Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 978
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-33047212

RESUMO

BACKGROUND: Kidney replacement therapy (KRT) is a lifesaving but costly treatment for patients with end-stage kidney disease (ESKD). The objective of this study was to review full economic evaluations comparing KRT modalities specified as hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KT) for patients with ESKD. METHODS: We conducted a systematic review of the literature from PubMed, Embase, EconLit (EBSCO), Web of Science, Cochrane Library, National Health Service Economic Evaluation Database (NHS EED), Centre for Reviews and Dissemination (CRD) Database of Abstracts of Reviews of Effects (DARE), and CRD Health Technology Assessment Database from inception until 5 January 2020. Full economic evaluations were included if they compared three forms of KRT specified as PD, HD, and KT. The reporting quality of included studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Ten studies were identified in the review. The majority of the studies were model-based evaluations and included a cost-utility analysis. Four studies were conducted from a public healthcare perspective, three from a societal perspective, and three from a third-party payer perspective. None of the studies adequately addressed all the applicable items of the CHEERS checklist. The most infrequently reported items were characterizing heterogeneity, target population, and characterizing uncertainty. There is a lack of studies that conduct from a societal perspective and take into account characterizing heterogeneity. All included studies indicate that KT is the most cost-effective KRT modality, with either a dominant position over HD and PD or an incremental cost-effectiveness ratio well below the accepted willingness-to-pay threshold. The majority of studies suggest that PD is less costly and offers comparable or better health outcomes than HD. CONCLUSIONS: Our systematic review suggests that KT is the most cost-effective KRT modality, but there is no firm conclusion about the cost-effectiveness of HD and PD. Further economic evaluations can be conducted from a societal perspective and detail the evidence for subsets of patients with different characteristics.

2.
J Zhejiang Univ Sci B ; 21(10): 767-778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33043643

RESUMO

RNA helicases, the largest family of proteins that participate in RNA metabolism, stabilize the intracellular environment through various processes, such as translation and pre-RNA splicing. These proteins are also involved in some diseases, such as cancers and viral diseases. Autophagy, a self-digestive and cytoprotective trafficking process in which superfluous organelles and cellular garbage are degraded to stabilize the internal environment or maintain basic cellular survival, is associated with human diseases. Interestingly, similar to autophagy, RNA helicases play important roles in maintaining cellular homeostasis and are related to many types of diseases. According to recent studies, RNA helicases are closely related to autophagy, participate in regulating autophagy, or serve as a bridge between autophagy and other cellular activities that widely regulate some pathophysiological processes or the development and progression of diseases. Here, we summarize the most recent studies to understand how RNA helicases function as regulatory proteins and determine their association with autophagy in various diseases.

3.
Tree Physiol ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032322

RESUMO

Nervonic acid (24:1) is a major component in nerve and brain tissues and it has important applications in food and pharmaceutical industries. Malania oleifera seeds contain about 40% nervonic acid. However, the mechanism of nervonic acid biosynthesis and accumulation in seeds of this endangered tree species remains unknown. In this study, developmental changes in fatty acid composition within embryos and their pericarps were investigated. Nervonic acid proportions steadily increased in developing embryos but 24:1 was not detected in pericarps at any stage. Two 3-ketoacyl-CoA synthase (KCS) homologs have been isolated from M. oleifera developing seeds by homologous cloning methods. Both KCSs are expressed in developing embryos but not detected in pericarps. Based on a phylogenetic analysis, these two KCSs were named as MoKCS4 and MoKCS11. Seed-specific expression of the MoKCS11 in Arabidopsis led to about 5% nervonic acid accumulation, while expression of the MoKCS4 did not show an obvious change in fatty acid composition. It is noteworthy that the transformation of the same MoKCS11 construct into two Brassica. napus cultivars with high erucic acid did not produce the expected accumulation of nervonic acid, although expression of MoKCS11 was detected in the developing embryos of transgenic lines. In contrast, overexpression of MoKCS11 results in similar level of nervonic acid accumulation in camelina, a species which contains a similar level of 11Z-eicosenoic acid as does Arabidopsis. Taken together, the MoKCS11 may have a substrate preference for 11Z-eicosenoic acid, but not for erucic acid, in planta.

