The value of carcinoembryonic antigen stage in staging, prognosis, and management of colorectal cancer: results from two cohort studies

BackgroundCombining the carcinoembryonic antigen (CEA) level (C stage) with TNM staging can provide a more comprehensive prognostic assessment of colorectal cancer (CRC). However, the clinical value of incorporating CEA status into the TNM staging system needs to be evaluated.MethodsWe used the SEER database (N = 49,350) and a retrospective cohort from China (N = 1,440). A normal CEA level was staged as C0 and an elevated CEA level was staged as C1. Restricted cubic spline analysis was used to examine the dose-response relationship between the CEA level and survival. The Kaplan-Meier method with the log-rank test was used to plot survival curves. Multivariable Cox proportional hazards regression models with forward stepwise variable selection were used to estimate the hazard ratios and 95% confidence intervals.ResultsPatients with C1 were more likely to have advanced disease than those with C0. CEA on a continuous scale was positively associated with mortality risk. Compared with patients with C0 stage, those with C1 stage had significantly lower survival rates. In the SEER dataset, C1 was independently associated with poor prognosis in patients with CRC, with an approximately 70% increased risk of mortality. Patients with C1 stage had significantly lower survival than those with C0 stage at all clinical stages. Incorporating the C stage into the TNM staging refined the prediction of prognosis of patients with CRC, with a gradual decline in prognosis from stage I C0 to stage IV C1. A similar pattern was observed in the present retrospective cohort study. At each lymph node stage, patients with C1 had significantly lower 5-year survival rates than patients with C0. Compared with lymph node positivity, CEA positivity may have a stronger correlation with a worse prognosis.ConclusionOur findings not only validated the independent prognostic significance of CEA in CRC but also demonstrated its enhanced prognostic value when combined with TNM staging. Our study provides evidence supporting the inclusion of C stage in the TNM staging system

Serum creatinine/cystatin C ratio as a prognostic indicator for patients with colorectal cancer

BackgroundThis study aimed to explore the relationship between creatinine/cystatin C ratio and progression-free survival (PFS) and overall survival (OS) in colorectal cancer (CRC) patients undergoing surgical treatment.MethodsA retrospective analysis was conducted on 975 CRC patients who underwent surgical resection from January 2012 to 2015. Restricted three-sample curve to display the non-linear relationship between PFS/OS and creatinine-cystatin C ratio. Cox regression model and Kaplan-Meier method were used to evaluate the effect of the creatinine-cystatin C ratio on the survival of CRC patients. Prognostic variables with p-value ≤0.05 in multivariate analysis were used to construct prognostic nomograms. The receiver operator characteristic curve was used to compare the efficacy of prognostic nomograms and the traditional pathological stage.ResultsThere was a negative linear relationship between creatinine/cystatin C ratio and adverse PFS in CRC patients. Patients with low creatinine/cystatin C ratio had significantly lower PFS/OS than those with high creatinine/cystatin C ratio (PFS, 50.8% vs. 63.9%, p = 0.002; OS, 52.5% vs. 68.9%, p < 0.001). Multivariate analysis showed that low creatinine/cystatin C ratio was an independent risk factor for PFS (HR=1.286, 95%CI = 1.007–1.642, p=0.044) and OS (HR=1.410, 95%CI=1.087–1.829, p=0.010) of CRC patients. The creatinine/cystatin C ratio-based prognostic nomograms have good predictive performance, with a concordance index above 0.7, which can predict the 1–5-year prognosis.ConclusionCreatinine/cystatin C ratio may be an effective prognostic marker for predicting PFS and OS in CRC patients, aid in pathological staging, and along with tumour markers help in-depth prognostic stratification in CRC patients

Effect of Sodium-Glucose Co-transporter 2 Inhibitors on Bone Metabolism and Fracture Risk

