Overexpression of the c-myc proto-oncogene in colorectal carcinoma is associated with a reduced mortality that is abrogated by point mutation of the p53 tumor suppressor gene

The survival of 119 colorectal cancer patients was analyzed in the light of the overexpression status of the c-myc proto-oncogene mRNA and the point mutation status of the p53 tumor suppressor gene in the primary adenocarcinoma. The presence of >3 fold overexpression of c-myc mRNA in the primary tumor was found to be associated with a better prognosis than patients who evinced no overexpression (P = 0.02, log rank analysis). Point mutation of the p53 tumor suppressor gene was found to be associated with a poorer patient prognosis (P = 0.007, log rank analysis). Endogenous levels of c-myc and point mutation of p53 both contributed independently toward a poorer patient prognosis in Cox regression modeling. The better prognosis seen in patients who overexpress c-myc was offset when c-myc overexpression was coupled with a point mutated p53 gene. These results suggest that in colorectal adenocarcinoma c-myc deregulation leads to increased apoptotic death, but that this response may be modulated by a more downstream event such as point mutation of the p53 gene.     

An ABC transporter plays a developmental aggregation role in Myxococcus xanthus

Myxococcus xanthus is a gram-negative bacterium which has a complex life cycle. Autochemotaxis, a process whereby cells release a self-generated signaling molecule, may be the principal mechanism facilitating directed motility in both the vegetative swarming and developmental aggregation stages of this life cycle. The process requires the Frz signal transduction system, including FrzZ, a protein which is composed of two domains, both showing homology to the enteric chemotaxis response regulator CheY. The first domain of FrzZ (FrzZ1), when expressed as bait in the yeast two-hybrid system and screened against a library, was shown to potentially interact with the C-terminal portion of a protein encoding an ATP-binding cassette (AbcA). The activation domain-AbcA fusion protein did not interact with the second domain of FrzZ (FrzZ2) or with two other M. xanthus response regulator-containing proteins presented as bait, suggesting that the FrzZ1-AbcA interaction may be specific. Cloning and sequencing of the upstream region of the abcA gene showed the ATP-binding cassette to be linked to a large hydrophobic, potentially membrane-spanning domain. This domain organization is characteristic of a subgroup of ABC transporters which perform export functions. Cloning and sequencing downstream of abcA indicated that the ABC transporter is at the start of an operon containing three open reading frames. An insertion mutation in the abcA gene resulted in cells displaying the frizzy aggregation phenotype, providing additional evidence that FrzZ and AbcA may be part of the same signal transduction pathway. Cells with mutations in genes downstream of abcA showed no developmental defects. Analysis of the proposed exporter role of AbcA in cell mixing experiments showed that the ABC transporter mutant could be rescued by extracellular complementation. We speculate that the AbcA protein may be involved in the export of a molecule required for the autochemotactic process.     

Proton selective substate of the mitochondrial permeability transition pore: regulation by the redox state of the electron transport chain

The permeability transition pore of rat liver mitochondria can be closed by chelating free Ca2+, with respect to the passage of large molecules such as mannitol and sucrose. However, an apparent H+-conducting substate remains open under these conditions, as indicated by the persistence of maximal O2 consumption rates and by the failure to recover a membrane potential. Agents which favor a closed pore, such as cyclosporin A, ADP, Mg2+, or bovine serum albumin, do not close the H+-conducting substate, but it closes spontaneously when respiration becomes limited by the availability of O2. Closure provoked by an O2 limitation requires free Mg2+ in the sub-micromolar concentration range and becomes less efficient with increasing time spent in the presence of free Ca2+. The H+-conducting substate is apparently regulated by the redox status of the electron transport chain, with a reduced form favoring closure. A physical association (or equivalence) between the pore and one of the respiratory chain complexes is supported. These characteristics suggest that the transition is irreversible in vivo, if it involves a small fraction of total mitochondria, and would lead to their elimination and/or replacement by the cell. The implications of this proposal are considered, as they relate to a possible role for the transition in cellular apoptosis and the elimination of mitochondria containing mutated DNA.     

Developmental mechanics determine long bone allometry

Evolutionary and developmental factors responsible for the scaling relationships observed in animal skeletons are poorly understood. We have created a mathematical model for long bone cross-sectional development which incorporates both intrinsic growth and extrinsic, adaptive bone modeling in response to changes in bone mechanical strains during ontogeny. The model successfully simulates the developing morphology in individual animals and the bone geometric allometric relationships among adults across many species (range from mouse to elephant in size). Our results suggest that long bone scaling characteristics are not a result of intrinsic genetic factors but are the results of highly conserved, extrinsic biophysical processes whereby bone tissue strains modulate skeletal morphogenesis.     