4.
Orthop Surg ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33000562

RESUMO

OBJECTIVE: To investigate the biomechanical effects of different insertion angles of absorbable screws for the fixation of radial head fractures. METHODS: The finite element models used to simulate the fractures were created based on CT scans. Two absorbable screws were used to fix and maintain the stability of the fracture, and the angles between the screws were set to 0°, 15°, 30°, 45°, 60°, 75°, and 90°. A downward force of 100 N was applied at the stress point, which was coupled with the surface, and the distal radius was limited to six degrees of freedom. The direction and location of the applied force were the same in each model. The values of the von Mises stress and peak displacements were calculated. RESULTS: Under the applied load and different screw angles, the maximum von Mises stress in the screws was concentrated on the surface contacting the fracture surfaces. The maximum von Mises equivalent stress in the screw decreased when the angle increased from 0° (19.54 MPa) to 45° (13.11 MPa) and increased when the angle further increased to 90° (24.63 MPa). The peak displacement decreased as the angle increased from 0° (0.19 mm) to 45° (0.15 mm) and increased when the angle further increased to 90° (0.25 mm). CONCLUSION: The computational stress distribution showed that fixation with absorbable screws is safe for patients. Moreover, the minimum von Mises stress and displacements were generated when the angle between the screws was 45°; hence, this setting should be recommended for Mason type II radial fractures.

5.
Chembiochem ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32964656

RESUMO

De novo cancer-targeting immunostimulatory peptides have been designed and developed as synthetic antibody mimics.  A selected trimeric peptide displayed binding on GRP78 + HepG2 and A549 target cells with some degree of GRP78-binding dependence. Similarly, the selected trimeric peptide was also found to exhibit NK cell binding in an NKp30-dependent manner which translated into NK cell activation as indicated by cytokine secretion. In co-culture, fluorescence microscopy revealed that the target GFP-expressing A549 cells were visibly associated to the effector NK cells when pre-activated with lead trimeric peptide. Accordingly, A549 cells were found to be compromised as evidenced by the loss of GFP signal and notable detection of early/late stage apoptosis. Investigation of immunological markers related to toxicity revealed detectable secretion of pro-inflammatory cytokines and chemokines, including IFN-γ, TNF-α and IL-8. Furthermore, administration of peptide-activated NK cells into A549-tumor bearing mice resulted in a consistent decrease in tumor growth when compared to the untreated control group. Taken together, the identification of a lead trimeric peptide capable of targeting and activating NK cells' immunotoxicity directly towards GRP78 + /B7H6 - tumors provides a novel proof-of-concept for the development of cancer-targeting immunostimulatory peptide ligands that mimic antibody targeting and activating functions related to cancer immunotherapy applications.

6.
J Cell Mol Med ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32989896

RESUMO

Genetic analysis for germline mutations of RET proto-oncogene has provided a basis for individual management of medullary thyroid carcinoma (MTC) and pheochromocytoma. Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M RET germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent RET mutation screening using next-generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch-wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156 pg/mL) in an 87-year-old male. Two carriers of compound C634Y/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41 years, respectively). Further, the compound C634Y/V292M variant had a faster migration rate than either single point mutation in vitro (P < .05). In conclusion, the V292M RET variant could be classified as 'likely benign' according to ACMG (2015). The compound variant V292M/C634Y was associated with both more aggressive clinical phenotype and faster cell growth in vitro than was either single mutation.

7.
Mol Cancer Res ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32878967

RESUMO

Lung cancer, especially lung adenocarcinoma, is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin filament turnover. Recent evidence has shown that high expression of cofilin-1 is associated with invasion and poor prognosis of several types of human tumors, but the detailed mechanism is still entirely unclear, particularly in lung cancer tumorigenesis and malignancy. Here, we report that DSTN was highly expressed in a mouse lung cancer model induced by urethane and in clinical lung adenocarcinoma tissue samples. Its expression level was positively correlated with cancer development, as well as metastasis to the liver and lymph nodes. Consistently, it was directly associated with the poor prognosis of lung adenocarcinoma patients. Furthermore, we also found that DSTN promotes cell proliferation, invasion, and migration in vitro, and facilitates subcutaneous tumor formation and lung metastasis via intravenous injection in vivo. Mechanically, DSTN associates with and facilitates nuclear translocation of ß-catenin, which promotes epithelial-to-mesenchymal transition (EMT). Taken together, our results indicated that DSTN enhances lung cancer malignancy through facilitating ß-catenin nuclear translocation and inducing EMT. Combined with multivariate analyses, DSTN might potentially serve as a therapeutic target and an independent prognostic marker of lung adenocarcinoma. IMPLICATIONS: This finding indicates that DSTN facilitates ß-catenin nuclear translocation and promotes malignancy in lung adenocarcinoma.

