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Type-IV radio bursts have been studied for over 50 years. However, the specifics of the radio emission mechanisms is still an open question. In order to provide more information about the emission mechanisms, we studied a moving Type-IV radio burst with fine structures (spike group) by using the high-resolution capability of the Low-Frequency Array (LOFAR) on August 25, 2014. We present a comparison of Nançay Radioheliograph (NRH) and the first LOFAR imaging data of the Type-IV radio burst. The degree of circular polarization (DCP) is calculated at frequencies in the range 20 - 180 MHz using LOFAR data, and it was found that the value of DCP gradually increased during the event, with values of 20 - 30%. LOFAR interferometric data were combined with white-light observations in order to track the propagation of this Type-IV burst. The kinematics shows a westward motion of the radio sources, slower than the CME leading edge. The dynamic spectrum of LOFAR shows a large number of fine structures with durations of less than 1 s and high brightness temperatures ( T B ), i.e., 10 12 - 10 13 K. The gradual increase of DCP supports gyrosynchrotron emission as the most plausible mechanism for the Type IV. However, coherent emissions such as Electron Cyclotron Maser (ECM) instability may be responsible for small-scale fine structures. Countless fine structures altogether were responsible for such high T B . Supplementary Information: The online version contains supplementary material available at 10.1007/s11207-022-02042-0.
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Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [14C]ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzymes involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was â¼63%, with â¼26% and â¼37% recovered from urine and feces, respectively. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124, which together accounted for 50% of the circulating total radioactivity exposure, whereas ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 14 metabolites identified, including two major active metabolites (CC112273 and CC1084037) and one major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways, including aldehyde dehydrogenase and alcohol dehydrogenase, cytochrome P450 isoforms 3A4 and 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B, which further undergoes reduction by carbonyl reductases to form CC1084037 or CYP2C8-mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase 1C1/1C2 and/or 3ß- and 11ß-hydroxysteroid dehydrogenase, and this reversible oxidoreduction between two active metabolites favors CC112273. The ozanimod example illustrates the need for conducting timely radiolabeled human absorption, distribution, metabolism, and excretion studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development. SIGNIFICANCE STATEMENT: Absorption, metabolism, and excretion of ozanimod were characterized in humans, and the enzymes involved in complex metabolism were elucidated. Disproportionate metabolites were identified, and the activity of these metabolites was determined.
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Indanos/administração & dosagem , Indanos/metabolismo , Oxidiazóis/administração & dosagem , Oxidiazóis/metabolismo , Moduladores do Receptor de Esfingosina 1 Fosfato/administração & dosagem , Moduladores do Receptor de Esfingosina 1 Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Administração Oral , Adulto , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Four-factor prothrombin complex concentrates (4F-PCCs) have been approved for urgent vitamin K antagonist reversal in Western countries for many years. Ethnicity and genetic variations between populations may influence the pharmacokinetic profile of 4F-PCC treatments. OBJECTIVE: To report plasma levels of vitamin K-dependent coagulation factors and proteins C and S in Japanese patients following administration of a 4F-PCC approved recently in Japan. METHODS: This was a subanalysis of a prospective, open-label, Phase IIIb study in Japanese patients requiring rapid vitamin K antagonist reversal owing to major bleeding (nâ¯=â¯6) or need for urgent surgery (nâ¯=â¯5). International normalized ratio and plasma levels of factors II, VII, IX, and X, and proteins C and S were measured before PCC infusion and at specific time points for the next 24 hours. Adverse events and serious adverse events were recorded up to Day 14 and 45, respectively. RESULTS: Rapid increases in plasma concentrations 30 minutes following 4F-PCC infusion were seen for all factors and proteins C and S, with median concentrations compared with baseline increasing by ≥100% and 70% in the bleeding and surgical groups, respectively. A concurrent decrease in international normalized ratio was observed. Plasma levels for each factor and protein remained within physiologic levels throughout the assessment period. No relationship between thromboembolic events and elevated plasma levels was identified. CONCLUSIONS: Administration of 4F-PCC in Japanese patients receiving vitamin K antagonist anticoagulation therapy resulted in rapid and sustained increases in plasma levels and was well tolerated, indicating that this treatment is effective for the urgent reversal of vitamin K antagonist therapy in this population.