The effect of anti-diabetic medications on bone metabolism has received increasing attention, considering that type 2 diabetes mellitus is a common metabolic disorder with adverse effects on bone metabolism. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are novel anti-diabetic medications that prevent glucose resorption at the proximal convoluted tubules in the kidney, increasing urinary glucose excretion, and decreasing the blood glucose level. The superiority of SGLT2 inhibitors shows in reducing the glucose level independent of insulin secretion, lowering the risk of hypoglycemia, and improving cardiovascular outcomes. SGLT2 inhibitors have been associated with genital mycotic infections, increased risk of acute kidney injury, dehydration, orthostatic hypotension, and ketoacidosis. Moreover, the effect of SGLT2 inhibitors on bone metabolism and fracture risk has been widely taken into consideration. Our review summarizes the results of current studies investigating the effects of SGLT2 inhibitors on bone metabolism (possibly including increased bone turnover, disrupted bone microarchitecture, and reduced bone mineral density). Several mechanisms are probably involved, such as bone mineral losses due to the disturbed calcium and phosphate homeostasis, as confirmed by an increase in fibroblast growth factor 23 and parathyroid hormone levels and a decrease in 1,25-dihydroxyvitamin D levels. SGLT2 inhibitors might indirectly increase bone turnover by weight loss. Lowering the blood glucose level might ameliorate bone metabolism impairment in diabetes. The effect of SGLT2 inhibitors on bone fractures remains unclear. Evidence indicating the direct effect of SGLT2 inhibitors on fracture risk is lacking and increased falls probably contribute to fractures

Association Between Bone Mineral Density, Bone Turnover Markers, and Serum Cholesterol Levels in Type 2 Diabetes

Purpose: The association between bone mineral density (BMD), bone turnover markers, and serum cholesterol in healthy population has already been proved. However, in patients with type 2 diabetes mellitus (T2D), it has not been adequately analyzed. In this study, we investigated the correlation between BMD, bone turnover markers, and serum cholesterol levels in people with T2D.Methods: We enrolled 1,040 men and 735 women with T2D from Zhongshan Hospital between October 2009 and January 2013. Their general condition, history of diseases and medication, serum markers, and BMD data were collected. We used logistic regression analysis to identify the association between serum cholesterol levels and BMD as well as bone turnover markers.Results: In multivariate regression analysis, we observed that in men with T2D, high high-density lipoprotein-cholesterol and total cholesterol levels were significantly associated with low total lumbar, femur neck, and total hip BMD, while low-density lipoprotein-cholesterol level was only inversely associated with total lumbar and femur neck BMD. Total cholesterol and low-density lipoprotein-cholesterol levels were also negatively associated with osteocalcin, procollagen type I N-terminal propeptide, and β-crosslaps. In women with T2D, high-density lipoprotein-cholesterol level was observed to be negatively correlated with total lumbar, femur neck, and total hip BMD, while total cholesterol and low-density lipoprotein-cholesterol levels were only associated with BMD at the total lumbar. Furthermore, total cholesterol was also negatively associated with osteocalcin, procollagen type I N-terminal propeptide, and β-crosslaps; high-density lipoprotein-cholesterol was only related to osteocalcin and parathyroid hormone, while low-density lipoprotein-cholesterol was only related to β-crosslaps in women.Conclusion: Our study suggests a significantly negative correlation between serum cholesterol levels and BMD in both men and women with T2D. The associations between serum cholesterol levels and bone turnover markers were also observed in T2D patients

