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BACKGROUND: Harsh temperature exposure has been associated with a high risk of cardiovascular events. We sought to investigate the influence of temperature change on long-term incidence of acute myocardial infarction (AMI) in Korean patients. METHODS: From the National Health Insurance Service (NHIS) customized health information database (from 2005 to 2014), data from a total of 192,567 AMI patients was assessed according to the International Classification of Disease 10th edition code and matched with temperature reports obtained from the Korea Meteorological Administration database. We analyzed data for a 10-year period on a monthly and seasonal basis. RESULTS: The incidence rate per 100,000 year of AMI exhibited a downward trend from 69.1 to 56.1 over the period 2005 to 2014 (P < 0.005), and the seasonal AMI incidence rate per 100,000 year was highest in spring (63.1), and winter (61.3) followed by autumn (59.5) and summer (57.1). On a monthly basis, the AMI incidence rate per 100,000 year was highest during March (64.4) and December (63.9). The highest incidence of AMI occurred during temperature differences of 8-10° in each season. Moreover, AMI incidence tended to increase as the mean temperature decreased (r = -0.233, P = 0.001), and when the mean daily temperature difference increased (r = 0.353, P < 0.001). CONCLUSION: The AMI incidence rate per 100,000 year has a decreasing trend over the 10-year period, derived from the Korean NHIS database. Modest daily temperature differences (8-10°) and the spring season are related to higher AMI incidence, indicating that daily temperature variation is more important than the mean daily temperature.
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Infarto del Miocardio , Humanos , Temperatura , Incidencia , Estaciones del Año , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Bases de Datos FactualesRESUMEN
With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 µM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 µM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 µM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.
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Antibacterianos , Arginina , Diseño de Fármacos , Ácido Glicirretínico , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Humanos , Antibacterianos/farmacología , Arginina/biosíntesis , Escherichia coli/efectos de los fármacos , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Sulfuro de Hidrógeno/metabolismoRESUMEN
OBJECTIVES: Salvage liver transplantation (sLT) is considered an effective method to treat hepatocellular carcinoma (HCC) recurrence. This multicenter research aimed to identify the prognostic factors associated with recurrence-free survival (RFS) and overall survival (OS) after sLT. MATERIAL AND METHODS: A retrospective analysis of 114 patients who had undergone sLT for recurrent HCC between February 2012 and September 2020 was performed. The baseline and clinicopathological data of the patients were collected. RESULTS: The 1-, 3-, and 5-year RFS rates after sLT were 88.9%, 75.2%, and 69.2%, respectively, and the OS rates were 96.4%, 78.3%, and 70.8%. A time from liver resection (LR) to recurrence < 1 year, disease beyond the Milan criteria at sLT and macrotrabecular massive (MTM)-HCC were identified as risk factors for RFS and were further identified as independent risk factors. A time from LR to recurrence < 1 year, disease beyond the Milan criteria at sLT and MTM-HCC were also risk factors for OS and were further identified as independent risk factors. CONCLUSIONS: Compared with primary liver transplantation (pLT), more prognostic factors are available from patients who had undergone LR. We suggest that in cases of HCC recurrence within 1 year after LR, disease beyond the Milan criteria at sLT and MTM-HCC patients, sLT should be used with caution.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Trasplante de Hígado/efectos adversos , Estudios Retrospectivos , Terapia Recuperativa/efectos adversos , Recurrencia Local de Neoplasia/patología , Hepatectomía/efectos adversos , Supervivencia sin EnfermedadRESUMEN
BACKGROUND: Strongyloidiasis, caused by Strongyloides stercoralis (S. stercoralis), is endemic worldwide, especially in countries with warm and humid climates. Strongyloides stercoralis hyperinfection syndrome (SHS) is an extremely serious manifestation of strongyloidiasis, which results from an acute exacerbation of auto-infection and is often fatal. CASE PRESENTATION: We present a case of SHS mimicking pseudomembranous enteritis with a final definitive diagnosis of a triple infection including S. stercoralis, Escherchia coli (E. coli) and Pneumocytis jirovecii (P. jirovecii) that occurred in a microscopic polyangiitis (MPA) patient after immunosuppressive therapy. SHS, together with E. coli bacteremia and Pneumocytis jirovecii pneumonia (PJP) in the same patient, is rare in clinical practice, which is first reported worldwide, to our knowledge. After the diagnosis was confirmed, the treatment protocol was quickly adjusted; however, the patient's life could not be saved. CONCLUSION: This case reminds us of the necessity to consider strongyloidiasis as a differential diagnosis in immunocompromised populations who live in or have visited to S. stercoralis endemic areas, especially patients with suspected pseudomembranous enteritis, even if stool examination, serological tests, and eosinophilia are negative. For this group, it is advisable to complete the relevant endoscopy and/or PCR as soon as possible. The fundamental solution to prevent this catastrophic outcome is to implement effective preventive measures at multiple levels, including physicians, patients, and relevant authorities.