9.
Artif Cells Nanomed Biotechnol ; 48(1): 1125-1134, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32885685

RESUMO

Inhalation of silicon dioxide (SD) results in pulmonary inflammatory responses and fibrosis. Isorhynchophylline (Isorhy) is the main alkaloid in the traditional Chinese herb Tripterygium wilfordii, which is reported to have anti-inflammatory activities in the nervous system. However, the effects of Isorhy on SD-induced pulmonary inflammation and fibrosis in mice are unknown. Male mice were exposed to a single dose of SD (2.5 mg/kg, intranasal inoculation) to induce pulmonary fibrosis (PF). The mice were woken up and immediately treated with Isorhy (20 mg/kg, intraperitoneal injection) for 14 or 42 days. The effects of Isorhy on inflammatory responses and lung fibrosis induced by SD were then investigated. After the 14-day treatment, there was a significant reduction in inflammatory cell infiltration in the lungs of mice, with reduced recruitment of inflammatory cells to the lungs. The concentration of pro-inflammatory factors in the bronchoalveolar lavage fluid was reduced, which alleviated inflammatory injury in the lung tissue. After the 42-day treatment, Isorhy alleviated inflammation and inhibited the release of fibrogenic factors in mice with PF. Isorhy also significantly reduced collagen deposition in the lung tissues of mice. Isorhy has the ability to reduce inflammatory responses and fibrosis associated with SD-induced acute lung injury.

10.
Medicine (Baltimore) ; 99(39): e22392, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991461

RESUMO

Assessment of skeletal maturity is crucial for managing growth related problems. Tanner and Whitehouse (TW) hand and wrist bone age assessment is an accurate method; however, it is complex and labor-intensive. Several simplified methods derived from the TW method were proposed, and each had its own character. The purpose of this study is to explore the relationship between these methods for accurate usage.Between 2018 and 2019, a cross-sectional study was performed with consecutive left hand and wrist x-rays obtained from a pediatric orthopedic clinic. Bone age assessments included the distal radius and ulna (DRU) classification, Sanders staging (S), thumb ossification composite index (T), and TW method. Somers delta correlation was conducted to determine the interchangeability of these stages. The mean bone age and standard deviation (SD) of each subgrade were compared and analyzed.Totally 103 films (92 girls) were analyzed with mean age of 12.1 years (range: 8.0-17.9 years). The radius (R) stages had good correlation with S, T, and U stages with a very high Somers delta correlation (P < .05). R5 had relatively large SD (1.5) and referred to T2 and T3; R6 and R7 had the smallest SD (0.3) with reference to T4 or S2; R8 referred to T5 or S3, S4, S5; R9 referred to S6 and S7.The internal relationship between the DRU and digital stages system was well proven. We also provided a simple and accurate way to assess the bone age by combination of some subgrades with smaller SD: 10y-proximal thumb covered without sesamoid (T2); 10.5y-sesamoid just appearing (T3); 11y-distal radial physis just covered (medial double joint line, R6); 11.5y-medial capping of distal radial physis (R7); 12y-bilateral capping of distal radial physis (R8) / phalangeal capping without fusion (S3); 12.5y-distal phalangeal physes start to fuse (S4); 13y-distal phalangeal physes fused (S5); 13.5y-proximal phalangeal physes start to fuse (S6); 14.5y-proximal phalangeal physes fused (S7); 15y-distal radial physis almost fused (R10).Level of Evidence: Diagnostic study, level III.


