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1.
Artigo em Inglês | MEDLINE | ID: mdl-34215997

RESUMO

Sandostatin long-acting release® (SLAR) is a long-acting injectable somatostatin analogue formulation composed of octreotide encapsulated in glucose-initiated poly(lactic-co-glycolic acid) (PLGA) microspheres. Despite the end of patent protection, SLAR remains resistant to generic competition likely due to complexity of production process, the uniqueness of the glucose star polymer, and the instability of octreotide in the formulation. Here, we describe development of glucose-PLGA-based composition-equivalent to SLAR formulations prepared by double emulsion-solvent evaporation method and the effect of variations in encapsulation variables on release kinetics and other formulation characteristics. The following encapsulation variables were adjusted at constant theoretical loading of 7.0% peptide: PLGA concentration, pH of inner water phase, and stirring rate. After final drying, the microspheres were examined with and without annealing at 50 °C under vacuum for 3 days. The loading and encapsulation efficiency (EE) of octreotide acetate, manufacturing yield, and in vitro drug release kinetics in PBStc (10 mM phosphate-buffered saline (PBS) with 1% triethyl citrate and 0.02% sodium azide at pH 7.4) were determined by UPLC. The in vitro release and acylation kinetics of octreotide for the solvent evaporation formulations prepared were similar to SLAR although the initial burst was slightly higher. Key formulation steps identified to maximize microsphere yield and minimize residual solvent and initial burst release included (a) addition of acetic acid to the peptide before preparation and (b) annealing the microspheres under vacuum after drying. Controlled release octreotide formulations prepared and investigated in this study could provide a better understanding of the effect of production variables on release performance and supply information useful for making progress in manufacturing of SLAR generic equivalents.

2.
Prev Sci ; 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34212300

RESUMO

Injury is a leading cause of morbidity and mortality among children in the USA. Understanding the impact of executive functions (EFs) on the risk of injuries is crucial for developing effective interventions. However, literature has failed to examine the relationship between multiple EFs and injury domains. The present paper quantitatively synthesized research on cool and hot EFs and children's intentional and unintentional injury risks using a novel meta-analytic structural equation modeling (MASEM) approach. A systematic review was conducted in the following databases: PsycINFO, Scopus, SafetyLit, Cochrane Central, and PubMed (Medline). After screening titles, abstracts, and full texts, a total of 31 studies were eligible for the MASEM analysis. One-stage MASEM was conducted on six conceptualized path analysis models according to the complexity of exogenous and endogenous variables. The MASEM models suggested that hot and cool EFs were negatively associated with children's risk of injury or injury-related risk behaviors regardless of mean age and proportion of females. Among cool EF skills, inhibitory control, but not working memory or cognitive flexibility, was significantly associated with risks of unintentional injuries. Emotion regulation was the dominant hot EF skill examined in the literature and was found significantly associated with risks of non-suicidal self-injuries (NSSIs). EF has a significant impact on children's risk of both unintentional and intentional injuries. Future research should focus on the combined force of hot and cool EF on children's risks of injuries and injury-related risk behaviors.

3.
J Hazard Mater ; 419: 126503, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34214857

RESUMO

Excess boron in water could result in a critical hazard to plants and humans. Traditional treatment approaches cannot efficiently remove boron from water, especially during seawater desalination using reverse osmosis technology. Achieving satisfactory adsorption capacity and rate for boron remains an unmet goal for decades. Herein, we report cellulose-derived polyols as high-performance adsorbents that can rapidly remove boron and organic pollutants from water. Cellulose-derived polyols were synthesized from saccharides and cellulose via controlled radical polymerization and click reaction. Remarkably, CA@NMDG can adsorb boron with an astonishing capacity of ~34 mg g-1 in 10 min, which surpasses all those cellulose-based materials reported thus far, meanwhile, much faster than those of commercial adsorption resin. Moreover, cellulose-derived polyols also showed high removal efficiencies (70-98% in several minutes) toward certain organic pollutants, including Congo red and Reactive Blue 19. The water-insoluble characteristic of cellulose-derived polyols is advantageous to be separated from the treated sewage after adsorption for reuse. This work provides a novel insight into the fabrication of safe, fast, and high-capacity cellulose adsorbents for water purification.

