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1.
Appl Opt ; 58(30): 8194-8199, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31674489

RESUMO

Few-layered ${{\rm MoSe}_2}$MoSe2 nanosheets were prepared by the low-cost, simple liquid-phase exfoliation method. The ${{\rm MoSe}_2}$MoSe2 nanosheets possessed the modulation depth of 16.5% with a saturation intensity of ${0.84}\;{{\rm MW/cm}^2}$0.84MW/cm2 at 1.34 µm, indicating the performance as the saturable absorber. The passively $Q$Q-switched c-cut ${\rm Nd}:{{\rm GdVO}_4}$Nd:GdVO4 laser at 1.34 µm was demonstrated with the few-layered ${{\rm MoSe}_2}$MoSe2 saturable absorber for the first time. The minimum pulse duration of 420 ns at a repetition rate of 238 kHz could be obtained. In order to significantly reduce the pulse duration, dual-loss modulation simultaneously using both ${{\rm V}^{3 + }}:{\rm YAG}$V3+:YAG and ${{\rm MoSe}_2}$MoSe2 saturable absorbers was implemented. The pulse duration was compressed to a 82.4 ns pulse at a repetition rate of 409.3 kHz at the pump power of 10.66 W. The experimental results provide a solid fundament for the short pulse generation with ${{\rm MoSe}_2}$MoSe2 saturable absorber at 1.34 µm.

2.
Mol Biol Rep ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677036

RESUMO

Hexokinase (HXK) plays important roles in hexose phosphorylation and sugar signaling. HXK regulates the glucose-induced accumulation of anthocyanin in many species. Little is known about the biological function of the HXK gene family in Paeonia suffruticosa. cDNA sequences of two hexokinase genes PsHXK1 and PsHXK2 were isolated using RACE-PCR and RT-PCR from P. suffruticosa. PsHXK1 encodes 498 amino acids with a 1497-bp open reading frame (ORF), and PsHXK2 contains 493 amino acids with a 1482-bp ORF. Sequence and phylogenetic analyses suggest that PsHXK1 and PsHXK2 belong to type-B HXK and may function as glucose sensors. PsHXK1 and PsHXK2 mRNA were detected in all tested tissues. PsHXK1 is highly expressed in petals and stamens, while PsHXK2 is highly expressed in stamens. At the former stages of flower opening, PsHXK1 and PsHXK2 show higher expression levels in on-tree flowers compared with cut flowers. Overexpressing PsHXK1 and PsHXK2 in Arabidopsis enhances glucose sensitivity, inhibits plant growth in response to glucose, and induces anthocyanin accumulation in response to the high level of glucose. Overall, our results primarily reveal the biological function of PsHXK1 and PsHXK2, especially their involvement in glucose-induced anthocyanin accumulation.

3.
Blood ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31697823

RESUMO

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, where multiple subclones harbor mutations in the same drug resistance gene, was observed in six relapses and confirmed by single-cell sequencing in one case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently two-step process where a persistent clone survived initial therapy, and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from pre-existing resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2,540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

4.
Ying Yong Sheng Tai Xue Bao ; 30(10): 3435-3442, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31621230

RESUMO

To examine the effects of soil structure improvement due to the amendment of biochar and polyacrylamide (PAM) on the chlorophyll fluorescence characteristics of rice leaves and the yield of rice, a pit cultivation experiment was carried out in a coastal reclamation region. Three levels of biochar (0%, 2% and 5% by the mass of 0-20 cm surface soil and noted as B1, B2 and B3, respectively) and PAM (0‰, 0.4‰ and 1‰ by the mass of 0-20 cm surface soil and noted as P1,P2 and P3, respectively) were applied to the adopted soil, respectively. The results of the three-year experiment showed that an appropriate application quantity of biochar and PAM could improve the fluorescence characteristics of rice leaves. However, high levels of biochar and PAM had no obvious or even a negative effect. Among all the treatments, the B2P2 treatment always had the highest the maximum photochemical efficiency (Fv/Fm), the actual photochemical efficiency of photosystem II (ΦPS2), the photochemical quenching coefficient (qP) and the non-photochemical quenching coefficient (NPQ) values during the whole growth period. The chlorophyll content (SPAD value) of rice leaves showed no significant difference among different biochar application levels. However, it showed significant differences among different PAM application levels, with the highest value under the soil amended with 0.4‰ PAM (the P2 treatment). The application of biochar and PAM had significant impacts on rice yield, with the highest yield, namely 7236 kg·hm-2, presenting under the B2P2 treatment, which was 28.5% higher than that of the control. The improved soil structure of the coastal saline soil due to the amendment of biochar and PAM affects rice yield mainly through its influences on the 1000-grain weight, the spike number per hole, the grain number per spike and the seed setting rate. It is concluded that improving soil structure by applying an appropriate quantity of biochar and PAM is conducive to increase the chlorophyll fluorescence characteristics and the yield of rice in the coastal reclamation region.