Assuntos
Determinação da Idade pelo Esqueleto/métodos , Ossos da Mão/diagnóstico por imagem , Articulação do Punho/diagnóstico por imagem , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Valores de Referência
11.
Medicine (Baltimore) ; 99(39): e22489, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991488

RESUMO

RATIONALE: Primary sarcomatoid hepatocellular carcinoma (SHC) is a rare subtype of morphologic hepatocellular carcinoma reported on less than 1% of surgical pathology specimens. Herein, we report a rare case of SHC. The case in question was initially misdiagnosed as a liver abscess due to the clinical and radiological similarity between these 2 pathologies. Ultrasound(US)- and contrast-enhanced ultrasound (CEUS)- guided biopsies are helpful in making an accurate diagnosis under the appropriate biopsy area and angle of puncture. PATIENT CONCERNS: A 56-year old male presented to our hospital with a 2-month history of dull, upper abdominal pain without radiation. DIAGNOSES: Upon initial investigation with computed tomography, a cystic mass was found in the hepatic V segment and an infectious etiology was presumed. Further diagnostic examination with CEUS and magnetic resonance imaging suggested a hepatic abscess. However, a diagnosis of atypical intrahepatic cholangiocarcinoma was not excluded. The patient received the standard antibiotic treatment without alleviation of his symptoms. Through 3 diagnostic US-and CEUS-guided biopsies over a 3-month period, the pathological diagnosis of SHC was finally confirmed. INTERVENTIONS: The patient was diagnosed by 3 diagnostic US-and CEUS-guided biopsies, the pathological diagnosis of SHC was finally confirmed. OUTCOMES: Due to the delay in diagnosis, the patient was not a candidate for surgical resection, and showed dissemination of the lesion to the portal vein. Therefore, treatment with chemotherapy was initiated. After 4 courses of this regimen, tumor progression was found on enhanced magnetic resonance imaging. Therefore, the patient received immunotherapy and targeted therapy with limited response. The patient passed away 3 months later due to tumor progression. LESSONS: A hepatic abscess should be considered as a malignant lesion when clinical symptoms do not resolve upon standard treatment. US- and CEUS- guided biopsies are helpful in making an accurate diagnosis under the appropriate biopsy area and angle of puncture.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Abscesso Hepático/diagnóstico , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/patologia , Carcinoma Hepatocelular/patologia , Diagnóstico Diferencial , Evolução Fatal , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Ultrassonografia
12.
Int J Biol Sci ; 16(13): 2414-2429, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760209

RESUMO

Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.

13.
Mol Ther Nucleic Acids ; 21: 1017-1028, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32829178

RESUMO

MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional levels. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MicroRNA (miR)-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of mesenchymal stem cells (MSCs) derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed, whereas anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members, Wnt6 and Wnt10a, were identified as bona fide targets of miR-378, and their expression was decreased by this miRNA, which eventually induced the inactivation of Wnt/ß-catenin signaling. Finally, the short hairpin (sh)-miR-378-modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate the healing process in vivo. In conclusion, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/ß-catenin signaling, suggesting that miR-378 may be a potential therapeutic target for bone diseases.

14.
ACS Nano ; 14(8): 9780-9795, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32806062

RESUMO

The tumor microenvironment maintains a sufficient immunosuppressive state owing to the existence of the immunosuppressive factors. The most prominent such factor is transforming growth factor ß (TGF-ß), which is mainly provided by platelets. Moreover, platelets have been shown to be the main accomplice in assisting tumor metastasis. Therefore, blocking tumor-associated platelets is endowed with functions of enhancing immunity and reducing metastasis. Herein, we designed a tumor microenvironment-responsive nitric oxide (NO) release nanoparticle, Ptx@AlbSNO, which was able to specifically and safely co-deliver the antiplatelet agent NO and the chemotherapeutic agent paclitaxel (Ptx) into tumor tissues and inhibit platelet-tumor cell interactions. We discovered that Ptx@AlbSNO could successfully block tumor-specific platelet functions, thereby suppressing the process of tumor epithelial-mesenchymal transition (EMT), preventing platelet adhesion around circulating tumor cells (CTCs) and reducing distant metastasis. In vivo studies demonstrate that the co-delivery of NO and Ptx can suppress primary tumor growth. With the ability to effectively inhibit activated platelets and TGF-ß secretion in tumors, Ptx@AlbSNO can enhance intratumoral immune cell infiltration to reverse the immunosuppressive tumor microenvironment.