4.
Dis Markers ; 2021: 5574472, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34257746

RESUMO

Regulatory T cells (Tregs) expressing the Foxp3 transcription factor are indispensable for the maintenance of immune system homeostasis. Tregs may lose Foxp3 expression or be reprogrammed into cells that produce proinflammatory cytokines, for example, Th1-like Tregs, Th2-like Tregs, Th17-like Tregs, and Tfh-like Tregs. Accordingly, selective therapeutic molecules that manipulate Treg lineage stability and/or functional activity might have the potential to improve aberrant immune responses in human disorders. In particular, the transcription factor Helios has emerged as an important marker and modulator of Tregs. Therefore, the current review focuses on recent findings on the expression, function, and mechanisms of Helios, as well as the patterns of Foxp3+ Tregs coexpressing Helios in various human disorders, in order to explore the potential of Helios for the improvement of many immune-related diseases. The studies were selected from PubMed using the library of the Nanjing Medical University in this review. The findings of the included studies indicate that Helios expression stabilizes the phenotype and function of Foxp3+ Tregs in certain inflammatory environments. Further, Tregs coexpressing Helios and Foxp3 were identified as a specific phenotype of stronger suppressor immune cells in both humans and animal models. Importantly, there is ample evidence that Helios-expressing Foxp3+ Tregs are relevant to various human disorders, including connective tissue diseases, infectious diseases, solid organ transplantation-related immunity, and cancer. Thus, Helios+Foxp3+CD4+ Tregs could be a valuable target in human diseases, and their potential should be explored further in the clinical setting.

5.
Cell Death Differ ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262144

RESUMO

Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for CRC patients. Here, we found that CDK15 was highly expressed in human CRC and negatively correlated with patient prognosis and overall survival in tissue microarray. Knockdown of CDK15 suppressed cell proliferation and anchorage-independent growth of CRC cells and inhibited tumor growth in cell line-derived xenograft (CDX) model. Importantly, knockout of CDK15 in mice retarded AOM/DSS-induced tumorigenesis and CDK15 silencing by lentivirus significantly suppressed tumor progression in patient-derived xenograft (PDX) model. Mechanistically, CDK15 could bind PAK4 and phosphorylate PAK4 at S291 site. Phosphorylation of PAK4 at the S291 residue promoted cell proliferation and anchorage-independent growth through ß-catenin/c-Myc, MEK/ERK signaling pathway in CRC. Moreover, inhibition of PAK4 reversed the tumorigenic function of CDK15 in CRC cells and pharmacological targeting PAK4 suppressed tumor growth in PDX models. Thus, our data reveal the pivotal role of CDK15 in CRC progression and demonstrate CDK15 promotes CRC tumorigenesis by phosphorylating PAK4. Hence, the CDK15-PAK4 axis may serve as a novel therapeutic target for CRC.

6.
Int Urol Nephrol ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34263435

RESUMO

BACKGROUND: We evaluated the prognostic impact of AKI duration on the 1-year mortality rate in elderly patients diagnosed based on the 48-hour and 7-day changes in serum creatinine (Scr) levels recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. METHODS: This retrospective study was conducted from 2007 to 2018 on elderly patients in the Geriatric Department of the Chinese PLA General Hospital. Based on the two diagnostic criteria in the KDIGO guidelines, the patients were divided into a 48-hour diagnostic window and a 7-day diagnostic window group, and into transient AKI (lasting 1-2 days) and persistent AKI (lasting 3-6 days, and ≥ 7 days) based on the time at which the Scr level returned to the baseline value. The primary outcome was the 1-year mortality rate after AKI. RESULTS: In total, 688 patients were enrolled, including 367 (53.3%) with a 48-hour and 321 (46.7%) with a 7-day diagnostic window. Of the 688 patients, in the 48-hour window group, 12.0% had transient AKI, 31.1% had lasting 3-6 days, and 56.9% had lasting ≥ 7 days; in the 7-day window group, 5.3% had transient AKI, 24.0% had lasting 3-6 days, and 70.7% had lasting ≥ 7 days. Overall, 332 patients (33.6%) died within 1 year, including 189 (51.5%) in the 48-hour and 143 (44.5%) in the 7-day diagnostic window group. After adjusting for multiple covariates, AKI duration was associated with a significantly higher 1-year mortality rate (3-6 days: HR = 3.535; 95% CI = 1.685-7.417, P = 0.001; ≥ 7 days: HR = 2.400; 95% CI = 1.152-5.001, P = 0.019) in the 48-hour diagnostic window group, but it did not differ in the 7-day diagnostic window group (P = 0.452). CONCLUSIONS: Persistent AKI was common in elderly hospitalized patients, accounting for 88% and 95% of patients with 48-hour and 7-day diagnostic windows, respectively. Moreover, AKI duration was associated with different clinical outcomes depending on the diagnostic window. Further studies should focus on the mechanism underlying the relationship of AKI outcomes with diagnostic criteria.