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Hospital acquired complications (HACs) are serious problems affecting modern day healthcare institutions. It is estimated that HACs result in an approximately 10% increase in total inpatient hospital costs across US hospitals. With US hospital spending totaling nearly $900 billion per annum, the damages caused by HACs are no small matter. Early detection and prevention of HACs could greatly reduce strains on the US healthcare system and improve patient morbidity & mortality rates. Here, we describe a machine-learning model for predicting the occurrence of HACs within five distinct categories using temporal clinical data. Using our approach, we find that at least $10 billion of excessive hospital costs could be saved in the US alone, with the institution of effective preventive measures. In addition, we also identify several keystone features that demonstrate high predictive power for HACs over different time periods following patient admission. The classifiers and features analyzed in this study show high promise of being able to be used for accurate prediction of HACs in clinical settings, and furthermore provide novel insights into the contribution of various clinical factors to the risk of developing HACs as a function of healthcare system exposure.
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Infecção Hospitalar/classificação , Registros Eletrônicos de Saúde/classificação , Hospitalização/estatística & dados numéricos , Informática Médica/métodos , Complicações Pós-Operatórias/classificação , Codificação Clínica , HumanosRESUMO
OBJECTIVE: To assess the safety and efficacy of ultrasonographic vs. fluoroscopic access for percutaneous nephrolithotomy (PCNL). METHODS: Medline (PubMed), Embase, Ovid, Cochrane, and the Chinese Biomedical Literature databases were searched to identify clinically controlled trials (CCTs) and randomized controlled trials (RCTs) that compared ultrasonographic access with fluoroscopic access for PCNL. RevMan 5.1 software and Stat Manager V4.1 software were used for the meta-analysis. RESULTS: Five RCTs and nine CCTs were included in our study, which contained a total of 3,019 patients. Of these, 1,574 (52%) had undergone ultrasonographic access, and 1,445 (48%) had undergone fluoroscopic access. The pooled results revealed that the ultrasonographic access patients had shorter duration of access (min) by 2.56 min (weighted mean difference (WMD) = -2.56, 95% confidence interval (CI): -4.40 to -0.72, p = 0.006). There was a higher stone-free rate in the ultrasonographic access group (odds ratio (OR) = 1.26, 95% CI: 1.02-1.55, p = 0.03), as well as a lower rate of operative complications (OR = 0.72, 95% CI: 0.56-0.93, p = 0.01), reduced intraoperative blood loss (ml) (WMD = -14.55 ml, 95% CI: -27.65 to -1.46, p = 0.03), and a lower rate of blood transfusion requirement (OR = 0.39, 95% CI: 0.24-0.63, p = 0.0001). Sensitivity and subgroup analyses were also performed. CONCLUSION: Except for no radiation exposure, our meta-analysis revealed that ultrasonographic access had many advantages, such as a shorter access time, reduced intraoperative blood loss, a lower rate of operative complications, a lower rate of blood transfusion, and a higher stone-free rate. Because of these significant advantages, we recommend the use of ultrasonographic access for PCNL.