Assuntos
Oryza , Solo , Clorofila , Fluorescência , Folhas de Planta
5.
J Biopharm Stat ; 29(5): 749-759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31590626

RESUMO

A question that routinely arises in medical device clinical studies is the homogeneity across demographic subgroups, geographical regions, or investigational sites of the enrolled patients in terms of treatment effects or outcome variables. The main objective of this paper is to discuss statistical concepts and methods for the assessment of such homogeneity and to provide the practitioner a statistical framework and points to consider in conducting homogeneity assessment. Demographic subgroups, geographical regions, and investigational sites are discussed separately as each has its unique issues. Specific considerations are also given to randomized controlled trials, non-randomized comparative studies, and single-arm studies. We point out that judicious use of statistical methods, in conjunction with sound clinical judgment, is essential in handling the issue of homogeneity of treatment effect in medical device clinical studies.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31564506

RESUMO

BACKGROUND: Increasing evidence indicates that Six2 contributes to tumorigenesis in various tumor including hepatocellular carcinoma (HCC). This study aimed to determine the role of Six2 in HCC and to elucidate the association of Six2 with clinical pathological characteristics. METHODS: The expressions of Six2 in HCC tumor, para-tumor tissue and portal vein tumor thrombus (PVTT) were detected by tissue microarray technique, immunohistochemistry, real-time RT-PCR and Western blotting. Chi-square and Kaplan-Meier analysis were used to analyze the correlation between Six2 expression and prognosis of HCC patients. Lentivirus mediated Six2 knockdown, spheroid formation assay, proliferation assay and subcutaneous tumor implantation were performed to determine the function of Six2. RESULTS: In 274 HCC samples, Six2 was strongly expressed. Kaplan-Meier analysis revealed that high expression of Six2 was correlated with a shorter overall survival (OS) and disease-free survival (DFS). Moreover, Six2 expression was associated with sex, alpha-fetoprotein, tumor size and portal vein invasion. Six2 was highly expressed in PVTT. Six2 knockdown inhibited HCC cell lines proliferation, migration, and self-renewal in vitro and in vivo. In addition, low-expression of Six2 weakened TGF-ß induced Smad4 activation and epithelial-mesenchymal transition in HCC cell lines. CONCLUSIONS: Elevated Six2 expression in HCC tumor patients was associated with negative prognosis. Upregulated Six2 promoted tumor growth and facilitated HCC metastasis via TGF-ß/Smad signal pathway.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31574240

RESUMO

The present research was to assess the relationship between ABCB1 (G2677T/A, C3435T) polymorphisms and lipid homeostasis, as well as risk of liver injury induced by atorvastatin in inpatients from China. The lipids levels (TC, HDL, TG) as well as metabolic enzyme of hepar (ALT, AST, ALP, GGT) in plasma for 162 patients were measured at baseline and after approximately six months of atorvastatin treatment. Polymorphisms of the ABCB1 gene were determined using the Snapshot technique. The associations between genetic polymorphisms and lipids levels, as well as hepar indexes were evaluated at the end of medical treatment. Based on one-way ANOVA analysis, patients with the 2677GG or 3435TT genotypes showed a remarkable decrease percentage when the level of TC was above 4.00 mmol·L-1, separately (P<0.05). There was a significant decrease percentage in the frequency of patients with 2677GG genotype (LDL-C>2.00 mmol·L-1) (P<0.05). The level of ALT in patients with the 2677 GG or 3435CC genotypes displayed a significantly increase percentage, respectively (P<0.05). The ABCB1 G-C haplotype carriers were associated with an increased risk of AILI. The results provide evidence for clinically individualised utilisation of atorvastatin for lipid homeostasis as well as risk of induced liver injury in Chinese population.

