Prognostic impact of the red cell distribution width in esophageal cancer patients: A systematic review and meta-analysis
INTRODUCTION
Esophageal cancer (EC) is one of the most common digestive malignancies worldwide[1,2], ranking as the fourth leading cause of cancer-related death[3] and leading to approximately 400000 deaths in 2012[4]. The incidence of EC varies widely across different countries and regions[5]. According to the latest national statistics,EC is the fourth most common malignant tumor type in China[1], with cancer-related morbidity and mortality rates of 11.1% and 13.3%, respectively, in 2015,which has emerged as a severe public health problem,particularly in some high-risk rural areas[6]. However, in 2012, the cancer-related morbidity and mortality rates of EC (3.41% and 2.98%, respectively) were lower in North America and Europe than those in China[4].
EC is a highly aggressive digestive malignancy characterized by rapid growth and early metastasis.The rate of distant metastasis in EC patients is as high as 20%-30% at the time of initial diagnosis[7]. Despite the progress in radical resection and adjuvant therapy(radiation and chemotherapy), the 5-year overall survival(OS) rate of patients with EC remains approximately 20% in China[8], emphasizing an urgent need to detect effective prognostic biomarkers which could guide personalized therapeutic strategy for EC patients[9,10].
In recent years, accumulating evidence has shown that systemic inflammatory responses are closely associated with tumor initiation, progression and invasion[11-14]. Therefore, a variety of inflammatory indicators have been explored to assess their potential prognostic roles in various cancers. One such marker is the red blood cell distribution width (RDW), which is defined as the coefficient of variation in the red blood cell size. An elevated RDW indicates anisocytosis, which is considered as the basis for the clinical diagnosis of iron de ficiency anemia[15]. However, fluctuations in the RDW have recently been reported as involved in many other pathophysiological conditions. For example, an elevated RDW is strongly associated with chronic inflammation,poor nutritional status, and age-associated diseases,which is indicative of changes in erythropoiesis. In addition, a number of studies have demonstrated a significant correlation between RDW and conventional inflammatory parameters, such as the C-reactive protein, interleukin-6 and tumor necrosis factor-α levels and erythrocyte sedimentation rate. Cancer has been revealed to be associated with chronic inflammation, and the latter is a key determinant of disease progression and survival in various cancers[16,17]. In 2007, Felker et al[18]found that RDW could serve as an independent predictor of morbidity and mortality in heart failure. Recent studies have revealed that RDW is associated with prognosis in several types of cancer, such as lung cancer[19], prostate cancer[20] and EC[21].
RDW is an important complete blood count parameter that is routinely monitored in cancer patients. Several studies conducted in recent years[21-26] have investigated the relationship between EC prognosis and RDW due to the easy accessibility of obtaining blood samples and the low cost of analyzing RDW. However, the results of these studies show some discrepancies, which could be attributed to differences in the study design and relatively small sample sizes. To this end, in the present study, a meta-analysis was performed to identify the correlation between RDW and survival in EC patients.
首先,高校学风建设是一个长久的系统工程,在这个过程中,各种问题层出不穷,这就需要一个不断循环、可时时改进的管理方法来解决新出现的问题。
Table 1 PubMed search strategy
![pagenumber_ebook=79,pagenumber_book=2122](https://qkk.lw71.com/uploads/image/2018/19/c4a764dfb8e7a6c070f61e6954c91134.png)
Number Search items#1 Esophageal Neoplasm.ti,ab#2 esophagus neoplasm.ti,ab#3 esophagus neoplasms.ti,ab#4 cancer of esophagus.ti,ab#5 cancer of the esophagus.ti,ab#6 esophagus cancer.ti,ab#7 esophagus cancers.ti,ab#8 esophageal cancer.ti,ab#9 esophageal cancers.ti,ab#10 esophageal squamous cell cancer.ti,ab#11 ESCC.ti,ab#12 esophageal adenocarcinoma.ti,ab#13 or #1- #12#14 red cell distribution. ti,ab#15 RDW.ti,ab#16 or #14- #15#17 #13 and #16
MATERIALS AND METHODS
This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Data sources and search strategies
A systematic review of studies that evaluated the prognostic value of RDW in EC patients was performed.Four databases were electronically searched: Medline(host: OVID) from 1946 to April 2017; EMBASE (host:OVID) from 1974 to April 2017; and Web of Science and Cochrane Database of Systematic Reviews from 2005 to June 2017. The search terms used in our study were “RDW”, “red cell distribution width with esophageal neoplasm”, “esophagus neoplasm”, “esophagus neoplasms”, “cancer of esophagus”, “cancer of the esophagus”, “esophagus cancer”, “esophagus cancers”,“esophageal cancer”, “esophageal cancers”, “esophageal squamous cell cancer” (ESCC), and “esophageal adenocarcinoma”. Both free text and MeSH terms were used as keywords. The search strategy used for the PubMed database is shown in Table 1, and the presented search strategy was also used for the other electronic databases.
Study selection
28 Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in metaanalyses. Eur J Epidemiol 2010; 25: 603-605 [PMID: 20652370 DOI: 10.1007/s10654-010-9491-z]
刘志芳,胡菊华,卢艳君等研究中明确指出,对CT增强扫描患者采用静脉留置针穿刺能显著提高CT增强成功率,降低造影剂外渗发生率,减少对机体刺激性,确保患者血管顺畅,同时穿刺点紧密贴近患者血管,即便更换体位能加快注射速度,针头不易脱落,从而显著提高注射成功率,因此在临床被广泛应用。
Inclusion and exclusion criteria
Studies that met the following criteria were considered eligible: (1) A study of EC patients who underwent radical esophagectomy; (2) a study of patients with localized disease without distant metastasis; (3) a study of patients without preoperative neoadjuvant therapy; (4)a study of patients without previous antiinflammatory therapies and with available preoperative laboratory outcomes; (5) a study of the association between the preoperative RDW and OS/disease-free survival (DFS)/cancer-specific survival (CSS); and (6) a complete paper published in English. Studies that met the following criteria were excluded: (1) Letters, case reports, reviews or preclinical studies; (2) studies describing a repeated analysis or duplicate data; (3) studies lacking key information for further analysis; and (4) nonhuman studies.
Data extraction
We used predesigned extraction forms for data collection. The following information was extracted from each study: first author’s name, year of publication, country of the patients, research type, number of male/female patients included in the study, pathological types, RDW cut-off value, hazard ratio (HR) of elevated RDW for OS,CSS and DFS with 95% confidence interval (CI) and P-value. Assuming that most of the deaths were related to cancer, in the case of unavailability of OS information,data for CSS were extracted. HRs from multivariable analyses were extracted when available; otherwise, HRs from univariable analyses were extracted or estimated from Kaplan-Meier survival curves as described by Parmar and colleagues[27]. HRs for subgroups were compared de fined by different markers.
Data synthesis and statistical analyses
HRs and the corresponding 95%CIs were directly obtained from each publication. If the values were not directly reported, the values were calculated according to the method described by Parmar and colleagues[27].The meta-analysis was performed with STATA software version 12.0 (STATA Corporation, College Station, TX,United States) to combine the HRs with 95%CIs for categorical data and the weighted mean difference or standardized mean difference with 95%CIs for continuous data. All statistical tests were bilateral, and a P value < 0.05 was considered as statistical significance.If the data were not suitable for pooling, a systematic narrative synthesis of the information was performed,which was presented in the text to understand and to summarize the findings as well as characteristics of the included studies.
![pagenumber_ebook=80,pagenumber_book=2123](https://qkk.lw71.com/uploads/image/2018/19/7f932bf601cec449a95f49b32ec98774.png)
Figure 1 Methodological flow diagram of the meta-analysis.
Heterogeneity analysis
The heterogeneity of the pooled results was assessed through Cochran’s Q test and Higgins I-squared statistic. Significant heterogeneity was identified by P <0.05 and/or I2 > 50%, and the random-effects model(DerSimonian-Laird method) was used to combine the data. Otherwise, the fixed-effects model (Mantel-Haenszel method) was employed. To explore the potential source of heterogeneity among studies, subgroup analyses were performed according to various variables, such as the RDW cut-off value, the patient number in each study,and the study type and quality.
Assessment of study quality
The quality of the included studies was assessed by using the Newcastle-Ottawa quality scale (NOS)[28]. Three aspects, namely, selection, comparability and outcomes,were assessed on this scale, which had a maximum score of 9. Studies with scores ≥ 7 were considered to be of high quality.
Sensitivity analysis
If significant heterogeneity was observed, a sensitivity analysis was performed after data extraction and subgroup analyses. This sensitivity analysis, which included the sequential omission of each study using the “metaninf” STATA command, aimed to validate the findings of this meta-analysis.
Assessment of publication bias
Begg’s funnel plot and Egger’s linear regression test were performed to evaluate publication bias, and a P value of < 0.05 was considered statistically significant.
RESULTS
Search results and study characteristics
Initially, 17 studies were selected from the electronic databases, and 10 studies remained after the removal of duplicates. After reading the titles and/or abstracts,four unrelated studies were excluded, and six fulltext articles[21-26] were further assessed. None of these studies were excluded after thorough review of full-text.These six studies[21-26], which included 3826 patients,were included in this meta-analysis. The detailed search method and a flowchart representing the selection process are shown in Figure 1. These studies included five retrospective studies and one prospective study. The sample sizes varied from 144 to 2396, with a median value of 638. All six studies were conducted in Asian countries. The cut-off values for the RDW ranged from 12.2% to 15.3%. All six studies reported a correlation between RDW and OS/CSS, and two of the studies also investigated the association between RDW and DFS.with patient number ≤ 400, a high RDW was significantly associated with poor OS/CSS in patients with EC.
![pagenumber_ebook=82,pagenumber_book=2125](https://qkk.lw71.com/uploads/image/2018/19/a9702f86614e4279ad59ec2673096d54.png)
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Finally, when the subgroups were stratified by NOS scores (≤ 6 or > 6), heterogeneity was effectively reduced or eliminated after omitting the studies with NOS scores > 6 (I2 = 0.0%, P = 0.876; Supplementary Figure 5), and the corresponding pooled HR was increased (HR= 1.42, 95%CI: 1.09-1.74, P = 0.000; Supplementary Figure 5). Thus, the study quality might be another source of heterogeneity.
![pagenumber_ebook=82,pagenumber_book=2125](https://qkk.lw71.com/uploads/image/2018/19/c7c8ec88e2a3c3217f52383fe631c621.png)
Figure 2 Forest plots of studies evaluating HR with 95%Cl of red cell distribution width for overall survival in esophageal cancer patients. CI: Con fidence interval; HR: Hazard ratio.
![pagenumber_ebook=82,pagenumber_book=2125](https://qkk.lw71.com/uploads/image/2018/19/d5a59c2920f02091952221362f502482.png)
Figure 3 Effect of individual studies on the pooled HR for red cell distribution width and overall survival of esophageal cancer patients. HR: Hazard ratio;RDW: Red cell distribution width.
![pagenumber_ebook=82,pagenumber_book=2125](https://qkk.lw71.com/uploads/image/2018/19/9b3235bd558f28185c1258474904e78b.png)
Figure 4 Forest plots of RDW > 13% vs RDW ≤ 13% evaluating HR with 95%Cl of red cell distribution width for overall survival in esophageal cancer patients. CI: Con fidence interval; HR: Hazard ratio; RDW: Red cell distribution width. 0: RDW > 13%; 1: RDW ≤ 13%.
Publication bias
Begg’s funnel plot and Egger’s linear regression analyses were performed to estimate the potential publication bias in the present meta-analysis. The P values regarding OS/CSS were 0.133 (Begg’s test; Supplementary Figure 6) and 0.005 (Egger’s test; Supplementary Figure 7).Due to the small sample sizes of the included studies,there was significant publication bias in our study, which was also demonstrated by the funnel plot (Funnel plot;Supplementary Figure 8). Therefore, publication bias might be another source of heterogeneity.
DISCUSSION
To the best of our knowledge, this study constitutes the first meta-analysis investigating the prognostic value of the RDW in EC. The most notable finding is that RDW is not associated with the prognosis of EC patients, including both OS/CSS and DFS. This novel finding is inconsistent with previous conclusions regarding the prognostic value of RDW in EC. Significant heterogeneity was observed across the included studies.After investigating the source of this heterogeneity by subgroup and sensitivity analyses, we derived four major conclusions. (1) In the retrospective studies, an elevated RDW was associated with poor OS/CSS, which did not affect DFS. (2) In the included prospective study, an elevated RDW was associated with a favorable prognosis in male ESCC patients, which is contradictory to the conclusions of most previous studies on cancers[20,29-32].Additionally, RDW was not associated with prognosis in female patients. (3) When the patient number was ≤400, an elevated RDW was associated with poor OS/CSS, but this prognostic correlation was not observed when the number of patients was > 400. And, finally, (4)an elevated RDW was significantly associated with poor OS/CSS when the RDW cut-off value was > 13%, but this association was not observed when the cut-off value was ≤ 13%.
The role of the RDW is being increasingly appreciated due to its close correlation with the risks of cardiovascular diseases and systematic inflammation[33,34]. Previous studies have identified RDW as an accurate predictor of inflammation in hepatitis B infection, mortality due to acute pancreatitis, and activity of inflammatory bowel disease[34-36]. Moreover, an elevated RDW has been found to be a risk factor and progression indicator in multiple malignancies[19,31,37,38].
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In the last 2 to 3 years, studies concerning the correlation between RDW and EC prognosis have become increasingly prominent. However, the conclusions of these studies are varied and sometimes even conflicting.Four small-scale retrospective studies[21-24] included in this meta-analysis concluded that an elevated RDW was significantly associated with worse OS in EC patients. In addition, one intermediate-scale retrospective study[25]concluded that the RDW was not associated with OS at all. Moreover, one large-scale prospective study[26]concluded that an elevated RDW was associated with better OS in male but not female EC patients.Considering that men are three to four times more likely to suffer from EC than women[7], this finding harbors important clinical implications in guiding therapeutic strategies for EC.
There are several reasons for the discrepant conclusions from diverse studies. Four small-scale retrospective studies[21-24] demonstrated that an elevated RDW was a predictor of unfavorable prognosis in EC patients, and the underlying mechanism might be one of the following. First, since Rudolf Virchow noted the presence of leucocytes within tumor tissues approximately 150 years ago and suggested that cancer might be initiated as a result of chronic inflammation[11,39],numerous preclinical and population-based studies have verified his observation. Inflammation might contribute to increased RDW levels by not only impairing iron metabolism but also inhibiting the production of or response to erythropoietin or by reducing red blood cell survival[40,41]. Second, chronic inflammation has also been associated with poor response to chemotherapy[42]. Third,RDW has been found to be correlated with malnutrition,which is an independent risk factor for nosocomial infections associated with poor therapeutic response,an increased rate of treatment-related toxicity, reduced survival rates, and poor quality of life[43,44].
In contrast, one large-scale prospective study[26] concluded that an elevated RDW was a positive predictor of prognosis in male EC patients, however the actual mechanism remains largely undefined. This finding is consistent with the results of another cohort study[45] with data from 26709 nondiabetic adults with more than 14 years of follow-up, which indicated that a low RDW was significantly associated with an increased incidence of diabetes mellitus independent of traditional risk factors.The underlying mechanism might be as follows. Aerobic glycolysis has been proposed as a hallmark of cancer,and the acidic environment caused by aerobic glycolysis is a necessary component of carcinogenesis[46]. Due to the significant association between a low RDW and an increased incidence of diabetes mellitus, it is reasonable to speculate that an elevated RDW might be a surrogate indicator of improved glucose metabolism, which is a key factor for prolonged survival in EC patients. Nevertheless,further clinical evidence and preclinical experiments are warranted to support and verify the accurate mechanism and to identify the real prognostic significance of the RDW in EC.
However, when the data from female patients were included in the present study, the RDW was not found to be associated with OS (HR = 0.92, 95%CI: 0.75-1.08,P = 0.000; Supplementary Figure 9), which is consistent with the conclusions of an intermediate-scale retrospective study[25] included in this meta-analysis.Further analyses revealed that the two above studies have some common characteristics-the sample size was relative large (468 vs 2396) and the RDW cut-off values were 13%. This finding is consistent with the results of a study[47] conducted in 2012, which revealed that the RDW was elevated (> 14.8%) in 31.6% of benign biliary obstruction cases and 68.4% of malignant biliary stricture cases, whereas the RDW was reduced (< 14.8%) in 72.9% of benign cases and 27.1% of malignant cases(these differences were statistically significant, P <0.001). Therefore, an RDW cut-off of 14.8% was the most suitable for predicting a malignant biliary stricture,with a sensitivity of 72% and a specificity of 69% (area under the curve = 0.755, 95%CI: 0.649-0.810). The conclusions of the two studies might be partly attributed to the lower RDW cut-off value. Thus, more large-scale studies exploring the actual relationship between RDW and the prognosis of EC patients are urgently needed in the future. Furthermore, it is necessary to establish a reasonable method for identifying the appropriate RDW cut-off value for predicting the prognosis of EC patients.
However, in contrast to the findings obtained from male EC patients, an elevated RDW was not associated with the prognosis of female EC patients[26]. Despite the prospective nature of the study demonstrating these results, we cannot neglect a potential correlation between the RDW and sex due to the large sample size in that study. However, more studies are needed to investigate and con firm this correlation and to explore the underlying mechanisms.
There are certain limitations that should be acknowledged in this meta-analysis. First, most of the studies included in this meta-analysis were retrospective in nature, and the numbers of patients in these retrospective studies were relatively small.Only one study was prospective, which might prevent generalization of the results. Second, this meta-analysis was performed based on the pooled HRs and 95%CIs from eligible studies, rather than detailed individual information. We were unable to exclude uncontrolled or unmeasured risk factors from the original studies, which might have confounded the true association, resulting in potential bias. Third, the cut-off values for the RDW varied across the included studies due to differences in the study populations and experimental methods.Although the patients were divided into RDW-high and RDW-low populations, the stratification might change depending on the cut-off values. Therefore, a standard and uniform cut-off value is needed to accurately de fine high versus low RDW. Fourth, all of the included articles were in English, most of the included studies included a small number of patients, and potential publication bias cannot be neglected. Thus, more large-scale,well-designed and high-quality prospective studies are required to elucidate the precise mechanisms linking the RDW to survival in EC patients.
In conclusion, an elevated RDW is not associated with the prognosis of EC patients, including both OS/CSS and DFS. This finding is contrary to previous knowledge regarding the prognostic value of the RDW in malignant tumors, particularly in EC. However, when the RDW cut-off value is > 13%, the patient number is≤ 400, and the study type is retrospective, an elevated RDW is indeed significantly associated with worse OS/CSS in EC patients.
ARTICLE HIGHLIGHTS
Research background
Esophageal cancer (EC) was the eighth most common cancer globally, with about half of all cases occurring in China. Prominent symptoms usually do not appear until the cancer has infiltrated over 60% of the circumference of the esophageal tube, by which time the tumor is already in an advanced stage and the prognosis generally tends to be fairly poor. Therefore, finding a simple and effective prognostic indicator is particularly urgent for individualized treatment of EC patients. Recently, red blood cell distribution width (RDW), as an important complete blood count parameter which has a close correlation with cancerrelated inflammation, has been investigated as an important prognostic factor for EC patients in more and more studies, but the conclusions of these studies have not been consistent. Therefore, we conducted this meta-analysis to explore and verify the real role of RDW in the prognosis of patients with EC.
Research motivation
We systematically reviewed the existing studies regarding the role of RDW in the prognosis of EC patients and performed a meta-analysis with the extracted data to clarify the real impact of RDW on the outcomes of the EC patients.Identifying the real role of RDW in the prognosis of patients with EC and the defects existing in the previous and current studies can guide the future researchers to conduct more well-designed related studies on this topic and the upstream or downstream research related to RDW.
Research objectives
The main objectives of this article were to perform a meta-analysis of the data provided in these studies with inconsistent conclusions about the prognostic effect of RDW on EC patients, and to verify the real impact of RDW on the prognosis of EC patients by increasing the sample size. In the end, we could determine whether we need to conduct further studies on this topic according to the conclusion of this systematic review and meta-analysis.
Research methods
First, we searched four related electronic databases (PubMed, EMBASE,Web of Science and Cochrane Library) using the identified MESH terms, and finally identified six studies which met the standards based on the inclusion and exclusion criteria of the selected literature, then we assessed the quality of the included studies according to Newcastle-Ottawa quality scale. Second, we used the electronic EXCEL table to collect the data from the included studies that we needed and utilized statistical software (STATA version 12.0) to conduct statistical analysis of the related data. Third, we performed the sensitivity analysis, subgroup analysis, Begg’s funnel plot and Egger’s linear regression test to explore the potential source of heterogeneity among studies, to find the influencing factors that affect the role of RDW in the prognosis of EC patients and point out the directions for further related research in the future.
Different from the traditional review, we used meta-analysis methods to synthesize data and perform statistical analysis to the relevant literature and quantify the effect of RDW on the prognosis of EC patients. Moreover,in addition to sensitivity analysis and subgroup analyses to find sources of heterogeneity, we also used the Begg’s funnel plot and Egger’s linear regression test to quantify publication bias rather than just using the traditional funnel plot for qualitative analysis. These were the characteristics and indicate the novelty of the research methods used in our study.
Research results
This systematic review and meta-analysis indicated that elevated RDW was not an independent risk factor for the worse outcome of EC patients overall,whether it’s for overall survival/cancer-specific survival [hazard ratio (HR)= 1.27, 95% confidence interval (CI): 0.97-1.57, P = 0.000] or disease-free survival (HR = 1.42, 95% CI: 0.96-1.88, P = 0.000). The prognostic value of RDW in patients with EC is only reflected in the retrospective study (HR = 1.42,95%CI: 1.16-1.69, P = 0.000) of small samples (sample size ≤ 400, HR = 1.45,95% CI = 1.13-1.76, P = 0.000) currently, and there is a need to choose the appropriate RDW cutoff value (RDW > 13%, HR = 1.45, 95%CI: 1.13-1.76, P =0.000) as a prerequisite. Therefore, the actual effect of RDW on the prognosis of EC patients needs further prospective multicenter large-sample studies to be validated in the future.
智能仓储机器人的前端感应装置是装在比较中间的地方,操作人员有时候走到侧边,就会容易和机器人发生碰撞,影响拣货人员的安全。其次,因货架的设置是四方形的,在上架或是拣货时拿掉了一侧的货物,机器人在抬起货架时就会发生倾斜,重心无法落在中间。若是没有及时发现,在前进过程中就会发生货架相撞的情况。
Research conclusions
Different from the traditional viewpoints, our systematic and meta-analysis demonstrated that RDW had no correlation with the prognosis of EC patients,no matter favorable or unfavorable. Therefore, such traditional theories and assumptions, that cancer-related inflammation leads to an increased RDW in the blood, and elevated RDW in turn suggests the occurrence of cancer, were challenged and questioned by the results of our meta-analysis. At the same time, it also suggests that we could perform the meta-analysis to statistically analyze the inconsistent result data of different types of small-sample studies and achieve a conclusion that is completely different from our previous understanding. This leads to the emergence of new theories and assumptions and provides direction for our future research design and potential mechanism research. Our systematic reviews and meta-analysis suggest that we should be more cautious and rational to see the impact of increased RDW on the prognosis of EC patients in our future clinical work.
Research perspectives
From our study, we could learn that we can’t blindly believe in traditional ideas that already exist. When the opinions of previous studies are inconsistent and chaotic, we should use statistical methods to perform statistical clustering analysis on various data, and draw a scientific conclusion to guide our clinical work and indicate the future research direction. Moreover, through the systematic analysis of the previous research, we should carry out more multicenter, large-sample prospective studies in the future to overcome the defects of the current research in the study design to further verify the role of RDW in the prognosis of EC patients. In addition, we also need to conduct further basic experiments based on the results of such above-mentioned optimized research to uncover its underlying mechanisms.
