The genotype of the human cancer cell: implications for risk analysis

An extremely large database describes genotypes associated with the human cancer phenotype and genotypes of human populations with genetic predisposition to cancer. Aspects of this database are examined from the perspective of risk analysis, and the following conclusions and hypotheses are proposed: (1) The genotypes of human cancer cells are characterized by multiple mutated genes. Each type of cancer is characterized by a set of mutated genes, a subset from a total of more than 80 genes, that varies between tissue types and between different tumors from the same tissue. No single cancer-associated gene nor carcinogenic pathway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and provide a model for associating cancer rates with induced genetic changes. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of putative carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce these events varies significantly. There is a paradox between the observed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggesting events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hyperproliferation and hypermutation may be such events. (4) Four sets of data suggest that hypermutation may be an important carcinogenic process. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or to increase mutation in hypermutable cells. (5) High-dose exposure to carcinogens in model systems changes patterns of gene expression and may induce protective effects through delay in cell progression and other processes that affect mutagenesis and toxicity. Paradigms in risk analysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effects of test agents at environmental levels. Characteristics of the human cancer genotype suggest that approaches to risk analysis must be broadened to consider the multiplicity of carcinogenic pathways and the relative roles of hyperproliferation and hypermutation. Further, estimation of risk to general human populations must consider effects on hypersusceptible individuals. The extrapolation of effects over wide exposure levels is an imprecise process.     

Moving on and moving up: The experience of households who resell public sector dwellings

The long‐term consequences of the sale of public sector dwellings to sitting tenants are under‐researched; in particular, the experience of tenant purchasers in the housing market subsequent to purchase is little known. This paper reports research designed to fill this gap in knowledge. Over 200 tenants who had bought their dwelling from the Scottish Special Housing Association and subsequently resold on the open market were traced using the Register fo Sasines and the Land Register and interviewed. Most had made considerable capital gains on resale and had used some of the realised capital to trade up in the housing market. They were, on average, slightly more affluent and younger than sitting tenant purchasers generally; they represented a group of households who were privileged within the public sector through living as tenants in the best stock and who were enabled by the Right to Buy to convert that good luck into hard cash and move into mainstream owner occupation. This good luck compounded the advantaged position vis‐à‐vis other tenants that they enjoyed in the labour market.     

Effect of the approximately 2400-year solar climatic cycle on the lives of peoples

2400-year solar cycle ascertained by us in the long-term series of various natural characteristics (e.g. the radiocarbon content in samples of well-known ages, oscillations of the sea and ocean levels etc.) includes three parts roughly equal in duration: a phase of high activity, a phase of depression and a phase of moderate activity. In climate oscillations, which are connected with this cycle, the next phenomena are established: a little climatic optimum, a little Ice Age, and a temperate climate epoch.     

Peritoneal healing after fibrin glue application: a comparative study in a rat model

The influence of fibrin glue on adhesion formation and peritoneal healing is evaluated in a prospective, randomized, controlled study. In all, 20 Wistar rats underwent microsurgical suturing of two silicone sheets, one covered with a fibrin glue barrier, to the anterior peritoneum. Each animal thus served as its own control. After 10 days, adhesions and peritoneal healing were evaluated by a blinded observer through a second-look laparotomy. Adhesions were scored using a modification of the classification of Diamond. Tissue around the silicone sheet was examined histologically and by scanning electron microscopy to evaluate the inflammatory reaction and peritoneal healing (ingrowth of blood vessels and quality of peritoneal cells). Adhesion scores for treated and control sides were (mean +/- SD) 2.89 +/- 4.68 and 6.79 +/- 9.09 (P = 0.181) respectively, and the percentage of the sheet covered by peritoneum was 26.25 +/- 31.50 and 29.21 +/- 40.21 (P = 0.226) respectively. Using the paired Wilcoxon rank test, the P values for the ingrowth of blood vessels and peritoneal healing evaluated by histology and scanning electron microscopy were 0.842, 0.692 and 0.695 respectively. We conclude that although the mean adhesion score was reduced by > 50% by fibrin glue, there is no statistically significant difference concerning adhesion formation or peritoneal healing with the use of fibrin glue.     