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Bacteriemia , Enterocolitis Seudomembranosa , Infecciones por Escherichia coli , Neumonía por Pneumocystis , Strongyloides stercoralis , Estrongiloidiasis , Animales , Bacteriemia/complicaciones , Escherichia coli , Infecciones por Escherichia coli/complicaciones , Humanos , Terapia de Inmunosupresión , Neumonía por Pneumocystis/complicaciones , Estrongiloidiasis/complicaciones , Estrongiloidiasis/diagnóstico , Estrongiloidiasis/tratamiento farmacológico , SíndromeRESUMEN
Podophyllotoxin's undifferentiated cytotoxicity and poor selectivity limit its clinical application. To improve above disadvantages, conjugation of bile acids with podophyllotoxin could improve cell line selectivity of liver cancer to achieve clinical translation further. Enlightened by the bile acids' moiety magic characters, thirty podophyllotoxin-linked bile acid derivatives had been designed and synthesized. The cytotoxicity of these compounds in vitro was evaluated on HepG2, HCT-116, A549 and MDCK cell lines. After conjunction with bile acids, most of the derivatives (IC50 = 0.066-0.831 µM) were more potent against above three types of tumor cells than Etoposide (VP-16, IC50 = 4.319-41.080 µM) and exhibited similar antitumor activity compared with doxorubicin (DOX, IC50 = 0.230-0.745 µM). Moreover, structure-activity relationship displayed the length of the linker chain between podophyllotoxin and bile acids affected the cytotoxicity. Especially, compound 23 exhibited strong activity against HepG2 cell lines (IC50 = 0.188 ± 0.01 µM) than MDCK cell lines (IC50 = 4.780 ± 0.50 µM) and its SI (IC50MDCK/IC50HepG2) value of compound 23 was 25.4. Further antitumor mechanism studies showed that compound 23 acted as Topo â ¡ inhibition and induced cell apoptosis with S cell cycle arrest. In particular, compound 23 showed valid antitumor efficacy at 10 mg/kg by intraperitoneal administration with a tumor inhibition rate of 60.9% in the Hepa1-6 xenograft mice model. The current research displayed that introduction of bile acids contributed to improve selectivity and activity to cell, and compound 23 could be a promising anti-tumor candidate.
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Antineoplásicos , Neoplasias , Animales , Antineoplásicos/farmacología , Apoptosis , Ácidos y Sales Biliares/farmacología , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Etopósido/farmacología , Glucósidos/farmacología , Humanos , Ratones , Estructura Molecular , Podofilotoxina , Relación Estructura-ActividadRESUMEN
Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Humanos , Inmunosupresores/efectos adversos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/métodos , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Prospectivos , Calidad de Vida , Sirolimus/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore prognostic factors by comparing the efficacy of salvage liver transplantation (sLT) and rehepatectomy (RH) for the treatment of recurrent hepatocellular carcinoma after hepatectomy. METHODS: Clinical data were collected for 124 patients treated at our center from January 2012 to August 2018. The median follow-up time for the patients was 39 months. By analyzing the clinical data between the sLT group (46 cases) and RH group (78 cases), the factors affecting the prognosis of patients were compared. RESULTS: The proportion of alpha-fetoprotein (AFP) ≥ 100 µg/L in the recurrence group was significantly higher than that in the recurrence-free group (70.0% vs 22.2%, P = .014). The postoperative overall survival (OS) and recurrence-free survival (RFS) were better in the sLT group than in the RH group (81.2% vs 36.9%, P < .01; 77.1% vs 55.6%, P = .019). In the sLT group, the OS and RFS in the AFP < 100 µg/L group were superior to those in the AFP ≥ 100 µg/L group (P = .046 and P = .002). CONCLUSION: The sLT group had achieved better efficacy than RH group, but when AFP ≥ 100 µg/L, sLT did not achieve better efficacy than RH.
