Tumor microenvironment (TME) cells constitute a vital element of tumor tissue. Increasing evidence has elucidated their clinicopathologic significance in predicting outcomes and therapeutic efficacy. ...Nonetheless, no studies have reported a systematic analysis of cellular interactions in the TME. In this study, we comprehensively estimated the TME infiltration patterns of 1,524 gastric cancer patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathologic features of gastric cancer using two proposed computational algorithms. Three TME phenotypes were defined, and the TMEscore was constructed using principal component analysis algorithms. The high TMEscore subtype was characterized by immune activation and response to virus and IFNγ. Activation of transforming growth factor β, epithelial-mesenchymal transition, and angiogenesis pathways were observed in the low TMEscore subtype, which are considered T-cell suppressive and may be responsible for significantly worse prognosis in gastric cancer hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.33
0.54;
< 0.001. Multivariate analysis revealed that the TMEscore was an independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (IMvigor210 cohort: HR, 0.63; 95% CI, 0.46-0.89;
= 0.008; GSE78220 cohort: HR, 0.25; 95% CI, 0.07-0.89;
= 0.021). Depicting a comprehensive landscape of the TME characteristics of gastric cancer may, therefore, help to interpret the responses of gastric tumors to immunotherapies and provide new strategies for the treatment of cancers.
Tumour-infiltrating immune cells are a source of important prognostic information for patients with resectable colon cancer. We developed a novel immune model based on systematic assessments of the ...immune landscape inferred from bulk tumor transcriptomes of stage I–III colon cancer patients. The “Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT)” algorithm was used to estimate the fraction of 22 immune cell types from six microarray public datasets. The random forest method and least absolute shrinkage and selection operator model were then used to establish immunoscores for diagnosis and prognosis. By comparing immune cell compositions in samples of 870 colon cancer patients and 70 normal controls, we constructed a diagnostic model, designated the diagnostic immune risk score (dIRS), that showed high specificity and sensitivity in both the training area under the curve (AUC) = 0.98,
p
< 0.001 and validation (AUC 0.96,
p
< 0.001) sets. We also established a prognostic immune risk score (pIRS) that was found to be an independent prognostic factor for relapse-free survival in every series (training: HR 2.23; validation: HR 1.65; entire: HR 2.01;
p
< 0.001 for all), which showed better prognostic value than TNM stage. In addition, integration of the pIRS with clinical characteristics in a composite nomogram showed improved accuracy of relapse risk prediction, providing a higher net benefit than TNM stage, with well-fitted calibration curves. The proposed dIRS and pIRS models represent promising novel signatures for the diagnosis and prognosis prediction of colon cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
An increasing number of randomized controlled trials (RCTs) have measured the impact of interventions on work productivity loss. Productivity loss outcome is inflated at zero and ...max loss values. Our study was to compare the performance of five commonly used methods in analysis of productivity loss outcomes in RCTs.
Methods
We conducted a simulation study to compare Ordinary Least Squares (OLS), Negative Binominal (NB), two-part models (the non-zero part following truncated NB distribution or gamma distribution) and three-part model (the middle part between zero and max values following Beta distribution). The main number of observations each arm, N
obs
, that we considered were 50, 100 and 200. Baseline productivity loss was included as a covariate.
Results
All models performed similarly well when baseline productivity loss was set at the mean value. When baseline productivity loss was set at other values and N
obs
= 50 with ≤5 subjects having max loss, two-part models performed best if the proportion of zero loss> 50% in at least one arm and otherwise, OLS performed best. When N
obs
= 100 or 200, the three-part model performed best if the two arms had equal scale parameters for their productivity loss outcome distributions between zero and max values.