8.
Biochim Biophys Acta Mol Basis Dis ; : 165556, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31521821

RESUMO

Epithelial-mesenchymal transition (EMT) is considered to be one of the most important mechanisms for the progression of renal interstitial fibrosis (RIF). Recently the relationship between post-translational modifications and EMT has been reported. O-GlcNAcylation, one of the key post-translational modifications, was rarely mentioned about its role in EMT, especially in EMT during the process of RIF. The current study aimed to determine whether O-GlcNAcylation participates in the regulation of EMT during RIF. We proved that O-GlcNAcylation prompted the EMT of HK2 cells. Mass spectral analysis identified RAF1 to be one of the O-GlcNAcylated proteins. Moreover, O-GlcNAcylation of RAF1 stabilized RAF1 protein and prompted EMT of HK2 cells. In terms of mechanism, we verified that O-GlcNAcylation of RAF1 inhibited its ubiquitination and thus stabilized RAF1. The upregulation of RAF1 and O-GlcNAcylation products (O-GlcNAc) in vivo were also observed in unilateral ureteral obstruction (UUO) animal models. Collectively, our study indicated that O-GlcNAcylation suppressed the ubiquitination of RAF1, stabilized RAF1 and then modulated the EMT in HK2 cells. These results may give us several new targets for the treatment of RIF.

9.
Dermatol Surg ; 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31490300

RESUMO

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory condition characterized by recurrent nodules, sinus tracts, comedones, and scarring. Hidradenitis suppurativa is often associated with pain and decreased quality of life. Limited clinical trial data exist regarding the management of acute HS lesions, but clinical experience and a prospective case series suggest that intralesional triamcinolone may be useful. OBJECTIVE: To compare the efficacy of intralesional triamcinolone to placebo for the treatment of HS inflammatory lesions. MATERIALS AND METHODS: This is a double-blind, randomized, placebo-controlled trial comparing intralesional triamcinolone 10 mg/mL, triamcinolone 40 mg/mL, and normal saline (NS). Thirty-two subjects at University of North Carolina Dermatology and Skin Cancer Centers were enrolled for a total of 67 lesions. Subjects reported pain scores, days to resolution, and satisfaction on a standardized survey over a 14-day period. RESULTS: When intralesional injections of triamcinolone 10 mg/mL, triamcinolone 40 mg/mL, and NS were compared, no significant difference was found for days to HS inflammatory lesion clearance, pain reduction at Day 5, or patient satisfaction. CONCLUSION: No statistically significant difference was found between varying concentrations of triamcinolone and NS for the treatment of HS lesions. Steroid injections may be less effective for the management of acute HS than typically presumed.

10.
Med Sci Monit ; 25: 7126-7137, 2019 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-31542788

RESUMO

BACKGROUND Degenerative spinal disorders have adverse impacts on patients' quality of life. Because the main objectives of any surgical intervention are to improve health-related quality of life and to reduce disability, instruments capable of measuring patient-oriented outcomes are now increasingly used. The aim of this study was to evaluate the use of the Short Form 36 Health Survey Questionnaire (SF36) for assessing patient-oriented outcomes of degenerative cervical myelopathy surgery. MATERIAL AND METHODS A literature search was conducted in electronic databases (Google Scholar, Ovid SP, PubMed, Science Direct, and Springer). Studies were included if they reported SF36 scores by following patients for at least 12 months. Random effects meta-analyses were performed to estimate changes in SF36 physical/mental component summary (SF36-PCS/MCS), SF36 dimensional, Japanese Orthopedics Association (JOA)/modified JOA (mJOA), and Neck Disability Index (NDI) scores by latest follow-up. RESULTS Fourteen studies (1966 patients; age 58.2 years [95% confidence interval (CI), 56.6 to 59.9]; 60% males [95% CI, 55 to 64]; follow-up 24.8 months [95% CI, 20.9 to 28.7]) were included in meta-analysis. SF36-PCS (6.60 [95% CI, 4.91 to 8.28]; p<0.00001), SF36-MCS (6.33 [95% CI, 4.31 to 8.35]; p<0.00001) and SF36 dimensional (p<0.05) scores improved significantly at latest follow-up. Surgery significantly improved JOA/mJOA (3.43 [95% CI, 2.80 to 4.06]; p<0.00001) and NDI (-13.70 [95% CI, -17.35 to -10.06]; p<0.00001) scores also. Change in SF36-PCS score were correlated (r=-0.554) with change in NDI score, whereas change in SF36-MCS score was correlated with change in JOA score (r=0.550). CONCLUSIONS Surgery for degenerative cervical myelopathy is associated with significantly improved SF36-measured patient-oriented outcomes.