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Carcinoma Hepatocelular , Hepatectomía , Neoplasias Hepáticas , Trasplante de Hígado , Carcinoma Hepatocelular/cirugía , Humanos , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/cirugía , Estudios Retrospectivos , Terapia RecuperativaRESUMEN
Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy exhibiting great clinical and genetic heterogeneity. Here, the identification of two heterozygous missense mutations in the C1orf194 gene at 1p21.2-p13.2 with Charcot-Marie-Tooth disease are reported. Specifically, the p.I122N mutation was the cause of an intermediate form of Charcot-Marie-Tooth disease, and the p.K28I missense mutation predominately led to the demyelinating form. Functional studies demonstrated that the p.K28I variant significantly reduced expression of the protein, but the p.I122N variant increased. In addition, the p.I122N mutant protein exhibited the aggregation in neuroblastoma cell lines and the patient's peroneal nerve. Either gain-of-function or partial loss-of-function mutations to C1ORF194 can specify different causal mechanisms responsible for Charcot-Marie-Tooth disease with a wide range of clinical severity. Moreover, a knock-in mouse model confirmed that the C1orf194 missense mutation p.I121N led to impairments in motor and neuromuscular functions, and aberrant myelination and axonal phenotypes. The loss of normal C1ORF194 protein altered intracellular Ca2+ homeostasis and upregulated Ca2+ handling regulatory proteins. These findings describe a novel protein with vital functions in peripheral nervous systems and broaden the causes of Charcot-Marie-Tooth disease, which open new avenues for the diagnosis and treatment of related neuropathies.
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Enfermedad de Charcot-Marie-Tooth/genética , Animales , Calcio/metabolismo , Técnicas de Sustitución del Gen , Humanos , Ratones , Ratones Transgénicos , Mutación Missense , LinajeRESUMEN
OBJECTIVES: To investigate the morbidity, clinical characteristics, and risk factors for postoperative recurrent gout flares (PRGFs). METHODS: This cross-sectional study included all surgical patients at 2 academic institutions between 2010 and 2018. Data including demographics, prior history of gout, clinical variables, medications, and the occurrence of PRGFs were abstracted from medical records. Forward stepwise multivariable logistic regression analysis was used in the statistical analyses. RESULTS: Among the 518 (0.5% [518/114,760]) surgical patients with a prior diagnosis of gout, 474 had sufficient documentation for analysis. Of these, 191 (40.3%) had experienced a PRGF. Most PRGFs (54.4%) were polyarticular gout; 79.6% had a pretreatment pain score of PRGFs ≥7, and 59.2% required combination pharmacologic therapy. The mean (SD) serum urate (SU) level decreased postoperatively (500.33 [122.77] vs. 380.15 [118.35] µmol/L; p = 0.000), with an average decrease of 125.86 µmol/L. The decrease in the postsurgical SU level was greater in patients who received postoperative total parenteral nutrition (PTPN) than in those who did not (p = 0.009), and it was correlated with the duration of PTPN (r = 0.156, p = 0.031). Factors independently associated with PRGFs were decrease in the postsurgical SU level by ≥126 µmol/L, previous flares involving the ankle, failure to take prophylactic colchicine therapy, and abdominal surgery. CONCLUSIONS: Recurrent gout flares often occur postoperatively and are severe. For high-risk patients, especially those undergoing abdominal surgeries, timely monitoring of postsurgical SU level, colchicine prophylaxis, and avoiding the overuse of PTPN may help prevent PRGFs.
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Supresores de la Gota , Gota , China/epidemiología , Estudios Transversales , Gota/diagnóstico , Gota/tratamiento farmacológico , Gota/epidemiología , Supresores de la Gota/uso terapéutico , Humanos , Brote de los Síntomas , Ácido ÚricoRESUMEN
BACKGROUND: AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of the mammary SWI/SNF chromatin remodeling complex and a tumor suppressor protein. The loss of ARID1A been observed in several types of human cancers and associated with poor patient prognosis. Previously, we have reported that ARID1A protein was rapidly ubiquitinated and destructed in gastric cancer cells during DNA damage response. However, the ubiquitin e3 ligase that mediated this process remains unclear. MATERIALS AND METHODS: The interaction between ARID1A and ß-TRCP was verified by co-immunoprecipitation (Co-IP) assay. The degron site of ARID1A protein was analyzed by bioinformatics assay. Short hairpin RNAs (shRNAs) were used to knockdown (KD) gene expression. RESULTS: Here we show that DNA damage promotes ARID1A ubiquitination and subsequent destruction via the ubiquitin E3 ligase complex SCFß-TRCP. ß-TRCP recognizes ARID1A through a canonical degron site (DSGXXS) after its phosphorylation in response to DNA damage. Notably, genetic inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase impaired DNA damage-induced ARID1A destruction. CONCLUSIONS: Our studies provide a novel molecular mechanism for the negative regulation of ARID1A by ß-TRCP and ATM in DNA damaged gastric cancer cells.
