Loss of heterozygosity (LOH) on chromosome 10 is the most frequent genetic alteration associated with the evolution of malignant astrocytic tumors and it may involve several loci. The tumor suppressor gene PTEN (MMAC1) on chromosome 10q23 is mutated in approximately 30% of glioblastomas (WHO Grade IV). In this study, we assessed the frequency of PTEN mutations in primary glioblastomas, which developed clinically de novo, and in secondary glioblastomas, which evolved from low-grade (WHO Grade II) or anaplastic astrocytomas (WHO Grade III). Nine of 28 (32%) primary glioblastomas contained a PTEN mutation and an additional case showed a homozygous PTEN deletion. This indicates that after overexpression/amplification of the EGF receptor, loss of PTEN function is the most common alteration in primary glioblastomas. In this series, 5 of 28 (18%) primary glioblastomas showed both a PTEN mutation and EGFR amplification. In contrast, only 1 of 25 (4%) secondary glioblastomas contained a PTEN mutation, and none of them showed a homozygous PTEN deletion. The secondary glioblastoma with a PTEN mutation developed from an anaplastic astrocytoma that already carried the mutation. The observation that secondary glioblastomas have a p53 mutation as a genetic hallmark but rarely contain a PTEN mutation supports the concept that primary and secondary glioblastomas develop differently on a genetic level.

Several lines of evidence from family and twin studies have strongly suggested that genetic factors are involved in the development of diabetic microangiopathy [1--3]. Several candidate genes have been investigated to elucidate genetic factor(s) responsible for the vascular complications, but little is known about the genetic basis of these complications [4,5]. Elucidation of the genetic factors predisposing to chronic vascular complications in diabetes mellitus will permit identification of individuals genetically predisposed to the complications and, in turn, will allow us an effective intervention tailored to the specific underlying abnormalities.The renin-angiotensin system regulates the systemic circulation and local haemodynamics, and also regulates cell growth and matrix production via its action on angiotensin II production. Angiotensin I-converting enzyme (ACE; EC 3.4.15.1) is not only a key enzyme in the renin-angiotensin system but also regulates kinin metabolism [6]. The plasma ACE level is under genetic control and is strongly associated with an insertion/deletion (I/D) polymorphism of the ACE gene, defined by the presence or absence of the 287 base-pair Alu -repetitive sequence in intron 16 [7]. Accordingly, the I/D polymorphism has been investigated as a strong candidate marker for genetic predisposition to diabetic vascular complications. Association studies of the ACE genotype with diabetic complications, however, have yielded conflicting results. Diabetologia (1998) 41: 47--53 Meta-analysis of association of insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy Summary An insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene has repeatedly been shown to be associated with ischaemic heart disease, but the association of this genetic marker with diabetic microangiopathy is controversial. To assess the association of the genotypes with the development of diabetic nephropathy or retinopathy, we performed a meta-analysis of data from the literature, using Mantel-Haenszel method followed by the Breslow-Day test for assessing homogeneity among data. In a total of 4773 diabetic patients from 18 studies with (n = 2495) and without (n = 2278) renal complications, the D allele was significantly associated with diabetic nephropathy (p < 0.0001) in a dominant model (summary odds ratio 1.32, 95 % confidence interval: 1.15 to 1.51). There was no significant evidence against homogeneity of the odds ratios (c 2 = 18.9, 20 df; p = 0.53). The association was significant both in non-insulin-dependent (p < 0.005) and in insulin-dependent diabetes mellitus (p < 0.05). Likewise, in a total of 2010 diabetic patients with (n = 1008) and without (n = 1002) retinopathy, there was no association of the I/D polymorphism with diabetic retinopathy. These data suggest that the ACE I/D polymorphism affects the risk for diabetic nephropathy, but not for diabetic retinopathy. [Diabetologia (1998) 41: 47--53]

Thymidine Phosphorylase (dThdPase) is the rate-tissues expressed high levels of DPD (median >70 U/mg limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine protein), while high concentrations of the dThdPase were (5'-dFUrd, doxifluridine), an intermediate metabolite of expressed in esophageal, cervical, breast, and pancreatic capecitabine, to the active drug 5-fluorouracil (5-FUra), while cancers and hepatoma (median >150 U/mg protein). The dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra dThdPase/DPD ratio, which was reported to correlate with to an inactive molecule. The susceptibility of tumors to the susceptibility of human cancer xenografts to capecitabine, fluoropyrimidines is reported to correlate with tumor levels was high in esophageal, renal, breast, colorectal, and gastric of these enzymes. To obtain some insight into the tumor cancers (median ratio of > 1.5). In any of these three parameters, types susceptible to fluoropyrimidine therapy, we measured the inter-patient DPD variability for each cancer type was expression levels of these two enzymes in various types of much larger than the DPD variability among cancer types; human cancer tissues (241 tissue samples) by the ELISA highest/lowest ratios for dThdPase, DPD, and dThdPase/DPD methods. DPD exists in all the cancer types studied, such were 10-321, 7-513, and 2-293, respectively. These results as bladder, breast, cervical, colorectal, esophageal, gastric, indicate that measurements of the three parameters, DPD, hepatic, pancreatic, prostate, and renal cancers. Among them, dThdPase and dThdPase/DPD, would be useful criteria for the cervical, hepatic, pancreatic, esophageal, and breast cancer selecting cancer patients suitable for fluoropyrimidine therapy rather than for selecting cancer types.