7.
Drug Deliv ; 28(1): 1510-1523, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34263685

RESUMO

Non-small cell lung cancer (NSCLC) is a highly lethal disease and the majority of NSCLC patients are desperate for therapies that can effectively target their cancer and ultimately improve their overall survival. Docetaxel (DTX) represents the first-line of the antitumor agent that is used to treat NSCLC; however, it has poor solubility in water and unsatisfactory encapsulation efficiency. In our study, exosomes were isolated from A549 cancer cells by ultracentrifugation and then characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). The particle size changes of EXO and EXO-DTX were measured daily for seven days to test the stability. DTX was selected payload by electroporation (EXO-DTX). For the in vitro evaluation, cell proliferation, cell cycle, cell apoptosis, reactive oxygen species (ROS) assay and cellular uptake were evaluated in the A549 cells. Also, this study evaluated the target and therapeutic effect of DTX as an antitumor agent in vivo. As a result, EXO-DTX with a particle size of 149.5 nm were successfully prepared and the cytotoxicity of the EXO-DTX was much greater than that of DTX monomers. Exosomes significantly increased the cellular uptake in vitro evaluation and showed better targeting to tumor tissue compared to the free DTX in the mice. We also explored the potential of tumor cell-derived exosomes as a drug delivery agent to target the parent cancer. Hence, we conclude that exosomes might be used as a potential antitumor drug delivery system (DDS).

8.
Dalton Trans ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34263898

RESUMO

To research the effect of structural diversity on citrate-based coordination polymers (CPs), citric acid (H4cit) was selected to combine with Cu(ii) under hydrothermal conditions. A new CP [Cu2(cit)(H2O)2] (1) was synthesized and structurally characterized. The title complex shows a 3D 2,4,6-connected topology with the point symbol of {43·63}{44·66·85}{4}. Inspired by the decomposition and functional molybdenum component, 1 was used as a catalyst precursor to synthesize a carbon-based material (C-1) and a C@Mo material (C-Mo-1) by the chemical vapor deposition (CVD) method and characterized in detail. The selective removal of a contaminant (Congo red) by complex 1, C-1 and C-Mo-1 in the aqueous phase was also comparatively investigated.

9.
Rice (N Y) ; 14(1): 68, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34264425

RESUMO

BACKGROUND: In rice, panicle apical abortion is a common phenomenon that usually results in a decreased number of branches and grains per panicle, and consequently a reduced grain yield. A better understanding of the molecular mechanism of panicle abortion is thus critical for maintaining and increasing rice production. RESULTS: We reported a new rice mutant panicle apical abortion 3 (paa3), which exhibited severe abortion of spikelet development on the upper part of the branches as well as decreased grain size over the whole panicle. Using mapping-based clone, the PAA3 was characterized as the LOC_ Os04g56160 gene, encoding an H+-ATPase. The PAA3 was expressed highly in the stem and panicle, and its protein was localized in the plasma membrane. Our data further showed that PAA3 played an important role in maintaining normal panicle development by participating in the removal of reactive oxygen species (ROS) in rice. CONCLUSIONS: Our studies suggested that PAA3 might function to remove ROS, the accumulation of which leads to programmed cell death, and ultimately panicle apical abortion and decreased seed size in the paa3 panicle.

