel outside the index lesion. During the follow-up period (median: 1,265 days), non-target events were observed in 16 patients (11%). Using the Cox proportional hazard model, LRP (odds ratio [OR], 6.06; 95% confidence interval [CI]: 1.81-20.4, P = 0.0035), elevated serum C-reactive protein (CRP) levels (OR, 6.83; 95%CI: 2.19-21.3, P = 0.0009) and acute coronary syndrome present at baseline (OR, 4.08; 95%CI: 1.21-13.8, P = 0.024) were significantly and independently associated with non-target events. Synergistic effects of LRP and elevated serum CRP levels for prediction of non-target events (OR, 14.8; 95%CI: 4.57-48.0, P < 0.0001) were found even after adjusting for confounders. CONCLUSIONS: LRP measured using IB-IVUS proved to be an independent morphologic predictor of non-target ischemic events after PCI, particularly enhancing the risk in patients with elevated serum CRP levels.
Assuntos
Síndrome Coronariana Aguda/terapia , Angina Pectoris/terapia , Angioplastia Coronária com Balão/efeitos adversos , Lipídeos/análise , Isquemia Miocárdica/etiologia , Ultrassonografia de Intervenção , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/metabolismo , Síndrome Coronariana Aguda/mortalidade , Idoso , Angina Pectoris/diagnóstico por imagem , Angina Pectoris/metabolismo , Angina Pectoris/mortalidade , Angioplastia Coronária com Balão/mortalidade , Biomarcadores/sangue , Proteína C-Reativa/análise , Distribuição de Qui-Quadrado , Angiografia Coronária , Intervalo Livre de Doença , Feminino , Humanos , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/mortalidade , Variações Dependentes do Observador , Razão de Chances , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para CimaRESUMO
A new member of the dunaimycin family, dunaimycin C3 (2), was isolated from a fermented broth of Streptomyces sp. RAN389. The molecular formula of 2 was established as C42H70O10 by high-resolution FAB-MS, and the structure was elucidated by NMR spectroscopic analyses. Dunaimycin C3 inhibited the expression of the molecular chaperone GRP78 in HT1080 G-L cells in the presence of 10 mM of 2-deoxyglucose with an IC50 of 8.4 nM.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Choque Térmico/metabolismo , Streptomyces/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Humanos , Concentração Inibidora 50 , Estrutura MolecularRESUMO
We explore LiNiO2-based cathode materials with two-element substitutions by an ab initio simulation-based materials informatics (AIMI) approach. According to our previous study, a higher cycle performance strongly correlates with less structural change during the charge-discharge cycles; the latter can be used for evaluating the former. However, if we target the full substitution space, full simulations are infeasible even for all binary combinations. To circumvent such an exhaustive search, we rely on Bayesian optimization. Actually, by searching only 4% of all of the combinations, our AIMI approach discovered two promising combinations, Cr-Mg and Cr-Re, whereas each atom itself never improved the performance. We conclude that the synergy never emerges from a common strategy restricted to combinations of "good" elements that individually improve the performance. In addition, we propose a guideline for the binary substitutions by elucidating the mechanism of the crystal structure change.