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Fluoroscopia/métodos , Cálculos Renais/diagnóstico por imagem , Nefrostomia Percutânea/métodos , Ultrassonografia/métodos , Perda Sanguínea Cirúrgica , Transfusão de Sangue , Ensaios Clínicos como Assunto , Humanos , Cálculos Renais/cirurgia , Razão de Chances , Duração da Cirurgia , Segurança do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Software , Resultado do TratamentoRESUMO
Numbers of observational studies suggest that the JAK2 46/1 (GGCC) haplotype may increase the risk of myeloproliferative neoplasms (MPNs) and splanchnic vein thrombosis (SVT), but the results remain controversial. We aimed to examine the association between the JAK2 46/1 haplotype and risk of MPNs and SVT by conducting a meta-analysis. PubMed, EMBASE, Cochrane Library, CBM, and CNKI databases were searched to identify eligible studies without restrictions and by reviewing reference lists of obtained articles. Both fixed and random-effects models were used to calculate the summary risk estimates. We identified 26 observational studies of the JAK2 46/1 haplotype and risk of MPNs and SVT involving 8,561 cases and 7,434 participants. In the overall analysis, it was found that the JAK2 46/1 haplotype significantly elevated the risk of MPNs (rs10974944: C vs T: odds ratio (OR) = 2.19, 95 % confidence interval (CI) = 1.86-2.57, P < 0.0001; CC vs TT: OR = 4.63, 95 % CI = 3.32-6.47, P < 0.0001; CT vs TT: OR = 2.49, 95 % CI = 2.11-2.95, P < 0.0001; (CC + CT) vs TT: OR = 2.92, 95 % CI = 2.51-3.39, P < 0.0001; rs12343867: C vs T: OR = 1.88, 95 % CI = 1.59-2.22, P < 0.0001; CC vs TT: OR = 3.16, 95 %CI = 2.14-4.65, P < 0.0001; CT vs TT: OR = 2.04, 95 % CI = 1.51-2.74, P < 0.0001; (CC + CT) vs TT: OR = 2.25, 95 % CI = 1.73-2.95, P < 0.0001) and SVT (C vs T: OR = 1.27, 95 % CI = 1.06-1.52, P = 0.011; CC vs TT: OR = 2.33, 95 % CI = 1.42-3.81, P = 0.001; (CC + CT) vs TT: OR = 1.25, 95 % CI = 1.02-1.53, P = 0.034). There was no evidence of a significant association between the rs12343867 and the risk of SVT in the genetic model (CT vs TT: OR = 1.01, 95 % CI = 0.80-1.29, P = 0.906). This meta-analysis provides new evidence supporting the conclusion that the JAK2 46/1 haplotype enrichment is significantly associated with the development of MPNs and SVT in these patients.
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Neoplasias da Medula Óssea/genética , Haplótipos/genética , Janus Quinase 2/genética , Circulação Esplâncnica/fisiologia , Trombose Venosa/genética , Neoplasias da Medula Óssea/diagnóstico , Neoplasias da Medula Óssea/enzimologia , Humanos , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/enzimologia , Transtornos Mieloproliferativos/genética , Estudos Observacionais como Assunto/métodos , Trombose Venosa/diagnóstico , Trombose Venosa/enzimologiaRESUMO
BACKGROUND AND AIM: The presence of JAK2V617F was reported to be associated with JAK2 46/1 haplotype, which was considered as an independent risk factor for Budd-Chiari syndrome (BCS) in Western countries. However, little is known in China. Therefore, the aim of this study was to determine whether the 46/1 haplotype is associated with such patients. METHODS: Patients with primary BCS and controls were consecutively admitted in our study from October 2009 to December 2012. The subjects were detected for the JAK2V617F mutation by allele-specific polymerase chain reaction (AS-PCR) and the JAK2 46/1 haplotype by real-time PCR. RESULTS: The prevalence of JAK2V617F mutation was 2.37% (7/295) in BCS patients, and 46/1 haplotype was overrepresented in JAK2V617F-positive BCS patients compared with controls (P < 0.01). The risk for the JAK2V617F-positive BCS with CC genotype was elevated compared with subjects presented TT genotype (OR = 13.4, 95%CI = 2.01-89.5) and non-CC genotype (OR = 15.0, 95%CI = 2.45-91.7). CONCLUSIONS: Our study showed that the presence of 46/1 haplotype increased the risk of JAK2V617F-positive BCS in China. In addition, low prevalence of JAK2V617F mutation in BCS patients suggested that myeloproliferative neoplasms (MPNs) should not be an etiological factor of BCS in China.