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Tagetespatula L. is a widely cultivated herbal medicinal plant in China and other countries. In this study, two new 2, 3-dihydrobenzofuran glucosides (1, 2) and fourteen known metabolites (3-16) were isolated from the stems and leaves of T. patula (SLT). The chemical structures of the isolated compounds were characterized comprehensively based on one- and two-dimensional NMR spectroscopy and high resolution mass spectrometry. Absolute configurations of compounds 1 and 2 were determined by ECD calculations. Compounds 1 and 2 exhibited moderate in vitro inhibitory activities against human gastric cancer cell lines (AGS) with IC50 values of 41.20 µmol/L and 30.43 µmol/L, respectively. The fingerprint profiles of stems and leaves of T. patula with three color types of flowers (Janie Yellow Bright, Jinmen Orange, Shouyao Red and Yellow color) were established by high-performance liquid chromatography (HPLC). Ten different batches of stems and leaves were examined as follow: Shouyao Red and Yellow color (1, 2, 3), Janie Yellow Bright (4, 5, 6, 7) and Jinmen Orange (8, 9, 10). Twenty-two common peaks were identified with similarity values ranging from 0.910 to 0.977. Meanwhile, the average peak area of SLT in the three types of flowers was different and it was the highest in Janie Yellow Bright.
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Fitoquímicos/análisis , Hojas de la Planta/química , Tallos de la Planta/química , Tagetes/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión/métodos , Humanos , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacologíaRESUMEN
OBJECTIVE: To evaluate the clinical effect of bortezomib with different dose-frequency in the treatment of multiple myeloma. METHODS: 86 patients with multiple myeloma in our hospital from February 2011 to February 2017 were included in the study. The patients were randomly divided into the experimental group (43 cases) and the control group (43 cases). The patients in the control group were treated with high dose bortezomib (1.6 mg/m2) on day 1, day 8, day 15 and day 22, with 35 d as a chemotherapy cycle. The patients in experimental group was treated with low dose bortezomib (1.0-1.3 mg/m2) on day 1, day 4, day 8 and day 11, with 21 d as a chemotherapy cycle. The patients in both groups were given dexamethasone(40 mg/d) and doxorubicin (10 mg/m2) from day 1 to day 4, and thalidomide was given orally at the intervals of 6 chemotherapy cycles. The clinical effect and the incidence of adverse drug reactions were compared between the two groups. RESULTS: The overall response rate (ORR) and disease control rate (DCR) were 88.37% and 95.35% respectively in the experimental group, while those of the control group were 81.40% and 90.70% respectively. There was no significant difference in ORR and DCR between the two groups. In the incidence of leukopenia, thrombocytopenia and neutropenia showed no significant difference between the two groups. The incidences of grade â ¢ to grade â £ peripheral neuropathy, herpes zoster, fatigue and abdominal distension in the experimental group were 2.33%, 4.65%, 13.95% and 2.33% respectively, while those of the control group were 16.28%, 27.91%, 34.88% and 18.60% respectively. The differences of the above incidences between the two groups were significant (P < 0.05). All the patients were followed up for 24 months. There was no significant difference in the overall survival (OS) rate, progression-free survival (PFS) rate and cumulative recurrence rate between the two groups. CONCLUSIONS: The effect of bortezomib in the treatment of multiple myeloma was similar at different dose-frequency group. The patients treated with low dose bortezomib (day 1, day 4, day 8 and day 11) had the better tolerance and lower incidences of adverse drug reactions.
