Enhancing the Response Rate to Recombinant Uricases in Patients with Gout.
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ABSTRACT:
SUBMITTER: Schlesinger N
PROVIDER: S-EPMC8938732 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AIMS:The primary aim of this research was to predict the allopurinol maintenance doses required to achieve the target plasma urate of ?0.36 mmol l(-1) . METHODS:A population analysis was conducted in nonmem using oxypurinol and urate plasma concentrations from 133 gout patients. Maintenance dose predictions to achieve the recommended plasma urate target were generated. RESULTS:The urate response was best described by a direct effects model. Renal function, diuretic use and body size were found to be significant covariates. Dose requirements increased approximately 2-fold over a 3-fold range of total body weight and were 1.25-2 fold higher in those taking diuretics. Renal function had only a modest impact on dose requirements. CONCLUSIONS:Contrary to current guidelines, the model predicted that allopurinol dose requirements were determined primarily by differences in body size and diuretic use. A revised guide to the likely allopurinol doses to achieve the target plasma urate concentration is proposed.
| S-EPMC4833152 | biostudies-literature
Project description:Proteins that contain disulfide bonds mainly mature in the oxidative environment of the eukaryotic endoplasmic reticulum or the periplasm of Gram-negative bacteria. In E. coli, disulfide bond containing recombinant proteins are often targeted to the periplasm by an N-terminal signal peptide that is removed once it passes through the Sec-translocon in the cytoplasmic membrane. Despite their conserved targeting function, signal peptides can impact recombinant protein production yields in the periplasm, as can the production rate. Here, we present a combined screen involving different signal peptides and varying production rates that enabled the identification of more optimal conditions for periplasmic production of recombinant proteins with disulfide bonds. The data was generated from two targets, a single chain antibody fragment (BL1) and human growth hormone (hGH), with four different signal peptides and a titratable rhamnose promoter-based system that enables the tuning of protein production rates. Across the screen conditions, the yields for both targets significantly varied, and the optimal signal peptide and rhamnose concentration differed for each protein. Under the optimal conditions, the periplasmic BL1 and hGH were properly folded and active. Our study underpins the importance of combinatorial screening approaches for addressing the requirements associated with the production of a recombinant protein in the periplasm.
| S-EPMC6664373 | biostudies-literature
Project description:INTRODUCTION:Reported adherence to urate-lowering therapy (ULT) in gout varies widely (17%-83.5%). Variability may partly be due to different adherence measurement methods. This review aimed to quantify ULT adherence in adult patients with gout. METHODS:This analysis examined studies in PubMed, Web of Science, CNKI Scholar and WanFang databases from inception to January 2017. Papers were selected by inclusion and exclusion criteria in the context. Random-effect meta-analysis estimated adherence. RESULTS:22 studies were found by the inclusion criteria, which involved 1?37?699 patients with gout. Four ways to define adherence were reported. Meta-analysis revealed that the overall adherence rate was 47% (95% CI 42% to 52%, I2=99.7%). Adherence rate to ULT was 42% (95% CI 37% to 47%, I2=99.8%) for prescription claims, 71% (95% CI 63% to 79%) for pill count, 66% (95% CI 50% to 81%, I2=86.3%) for self-report and 63% (95% CI 42% to 83%, I2=82.9%) for interview, respectively. The influential factor on adherence rate was country of origin. CONCLUSIONS:Among adult patients with gout, overall adherence rate to ULT was as low as 47%, which suggested that clinicians should pay more attention to medication adherence in patients with gout to effectively improve adherence to ULT.
| S-EPMC5898304 | biostudies-literature
Project description:Overall aim of this study was to investigate the role of up-regulated genes in the generation of cellular stress response that is triggered upon induction of recombinant protein synthesis. Up-regulated genes identified previously by transcriptomic analysis, were knocked out from the host genome and their impact on cellular health and expression capabilities was analyzed. Transcriptomic profiling of the top performing double knock out (∆(elaA+cysW) having significantly higher protein expression levels was compared with the control to demonstrate the ability of this knock-out strain to counter cellular stress.