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Povo Asiático/genética , Síndrome de Budd-Chiari/genética , Haplótipos/genética , Janus Quinase 2/genética , Mutação , Adulto , Síndrome de Budd-Chiari/epidemiologia , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos , Prevalência , Risco , Adulto JovemRESUMO
A fiber-taper-microsphere-coupled system was used to research the characteristics of laser oscillation and upconversion luminescence of Yb3+:Er3+ co-doped phosphosilicate (YECP) microspheres. The YECP microspheres were fabricated by melting the end of phosphosilicate filaments. Single- and multimode laser oscillation at 1535-1565 nm within the C-band were obtained. In addition, the output power of the single-mode laser at 1545.5 nm can be as high as 48.98 µW, which was achieved under pump power of 9.63 mW, and the side-mode suppression ratio was 51.49 dB. Upconversion fluorescence of Er3+ at 521, 532, and 544 nm also were measured, and the pump power dependence was studied. The fluorescence intensity was lower than that of Yb3+:Er3+ co-doped silica and oxyfluoride glass ceramic microspheres. Moreover, the physical mechanism of upconversion suppression and laser oscillation enhancement observed in our experiment was presented, which is beneficial to the preparation of rare-earth-doped microcavity lasers.
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Importance: Cendakimab selectively targets interleukin (IL)-13, a type 2 cytokine implicated in atopic dermatitis (AD) pathogenesis, by inhibiting binding to its receptors (IL13R-α1 and IL13R-α2). Proof-of-concept work in AD supports using cendakimab for type 2 inflammatory diseases. Objective: To evaluate the efficacy and safety of cendakimab compared with placebo in patients with moderate to severe AD. Design, Setting, and Participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial was conducted from May 2021 to November 2022. Adult patients with moderate to severe AD and inadequate response to topical medications were enrolled at 69 sites in 5 countries (US [n = 26], Japan [n = 17], Canada [n = 9], Poland [n = 9], and Czech Republic [n = 8]). Data were analyzed between April 25, 2023, and October 16, 2023. Interventions: Patients were randomized (1:1:1:1) to receive subcutaneous cendakimab, 360 mg, every 2 weeks; 720 mg, every 2 weeks; 720 mg, once weekly; or placebo. Main Outcome and Measure: Mean percentage change in Eczema Area and Severity Index scores from baseline to week 16. Hierarchical testing with multiplicity adjustment was performed for 720 mg, once weekly vs placebo, then 720 mg, every 2 weeks vs placebo, and then 360 mg, every 2 weeks vs placebo. Results: Overall, 221 patients were randomized, and 220 received study drug (95 women [43%]; mean [SD] age, 37.7 [13.9] years; 720 mg, once weekly [54 (24%)]; 720 mg, every 2 weeks [55 (25%)]; 360 mg, every 2 weeks [55 (25%)]; placebo [56 (26%)]). The primary efficacy end point was met for cendakimab, 720 mg, once weekly vs placebo (-84.4 vs -62.7; P = .003) but missed statistical significance for 720 mg, every 2 weeks (-76.0 vs -62.7; P = .06). The treatment effect for 360 mg, every 2 weeks (-16.3; nominal P = .03 vs placebo) was comparable with 720 mg, once weekly (-21.8); however, significance was not claimed because the hierarchical testing sequence was interrupted. Of patients with treatment-emergent adverse events leading to discontinuation, 4 (7.4%) received 720 mg, once weekly; 2 (3.6%) 720 mg, every 2 weeks; 1 (1.8%) 360 mg, every 2 weeks; and 2 (3.6%) placebo. Conclusions and Relevance: The results of this randomized clinical trial indicated that cendakimab was effective, generally safe, and well-tolerated in patients with moderate to severe AD. The primary end point was met with a significant reduction in Eczema Area and Severity Index scores with 720 mg, once weekly at week 16. Cendakimab demonstrated progressive AD improvement at all doses during 16 weeks of treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04800315.