11.
Int J Biochem Cell Biol ; 116: 105612, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31546020

RESUMO

BACKGROUND/AIMS: Epigallocatechin-3-gallate (EGCG), a major catechin found in green tea, plays an important anti-tumor role and is involved in various other biological processes, such as, neuroprotection by prevention of aggregation of misfolded proteins generated because of genetic defects. Surfactant protein A2 mutations (G231V and F198S) have been identified to be associated with pulmonary fibrosis and lung cancer, and these mutations cause protein aggregation, instability as well as secretion deficiency. The present study focused on investigating the inhibitory effects of EGCG on aggregation of mutant SP-A2 and elucidating the potential mechanisms underlying this action. METHODS: Wild-type and mutant SP-A2 were transiently expressed in CHO-K1 cells. The aggregated and soluble proteins were separated into NP-40-insoluble and NP-40-soluble fractions. Protein stability was validated by chymotrypsin limited proteolysis assay. Western blot and RT-PCR were used to determine the protein and mRNA expression level, respectively. RESULTS: Mutant SP-A2 alone or wild-type SP-A2 co-expressed with G231V formed NP-40-insoluble aggregates in CHO-K1 cells. EGCG significantly suppressed this aggregation and alleviated mutant SP-A2 accumulation in the ER. When combined with 4-PBA, EGCG treatment completely blocked mutant SP-A2 aggregate formation. Though secretion of mutant protein was not affected, EGCG facilitated protein instability in both wild-type and mutant protein. Importantly, MG132, a proteasome inhibitor, reversed EGCG-induced aggregate reduction. CONCLUSIONS: EGCG inhibits aggregation of misfolded SP-A2 via induction of protein instability and activation of proteasomal pathway for aggregate degradation.

13.
Hepatology ; 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31541481

RESUMO

Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is mainly regulated by NRF2 during tumorigenesis. Here, we demonstrated that deletion of RBP5-mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. RMP-overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 via the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP-KEAP1-NRF2 axis promotes ICC tumorigenesis, metastasis and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis. CONCLUSION: These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.

14.
Mol Med Rep ; 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31545412

RESUMO

Lipopolysaccharide (LPS) induces stress inflammation and apoptosis. Pulmonary epithelial cell apoptosis, which accelerates the progression of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), is the leading cause of mortality in patients with ALI/ARDS. The nephroblastoma overexpressed protein (CCN3), an inflammatory modulator, is reported to be a biomarker in ALI. Using the LPS-induced ALI model, this study investigated the expression of CCN3 and its possible molecular mechanism in lung alveolar epithelial cell inflammation and apoptosis. Our data revealed that LPS treatment greatly increased the level of CCN3 in A549 cells. The A549 cells were transfected with specific CCN3 small interfering RNA (siRNA) using transfection reagent. CCN3 siRNA not only largely attenuated the expressions of the inflammatory cytokines interleukin (IL)-1ß and transforming growth factor (TGF)-ß1, but also reduced the apoptotic rate of the AEC II cells and affected the expressions of the apoptosis-associated proteins (Bcl-2 and caspase-3). Furthermore, CCN3 knockdown greatly inhibited the activation of nuclear factor-κB p65 in A549 cells. In addition, TGF-ß/p-Smad inhibitor (TP0427736) and NF-κB inhibitor (PDTC) significantly attenuated the expression level of CCN3 in A549 cells. In conclusion, our data indicated that CCN3 siRNA affected downstream signal through TGF-ß/ p-Smad or NF-κB pathway, leading to the inhibition of cell inflammation and apoptosis in human alveolar epithelial cells.

