Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood

A newly recognized family of proteins that inhibit cyclin-dependent kinases (CDKs) termed cyclin-dependent kinase inhibitors (CDKI) have an important role in regulation of cell-cycle progression. A subfamily of these CDKIs (p15INK4B/MTS2, p16INK4/MTS1, and p18) have a high degree of structural and functional homology and are candidate tumor- suppressor genes. We evaluated the mutational status of the p15, p16, and p18 genes in 103 childhood acute lymphoblastic leukemia (ALL) samples and correlated these results with both their clinical data and additional results concerning their loss of heterozygosity in the region of the p15/p16 genes. Homozygous deletions of the p16 gene occurred extremely frequently in T-ALLs (17/22; 77%), and it was also frequent in precursor-B ALLs (12/81; 15%). Homozygous deletions of the p15 gene were also very frequent in T-ALLs (9/22; 41%), and it occurred in 5 of 81 (6%) precursor-B ALL samples. No deletions of p18 was found in any of the 103 ALL samples. Also, no point mutations of the p15, p16, and p18 genes were detected. We correlated p15/p16 alterations at diagnosis with their clinical characteristics as compared with 2,927 other patients treated similarly. Those with p15/p16 alterations were older; had higher white blood cell counts, often with T-cell ALL phenotype; and more frequently had a mediastinal mass at presentation; but they had the same nonremission, relapse, and survival rates at 5 years as did those patients whose blast cells did not have a p15/p16 deletion. To better understand the extent of alterations affecting chromosome 9p21 (location of the p15/p16 genes), loss of heterozygosity (LOH) was examined at D9S171, which is about 1 megabase proximal to the p15/p16 genes. LOH was detected in 15 of 37 (41%) informative samples. Interestingly, of the 24 informative samples that had no detectable alteration of the p15/p16 genes, 7 samples (29%) had LOH at D9S171. In summary, we show in a very large study that p15 and p16, but not p18, CDKI genes are very frequently altered in ALL; those with p15/p16 alterations are more frequently older children, have higher white blood cells at presentation, and often have a T-cell ALL phenotype. The LOH analysis suggests that another tumor-suppressor gene important in ALL also is present on chromosome 9p21.     

Nonalcoholic Steatohepatits and Liver Steatosis Modify Partial Hepatectomy Recovery

Background: The impact of nonalcoholic fatty liver disease (NAFLD) comprising simple steatosis (NAFL) and steatohepatitis (NASH) on liver recovery after partial hepatectomy has not been evaluated. This pilot study investigated whether there is an effect of proven NAFLD on liver recovery. Methods: Thirty-one patients elected for partial hepatectomy were characterized and included into a prospective study. Liver samples were staged according to the NAFLD activity score. Liver function was measured by using the LiMAx method on postoperative days (POD) 1, 3, 5, and 10. Results: Nineteen patients were identified to suffer from NAFLD (NAFL, n = 11; NASH, n = 8). In NAFL, preoperative liver function (p = .48) and hepatic recovery on POD 1, 3, and 5 was comparable to controls (p > .05, respectively), while it was impaired on POD 10 (p = .022). NASH patients had preoperative enzymatic function comparable to controls (p = .10), but there was a trend to reduced levels on POD 1 (p = .082) and 5 (p = .062), which became significant on POD 10 (p = .003). Conclusion: This study suggests that NAFLD impairs functional recovery assessed by LiMAx after partial hepatectomy.     

Acquired erythropoietin responsiveness of interleukin-2-dependent T lymphocytes retrovirally transduced with genes encoding chimeric erythropoietin/interleukin-2 receptors

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TILs) causes regression of some human tumors. However, the sustained proliferation and antitumor activity of TILs requires the coadministration of potentially toxic amounts of interleukin-2 (IL-2). In an effort to overcome the requirement by T cells for IL-2, we have introduced alternative growth factor receptors that use the relatively nontoxic cytokine erythropoietin (Epo) as a ligand. In our model system, the coexpression of chimeric receptors consisting of the extracellular portion of the Epo receptor (EpoR) and the intracellular portions of the IL-2 receptor subunits, beta and gamma, conferred Epo responsiveness on a T-cell line. By contrast, cells expressing the wild- type EpoR did not proliferate in response to Epo. This suggested that Epo binding caused the activation of an IL-2 signal pathway mediated by the chimeric receptors. This approach can be used to minimize toxicity and potentially improve cancer immunotherapy with TILs.     

The familial occurrence of polycythemia vera: report of a father and son, with consideration of the possible etiologic role of exposure to organic solvents, including tetrachloroethylene

The occurrence of polycythemia vera in a father and son, both of whom had intermittent exposure to organic solvents, including tetrachloroethylene and Stoddard solvent, is reported. Only three other well substantiated familial occurrences of polycythemia vera, none encompassing successive generations, were found among many reported instances.     