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Bortezomib/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Humanos , Recurrencia Local de Neoplasia , Resultado del TratamientoRESUMEN
BACKGROUND: Real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) is a critical tool for evaluating the levels of mRNA transcribed from genes. Reliable RT-qPCR results largely depend on normalization to suitable reference genes. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) are models that are commonly used to study ischemic stroke. However, the proper reference genes for RNA analysis in these two models have not yet been determined. RESULTS: In this study, we evaluated the expression levels of six candidate housekeeping genes and selected the most suitable reference genes for RT-qPCR analyses of the cortices of MCAO mice and OGD/R-injured N2a cells. Four software programs, geNorm, NormFinder, BestKeeper and RefFinder, were used to validate the stabilities of the candidate reference genes. The results revealed that HPRT and 18S were the most stable reference genes in the cortices of MCAO mice and that ß-actin and cyclophilin were the most stable reference genes in the OGD/R-injured N2a cells; in contrast, GAPDH and Sdha were the least stable genes in the cortices of MCAO mice and the OGD/R-injured N2a cells, respectively. Moreover, a combination of HPRT, 18S and cyclophilin was most suitable for normalization in analyses of the cortices of MCAO mice, and a combination of ß-actin, cyclophilin, GAPDH, and 18S was most suitable for analyses of the OGD/R-injured N2a cells. CONCLUSIONS: This study provides appropriate reference genes for further RT-qPCR analyses of in vivo and in vitro ischemic stroke and demonstrates the necessity of validating reference genes for RNA analyses under variable conditions.
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Isquemia Encefálica/genética , Perfilación de la Expresión Génica , Expresión Génica/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Accidente Cerebrovascular/genética , Animales , Línea Celular , Expresión Génica/fisiología , Ratones , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodosRESUMEN
Ultrasound detection is performed by measuring laser reflection off a surface plasmon resonance cavity which is integrated at a single-mode fiber end facet. It shows a total noise (or laser RIN) equivalent pressure of 9.7 KPa (or 5.2 KPa) over 0-20 MHz, a 6-dB angular detection range as large as 70° near 10 MHz, a detection bandwidth larger than 125 MHz, and a stable performance for over 20 min without feedback in ambient conditions. Its small form factor, fiber-optic integration, almost omnidirectional responsivity and large bandwidth are favorable for in vivo applications and high resolution imaging.
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Optical-resolution photoacoustic microscopy (OR-PAM) is an emerging imaging modality for studying biological tissues. However, in conventional single-view OR-PAM, the lateral and axial resolutions-determined optically and acoustically, respectively-are highly anisotropic. In this Letter, we introduce dual-view OR-PAM to improve axial resolution, achieving three-dimensional (3D) resolution isotropy. We first use 0.5 µm polystyrene beads and carbon fibers to validate the resolution isotropy improvement. Imaging of mouse brain slices further demonstrates the improved resolution isotropy, revealing the 3D structure of cell nuclei in detail, which facilitates quantitative cell nuclear analysis.
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Microscopía/métodos , Técnicas Fotoacústicas/métodos , Carbono , Fibra de Carbono , Imagenología TridimensionalRESUMEN
BACKGROUND: Diminished vascular tone is an established biomarker of heart damage. Little is known about the extent of coronary vessel tone (CVT) with spasm as assessed by dual-acquisition multidetector computed tomography angiography (MCTA) in patients with vasospastic angina (VSA). OBJECTIVE: We evaluated the CVT modulated by intravenous nitrate injection (INI) using MCTA imaging in VSA patients. METHODS: Twenty-one VSA patients (60 ± 9 years; 76% males) who underwent initial MCTA (without morning vasodilation), followed by an intracoronary ergonovine provocation test were included. Within 3 days after the initial MCTA patients received INI followed by 28-vessel segment spasm analyzed by MCTA 3D software, applying the following formula as the definition of CVT index (CVTI): (CSAIV nitrate - CSAinitial/CSAIV nitrate) ×100 %, where CSA is the cross-sectional area. RESULTS: Compared to the initial MCTA measures, the INI provocation resulted in the significant increase of average diameter and CSA at the spasm site (2.60 mm [2.11-3.16] vs. 1.42 mm [1.13-2.13]; 5.37 mm2 [3.67-7.54] vs. 1.62 mm2 [1.02-3.02]; p < 0.001). The CVTI at the spastic segments was higher than at the proximal reference segments (41.0% [21.8-52.3] vs. 18.8% [5.9-26.6] for CVTI diameter; 65.1% [38.6-77.0] vs. 33.9% [5.2-48.1] for CVTI CSA, respectively). To predict VSA, the cut-off value for CVTI diameter was 38.6% (AUC 0.777; 95% CI 0.653-0.901) and 62.5% (AUC 0.779; 95% CI 0.657-0.902) for CVTI CSA in a receiver-operating characteristic curve analysis, with 57.1% sensitivity and 92.9% specificity. CONCLUSIONS: This novel imaging technique for assessing CVT by dual-acquisition MCTA after applying INI provocation is suitable for the detection of coronary artery spasm in patients with VSA.