The Influence of cis-Regulatory Elements on DNA Methylation Fidelity

It is now established that, as compared to normal cells, the cancer cell genome has an overall inverse distribution of DNA methylation (“methylome”), i.e., predominant hypomethylation and localized hypermethylation, within “CpG islands” (CGIs). Moreover, although cancer cells have reduced methylation “fidelity” and genomic instability, accurate maintenance of aberrant methylomes that underlie malignant phenotypes remains necessary. However, the mechanism(s) of cancer methylome maintenance remains largely unknown. Here, we assessed CGI methylation patterns propagated over 1, 3, and 5 divisions of A2780 ovarian cancer cells, concurrent with exposure to the DNA cross-linking chemotherapeutic cisplatin, and observed cell generation-successive increases in total hyper- and hypo-methylated CGIs. Empirical Bayesian modeling revealed five distinct modes of methylation propagation: (1) heritable (i.e., unchanged) high- methylation (1186 probe loci in CGI microarray); (2) heritable (i.e., unchanged) low-methylation (286 loci); (3) stochastic hypermethylation (i.e., progressively increased, 243 loci); (4) stochastic hypomethylation (i.e., progressively decreased, 247 loci); and (5) considerable “random” methylation (582 loci). These results support a “stochastic model” of DNA methylation equilibrium deriving from the efficiency of two distinct processes, methylation maintenance and de novo methylation. A role for cis-regulatory elements in methylation fidelity was also demonstrated by highly significant (p<2.2×10−5) enrichment of transcription factor binding sites in CGI probe loci showing heritably high (118 elements) and low (47 elements) methylation, and also in loci demonstrating stochastic hyper-(30 elements) and hypo-(31 elements) methylation. Notably, loci having “random” methylation heritability displayed nearly no enrichment. These results demonstrate an influence of cis-regulatory elements on the nonrandom propagation of both strictly heritable and stochastically heritable CGIs

Physiological and Molecular Function of HAP3b in Flowering Time Regulation and Cold Stress Response

Heme-activated proteins (HAPs) are transcription factors that have multiple roles in plant growth and development, such as embryogenesis, flowering time control, and drought tolerance. In the present study I found that HAP3b was also involved in controlling response to cold stress. Transcript profiling and gene expression analyses indicated that HAP3b repressed the CBF3 regulon under normal growth conditions. As a result, plants with HAP3b-overexpressed showed decreased survival rates while plants homozygous for the null allele hap3b showed an improved freezing tolerance compared to wild-type plants. To understand the mechanism of HAP3b in Arabidopsis, i.e. whether it also acts through forming a heterotrimer, the yeast two-hybrid system and the protein coimmunoprecipitation method were used to identify the proteins that could interact with HAP3b. From yeast two-hybrid analyses, it was found that HAP3b could interact with one (At3g14020) of ten HAP2s and all ten HAP5s tested. Further analyses showed that the newly identified HAP2 protein could only interact with two HAP5 proteins, those encoded by At5g63470 and At1g56170. To address whether HAPs also play important roles in major crop plants, HAP3 genes in barley (Hordeum vulgare L.) were identified and characterized. From database sequence analyses, cloning, and sequencing, it was found that barley plants have at least six full-length members in the HAP3 family. Phylogenetic analyses showed that each barley HAP3 was different, forming its own cluster with the HAP3s from other plant species. Each barley HAP3 also showed its own expression pattern in different tissues, at different developmental stages and under various environmental stresses. In particular, TC176294 showed the highest sequence similarity to HAP3b in Arabidopsis and its high expression was associated with flowering. In addition, TC176294 was upregulated by various abiotic stresses and by abscisic acid (ABA). Thus, TC176294 might be a barley ortholog of HAP3b. TC191694 showed the highest sequence similarity to HAP3c and might be a barley ortholog of HAP3c. TC191694 overexpression plants were early flowering compared to HAP3b-overexpression and wild-type plants while overexpression of TC176294 plants were not

Early Warning and Joint Regulation of Water Quantity and Quality in the Daqing River Basin