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Dermatite Atópica , Índice de Gravidade de Doença , Humanos , Dermatite Atópica/tratamento farmacológico , Masculino , Feminino , Adulto , Método Duplo-Cego , Pessoa de Meia-Idade , Resultado do Tratamento , Injeções Subcutâneas , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Interleucina-13/antagonistas & inibidores , Relação Dose-Resposta a Droga , Adulto JovemRESUMO
BACKGROUND The aim of this study was to evaluate the psychological status of anxiety and depression of hospital staff in the designated hospital in the city of Shannan during the COVID-19 pandemic in order to provide a theoretical basis for effective psychological intervention. MATERIAL AND METHODS A cross-sectional survey was performed from September 10 to 16, 2022, by administering an online questionnaire to the hospital staff on duty in the hospital. We collected participants' demographic and general information. The Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were used to investigate the anxiety and depression of hospital staff. RESULTS Among 267 hospital staff, anxiety was found in 98 individuals, with a prevalence of 36.70%. Depression was found in 170 individuals, with a prevalence of 63.67%. Anxiety combined with depression was found in 84 individuals, with a prevalence of 31.46%. The prevalence of depression was higher in women, Tibetan personnel, hospital staff with primary or lower titles, staff without career establishment, and non-aid Tibetan personnel, and the differences were all statistically significant (P.
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COVID-19 , Humanos , Feminino , COVID-19/epidemiologia , Estudos Transversais , Pandemias , SARS-CoV-2 , Ansiedade/epidemiologia , Recursos Humanos em Hospital/psicologia , Inquéritos e Questionários , HospitaisRESUMO
BACKGROUND: Ephedrine increased blood pressure due to the contractile properties of resistance vessels. Excessive contraction of the uterine arteries might cause fetal distress. This study was to determine the diameter of the uterine artery of female New Zealand rabbits after the administration of different doses of ephedrine using CT. METHODS: Thirty-two rabbits were randomly divided into a control group (Group C), low dosage group (Group L), medium dosage group (Group M) and high dosage group (Group H). Normal saline and doses corresponding to the human dose of 7.5, 15 and 30 mg of ephedrine were injected respectively. The marginal ear and uterine artery diameters were measured 5, 10, 15, 30, and 45 min after injection using CT, and the hemodynamic changes were recorded. RESULTS: The increase in mean arterial pressure in group M (p = 0.009), and H (p = 0.013) was higher than that in group C. Compared with group C, substantial contraction of the marginal ear artery was observed at the three doses of ephedrine. There were no differences in the uterine artery diameter among groups L, M and C, However, in Group H, a significant contraction of the uterine artery compared with the other groups (p < 0.001) was observed. DISCUSSION: CT can be used to evaluate the effects of drugs on organs and blood vessels. Ephedrine can not only constrict the peripheral blood vessels but also do not affect the uterine artery at a dose of 15 mg or less. However, the dose should not exceed 30 mg, which may cause severe uterine artery depression.
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Long non-coding RNAs (lncRNAs) can influence the proliferation, autophagy, and apoptosis of non-small cell lung cancer (NSCLC). LncRNAs also emerge as valuable prognostic factors for NSCLC patients. Consequently, we set out to discover more autophagy-associated lncRNAs. We acquired autophagy-associated genes and information on lncRNAs from The Cancer Genome Atlas database (TCGA), and the Human Autophagy Database (HADb). Then, the prognostic prediction signature was constructed through using co-expression and Cox regression analysis. The signature was constructed including 7 autophagy-associated lncRNAs (ABALON, NKILA, LINC00941, AL161431.1, AL691432.2, AC020765.2, MMP2-AS1). After that, we used univariate and multivariate Cox regression analysis to calculate the risk score. The survival analysis and ROC curve analysis confirmed good performances of the signature. GSEA indicated that the high-risk group was principally enriched in the adherens junction pathway. In addition, biological experiments showed that ABALON promoted the proliferation, metastasis and autophagy levels of NSCLC cells. These findings demonstrate that the risk signature consisting of 7 autophagy-associated lncRNAs accurately predicts the prognosis of NSCLC patients and should be investigated for potential therapeutic targets in clinic.