10.
J Autism Dev Disord ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34264487

RESUMO

Interoception is believed to underlie socio-cognitive functions which are often impaired in individuals with autism spectrum disorders (ASD). In this study, Experiment 1 examined in a sample of 114 neurotypical college students the associations among autistic traits, alexithymia, and interoceptive accuracy (IA), which was assessed by a novel paradigm "Eye-tracking Interoceptive Accuracy Task (EIAT). In Experiment 2, EIAT and the Autism Spectrum Quotient were administered to 52 preschool children, 50 adolescents, and 50 adults. Experiment 1 supported the association between autistic traits and alexithymia, but failed to support their association with multidimensional interoception. Experiment 2 strongly supported the association between age and IA. We conclude that cardiac IA differs between neurotypical age groups, but shows limited relationship with autistic traits.

11.
Biomed Pharmacother ; 141: 111884, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34243099

RESUMO

BACKGROUND: psoriasis is a chronic inflammatory skin disease. The accumulation of IL-17 cytokines in the lesions leads to epidermis proliferation. Traditional Chinese medicine has a significant effect on psoriasis treatment. Among them, Tuhuaiyin is a representative prescription, which has an outstanding curative effect in acute and remission stage. METHODS: To reveal the target and molecular mechanism of Tuhuaiyin, systematic pharmacology platform and database screening were used to construct the Tuhuaiyin interaction network with compounds, targets and diseases. The intervention of Tuhuaiyin on keratinocyte proliferation and inflammation was verified in the model of psoriasis-like lesions induced by imiquimod. The effect on the number and function of IL-17-producing cells was detected, and the regulatory effect of Tuhuaiyin on gut microbial was explored. RESULTS: 32 selected active molecules in Tuhuaiyin acted on psoriasis biological processes. Tuhuaiyin significantly alleviates erythema and scales in the psoriasis like mouse model induced by imiquimod. Excessive proliferation of keratinocytes and infiltration of inflammatory cells were restrained in the dermis by using Tuhuaiyin. The expression of IL-17 was down-regulated in skin and peripheral blood. The proportion of IL-17-producing cells was decreased in immune organs. And phosphorylation of JNK inhibited in skin lesions. At the same time, the change of gut microbial diversity in the psoriasis-like model was improved. CONCLUSION: our study predicted and verified the molecular immunological mechanism of Tuhuaiyin, alleviated the abnormal proliferation of keratinocytes by inhibiting the proportion of IL-17-producing cells and the expression of IL-17 cytokines. Taken together, our data identify the therapeutic potential of Tuhuaiyin for psoriasis.

12.
Chin J Nat Med ; 19(7): 551-560, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247780

RESUMO

The quality control of Chinese herbal medicine is a current challenge for the internationalization of traditional Chinese medicine. Traditional quality evaluation methods lack quantitative analysis, while modern quality evaluation methods ignore the origins and appearance traits. Therefore, an integrated quality evaluation method is urgent in need. Raw Rehmanniae Radix (RRR) is commonly used in Chinese herbal medicine. At present, much attention has been drwan towards its quality control, which however is limited by the existing quality evaluation methods. The present study was designed to establish a comprehensive and practical method for the quality evaluation and control of RRR pieces based on its chemical constituents, appearance traits and origins. Thirty-three batches of RRR pieces were collected from six provinces, while high-performance liquid chromatography (HPLC) was applied to determine the following five constituents, including catalpol, rehmannioside A, rehmannioside D, leonuride and verbascoside in RRR pieces. Their appearance traits were quantitatively observed. Furthermore, correlation analysis, principal components analysis (PCA), cluster analysis and t-test were performed to evaluate the qualities of RRR pieces. These batches of RRR pieces were divided into three categories: samples from Henan province, samples from Shandong and Shanxi provinces, and those from other provinces. Furthermore, the chemical constituents and appearance traits of RRR pieces were significantly different from diverse origins. The combined method of chemical contituents, appearance traits and origins can distinguish RRR pieces with different qualities, which provides basic reference for the quality control of Chinese herbal medicine.