Conclusions
Our findings suggest that when treatment effect at any given values of one single covariate is of interest, the model selection depends on the sample size, the proportions of zero loss and max loss, and the scale parameter for the productivity loss outcome distribution between zero and max loss in each arm of RCTs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Middle-aged and older adults are more likely to suffer from chronic conditions, which can increase their need for both formal and informal care. This study seeks to assess and compare the ...extent to which the use of formal and informal care is attributed to different chronic conditions among middle-aged and older women and men in Canada. Methods We used baseline data from the Canadian Longitudinal Study on Aging (CLSA). Outcomes of interest were the number of hours of formal care and informal care received during the past 12 months. All chronic conditions were first classified according to existing classification frameworks. If total formal and informal care hours for a particular condition differed greatly from other conditions, we considered it as a stand-alone classification. We used a two-part model consisting of a logistic regression for the probability of receiving formal/informal care and a generalized linear model for the hours of formal/informal care for those who received care. Results Our final analytic sample was 23,206 women and 22,903 men who did not have missing data. Among the 16 chronic conditions considered, multiple sclerosis, memory problems, Parkinsonism, and stroke had the greatest average marginal effects on overall hours of formal care among women (53.07, 13.95, 9.13 and 8.14 incremental hours annually, respectively) and men (152.17, 8.13, 13.95 and 6.00 incremental hours). Similarly, the average marginal effects of these four conditions on informal care were the greatest (77.78, 29.52, 26.18 and 34.95 incremental hours for women and 133.94, 34.99, 104.86 and 17.85 incremental hours for men). Conclusions Chronic conditions, especially multiple sclerosis, Parkinsonism, memory problems, and stroke, are associated with substantial time of formal and informal care in middle-aged and older women and men. Findings will help decision-makers assess the potential impact of chronic disease prevention and management programs in an aging population.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Osimertinib was initially approved for T790M-positive non-small cell lung cancer (NSCLC) and, more recently, for first-line treatment of
-mutant NSCLC. However, resistance mechanisms to osimertinib ...have been incompletely described.
Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients.
In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months,
= 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months,
= 0.02).
Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients.
.
Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset ...with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.
Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are ...due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.
One source of productivity loss due to illness is the reduced “quantity” or “quality” of labor input while working, often referred to as presenteeism. Illness-related presenteeism has been found to ...be potentially more costly than absenteeism. To value presenteeism, existing methods use wages as a proxy for marginal productivity at the firm level. However, wage may not equal marginal productivity in some scenarios. One instance is when a job involves team production and perfect substitutes for workers are not readily available. Using a Canadian linked employer-employee survey (2001–2005), we test whether relative wage equals relative marginal productivity among team workers and non-team workers with different frequencies of presenteeism (reduction at work due to illness). For the pooled cross-sectional estimates (2001, 2003, 2005) we obtain 13,755 observations with 6842 unique workplaces. There are 6490 observations for the first differences estimates from the odd years and 5263 observations for the first differences estimates from 2001 to 2002 and 2003 to 2004. We find that in both small and large firms, team workers with frequent reductions at work are less productive but earn similarly compared with non-team workers without reductions. We also find that in small firms, workers with occasional work reductions are more productive than workers without reductions, but the reverse is true in large firms. The study findings partially support the literature stating that productivity loss resulting from employee presenteeism could exceed wages if team work is involved.
•Wages are commonly used as a proxy for marginal productivity to value presenteeism.•Employee self-reported presenteeism is linked to employers' production and payroll.•We test the equality of wage and marginal productivity with regard to presenteeism.•Productivity losses due to frequent presenteeism of team workers exceed wages.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mycotoxins are toxic compounds that pose a serious threat to animal health and food safety. Therefore, there is an urgent need for safe and efficient methods of detoxifying mycotoxins. As ...biotechnology has continued to develop, methods involving biological enzymes have shown great promise. Biological enzymatic methods, which can fundamentally destroy the structures of mycotoxins and produce degradation products whose toxicity is greatly reduced, are generally more specific, efficient, and environmentally friendly. Mycotoxin-degrading enzymes can thus facilitate the safe and effective detoxification of mycotoxins which gives them a huge advantage over other methods.
This article summarizes the newly discovered degrading enzymes that can degrade four common mycotoxins (aflatoxins, zearalenone, deoxynivalenol, and ochratoxin A) in the past five years, and reveals the degradation mechanism of degrading enzymes on four mycotoxins, as well as their positive effects on animal production. This review will provide a theoretical basis for the safe treatment of mycotoxins by using biological enzyme technology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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