The prospects for using the genetically engineered surface antigen of the hepatitis B virus (HBsAg) expressed by recombinant poxvirus strains as the basis for vaccines against hepatitis B

The use of a recombinant poxvirus (RPV) strain, expressing HBsAg in the process of reproduction in different bioreactor systems under stationary and bioreactor conditions of cultivation, made it possible to obtain highly purified HBsAg. The identity and purity of HBsAg was confirmed by the analysis of its amino acid composition, SDS electrophoresis in polyacrylamide gel, electron microscopy and high-performance liquid chromatography. Good prospects of the use of RPV-expressed gene engineering HBsAg as the basis vaccines against hepatitis B was demonstrated in 10 experimental batches of vaccine. All batches of the preparation had pronounced immunogenicity and were safe and nontoxic in animal experiments. The ID50 of experimental batches did not exceed 211 ng/ml, which, according to the data of comparative experiments, was lower than, or equal to, corresponding values of analogous foreign commercial preparations, based on plasma or yeast HBsAg.     

Perceptions of elder abuse and help-seeking patterns among African-American, Caucasian American, and Korean-American elderly women

Thirteen scenarios were used to measure and compare the perceptions of elder abuse and help-seeking behaviors of African-American, Caucasian American, and Korean-American elderly women. Significant group differences existed in their perceptions of elder abuse with regard to six scenarios, and the Korean-American women were substantially less likely to perceive a given situation as abusive than the other groups. The three groups also showed significant differences in their intended use of formal and informal sources of help in the case of elder abuse.     

Progressive scoliosis with vertebral rotation after lumbar intervertebral disc herniation in a 10-year-old girl

A case report of a 10-year old girl with a herniated disc is presented. The most significant symptoms were progressive scoliosis with a flat back and paravertebral muscle spasm. An absent H reflex on the left and an increased latency of the somatosensory-evoked potentials of the left posterior tibial nerve were found. The computed tomographic scan of the lumbar spine showed a large central left-sided disc protrusion at the L5-S1 level. Our case presents the youngest patient with documented intervertebral disc herniation and the only one with severe scoliosis and vertebral rotation. The curve was not structural because it improved with surgery and an orthosis was not necessary.     

TGF-beta mediated G1 arrest in a human melanoma cell line lacking p15INK4B: evidence for cooperation between p21Cip1/WAF1 and p27Kip1

We have studied TGF-beta mediated G1 arrest in WM35, an early stage human melanoma cell line. These cells have lost p15INK4B expression through loss of one chromosome 9 and rearrangement of the other. In asynchronously growing WM35, TGF-beta caused reductions in cyclin D1, cyclin A and cdk4 proteins and their associated kinase activities and an increase in both p21Cip1/WAF1 and p27Kip1. These findings were confirmed in cells released from quiescence in the presence of TGF-beta, in which TGF-beta inhibited or delayed the reduction in the cdk inhibitors that normally occurs in late G1. In contrast to observations in other cell types, there was an increased association of both p21Cip1/WAF1 and p27Kip1 with cyclin D1/cdk4 and with cyclin E/cdk2 during TGF-beta mediated arrest of asynchronously growing cells. Upregulation of p21Cip1/WAF1 preceded that of p27Kip1. Furthermore, p21Cip1/WAF1 and p27Kip1 were not present in the same cdk complexes but bound distinct populations of target cdk molecules. Both p21Cip1/WAF1 and p27Kip1 immunoprecipitates from asynchronously growing cells contained active kinase complexes. These KIP-associated kinase activities were reduced in TGF-beta arrested cells. It has been proposed that in TGF-beta arrested epithelial cells, up-regulation of p15INK4B and of p15INK4B binding to cdk4 serves to destabilize the association of p27Kip1 with cyclin D1/cdk4, promoting p27Kip1 binding and inhibition of cyclin E/cdk2. Our findings demonstrate that this is not a universal mechanism of G1 arrest by TGF-beta. In TGF-beta arrested WM35, which lack p15INK4B, the increased p21Cip1/WAF1 may serve a similar function to that of p15INK4B: initiating kinase inhibition and providing an additional mechanism to supplement the effect of p27Kip1 on G1 cyclin/cdks.