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Ca2+-activated Cl- channel A2 (CLCA2), a tumor suppressor, is associated with the development of several cancers. However, little is known about CLCA2 in human cervical cancer. Therefore, the aim of the present study was to investigate the effects of CLCA2 on cervical cancer. Reverse transcription-quantitative (RT-q)PCR was used to examine the mRNA expression levels of CLCA2 in eight pairs of cervical cancer tissues. Immunohistochemistry was used to investigate CLCA2 protein expression in 144 archived cervical cancer specimens. The association of the CLCA2 with clinicopathological parameters was statistically evaluated. Cell proliferation and invasion capability were examined by MTT and Transwell assays, respectively. RT-qPCR analysis revealed that CLCA2 expression was decreased in cervical cancer compared with that in adjacent normal tissues. The expression levels of CLCA2 in patients were correlated with tumor stage (P=0.028), tumor size (P=0.009), and human papillomavirus (HPV) infection status (P=0.041). In addition, CLCA2 upregulation was associated with longer overall and recurrence-free survival time after surgery (P=0.016 and P=0.009, respectively). Multivariate Cox regression analysis demonstrated that CLCA2 expression had a predictive value for overall survival of patients with cervical cancer (P=0.017 and P=0.025, respectively). Knockdown of CLCA2 by small interfering RNA suppressed tumor cell proliferation and migration. Mechanistically, CLCA2 was involved in Wnt/ß-catenin signaling. In conclusion, the results of the present study demonstrated that CLCA2 suppressed the proliferation, migration and invasion of cervical cancer cells, and that CLCA2 may be a potential therapeutic target of cervical cancer.
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Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed effects modeling. QTc was modeled linearly as the sum of a sex-related fixed effect, baseline, and concentration-related random effects that incorporated interindividual and residual variability. Common linear, power, and maximum effect (Emax ) functions were assessed for characterizing the relationship of QTc with concentrations. Model goodness-of-fit and performance were evaluated by standard diagnostic tools, including a visual predictive check. The placebo-corrected change from baseline in QTc (ΔΔQTc) was estimated based on the developed C-QTc model using a nonparametric bootstrapping approach. QTc was better derived using a study-specific population formula (QTcP). Among the investigated functions, an Emax function most adequately described the relationship of QTcP with concentrations. Separate models for individual analytes characterized the C-QTcP relationship better than combined analytes models. Attributing QT prolongation independently to CC1084037 or CC112273, the upper bound of the 95% confidence interval of the predicted ΔΔQTcP was ~ 4 msec at the plateau of the Emax curves. Therefore, ΔΔQTcP is predicted to remain below 10 msec at the supratherapeutic concentrations of the major active metabolites.