AimsThe goal of the study was to evaluate the efficacy of epalrestat, an aldose reductase inhibitor, on diabetic retinopathy and diabetic nephropathy, based on analysis of the results of the Aldose Reductase Inhibitor–Diabetes Complications Trial, a 3-year multicentre comparative clinical trial of conventional therapy (control group) and epalrestat therapy (epalrestat group) in Japanese patients with mild diabetic neuropathy.MethodsThe subjects of the study were patients enrolled in the Aldose Reductase Inhibitor–Diabetes Complications Trial for whom data for major patient characteristics, severity of diabetic neuropathy at the end of the study and time-courses of diabetic retinopathy and diabetic nephropathy were available (57 and 52 patients from the control and epalrestat groups, respectively). Progression of diabetic retinopathy/nephropathy (a primary endpoint) in relation to major patient characteristics, severity of diabetic neuropathy at the end of the study (assessed from the mean of z-scores in four neurological function tests) and epalrestat treatment were analysed using univariate analysis and multiple logistic regression analysis.ResultsProgression of diabetic retinopathy/nephropathy was significantly inhibited in the epalrestat group compared with the control group (odds ratio = 0.323, P = 0.014) and was dependent on the severity of diabetic neuropathy at the end of the study (odds ratio = 2.131, P = 0.025).ConclusionsEpalrestat prevented progression of diabetic neuropathy and retinopathy/nephropathy. The effect on diabetic retinopathy/nephropathy may have occurred indirectly because of the prevention of progression of diabetic neuropathy, in addition to the inhibitory action of epalrestat on aldose reductase.

Aims-To evaluate the eVects of hydrogen peroxide exposure on the survival and proliferation of cultured lens epithelial cells. Methods-TOTL-86 cells, a line of rabbit lens epithelial cells, were used. The survival and proliferation of TOTL-86 cells were quantified by a rapid colorimetric assay (MTT assay). To determine the eVects of hydrogen peroxide, TOTL-86 cells were exposed to diVerent concentrations of hydrogen peroxide. To determine the eVect of cell numbers on the survival and proliferation of TOTL-86 cells at a fixed concentration of hydrogen peroxide, diVerent numbers of cells were plated and exposed to hydrogen peroxide. To determine whether there is a synergistic eVect between hydrogen peroxide and EGF, bFGF, PDGF-AA, and insulin, TOTL-86 cells were exposed to hydrogen peroxide combined with one of these growth factors. Results-High levels (1 mM) of hydrogen peroxide killed TOTL-86 cells and sublethal levels (100 µM) suppressed their proliferation. From 1 nM to 1 µM of hydrogen peroxide, there was a dose dependent increase in the cell numbers. The initial seeded cell number dramatically aVected the response to hydrogen peroxide. Although growth factors showed no synergistic eVects with hydrogen peroxide on proliferation, both EGF and insulin, but not bFGF or PDGF, rescued TOTL-86 cells from the sublethal eVect. Conclusion-Hydrogen peroxide in cooperation with some growth factors plays an important role in the proliferation of lens epithelial cell. (Br J Ophthalmol 1999;83:1064-1068 Secondary cataract formation, which is one of the most common and serious complications of cataract surgery, 1 2 represents a wound healing process of the lens epithelial cells remaining after cataract surgery.3-6 While it is believed that growth factors contribute importantly to the proliferation of residual lens epithelial cells, 7-11 recent studies have shown that hydrogen peroxide also stimulates the growth of a variety of cell types. [12][13][14][15][16] The question then arises as to whether hydrogen peroxide also plays a role in the proliferation of residual lens epithelial cells. The anterior chamber of the eye is continuously exposed to oxidative stress, and significant levels of hydrogen peroxide have been reported in the aqueous humour of some cataract patients. [17][18][19] Although cataract researchers have focused on hydrogen peroxide as a possible cause of chronically inflicted damage to lens epithelial cells, [20][21][22][23][24] little is known about hydrogen peroxide as an intracellular signalling molecule in lens epithelial cells.As a first step, the present in vitro study was undertaken to evaluate the eVects of hydrogen peroxide on the growth and survival of lens epithelial cells. We also investigated the synergistic eVects of hydrogen peroxide and several growth factors on the growth and survival of lens epithelial cells. Materials and methodsThe experiments were performed on a rabbit lens epithelial cell line, TOTL-86, which we have established and described.25 26 All cultures were grown in 75...