13.
J Biochem Mol Toxicol ; : e22839, 2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34250696

RESUMO

Rosmarinic acid having potential anti-inflammatory and free radical scavenging activity. We examined the chemotherapeutic effect of rosmarinic against cisplatin (CIS)-induced ovarian toxicity via modulation of oxidative stress and inflammation. Swiss BALB mice used in experimental protocol and mice were divided into different groups. Intraperitoneal injection of CIS (7 mg/kg) was used for ovarian cancer induction. The rats were received rosmarinic acid (2.5, 5, and 10 mg/kg, body weight) treatment for 22 weeks. Body weight, ovary weight food, and water intake were estimated at regular time intervals. Hormonal and antioxidant parameters were estimated in the ovary tissue and serum at the end of the study. Cytokines, inflammatory, and apoptosis parameters were determined at the end of the study. Finally, the ovary tissue histopathology was performed at end of the experimental study. Rosmarinic acid significantly (p < 0.001) improved the body weight and reduced the ovary weight. Rosmarinic acid considerably reduced the hormonal assay parameters, such as antimullerian hormone, estradiol, luteinizing hormone, and follicle-stimulating hormone compared to model control mice. Rosmarinic treatment significantly (p < 0.001) reduced the level of nitric oxide, myeloperoxidase, and boosted the level of antioxidant parameters, such as glutathione, superoxide dismutase, catalase, and glutathione peroxidase in serum and ovary tissue. Rosmarinic acid downregulated the cytokines like interleukin-6, tumor necrosis factor-α, interleukin-1ß; inflammatory parameter includes prostaglandin E2 , cyclooxygenase-2, and inducible nitric oxide synthase at a dose-dependently. Ovary tissue histopathology showed improvement after rosmarinic acid treatment. The result suggests that rosmarinic acid is a protective effect in ameliorating CIS-induced ovary toxicity via alteration of inflammatory and apoptosis parameters.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34251177

RESUMO

The electrochemical oxygen reduction reaction (ORR) is regarded as an attractive alternative to the anthraquinone process for sustainable and on-site hydrogen peroxide (H2O2) production. It is however hindered by low selectivity due to strong competition from the four-electron ORR and needs efficient catalysts to drive the 2e- ORR. Here, an acid oxidation strategy is proposed as an effective strategy to boost the 2e- ORR activity of metallic TiC via in-site generation of a surface amorphous oxygen-deficient TiO2-x layer. The resulting a-TiO2-x/TiC exhibits a low overpotential and high H2O2 selectivity (94.1% at 0.5 V vs reversible hydrogen electrode (RHE)), and it also demonstrates robust stability with a remarkable productivity of 7.19 mol gcat.-1 h-1 at 0.30 V vs RHE. The electrocatalytic mechanism of a-TiO2-x/TiC is further revealed by density functional theory calculations.

15.
New Phytol ; 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34254312

RESUMO

Plants absorb sulfur from the environment and assimilate it into suitable forms for the biosynthesis of a broad range of molecules. Although the biochemical pathway of sulfur assimilation is known, how genetic differences contribute to natural variation in sulfur assimilation remains poorly understood. Here, using genome-wide association study (GWAS), we uncovered a single-nucleotide polymorphism (SNP) variant in the sulfite reductase (SiR) gene that was significantly associated with SiR protein abundance in a maize natural association population. We also demonstrated that the nonsynonymous C to G base change at SNP69 may repress translational activity by altering mRNA secondary structure, which leads to reduction in ZmSiR protein abundance and sulfur assimilation activity. Population genetic analyses showed that the SNP69C allele was likely a variant occurring after the initial maize domestication and accumulated with the spread of maize cultivation from tropical to temperate regions. This study provides the first evidence that genetic polymorphisms in the exon of ZmSiR could influence the protein abundance through a post-transcriptional mechanism and in part contribute to natural variation in sulfur assimilation. These findings provide a prospective target to improve maize varieties with proper sulfur nutrient levels assisted by molecular breeding and engineering.

17.
Aging (Albany NY) ; 13(undefined)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34292876

RESUMO

Agomelatine is a non-selective melatonin receptor agonist and an atypical antidepressant with anti-inflammatory, neuroprotective, and cardioprotective effects. The renin-angiotensin system modulates blood pressure and vascular homeostasis. Angiotensin II (Ang II) and its receptor Ang II type I receptor (AT1R) are recognized as contributors to the pathogenesis of cardiovascular and cardiometabolic diseases, including diabetes, obesity, and atherosclerosis. The recruitment and attachment of monocytes to the vascular endothelium is a major event in the early stages of atherosclerosis and other cardiovascular diseases. In the present study, we demonstrate that agomelatine reduced Ang II-induced expression of AT1R while significantly inhibiting the attachment of monocytes to endothelial cells induced by Ang II and mediated by ICAM-1 and VCAM-1. Additionally, Ang II inhibited the expression of the chemokines CXCL1, MCP-1, and CCL5, which are critical in the process of immune cell recruitment and invasion. Agomelatine also suppressed the expression of TNF-α, IL-8, and IL-12, which are proinflammatory cytokines that promote endothelial dysfunction and atherogenesis. Importantly, we demonstrate that the inhibitory effect of agomelatine against the expression of adhesion molecules is mediated through the downregulation of Egr-1 signaling. Together, our findings provide evidence of a novel mechanism of agomelatine that may be practicable in the treatment and prevention of cardiovascular diseases.