2020-12-21 | GSE108442 | GEO
Project description:Immunotherapy is a potential way to save the lives of patients with bladder cancer, but it only benefits approximately 20% of them. A total of 4,028 bladder cancer patients were collected for this study. Unsupervised non-negative matrix factorization and the nearest template prediction algorithms were employed for the classification. We identified the immune and non-immune classes from The Cancer Genome Atlas Bladder Urothelial Carcinoma (TCGA-BLCA) training cohort. The 150 most differentially expressed genes between these two classes were extracted, and the classification reappeared in 20 validation cohorts. For the activated and exhausted subgroups, a stromal activation signature was assessed by the NTP algorithm. Patients in the immune class showed highly enriched signatures of immunocytes, while the exhausted subgroup also exhibited activated transforming growth factor (TGF)-β1, and cancer-associated extracellular matrix signatures. Patients in the immune-activated subgroup showed a lower genetic alteration and better overall survival. Anti-PD-1/PD-L1 immunotherapy was more beneficial for the immune-activated subgroup, while immune checkpoint blockade therapy plus a TGF-β inhibitor or an EP300 inhibitor might achieve greater efficacy for patients in the immune-exhausted subgroup. Novel immune molecular classifier was identified for the innovative immunotherapy of patients with bladder cancer.
| S-EPMC7900642 | biostudies-literature
Project description:Background:One common ATP-binding cassette subfamily G member 2 (ABCG2) gene variant, which is encoded by the single nucleotide polymorphism (SNP) rs2231142, was identified to take an essential part in gouty arthritis. However, the relationship between rs2231142, gout comorbidities and therapeutic effect of allopurinol in Chinese Han male population is still unclear. Wherefore, this study explored into the association between ABCG2 SNP rs2231142 affecting common comorbidities and the therapeutic effect of allopurinol in Chinese Han male gout patients. Results:ABCG2 SNP rs2231142 and the gout comorbidities including nephrolithiasis and CKD were associated (P?=?0.014 and P?=?0.026). Group CKD stage?=?1 were significantly different from those in group CKD stage?2 regarding genotypes of ABCG2 gene polymorphism, while they were not significantly different from those in group CKD stage?3. Meanwhile, the genotypes of rs2231142 and allopurinol response were not significantly associated (P?=?0.588). Conclusions:ABCG2 rs2231142 may predict the risk of kidney comorbidities for Chinese Han male gout patients, but not allopurinol response.
| S-EPMC6651898 | biostudies-literature
Project description:BackgroundThe conventional one-size-fits-all approach has been criticized for almost all drugs used especially for chronic diseases, including gout. The present study was aimed to explore the need of individualization and optimization of the dose of anti-gout medications among gout patients.MethodsCross-sectional study was carried out among 384 randomly selected new gout patients visiting two gout treatment centers at Lalitpur Metropolitan City, Nepal and who were taking antigout medications. Patients not taking anti-gout medications and not showing willingness to participate were excluded. The eGFR was calculated with the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation (2009). Doses to be individualized were decided based on the Renal Drug Handbook and verified with the BNF 80. Data were analyzed via R 4.0.3 by applying the multinomial logistic regression to analyze statistical significance of risk with various predictors, and considering a p-value <0.05 statistically significant. Comorbidities were coded as per the ICD-11 coding and medicines were coded according to the WHO Guidelines for ATC classification and DDD assignment 2020.ResultsThe high risk of progression to CKD increased in the age range 54-63 and ≥84 years by 17.77 and 43.02 times, respectively. Also, high risk increased by 29.83 and 20.2 times for the overweight and the obese respectively. Aceclofenac 100mg was prescribed for maximum patients (30.5%). Need of dose individualization was realized in 30 patients, with maximum (7) in case of etoricoxib 90mg. Various glucocorticoids were prescribed for 36.9% patients, out of whom 3.8%required dose individualization and 15.9% patients with xanthine oxidase inhibitors, out of whom 1.3% required dose individualization.ConclusionThirty cases required dose individualization, which was although minimal but could have meaningful impact on the clinical success of the individual patient. Based on the recommendation on dose individualization, those patients could be optimized on their therapy on future follow ups.