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Indanos/farmacocinética , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Oxidiazóis/farmacocinética , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacocinética , Receptores de Esfingosina-1-Fosfato/metabolismo , Administração Oral , Adulto , Estudos de Casos e Controles , Método Duplo-Cego , Eletrocardiografia/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Indanos/administração & dosagem , Indanos/efeitos adversos , Síndrome do QT Longo , Masculino , Oxidiazóis/administração & dosagem , Oxidiazóis/efeitos adversos , Placebos/administração & dosagem , Valor Preditivo dos Testes , Moduladores do Receptor de Esfingosina 1 Fosfato/administração & dosagem , Moduladores do Receptor de Esfingosina 1 Fosfato/efeitos adversosRESUMO
OBJECTIVE: To explore the effect of miR106a on the growth of breast cancer xenografts and the sensitivity of chemotherapeutic agents. METHODS: Breast cancer cell lines (MDA-MB231 and MCF7) were transfected with an miR106 mimic and miR106a inhibitor. BALB/c female nude mice were selected to construct a transplanted-tumor model. Cisplatin treatment was performed 2 weeks after inoculation. After 5 weeks, tumor tissue was weighed. Apoptosis of tumor cells was detected by TUNEL staining. The expression of these proteins (Ki67, ß-catenin, cyclin D1 and cMyc) was detected by immunohistochemistry. The contents of P53, RUNX3, ABCG2, ß-catenin, BAX, and BCL2 mRNA were detected by qRT-PCR. RESULTS: The miR106a mimic (MM) group's tumor volume and weight were significantly bigger than those of the model group. miR106a mRNA content was higher than the blank control group, and ß-catenin and Ki67 protein were strongly positive. ß-catenin, BCL2, and ABCG2 mRNA content was were increased. P53, BAX, and RUNX3 mRNA content was decreased. The number of positive cells on TUNEL staining was significantly lower in the miR106a inhibitor (MI) group. After cisplatin treatment, inhibition of tumor growth was most obvious in the MI+DDP (cisplatin) group. Compared with the MM group, tumor growth in the MM+FH535 (Wnt-pathway inhibitor) group was significantly lower, and Wnt-pathway activity was decreased. CONCLUSION: Overexpression of miR106a can promote the growth of transplanted breast cancer and decrease the sensitivity of transplanted tumors to cisplatin. The mechanism may be related to abnormal activation of the Wnt-signaling pathway.
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INTRODUCTION: The aims of this study were to characterize the single-dose pharmacokinetics (PK) of the major active metabolites of ozanimod, CC112273 and CC1084037, and to evaluate the effect of gemfibrozil (a strong inhibitor of cytochrome P450 [CYP] 2C8), itraconazole (a strong inhibitor of CYP3A and P-glycoprotein [P-gp]), and rifampin (a strong inducer of CYP3A/P-gp and moderate inducer of CYP2C8) on the single-dose PK of ozanimod and its major active metabolites in healthy subjects. METHODS: This was a phase 1, randomized, parallel-group, open-label study with two parts. In part 1, 40 subjects were randomized to receive a single oral dose of ozanimod 0.46 mg (group A, n = 20) or oral doses of gemfibrozil 600 mg twice daily for 17 days with a single oral dose of ozanimod 0.46 mg on day 4 (group B, n = 20). In part 2, 60 subjects were randomized to receive a single oral dose of ozanimod 0.92 mg (group C, n = 20), oral doses of itraconazole 200 mg once daily for 17 days with a single oral dose of ozanimod 0.92 mg on day 4 (group D, n = 20), or oral doses of rifampin 600 mg once daily for 21 days with a single oral dose of ozanimod 0.92 mg on day 8 (group E, n = 20). Plasma PK parameters for ozanimod, CC112273, and CC1084037 were estimated using noncompartmental methods. RESULTS: Dose-proportional increases in maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) were observed for ozanimod, CC112273, and CC1084037. The mean terminal elimination half-life (t1/2) for ozanimod was approximately 20-22 h while the mean t1/2 for CC112273 and CC1084037 were approximately 10 days. CC112273 and CC1084037 exposures were highly correlated with or without interacting drugs. Itraconazole increased ozanimod AUC by approximately 13% while rifampin reduced ozanimod AUC by approximately 24%, suggesting a minor role of CYP3A and P-gp in the overall disposition of ozanimod. Gemfibrozil increased the AUC for CC112273 and CC1084037 by approximately 47% and 69%, respectively. Rifampin reduced the AUC for CC112273 and CC1084037, primarily via CYP2C8 induction, by approximately 60% and 55%, respectively. CONCLUSIONS: Ozanimod's major active metabolites, CC112273 and CC1084037, exhibited similar single-dose PK properties and their exposures were highly correlated. CYP2C8 is one of the important enzymes in the overall disposition of CC112273 and subsequently its direct metabolite CC1084037. TRIAL REGISTRATION: Clinical trial: NCT03624959.