18.
Artigo em Inglês | MEDLINE | ID: mdl-34291427

RESUMO

Salinity fluctuations have severe impacts on sea cucumbers and therefore important consequences in sea cucumber farming. The responses of sea cucumbers to salinity changes are reflected in the expression profiles of multiple genes and non-coding RNAs (ncRNAs). The microRNA (let-7) which is a developmental regulator, the ion transporter gene sodium potassium ATPase gene (NKAα), and the long ncRNA lncRNA001074 were previously shown to be involved in responses to salinity changes in various marine species. To better understand the relationship between ncRNAs and target genes, the let-7/NKAα/lncRNA001074 predicted interaction was investigated in this study using luciferase reporter assays and gene knockdowns in the sea cucumber Apostichopus japonicus. The results showed that NKAα was the target gene of let-7 and NKAα expression levels were inversely correlated with let-7 expression based on the luciferase reporter assays and western blots. The let-7 abundance was negatively regulated by lncRNA001074 and NKAα both in vitro and in vivo. Knockdown of lncRNA001074 led to let-7 overexpression. These results demonstrated that lncRNA001074 binds to the 3'-UTR binding site of let-7 in a regulatory manner. Furthermore, the expression profiles of let-7, NKAα, and lncRNA001074 were analyzed in sea cucumbers after the knockdown of each of these genes. The results found that lncRNA001074 competitively bound let-7 to suppress NKAα expression under low salinity conditions. The downregulation of let-7, in conjunction with the upregulation of lncRNA001074 and NKAα, may be essential for the response to low salinity change in sea cucumbers. Therefore, the dynamic balance of the lncRNA001074, NKAα, and let-7 network might be a potential response mechanism to salinity change in sea cucumbers.

19.
Pharmacoeconomics ; 39(8): 901-912, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34195967

RESUMO

BACKGROUND: Atypical hemolytic uremic syndrome is a rare disease caused by complement dysregulation that can lead to progressive kidney damage or death if untreated. Owing to its rarity, the impact of atypical hemolytic uremic syndrome and available therapies (eculizumab and ravulizumab) on patients' health-related quality of life is difficult to describe, but such data are required for an economic evaluation. OBJECTIVE: The objective of this study was to estimate utility values for atypical hemolytic uremic syndrome-related attributes in five countries for an economic evaluation. METHODS: Using discrete choice experiment surveys, key atypical hemolytic uremic syndrome-related attributes (life expectancy, administration frequency, risk of meningitis, need for hospitalization, and risk of kidney impairment) were evaluated in adult general population samples from Australia, Canada, the Netherlands, Sweden, and the UK. Survey choice sets were constructed using a published orthogonal array. A mixed-effects logit model estimated preference strength for each attribute. Utilities were estimated using marginal substitution rates between overall survival and other attributes, weighted against average life expectancy. RESULTS: Across all countries (N = 2382), utility weights revealed a consistent pattern: participants were averse to the risk of kidney impairment (disutility/utility weight range: -0.185 to -0.158), risk of meningitis (-0.041 to -0.032), and the need for hospitalization (-0.063 to -0.048), but preferred 8-weekly vs 2-weekly infusions over 1 h (0.013-0.039). CONCLUSIONS: Although all attributes played a role in determining treatment preferences, the largest drivers were life expectancy and risk of kidney impairment. Participants favored 8-weekly dosing (corresponding to ravulizumab administration frequency) vs 2-weekly dosing. The discrete choice experiment was designed such that estimated (dis)utility weights can be used in future cost-effectiveness models in atypical hemolytic uremic syndrome.

20.
Cell Death Dis ; 12(7): 678, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226501

RESUMO

Oncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-ß-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

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