15.
Anal Chem ; 91(19): 12525-12530, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31495175

RESUMO

A new method was developed to determine the nanoparticulate and ionic silver (Ag) species in bacteria (Escherichia coli, E. coli). By removal of the cell wall with lysozyme, the cell surface-adsorbed Ag species were separated from the intracellular Ag species, which were extracted by tetramethylammonium hydroxide and determined by size-exclusion chromatography coupled with inductively coupled plasma mass spectrometry (SEC-ICP-MS). The detection limit is 3 ng/107 CFU/mL (where CFU is colony-forming unit) for both silver nanoparticles (AgNPs) and ionic Ag(I) species. The cell wall-adsorbed Ag was calculated by subtracting the contents of the intra- and extracellular Ag from the total exposure dose of Ag, and therefore the biodistribution of Ag species was profiled. We then applied this strategy to quantitatively analyze extra- and intracellular Ag species in E. coli after respective exposure to Ag+ and 10 and 30 nm AgNPs at different effective concentrations (EC10, EC50, and EC90). Results showed that the intracellular and cell wall-bound Ag account for 5.98-15.21% and 25.13-64.43% of the exposed dose, respectively, and AgNPs could transform into complexed or free Ag+. Our method opens new avenues for the quantitative analysis of the uptake and biodistribution of nanoparticles and their transformation species in bacteria.

16.
J Invest Dermatol ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421124

RESUMO

Both systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases sharing similar genetic backgrounds. Genome-wide association studies have constantly disclosed numerous genetic variants conferring to both disease risks at 7q32.1, but the functional mechanisms underlying them are still largely unknown. Through a series of bioinformatics and functional analyses, we prioritized a potential independent functional single-nucleotide polymorphism (rs13239597) within TNPO3 promoter region, residing in a putative enhancer element and validated that IRF5 is the distal target gene (∼118 kb) of rs13239597, which is a key regulator involved in pathogenic autoantibody dysregulation, increasing risk of both SLE and SSc. We experimentally validated the long-range chromatin interactions between rs13239597 and IRF5 using chromosome conformation capture assay. We further demonstrated that rs13239597-A acted as an allele-specific enhancer regulating IRF5 expression, independently of TNPO3 by using dual-luciferase reporter assays and CRISPR-Cas9. Particularly, the transcription factor EVI1 could preferentially bind to rs13239597-A allele and increase the enhancer activity to regulate IRF5 expression. Taken together, our results uncovered a mechanistic insight of a noncoding functional variant acting as an allele-specific distal enhancer to directly modulate IRF5 expression, which might obligate in understanding of complex genetic architectures of SLE and SSc pathogenesis.

17.
Bioorg Med Chem Lett ; 29(19): 126608, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31444086

RESUMO

A series of hybrid molecules of scutellarein and tertramethylpyrazine's active metabolites have been synthesized. Compared to the original compound, these prepared compounds exhibited higher water solubility, more appropriate logP and better stability. Importantly, compounds 11b, 11d and 11e showed improved neuroprotective activity against the H2O2-induced cell death in PC12 cells, and better antithrombosis activity. The optimized compound 11b was further evaluated by cerebral ischemia/ reperfusion in the middle cerebral artery occlusion (MCAO) model, the results showed that the compound could significantly reduce the infarct area and decrease the neuronal cell damage in CA1 pyramidal neurons. Overall, we demonstrated that the twin drug strategy could be applied in the development of agents for the treatment of ischemic stroke.