Complex expression patterns of Eph receptor tyrosine kinases and their ephrin ligands in colorectal carcinogenesis

Aberrant expression of Eph and ephrin proteins in human cancers is extensively documented. However, data are frequently limited to one gene and therefore incomplete and in some instances conflicting. We analysed expression of all Eph and ephrin genes in colorectal cancer (CRC) cell lines and 153 clinical specimens, providing for the first time a comprehensive analysis of this system in CRC. Eph/ephrin mRNA expression was assessed by quantitative real-time PCR and correlated with protein expression (flow cytometry, Western blotting and immunocytochemistry). These data show that EphA1, EphA2, EphB2 and EphB4 were significantly over expressed in CRC. In all cases, at least one Eph gene was found in normal colon (EphA1, EphA2, EphB2, EphB4), where expression was observed at high levels in most CRCs. However, other Eph gene expression was lost in individual CRCs compared to the corresponding normal, EphA7 being a striking example. Loss of expression was more common in advanced disease and thus correlated with poor survival. This is consistent with the redundant functionality of Eph receptors, such that expression of a single Eph gene is sufficient for effector function. Overall, the data suggest a progressive loss of expression of individual Eph genes suggesting that individual CRCs need to be phenotyped to determine which Eph genes are highly expressed. Targeted therapies could then be selected from a group of specific antibodies, such as those developed for EphA1.     

Bone mineral densities in individuals with Gilbert’s syndrome: A cross-sectional,case-control pilot study

BACKGROUND

Unconjugated bilirubin inhibits osteoblastic proliferative activity in vitro, raising the possibility that Gilbert’s syndrome (GS) patients are at increased risk of osteoporosis.

OBJECTIVES

To compare bone mineral density (BMD), serum parathyroid hormone (PTH), C-telopeptide (CTX) and osteocalcin levels in GS subjects versus matched controls in a cross-sectional, case-control study.

METHODS

BMD determinations were obtained with central dual-energy x-ray absorptiometry. Serum PTH, CTX and osteocalcin levels were measured by enzyme immunoassay.

RESULTS

A total of 17 GS and 30 control subjects were studied. Overall, there were no significant differences in BMD, PTH, CTX or osteocalcin levels between the two groups. However, when older (older than 40 years of age) and younger (40 years of age and younger) cohorts were considered separately, the older GS cohort had significantly decreased total hip BMD, T scores and Z scores, and femoral neck BMD, T scores and Z scores (P<0.005 for each parameter, respectively) compared with older control subjects. Serum osteocalcin levels were lower in the older versus younger GS cohort (P=0.006). An inverse correlation existed between all subjects’ serum unconjugated bilirubin levels and total body BMD determinations (r=−0.42; P=0.04). On univariate analysis, the association between serum unconjugated bilirubin and total body BMD was not significant (P=0.066), nor was serum unconjugated bilirubin identified as a risk factor for low BMD when entered into multivariate analyses.

CONCLUSIONS

The results of the present pilot study warrant further research involving larger numbers of subjects and longitudinal measurements to determine whether GS is associated with decreased BMD, particularly in older GS subjects.     

Evaluation of a patient event report monitoring system

Background — Detection of adverse drug reactions needs improving. Consumer recruitment and reporting is controversial. Aim — Pilot a method of adverse drug event reporting by patients. Methods — Patients commencing on long‐term medications were asked to record adverse events in a diary for 8 months. Three methods of recruiting patients were compared, through community pharmacies by a pharmacist or a research nurse and by a clinical pharmacist in a teaching hospital. Results — 119 subjects: 77 recruited by community pharmacists, 20 by a research nurse located in community pharmacies and 22 by a clinical pharmacist. Refusal rates were 57.2, 78.0 and 53.2% respectively. Nineteen (16.0%) people withdrew and nine (7.6%) people were lost to follow‐up. Thirty (33.0%) people experienced an adverse event attributed to the medication they were taking. Conclusion — Evaluation of this patient event reporting monitoring system showed that patients can be recruited by pharmacists in community and hospital settings. Refusal rates were smaller when the community pharmacist was recruiting compared to the research nurse. Patients are capable of recording adverse medical events, particularly those that result in doctor visits or hospitalization. Copyright © 2000 John Wiley & Sons, Ltd.     

构建招收飞行员基本认知能力预测学业成绩的模型

目的：通过空军招收飞行员心理品质检测第一平台的基本认知能力测验,建立学生学业成绩的预测模型,提前淘汰高考成绩不良的学生,以节省开支. 方法：①实验1：采用完全随机设计的方法,于2005-12选取西安市某部队院校入校3个月的854名大学生,进行加法计算、比较刻度、找特殊图形、组合图形、填写数据、识符检数、判别方向、选词配对、找规律填数等9项基本能力测试,利用Pearson相关分析,选出与学业成绩显著相关的4项测验.②实验2：2006-12选取与实验1不同部队院校的2006级入校3个月的200名大学生,进行4项选定的测验,通过SPSS 12.0统计软件包进行多元回归分析最终建立预测学业成绩的基本认知能力模型,并分析其预测效度. 结果：①实验1结果：选定的4项能力测试与学业成绩的相关分别是：加法计算X1（r=0.233）、找特殊图形X2（r=0.226）、填写数据X3（r=0.100）、选词配对X4（r=0.176）.②实验2结果：最终建立的预测方程是Y=532.75＋1.001X1＋1.247X3＋1.257X4,它能解释学业成绩中13.0%的变异. 结论：基本认知能力测验能预测学业成绩,并且能达到较好的效度,可以应用到飞行员选拔的实际中.