15.
Clin Pharmacol Ther ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32757299

RESUMO

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) convened a working group (WG) to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose (MTD), efficacious dose (ED), or recommended Phase 2 dose (RP2D) was >100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven- and risk-based approach for selecting FIH starting doses.

16.
J Comput Assist Tomogr ; 44(4): 533-539, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697523

RESUMO

PURPOSE: The purpose of this study was to investigate the differences of gray matter volume (GMV) alteration patterns between hemodialysis with restless legs syndrome (HD-RLS) and hemodialysis without restless legs syndrome (HD-nRLS) patients using voxel-based morphometry. METHODS: Twenty-three HD-RLS patients, 27 HD-nRLS patients, and 27 age-, sex-, and education-matched healthy controls were included in this study. One-way analysis of covariance and post hoc analyses were used to assess differences in GMV, demographics, and clinical data among the 3 groups. Pearson correlation analysis was conducted between altered GMV in the HD-RLS group and clinical data. RESULTS: Compared with HD-nRLS patients, HD-RLS patients showed decreased GMV in the left primary motor cortex (false discovery rate corrected, P < 0.05). Compared with the healthy controls, both HD subgroups (ie, those with and without RLS) exhibited consistent GMV changes, including decreased GMV in the bilateral anterior cingulate and paracingulate gyrus and left middle temporal gyrus (false discovery rate corrected, P < 0.05). The GMV values in the left precentral gyrus were negatively correlated with the RLS rating scores (r = 0.2138, P = 0.0263). CONCLUSIONS: This abnormal decreased GMV in the sensorimotor cortex provides evidence for a sensory processing disorder in RLS that may be involved in the pathogenesis of RLS in HD patients.


Assuntos
Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Diálise Renal/efeitos adversos , Síndrome das Pernas Inquietas/diagnóstico por imagem , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/diagnóstico por imagem , Córtex Motor/patologia , Tamanho do Órgão , Síndrome das Pernas Inquietas/complicações
17.
J Pharmacol Exp Ther ; 375(1): 139-151, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32719071

RESUMO

Organic anion-transporting polypeptide (OATP) 1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4ß-hydroxycholesterol (4ßHC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared with RIF treatment. The trough concentration, area under plasma concentration-time curve (AUC), and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations compared with preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85-1.3-fold), whereas CYP3A8 expression was increased 3.7-5.0-fold, which correlated well with the predose levels of CP and 4ßHC. Rifampin treatment showed 2.0-3.3-fold increases in P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF, and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted. SIGNIFICANCE STATEMENT: In this study, combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys. For the first time, the study determines transporter gene expression in the nonhuman primate liver, gut, and kidney tissues after administration of RIF for 7 days, leading to a better understanding of the induction of OATP1B and other major drug transporters. Finally, it provides evidence to strengthen the claim that coproporphyrin is a suitable endogenous probe of OATP1B activity.

18.
Braz J Med Biol Res ; 53(8): e9886, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609262

RESUMO

The objective of this study was to compare the safety and efficacy of 0.2% hyaluronic acid (HA) topical gel and dexamethasone topical ointment in the treatment of recurrent aphthous ulcers (RAU) in children. This retrospective observational study included 104 patients who had more than two episodes of oral aphthous ulcers per year and were treated with HA (n=52) or dexamethasone (n=52) from August 15, 2014 to September 3, 2018. Therapy efficacy was evaluated based on the ulcer size and pain score before versus 7 days after either therapy. The paired t-test, chi-squared test, and independent t-test were utilized for statistical analyses. There was no significant difference in ulcer size or pain score between the HA and dexamethasone groups, on day 1 or day 7. Both treatments were tolerated well and no side effects were reported. No significant differences in body temperature, respiration rate, pulse, or systolic/diastolic blood pressure were observed between the start (day 1) and end of treatment (day 7), for either treatment. HA and dexamethasone showed similar efficacy in reducing ulcer size and pain scores, and were tolerated equally well in children with RAU. Future high-quality studies with larger numbers of patients are needed to confirm our findings.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Dexametasona/uso terapêutico , Ácido Hialurônico/uso terapêutico , Estomatite Aftosa/tratamento farmacológico , Criança , Feminino , Humanos , Masculino , Dor , Recidiva , Estudos Retrospectivos
19.
Rapid Commun Mass Spectrom ; 34(20): e8896, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32666620