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Vasoespasmo Coronario/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Tomografía Computarizada Multidetector , Anciano , Angiografía por Tomografía Computarizada/métodos , Vasoespasmo Coronario/fisiopatología , Vasos Coronarios/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de RiesgoRESUMEN
BACKGROUND: Parkinson's disease (PD), the second most common neurodegenerative disease, has serious clinical effects. Research on PD is increasing, but the quantity and quality of this research have not been reported. METHODS: To analyze the most-cited articles on PD and provide information about developments in this field, we searched for articles in the Web of Science for the keyword "Parkinson*" in the title. We selected the 100 most-cited articles and evaluated information including citation number, publication time, journal, impact factor, authors, original country, institution of corresponding author, and study type. RESULTS: Citation numbers for the 100 most-cited articles ranged from 669 to 6902, with a median of 944. The 100 articles were published from 1967 to 2009, with most appearing between 1996 and 2000 (n = 24) and 2001 to 2005 (n = 27). The publications appeared in a total of 31 journals, led by Science with 15 and the New England Journal of Medicine (NEJM) with 13. The majority (84%) of the 100 most-cited articles had ≥ 3 authors. The articles originated from 14 countries, led by the USA (n = 44) and England (n = 17). Among the 100 most-cited articles, 24 were clinical studies, 54 were laboratory studies, 20 were reviews, and 2 were clinical guidelines. None of these articles originated from South America, Oceania, or Africa. CONCLUSIONS: The present study provides historical perspectives on the progress of PD research and highlights trends and academic achievements in this field.
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Bibliometría , Enfermedad de Parkinson , Comunicación Académica , Animales , Humanos , Factor de Impacto de la Revista , Publicaciones Periódicas como Asunto , Proyectos de Investigación , Comunicación Académica/tendenciasRESUMEN
Clinical applications of camptothecin (CPT) have been heavily hindered due to its non-targeted toxicity, active lactone ring instability, and poor water solubility. Targeted drug delivery systems may offer the possibility to overcome the above issues as reported. In this research, a series of prostate-specific membrane antigen (PSMA)-activated CPT prodrugs were designed and synthesized by coupling water-soluble pentapeptide, a PSMA hydrolyzing substrate, to CPT through an appropriate linker. The cytotoxicity of CPT prodrugs was masked temporarily until they were hydrolyzed by the PSMA present within the tumor sites, which restored cytotoxicity. The in vitro selective cytotoxic activities of the prodrugs were evaluated against PSMA-expressing human prostate cancer cells LNCaP-FGC and non-PSMA-expressing cancer cells HepG2, Hela, MCF-7, DU145, PC-3 and normal cells MDCK, LO2 by standard methylthiazol tetrazolium (MTT) assay. Most of the newly synthesized CPT prodrugs showed excellent selective toxicity to PSMA-producing prostate cancer cells LNCaP-FGC with improved water solubility. From among the library, CPT-HT-J-ZL12 showed the best cytotoxic selectivity between the PSMA-expressing and the non-PSMA-expressing cancer cells. For example, the cytotoxicity of CPT-HT-J-ZL12 (IC50 = 1.00 ± 0.20 µM) against LNCaP-FGC (PSMAâº) was 40-fold, 40-fold, 21-fold, 5-fold and 40-fold, respectively, higher than that against the non-PSMA-expressing cells HepG2 (IC50 > 40.00 µM), Hela (IC50 > 40.00 µM), MCF-7 (IC50 = 21.68 ± 4.96 µM), DU145 (IC50 = 5.40 ± 1.22 µM), PC-3 (IC50 = 42.96 ± 3.69 µM) cells. Moreover, CPT-HT-J-ZL12 exhibited low cytotoxicity (IC50 > 40 µM) towards MDCK and LO2 cells. The cellular uptake experiment demonstrated the superior PSMA-targeting ability of the CPT-HT-J-ZL12, which was significantly accumulated in LNCaP-FGC (PSMAâº), while it was minimized in HepG2 (PSMA-) cells. Further cell apoptosis analyses indicated that it showed a dramatically higher apoptosis-inducing activity in LNCaP-FGC (PSMAâº) cells than in HepG2 (PSMA-) cells. Cell cycle analysis indicated that CPT-HT-J-ZL12 could induce cell cycle arrest at the S phase.
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Antígenos de Superficie/metabolismo , Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Glutamato Carboxipeptidasa II/metabolismo , Profármacos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Oligopéptidos/química , Profármacos/farmacología , Relación Estructura-Actividad CuantitativaRESUMEN
Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new Heâ»pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 µM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 µM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 µM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structureâ»activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.