An investigation into the relationships between area social characteristics and road accident casualties

This paper reports on the analysis of a data base created by merging road casualty information and census data for the former Lothian region in Scotland. The data base was established by assigning resident postcodes to each casualty record and relating these postcodes to the census data for the relevant census output area. Initially, consideration was given to the relationship between casualty frequencies and the distance of the accidents from the zones of residence. As might be anticipated, the casualty frequencies were higher nearer to the zones of residence, possibly due to higher exposure. Subsequently, the relationships between casualty rates and social deprivation indicators for the casualties' zone of residence were investigated. In general it was found that the casualty rates amongst residents from areas classified as relatively deprived were significantly higher than those from relatively affluent areas.     

The phosphorylation state of translation initiation factors is regulated developmentally and following heat shock in wheat

Several translation initiation factors in mammals and yeast are regulated by phosphorylation. The phosphorylation state of these factors is subject to alteration during development, environmental stress (heat shock, starvation, or heme deprivation), or viral infection. The phosphorylation state and the effect of changes in phosphorylation of the translation initiation factors of higher plants have not been previously investigated. We have determined the isoelectric states for the wheat translation initiation factors eIF-4A, eIF-4B, eIF-4F, eIF-iso4F, and eIF-2 and the poly(A)-binding protein in the seed, during germination, and following heat shock of wheat seedlings using two-dimensional gel electrophoresis and Western analysis. We found that the developmentally induced changes in isoelectric state observed during germination or the stress-induced changes were consistent with changes in phosphorylation. Treatment of the phosphorylated forms of the factors with phosphatases confirmed that the nature of the modification was due to phosphorylation. The isoelectric states of eIF-4B, eIF-4F (eIF-4E, p26), eIF-iso4F (eIF-iso4E, p28), and eIF-2alpha (p42) were altered during germination, suggesting that phosphorylation of these factors is developmentally regulated and correlates with the resumption of protein synthesis that occurs during germination. The phosphorylation of eIF-2beta (p38) or poly(A)-binding protein did not change either during germination or following a thermal stress. Only the phosphorylation state of two factors, eIF-4A and eIF-4B, changed following a heat shock, suggesting that plants may differ significantly from animals in the way in which their translational machinery is modified in response to a thermal stress.     

Lack of relations of hostility, negative affect, and high-risk behavior with low plasma lipid levels in the Coronary Artery Risk Development in Young Adults Study

BACKGROUND: Previous studies have suggested that low plasma cholesterol levels or cholesterol lowering may increase the risk of suicide and violent death. Increased aggression, risk-taking behavior, or depression has been associated with low cholesterol levels in some studies. METHODS: A total of 4240 subjects of the Coronary Artery Risk Development in Young Adults study, aged 23 to 35 years, were included in the study. Analyses were stratified by race (black or white) and sex. Persons in the lowest 10% of plasma total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were compared with the other participants in each race/sex group, using standardized measures of hostility, anger suppression, depressive symptoms, and anxiety. The relations between 5-year change in hostility and 5-year change in lipid levels also were examined. The relations between lipid levels and high-risk behavior (e.g., violent arguments or having a gun at home) were examined in a subset of subjects. All analyses were adjusted for relevant covariates. RESULTS: In cross-sectional analyses, low total cholesterol levels were not related to any of the psychological measures in any race/sex group. Among black women only, low low-density lipoprotein cholesterol was related to greater anxiety, and low triglycerides were related to lower anger suppression (P < or = .002). Among white men only, increases in hostility during the 5-year follow-up were related to increases in triglycerides (P < .01), but changes in hostility were unrelated to changes in cholesterol levels. Among a subset of 371 subjects with initially elevated total cholesterol (> or = 5.17 mmol/L [> or = 200 mg/dL]) and a non-medicated decrease of 0.52 mmol/L (> or = 20 mg/dL) or more during 5 years, hostility decreased in a univariate analysis (P < .001). High-risk behaviors also were not associated with low lipid levels. CONCLUSION: The results do not support a consistent relation between hostility, negative affect, or high-risk behaviors with low lipid levels or lipid-lowering among young adults.     

Angiosarcoma at unusual sites. A report of two cases with aspiration cytology and diagnostic pitfalls

BACKGROUND: Angiosarcomas are uncommon soft tissue neoplasms with a predilection for skin and superficial soft tissues. CASES: Two cases of angiosarcoma occurred at unusual sites, the parotid gland and lung. The parotid lesion was characterized by malignant cells present singly, in loose groups, in tight three-dimensional aggregates and in acinar formation initially misinterpreted as an adenocarcinoma. The lung mass showed malignant cells in association with vascular endothelium, suggestive of angiosarcoma. Both cases were negative for Ulex europaeus and Factor VIII-related protein but demonstrated strong immunopositivity for CD31, a highly specific endothelial marker. CONCLUSION: In the absence of vasoformative structures, important diagnostic pitfalls are pseudovascular adenoid squamous cell carcinoma, poorly differentiated adenocarcinoma, melanoma and lymphoma. Immunocytochemical studies and clinical history are essential to the correct diagnosis.