RESUMO

RATIONALE: High tumor expression of programmed cell death protein (PD1) and programmed death-ligand 1 (PD-L1) is thought to be associated with positive clinical outcomes after treatment with anti-PD1 or anti-PD-L1 agents. Several sensitive methods based on immunohistochemistry, ligand binding assay (LBA), and liquid chromatography/mass spectrometry involving the measurement of PD1 and PD-L1 expression have been reported. Here, we expand on the characterization of different tumor types using a highly specific, sensitive, and robust immunoaffinity liquid chromatography/tandem mass spectrometry (IA-LC/MS/MS)-based method for the simultaneous quantitation of PD1 and PD-L1 in tumor tissues. METHODS: Human tumor tissue samples were homogenized using a Precellys Evolution homogenizer. The samples were incubated with anti-PD1 and anti-PD-L1 capture polyclonal antibodies, which were bound to magnetic beads. Following enrichment, samples were digested with trypsin. A Waters iKEY HSS T3 1.8 um (150 µm × 100 mm) column with a gradient flow rate of 3 µL/min was used for chromatographic separation, and a Waters TQ-S triple quadrupole mass spectrometer was used for detection. Selected reaction monitoring (SRM) transitions with unit resolution for precursor/product ion masses were optimized for PD1 and PD-L1 surrogate peptides. RESULTS: The surrogate peptides LAAFPEDR for PD1 and FTVTVPK for PD-L1 yielded the most intense SRM transitions at m/z 459.7 > 516.2 and m/z 396.2 > 543.3, respectively, and thus were selected for the quantitation of PD1 and PD-L1. The lower limit of quantitation for PD1 and PD-L1 was 0.062 ng/mL with an assay range up to 10 ng/mL. Using this method, human PD1 and PD-L1 were detected and quantified from four different types of tumor tissues. The data show that PD1 expression level was highly correlated with that of PD-L1 in all tumor tissues analyzed here. CONCLUSIONS: A highly specific and sensitive immunoaffinity microflow LC/MS/MS method for the simultaneous quantification of PD1 and PD-L1 in tumor tissues was developed and implemented. This method combines the advantage of immuno-capture for analyte enrichment with the high specificity of detection of multiple surrogate peptides by LC/MS/MS. The quantification of PD1 and PD-L1 co-expression in tumor could help evaluate their role in assessing tumor type selection and patient stratification.

20.
Phys Chem Chem Phys ; 22(31): 17713-17724, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32728676

RESUMO

Electronic structure, collision-induced dissociation (CID) and bond properties of closo-[B6X6]2- (X = Cl-I) are investigated in direct comparison with their closo-[B12X12]2- analogues. Photoelectron spectroscopy (PES) and theoretical investigations reveal that [B6X6]2- dianions are electronically significantly less stable than the corresponding [B12X12]2- species. Although [B6Cl6]2- is slightly electronically unstable, [B6Br6]2- and [B6I6]2- are intrinsically stable dianions. Consistent with the trend in the electron detachment energy, loss of an electron (e- loss) is observed in CID of [B6X6]2- (X = Cl, Br) but not for [B6I6]2-. Halogenide loss (X- loss) is common for [B6X6]2- (X = Br, I) and [B12X12]2- (X = Cl, Br, I). Meanwhile, X˙ loss is only observed for [B12X12]2- (X = Br, I) species. The calculated reaction enthalpies of the three competing dissociation pathways (e-, X- and X˙ loss) indicated a strong influence of kinetic factors on the observed fragmentation patterns. The repulsive Coulomb barrier (RCB) determines the transition state for the e- and X- losses. A significantly lower RCB for X- loss than for e- loss was found in both experimental and theoretical investigations and can be rationalized by the recently introduced concept of electrophilic anions. The positive reaction enthalpies for X- losses are significantly lower for [B6X6]2- than for [B12X12]2-, while enthalpies for X˙ losses are higher. These observations are consistent with a difference in bond character of the B-X bonds in [B6X6]2- and [B12X12]2-. A complementary bonding analysis using QTAIM, NPA and ELI-D based methods suggests that B-X bonds in [B12X12]2- have a stronger covalent character than in [B6X6]2-, in which X has a stronger halide character.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA