Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America

To provide a resource for assessing continental ancestry in a wide variety of genetic studies, we identified, validated, and characterized a set of 128 ancestry informative markers (AIMs). The markers were chosen for informativeness, genome-wide distribution, and genotype reproducibility on two platforms (TaqMan assays and Illumina arrays). We analyzed genotyping data from 825 subjects with diverse ancestry, including European, East Asian, Amerindian, African, South Asian, Mexican, and Puerto Rican. A comprehensive set of 128 AIMs and subsets as small as 24 AIMs are shown to be useful tools for ascertaining the origin of subjects from particular continents, and to correct for population stratification in admixed population sample sets. Our findings provide general guidelines for the application of specific AIM subsets as a resource for wide application. We conclude that investigators can use TaqMan assays for the selected AIMs as a simple and cost efficient tool to control for differences in continental ancestry when conducting association studies in ethnically diverse populations.     

Exposure to Agent Orange is a significant predictor of prostate‐specific antigen (PSA)‐based recurrence and a rapid PSA doubling time after radical prostatectomy

OBJECTIVE

To investigate and report the clinicopathological characteristics and outcomes after radical prostatectomy (RP) in patients with prostate cancer and previous exposure to Agent Orange (AO), particularly in relationship to race.

PATIENTS AND METHODS

In 1495 veterans who had undergone RP the clinicopathological characteristics, biochemical progression rates, and prostate‐specific antigen (PSA) doubling time (DT) after recurrence between AO‐exposed and unexposed men were compared using logistic and linear regression and Cox proportional hazards analyses, and stratified by race.

RESULTS

The 206 (14%) men with AO exposure were more likely to be black (P = 0.001), younger (P < 0.001), treated more recently (P < 0.001), have a higher body mass index (P = 0.001), have clinical stage T1 disease (P < 0.001), and have lower preoperative PSA levels (P = 0.001). After adjusting for several clinical characteristics, AO exposure was not significantly related to adverse pathological features but was significantly associated with biochemical progression risk (relative risk 1.55, 95% confidence interval 1.15–2.09, P = 0.004) and shorter PSADT (P < 0.001) after recurrence (8.2 vs 18.6 months). When stratified by race, these associations were present and similar in both races, with no significant interaction between race and AO exposure for predicting biochemical recurrence or mean adjusted PSADT (P interaction >0.20).

CONCLUSIONS

Patients with AO exposure and treated with RP were more likely to be black, present with lower risk features, have an increased risk of biochemical progression, and shorter PSADT after recurrence. When stratified by race, the association between AO exposure and poor outcomes was present in both races. These findings suggest that among selected men who choose RP, AO exposure might be associated with more aggressive prostate cancer.     

Do nomograms predict aggressive recurrence after radical prostatectomy more accurately than biochemical recurrence alone?

OBJECTIVE

To compare the predictive accuracy (PA) of existing models in estimating risk of biochemical recurrence (BCR) vs aggressive recurrence (BCR with a prostate‐specific antigen, PSA, doubling time, DT, of <9 months).

PATIENTS AND METHODS

The study included 1550 men treated with radical prostatectomy (RP) between 1988 and 2007 within the Shared Equal Access Regional Cancer Hospital database. The PA of nine different risk stratification models for estimating risk of BCR and risk of aggressive recurrence after RP was assessed using the concordance index, c.

RESULTS

The 10‐year risks of BCR and aggressive recurrence were 47% and 9%, respectively. Across all nine models tested, the PA was a mean (range) of 0.054 (0.024–0.074) points higher for predicting aggressive recurrence than for predicting BCR alone (c = 0.756 vs 0.702). Similar results were obtained in four sensitivity analyses: (i) defining patients with BCR but unavailable PSADT (220) as having aggressive recurrence; (ii) defining these patients as not having aggressive recurrence; (iii) defining aggressive recurrence as a PSADT of <6 months; or (iv) defining aggressive recurrence as a PSADT of <12 months. The improvement in PA was greater for preoperative than for postoperative models (0.053 vs 0.036, P = 0.03).

CONCLUSION

Across nine different models the prediction of aggressive recurrence after RP was more accurate than the prediction of BCR alone. This is probably because current models mainly assess cancer biology, which correlates better with aggressive recurrence than with BCR alone. Overall, all models had relatively similar accuracy for predicting aggressive recurrence.     

Health-related quality of life 3 years after high-dose intensity-modulated radiotherapy with gold fiducial marker-based position verification

OBJECTIVE

To evaluate the change in quality of life (QoL) 3 years after high‐dose intensity‐modulated radiotherapy (IMRT) using gold fiducial marker‐based position verification in patients with locally advanced prostate cancer.

PATIENTS AND METHODS

Between October 2003 and November 2004, 95 patients with locally advanced prostate cancer were treated with 76 Gy IMRT with gold‐fiducial marker‐based position verification. Before treatment (baseline) and 1, 6 and 36 months after RT the QoL was measured using the RAND‐36, the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ‐C30(+3)) and the prostate tumour‐specific module (EORTC QLQ‐PR25). Changes in QoL with time of ≥10 points were considered clinically relevant.

RESULTS

After 3 years there was a statistically significant improvement in QoL for emotional role restriction and functioning, change in health, mental health and insomnia, compared with baseline. Emotional role restriction increased by >10 points and was therefore clinically relevant, while all other differences were of <10 points. There was a statistically significant deterioration of QoL after 3 years in physical and cognitive functioning, bowel symptoms/function and sexual activity. Only the sexual activity QoL score changed by 12 points and was therefore the only meaningful deterioration in QoL at 3 years after treatment.

CONCLUSION

IMRT and accurate position verification provide the possibility to deliver a high irradiation dose to the prostate without clinically relevant deterioration in long‐term QoL, except for a persistent decrease in sexual activity score.     

Does early prostate‐specific antigen doubling time (ePSADT) after radical prostatectomy,calculated using PSA values from the first detectable until the first recurrence value,correlate with standard PSADT? A report from the Shared Equal Access Regional Cancer Hospital Database Group

OBJECTIVE

To determine if prostate‐specific antigen doubling time (PSADT), calculated from the first detectable PSA level after radical prostatectomy (RP) to the first PSA level of ≥0.2 ng/mL (early PSADT or ePSADT), correlated with ‘standard’ PSADT (henceforth PSADT) calculated using values ≥0.2 ng/mL, as a short PSADT following biochemical recurrence (BCR) after RP portends a poor prognosis and poor response to salvage treatment but this is based upon PSADT calculated using PSA values of ≥0.2 ng/mL.

PATIENTS AND METHODS

We used Spearman’s correlation to determine the correlation between ePSADT and PSADT among 157 men in the Shared Equal Access Regional Cancer Hospital database who underwent RP between 1988 and 2005 and had a calculable ePSADT and PSADT. We systematically examined ePSADT thresholds and their positive and negative predictive values (PPV and NPV, respectively), to predict aggressive recurrences (PSADT of <9 months).

RESULTS

ePSADT was significantly, though poorly, correlated with PSADT (r = 0.30, P < 0.001). ePSADT more accurately predicted PSADT among men with a long ePSADT. Of men with an ePSADT of ≥20 or ≥15 months, the NPV for an aggressive recurrence was 98% and 93%, respectively. However, among men with an ePSADT of <3 months, the PPV for aggressive recurrence was only 39%.

CONCLUSIONS

Although ePSADT and PSADT were significantly related, the overall correlation was poor. This was highlighted by the finding that only 39% of men with the shortest ePSADT (<3 months) had a PSADT of <9 months. However, a long ePSADT correlated well with a long PSADT and is thus useful in identifying men at low risk for prostate cancer‐specific mortality very early in their BCR.     

多项肿瘤标志物联合检测对肝癌早期诊断的作用

目的 探讨多项肿瘤标志物联合检测在原发性肝癌中的诊断价值及建立判别方程.方法 采用蛋白芯片技术,检测2003年11月至2006年4月大坪医院收治的98例原发性肝癌患者(肝癌组)、67例良性肝病患者(肝病组)、46例健康体检者(对照组)血清中的12项肿瘤标志物,并在肝癌组与肝病组患者之间建立判别方程.采用方差分析和X2检验对检测结果进行分析.结果 肝癌组中87例患者肿瘤标志物呈阳性表达(89%),肝病组中有13例呈阳性表达(19%),对照组中有2例呈阳性表达(4%).3组中的AFP、CEA、铁蛋白、CA19-9和CA125检测结果比较,差异有统计学意义(F=59.530,40.472,31.708,75.897,153.066,P<0.05).联合检测这5项指标,肝癌临床诊断符合率提高为89%,明显高于单项AFP检测的64%(X2=16.362,P<0.05).所建判别方程的判断准确率为90%.结论 多项肿瘤标志物联合检测优于单独AFP检测,可用于对肝癌高危人群的筛查及原发性肝癌的早期诊断.     

早期急性重症胰腺炎预后因素分析

Objective Analysis of early risk predict markers within 24h after admission of prognosis in severe acute pancreatitis (SAP). Methods Medical records of 127 patients with sever acute pancreatitis admitted to our hospital within 72h after onset from February 2006 to July 2009 were retrospectively analyzed. These inpatients were grouped into survival group (102 cases) and death group (25 cases). The clinical and laboratory data within 24h after admission were compared between two groups. Results Compared with survival group, patients in death group had significantly difference in heart rate, respiratory, PaO2, pH value, serum calcium, serum kalium, serum creatine, BUN, BE, LDH, serum albumin and APCHE Ⅱscores (P<0.05). Higher APCHE Ⅱ scores after admission was an independent early high risk predicator of death. Conclusions Death group was characterized as severe multiple organ dysfunction and severe internal disturbance. Heart rate, respiratory, PaO2, pH value, serum calcium, serum potassium, serum creatine, BUN, BE, LDH, serum albumin and APCHE Ⅱ scores were early risk predict markers of death in patients with sever acute pancreatitis.     

不同医院多个检测系统血清酶检验结果的比对研究

目的探讨不同医院检测系统检测血清酶ALT、AST、ALP、GGT和AMS的可比性,为实现医院间检验结果的互认提供依据。方法参照EP9-A2文件,通过对6个自建检测系统检测患者新鲜血清的ALT、AST、ALP、GGT和AMS并与目标检测系统进行比对,计算自建检测系统和目标检测系统之间的相对偏差,以CLIA88规定的室间质量评价可接受范围的1／2为标准,判断是否为临床可接受。结果（1）检测系统3的GGT相关系数r〈0．975,检测系统4的ALP相关系数r〈0．975。与目标检测系统不具可比性;（2）ALT（检测系统1、4）、ALP（检测系统3、5、6）和AMS（检测系统2、4）在正常与病理水平偏倚率均超过1／2PT可接受范围,上述检测系统的有关项目与目标检测系统不具可比性。结论6个自建检测系统中部分项目与目标检测系统不具可比性,利用新鲜血进行医院间的比对,对于保证医院间检验结果的可比性具有重要作用。     

Introduction of a Phe377del Mutation in ANK Creates a Mouse Model for Craniometaphyseal Dysplasia

Craniometaphyseal dysplasia (CMD) is a monogenic human disorder characterized by thickening of craniofacial bones and flaring metaphyses of long bones. Mutations for autosomal dominant CMD have been identified in the progressive ankylosis gene ANKH. Previous studies of Ank loss‐of‐function models, Ank^null/null and Ank^ank/ank mice, suggest that Ank plays a role in the regulation of bone mineralization. However, the mechanism for Ank mutations leading to CMD remains unknown. We generated the first knockin (KI) mouse model for CMD expressing a human mutation (Phe377 deletion) in ANK. Homozygous Ank knockin mice (Ank^KI/KI) replicate many typical features of human CMD including hyperostosis of craniofacial bones, massive jawbones, decreased diameters of cranial foramina, obliteration of nasal sinuses, fusion of middle ear bones, and club‐shaped femurs. In addition, Ank^KI/KI mice have increased serum alkaline phosphatase and TRACP5b, as reported in CMD patients. Biochemical markers of bone formation and bone resorption, N‐terminal propeptide of type I procollagen and type I collagen cross‐linked C‐terminal telopeptide, are significantly increased in Ank^KI/KI mice, suggesting increased bone turnover. Interestingly, Ank^KI/KI bone marrow–derived macrophage cultures show decreased osteoclastogenesis. Despite the hyperostotic phenotype, bone matrix in Ank^KI/KI mice is hypomineralized and less mature, indicating that biomechanical properties of bones may be compromised by the Ank mutation. We believe this new mouse model will facilitate studies of skeletal abnormalities in CMD at cellular and molecular levels.