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Genfibrozila , Itraconazol , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Indanos , Oxidiazóis , RifampinaRESUMO
INTRODUCTION: The aims of this study were to characterize the multiple-dose pharmacokinetics (PK) of ozanimod's major active metabolites (CC112273 and CC1084037) and to evaluate the pharmacodynamic and PK interactions with pseudoephedrine (PSE). METHODS: In this phase 1, single-center, randomized, double-blind, placebo-controlled study, 56 healthy adult subjects were randomized to receive either placebo or ozanimod once daily for 30 days (0.23 mg on days 1-4, 0.46 mg on days 5-7, 0.92 mg on days 8-10, and 1.84 mg on days 11-30). On day 30, a single oral dose of PSE 60 mg was co-administered with placebo or ozanimod. Maximum time-matched change in systolic blood pressure (SBP) from baseline (day 29) following PSE administration on day 30 was calculated. Plasma PK parameters for ozanimod, CC112273, CC1084037, and PSE were estimated using noncompartmental methods. RESULTS: Fifty-two subjects (92.9%) completed the study. Following multiple dosing, approximately 94% of circulating total active drug exposure was represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%). Exposures of CC112273 and CC1084037 were highly correlated. Mean maximum time-matched change from baseline for SBP was not significantly different between ozanimod + PSE and placebo + PSE. Ozanimod also had no effect on the PK of PSE. Co-administration of ozanimod with a single dose of PSE in healthy subjects was generally well tolerated. While CC112273 and CC1084037 selectively inhibited monoamine oxidase (MAO)-B in vitro, both active metabolites do not inhibit platelet MAO-B activity in vivo. CONCLUSION: Concomitant administration of ozanimod with PSE, a sympathomimetic agent, did not potentiate the effects on blood pressure. TRIAL REGISTRATION: NCT03644576.
Assuntos
Indanos/farmacocinética , Oxidiazóis/farmacocinética , Pseudoefedrina/metabolismo , Simpatomiméticos/metabolismo , Administração Oral , Adulto , Pressão Sanguínea/efeitos dos fármacos , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Indanos/metabolismo , Masculino , Pessoa de Meia-Idade , Oxidiazóis/metabolismo , Equivalência Terapêutica , Adulto JovemRESUMO
OBJECTIVE: Venous thromboembolism is a common complex disorder, being the resultant of gene-gene and gene-environment interactions. Tumor necrosis factor-alpha is a proinflammatory cytokine which has been implicated in venous thromboembolism risk. A promoter 308G/A polymorphism in the tumor necrosis factor-alpha gene has been suggested to modulate the risk for venous thromboembolism. However, the published findings remain inconsistent. METHODS: In this study, we conducted a meta-analysis of all available data regarding this issue. Eligible studies were identified through search of Pubmed, EBSCO Medline, Web of Science, and China National Knowledge Infrastructure (CNKI, Chinese) databases up to June 2014. Pooled Odd ratios (ORs) with 95% confidence intervals were applied to estimating the strength of the genetic association in the random-effects model or fixed-effects model. RESULTS: A total of 10 studies involving 1999 venous thromboembolism cases and 2166 controls were included in this meta-analysis to evaluate the association between tumor necrosis factor-alpha-308G/A polymorphism and venous thromboembolism risk. Overall, no significantly increased risk venous thromboembolism was observed in all comparison models when all studies were pooled into the meta-analysis. However, in stratified analyses by ethnicity, there was a pronounced association with venous thromboembolism risk among West Asians in three genetic models (A vs. G: OR = 1.82, 95%CI = 1.13-2.94; GA vs. GG: OR = 1.82, 95%CI = 1.08-3.06; AA/GA vs. GG: OR = 1.88, 95%CI = 1.12-3.16). When stratifying by source of controls, no significant result was detected in all genetic models. CONCLUSION: This meta-analysis demonstrates that tumor necrosis factor-alpha 308G/A polymorphism may contribute to susceptibility to venous thromboembolism among West Asians. Studies are needed to ascertain these findings in larger samples and different racial groups.