18.
BMC Bioinformatics ; 20(1): 427, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419937

RESUMO

BACKGROUND: Biomedical named entity recognition (BioNER) is a fundamental and essential task for biomedical literature mining, which affects the performance of downstream tasks. Most BioNER models rely on domain-specific features or hand-crafted rules, but extracting features from massive data requires much time and human efforts. To solve this, neural network models are used to automatically learn features. Recently, multi-task learning has been applied successfully to neural network models of biomedical literature mining. For BioNER models, using multi-task learning makes use of features from multiple datasets and improves the performance of models. RESULTS: In experiments, we compared our proposed model with other multi-task models and found our model outperformed the others on datasets of gene, protein, disease categories. We also tested the performance of different dataset pairs to find out the best partners of datasets. Besides, we explored and analyzed the influence of different entity types by using sub-datasets. When dataset size was reduced, our model still produced positive results. CONCLUSION: We propose a novel multi-task model for BioNER with the cross-sharing structure to improve the performance of multi-task models. The cross-sharing structure in our model makes use of features from both datasets in the training procedure. Detailed analysis about best partners of datasets and influence between entity categories can provide guidance of choosing proper dataset pairs for multi-task training. Our implementation is available at https://github.com/JogleLew/bioner-cross-sharing .


Assuntos
Pesquisa Biomédica , Mineração de Dados/métodos , Disseminação de Informação , Algoritmos , Bases de Dados como Assunto , Humanos , Aprendizado de Máquina , Redes Neurais (Computação)
19.
Anesth Analg ; 129(3): 679-685, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31425207

RESUMO

BACKGROUND: There is a need for a clinically relevant and feasible outcome measure to facilitate clinical studies in perioperative care medicine. This large-scale retrospective cohort study proposed a novel composite outcome measure comprising invasive respiratory or vasopressor support (IRVS) and death. We described the prevalence of IRVS in patients undergoing major abdominal surgery and assessed the validity of combining IRVS and death to form a composite outcome measure. METHODS: We retrospectively collected perioperative data for 2776 patients undergoing major abdominal surgery (liver, colorectal, gastric, pancreatic, or esophageal resection) at Kyoto University Hospital. We defined IRVS as requirement for mechanical ventilation for ≥24 hours postoperatively, postoperative reintubation, or postoperative vasopressor administration. We evaluated the prevalence of IRVS within 30 postoperative days and examined the association between IRVS and subsequent clinical outcomes. The primary outcome of interest was long-term survival. Multivariable Cox proportional regression analysis was performed to adjust for the baseline patient and operative characteristics. The secondary outcomes were length of hospital stay and hospital mortality. RESULTS: In total, 85 patients (3.1%) received IRVS within 30 postoperative days, 15 of whom died by day 30. Patients with IRVS had a lower long-term survival rate (1- and 3-year survival probabilities, 66.1% and 48.5% vs 95.2% and 84.0%, respectively; P < .001, log-rank test) compared to those without IRVS. IRVS was significantly associated with lower long-term survival after adjustment for the baseline patient and operative characteristics (adjusted hazard ratio, 2.72; 95% confidence interval, 1.97-3.77; P < .001). IRVS was associated with a longer hospital stay (median [interquartile range], 65 [39-326] vs 15 [12-24] days; adjusted P < .001) and a higher hospital mortality (24.7% vs 0.5%; adjusted P < .001). Moreover, IRVS was adversely associated with subsequent clinical outcomes including lower long-term survival (adjusted hazard ratio, 1.78; 95% confidence interval, 1.21-2.63; P = .004) when the analyses were restricted to 30-day survivors. CONCLUSIONS: Patients with IRVS can experience ongoing risk of serious morbidity and less long-term survival even if alive at postoperative day 30. Our findings support the validity of using IRVS and/or death as a composite outcome measure for clinical studies in perioperative care medicine.

20.
Bioanalysis ; 11(14): 1347-1358, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31393160

RESUMO

Aim: The reliable measurement of receptor occupancy (RO) provides informative data for efficacy and safety evaluation. This study aimed to assess factors affecting RO measurement of anti-PD-1 antibodies in clinical studies. Materials & methods: RO performance was assessed using different T-cell activation markers measured by flow cytometry. The validated methodology was then used in support of a clinical study. Results: The optimized active cell population was comprised of CD45RO+ or CD45RA- T cells. The bioanalytical method was validated for inter- and intra-assay precision (coefficient of variation ≤30%) and sample storage stability for 3 days. Consistent RO saturation was observed in Phase Ia clinical trial, although receptor regulation appeared to be different. The formation of anti-drug antibodies had markedly influenced pharmacokinetics and RO. Conclusion: RO measurement in combination with pharmacokinetics and anti-drug antibodies data could allow the integrated evaluation and better understanding of efficacy and safety.

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