In the recent decades, the issue of water-resource security of the Daqing River Basin, which is one of the five major rivers in the Haihe River Basin, has become increasingly serious affected by climate change and human activities. In this paper, a dynamic simulation and early warning model of water quantity and quality in this basin based on the SWAT model was constructed to promote the implementation of water environment quality and safety bottom line in the Beijing-Tianjin-Hebei region. The results of the study are as follows: (1) When encountering a once-in-a-century rainstorm, the flood pressure of Zijingguan in the flood season is the highest, with the highest water level reaching 521.23 m, and the overall maximum runoff follows the order of Zijingguan &gt; Fuping &gt; Zhangfang. (2) When the NH3-N emissions are reduced by 37.64~85.10% in each month (based on the level in 2017), the water quality at the outlet of the basin can reach the standard, and the upper limit of NH3-N emissions is 504.5 t/m. (3) The regulation and control scheme seeking to &ldquo;ensure the base flow with standard water quality&rdquo; and &ldquo;optimize NH3-N annual emission&rdquo; is proposed in this paper. The NH3-N concentration at the outlet of all watersheds can reach the standard when the basic runoff of each sub-basin reaches 0.01 to 10.32 m3/s. In addition, concentrating the emission in July, August, and September and reducing the emission intensity of NH3-N in proportion can significantly reduce the monthly average NH3-N concentration (&lt;1.99 mg/L) at the outlet section of the basin

Early Warning and Joint Regulation of Water Quantity and Quality in the Daqing River Basin

In the recent decades, the issue of water-resource security of the Daqing River Basin, which is one of the five major rivers in the Haihe River Basin, has become increasingly serious affected by climate change and human activities. In this paper, a dynamic simulation and early warning model of water quantity and quality in this basin based on the SWAT model was constructed to promote the implementation of water environment quality and safety bottom line in the Beijing-Tianjin-Hebei region. The results of the study are as follows: (1) When encountering a once-in-a-century rainstorm, the flood pressure of Zijingguan in the flood season is the highest, with the highest water level reaching 521.23 m, and the overall maximum runoff follows the order of Zijingguan > Fuping > Zhangfang. (2) When the NH3-N emissions are reduced by 37.64~85.10% in each month (based on the level in 2017), the water quality at the outlet of the basin can reach the standard, and the upper limit of NH3-N emissions is 504.5 t/m. (3) The regulation and control scheme seeking to “ensure the base flow with standard water quality” and “optimize NH3-N annual emission” is proposed in this paper. The NH3-N concentration at the outlet of all watersheds can reach the standard when the basic runoff of each sub-basin reaches 0.01 to 10.32 m3/s. In addition, concentrating the emission in July, August, and September and reducing the emission intensity of NH3-N in proportion can significantly reduce the monthly average NH3-N concentration (<1.99 mg/L) at the outlet section of the basin

Attribution and Sensitivity Analysis of Runoff Variation in the Yellow River Basin under Climate Change

The Yellow River Basin is a typical arid and semi-arid area, which is very sensitive to climate change. In recent years, it has become the area with the greatest shortage of water resources in China. In this study, a new two-way coupling model of land surface and hydrology has been explored to analyze the impacts of climate change and human activities on the runoff. It is of great theoretical and practical significance for making better management countermeasures and strategies to cope with climate change in the Yellow River Basin. The results showed that: (1) the annual average precipitation in the basin was 470.1 mm, which was higher in the lower reaches than in the middle and upper reaches. The annual average temperature is 5.8 &deg;C. The entire basin showed a remarkable warming speed. The annual average pan evaporation is 1067.3 mm showing a downward trend throughout the basin; (2) from 1987 to 2009, the contribution rate of climate change to runoff change has not fluctuated by more than 5%. Since 2010, the precipitation caused by climate factors has increased runoff by 12~15%. The impact of land use change on runoff has been increasing annually. The influence of projects on runoff change was the leading factor of runoff reduction in the Yellow River Basin, with the contribution rate around 50%; and (3) for every 10% decrease in precipitation, the runoff decreases by 13~15.7%. When the temperature rises by 1.0 &deg;C, the runoff decreases by 2.1~4.2%. The runoff in the upper reaches of the Yellow River was most sensitive to precipitation and temperature changes. This showed that the runoff in the plateau and mountainous areas were highly sensitive to climate change