| S-EPMC8448378 | biostudies-literature
Project description:ImportanceGout is associated with cardiovascular diseases. The temporal association between gout flares and cardiovascular events has not been investigated.ObjectiveTo investigate whether there is a transient increase in risk of cardiovascular events after a recent gout flare.Design, setting, and participantsA retrospective observational study was conducted using electronic health records from the Clinical Practice Research Datalink in England between January 1, 1997, and December 31, 2020. A multivariable nested case-control study was performed among 62 574 patients with gout, and a self-controlled case series, adjusted for season and age, was performed among 1421 patients with gout flare and cardiovascular event.ExposuresGout flares were ascertained using hospitalization, primary care outpatient, and prescription records.Main outcomes and measuresThe primary outcome was a cardiovascular event, defined as an acute myocardial infarction or stroke. Association with recent prior gout flares was measured using adjusted odds ratios (ORs) with 95% CIs in a nested case-control study and adjusted incidence rate ratios (IRRs) with 95% CIs in a self-controlled case series.ResultsAmong patients with a new diagnosis of gout (mean age, 76.5 years; 69.3% men, 30.7% women), 10 475 patients with subsequent cardiovascular events were matched with 52 099 patients without cardiovascular events. Patients with cardiovascular events, compared with those who did not have cardiovascular events, had significantly higher odds of gout flare within the prior 0 to 60 days (204/10 475 [2.0%] vs 743/52 099 [1.4%]; adjusted OR, 1.93 [95% CI, 1.57-2.38]) and within the prior 61 to 120 days (170/10 475 [1.6%] vs 628/52 099 [1.2%]; adjusted OR, 1.57 [95% CI, 1.26-1.96]). There was no significant difference in the odds of gout flare within the prior 121 to 180 days (148/10 475 [1.4%] vs 662/52 099 [1.3%]; adjusted OR, 1.06 [95% CI, 0.84-1.34]). In the self-controlled case series (N = 1421), cardiovascular event rates per 1000 person-days were 2.49 (95% CI, 2.16-2.82) within days 0 to 60; 2.16 (95% CI, 1.85-2.47) within days 61 to 120; and 1.70 (95% CI, 1.42-1.98) within days 121 to 180 after a gout flare, compared with cardiovascular event rates of 1.32 (95% CI, 1.23-1.41) per 1000 person-days within the 150 days before or the 181 to 540 days after the gout flare. Compared with 150 days before or the 181 to 540 days after a gout flare, incidence rate differences for cardiovascular events were 1.17 (95% CI, 0.83-1.52) per 1000 person-days, and adjusted IRRs were 1.89 (95% CI, 1.54-2.30) within days 0 to 60; 0.84 (95% CI, 0.52-1.17) per 1000 person-days and 1.64 (95% CI, 1.45-1.86) within days 61 to 120; and 0.38 (95% CI, 0.09-0.67) per 1000 person-days and 1.29 (95% CI, 1.02-1.64) within days 121 to 180 after a gout flare.Conclusions and relevanceAmong individuals with gout, those who experienced a cardiovascular event, compared with those who did not experience such an event, had significantly higher odds of a recent gout flare in the preceding days. These findings suggest gout flares are associated with a transient increase in cardiovascular events following the flare.
| S-EPMC9346550 | biostudies-literature
Project description:To determine the expression profile and clinical significance of long non-coding RNAs (lncRNAs) in peripheral blood mononuclear cells (PBMCs) of patients with primary gout and healthy control subjects. Human lncRNA microarrays were used to identify the differentially expressed lncRNAs and mRNAs in primary gout (n=6) and healthy subjects (n=6). Bioinformatics analyses were performed to predict the roles of differently expressed lncRNAs and mRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to validate the results in 64 gout patients, and 32 healthy control subjects (HC). The microarray analysis identified 1479 differentially expressed lncRNAs (879 up-regulated and 600 down-regulated), 862 differentially expressed mRNAs (390 up-regulated and 472 down-regulated) in primary gout (fold change>2, P<0.05), respectively. The bioinformatic analysis indicated that the differentially expressed lncRNAs regulated the abnormally expressed mRNAs, which were involved in the pathogenesis of gout through several different pathways. Significant association was observed between these lncRNAs and the Clinical inflammation indicators and lipid metabolism indicators. Our results provide novel insight into the mechanisms of primary gout, and reveal that ENST00000566457 and NR-026756 could effectively discriminate the gout group and the healthy control groups.
2020-11-03 | GSE160170 | GEO
Project description:AimMedication non-adherence influences outcomes of therapies for chronic diseases. Allopurinol is a cornerstone therapy for patients with gout; however, non-adherence to allopurinol is prevalent in Singapore and limits its effectiveness. Between 2008-2010, an adherence-enhancing program was implemented at the rheumatology division of a public tertiary hospital. The cost-effectiveness of this program has not been fully evaluated. With healthcare resources being finite, the value of investing in adherence-enhancing interventions should be ascertained. This study aims to evaluate the cost-effectiveness of this adherence-enhancing program to inform optimal resource allocation toward better gout management.MethodAdopting a real-world data approach, we utilized patient clinical and financial records generated in their course of routine care. Intervention and control groups were identified in a standing database and matched on nine risk factors through propensity score matching. Cost and effect data were followed through 1-2 years. A decision tree was developed in TreeAge using a societal perspective. Deterministic and probabilistic sensitivity analyses were performed to assess parameter uncertainty.ResultsAt an assumed willingness-to-pay threshold of $50 000 USD ($70 000 SGD) per quality-adjusted life year (QALY), the intervention had an 85% probability of being cost-effective compared to routine care. The incremental cost-effectiveness ratio was $12 866 USD per QALY for the base case and ranged from $4 139 to $21 593 USD per QALY in sensitivity analyses.ConclusionThe intervention is cost-effective in the short-term, although its long-term cost-effectiveness remains to be evaluated.
| S-EPMC6590285 | biostudies-literature