4 Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359-E386 [PMID: 25220842 DOI:10.1002/ijc.29210]
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意料中的事发生了,望着仅有20多平米的简陋的出租屋,方勋梅眉头一皱:“你怎么住这种地方啊?这是人住的地方吗?”“对不起,阿梅,你没问,我事先也没说明。我的梦想就是拥有凯迪拉克,至于房子,我知道也很重要,相信我,我会拥有的,一定会的。”程晓要去拥抱她,方勋梅挣脱了,鄙夷地说:“是的,有人说,现在女孩理想中的老公是开凯迪拉克的。但谁也想不到穷人也会开上凯迪拉克,你简直是个创举!”说完,方勋梅呆坐了一会儿,默默地离开了。
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《中华道藏》是2003年中国道教协会发起并组织编纂整理的一部道藏,它以三家本《道藏》为底本,对原三家本《道藏》所收各种道书作校补、标点、重新分类,并从近代发现的古道经中选取了50种增补其中,总计收录道籍1526种,5500多卷,4000余万字。与此前出版的各种影印本道藏不同的是,《中华道藏》是重新排版印制,繁体字,竖排版,加了新式标点,并进行了必要的文字校勘。这是继明代《正统道藏》之后,对道教经书首次进行的系统规范的整理重修,为道藏使用者提供了一个内容丰富、阅读方便的点校本。
5 Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM.Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893-2917 [PMID: 21351269 DOI:10.1002/ijc.25516]
6 Zhang SW, Min z, Guang-Lin LI. An Analysis of Incidence and Mortality of Esophageal Cancer in China, 2003-2007. China Cancer 2012
加快落实最严格水资源管理制度,是解决我国日益复杂的水资源问题的关键所在,需要全社会的共同努力。如何将最严格水资源管理制度落到实处?有哪些先进经验可资借鉴?与会代表围绕中国水资源管理制度建设这一主题,通过互动、对话和讨论,对我国最严格水资源管理制度建设提出了建议。
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(5)大粒径沥青混合料运输。采用19t以上的自卸汽车将拌和完成后的大粒径沥青混合料进行装车运输,运输过程中需保证运输车辆连续工作。运输前将车厢清扫干净,并在车厢四壁涂上隔离剂,防止沥青黏结在车厢上[4]。运输过程中要保持匀速行驶,且行驶时间不宜过长,防止混合料温度过低,一般情况下应保证混合料到达施工现场时温度不低于170℃。
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产销差率是指销售水量和供给水量的比值。有研究表明,全球产销差率平均在27%左右,欧美、日本等发达国家的产销差率比较低,在10%以下。而非洲、拉丁美洲等发展中国家产销差率高,达到了40%以上[1]。
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2013年,中国灌溉排水发展中心、水利部农村饮水安全中心按照部党组总体部署,深入学习贯彻党的十八大和十八届三中全会精神,扎实开展以为民务实清廉为主要内容的党的群众路线教育实践活动,紧紧围绕农村水利发展目标任务,全力做好重点领域技术支撑和服务工作,为提高农业综合生产能力、保障农村饮水安全发挥了重要支撑保障作用。
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宠物专车公司会根据主人的需求,派人上门接宠物,带它们去美容院、医院等。在接送过程中,司机们还会在车里放古典音乐,以安抚宠物的情绪。
The search was performed by two investigators (Xu and Wang) who also evaluated the titles and abstracts of all candidate articles. Full-text was reviewed when the articles could not be categorized based on the title and abstract. Articles were included and excluded in accordance with the corresponding criteria defined in this study. Any disputes during the selection period were discussed with and resolved by a third investigator(Xiong). A flowchart demonstrating the details of the study selection according to the PRISMA guidelines is shown in Figure 1.
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明天从不向任何人作保证,无论青年或老人,今天可能就是你最后一次看到你所爱的人。因此,别再等待了,今天就开始!因为如果明天永远不来,你也许会遗憾今天没来得及微笑、拥抱、亲吻,会遗憾自己忙碌得只能把它们归为一个最后的愿望。保护周围你爱的人吧,告诉他们你多么需要他们。爱他们,善待他们,用些时间对他们说:“对不起”,“原谅我”,“劳驾”,“谢谢”,以及你知道的所有爱的话语。
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