Identifying common prognostic factors in genomic cancer studies: A novel index for censored outcomes

Background  

With the growing number of public repositories for high-throughput genomic data, it is of great interest to combine the results produced by independent research groups. Such a combination allows the identification of common genomic factors across multiple cancer types and provides new insights into the disease process. In the framework of the proportional hazards model, classical procedures, which consist of ranking genes according to the estimated hazard ratio or the p-value obtained from a test statistic of no association between survival and gene expression level, are not suitable for gene selection across multiple genomic datasets with different sample sizes. We propose a novel index for identifying genes with a common effect across heterogeneous genomic studies designed to remain stable whatever the sample size and which has a straightforward interpretation in terms of the percentage of separability between patients according to their survival times and gene expression measurements.     

Development of gastric sensitivity to histamine in the rat

Sensitivity of the developing rat stomach to histamine (HA) was examined on isolated gastric mucosae of rats of various ages from the fetal to adult periods. Spontaneous acid secretion in mu eq/h.cm2 occurred at all the ages studied, at a basal rate of 0.45 +/- 0.07 in fetuses to 0.22 +/- 0.03 (day 5), 0.11 +/- 0.04 (day 10), 0.12 +/- 0.04 (day 12), 0.22 +/- 0.08 (day 16) and 0.33 +/- 0.04 (adults). In the fetal rats as in the adults, marked responses to respectively 10(-5) and 10(-4) M HA were demonstrated. The H2-receptor antagonist cimetidine diminished HA-induced secretion by 66 and 57% in fetuses and adults respectively. Between these two stages (from days 5 to 12), basal secretion and the response to HA dropped significantly. On day 21 of gestation, as well as on the critical days 5 and 12 after parturition, db-cAMP (10(-4) M) caused maximal stimulation of acid secretion. These results indicate that the development of responsiveness to HA in the rat is biphasic. They suggest that after birth, the H2-receptor adenylate cyclase system undergoes major modifications which might lead to the complete lack of responsiveness to HA by day 12.     

About the specificity of photoinduced affinity labeling of Escherichia coli ribosomes by dihydrorosaramicin, a macrolide related to erythromycin

Photoactivation of the [3H]dihydrorosaramicin chromophore at a wavelength above 300 nm allows the covalent attachment of the macrolide antibiotic to the bacterial ribosome. Bidimensional electrophoresis shows that the radioactivity is mainly associated with proteins L1, L5, L6, L15, L18, L19, S1, S3, S4, S5 and S9. When photoincorporation of the drug is conducted in the presence of puromycin as effector of [3H]dihydrorosaramicin-binding sites, a decrease in the labeling of most proteins is observed, except for L18 and L19, which are radiolabeled to a larger extent. These results allow us to speculate that L18 and L19 belong to the high-affinity binding site of rosaramicin antibiotic.     

Effects of experimental acidification on a lotic macroinvertebrate community

A three month experimental acidification was carried out on lotic bottom communities. Experiments were conducted under semi-natural conditions in plasticized wooden channels. Acidified communities (pH 4.0), with or without added aluminum, were compared with a reference community (pH 6.3–6.9). Added aluminum concentrations were respectively 0.2 and 0.4 mg 1^–1 in experiments performed in 1982 and 1983. Water chemistry and taxonomic composition of the macroinvertebrate communities were monitored. Under acidified conditions, results were similar, with or without added aluminum. Mean abundances of all groups of organisms were lowered. Mayflies nearly completely disappeared from the acidified channels. The only organism not affected by the acidification was Microtendipes sp. Differences in the organism response were observed: Orthocladiinae (Rheocricotopus, Parametriocnemus, Corynoneura, Thienemanniella, Nanocladius, Cricotopus) and Ephemeroptera (Baetis, Habrophlebia, Habrophlebiodes, Paraleptophlebia, Ephemerella), especially early instars, were very sensitive to low pH, Chironomini and Tanypodinae were much less sensitive, while Tanytarsini were intermediate; Oligochaeta and Nematoda were difficult to classify, their response being different from one year to another. Organisms inhabiting the surface of artificial substrates disappeared very rapidly from the system, while those buried inside had a delayed reaction to acidification. Aluminum which was mainly in the monomeric form was not responsible for community modifications. Direct action of hydrogen ions through a physiological stress seems a more credible explanation. These results, induced by a continuous experimental acidification, suggest that if this small headwater stream undergoes acidification, the resulting invertebrate community will be very simplified, with only resistant species able to cope with the acid conditions.     

Evidence for negative regulation of T cell growth by low affinity interleukin 2 receptors

Two experimental situations have been studied, and the results provide evidence for a negative regulatory role for the low affinity interleukin 2 receptor (LA-IL 2R). The IL 2-dependent T helper cell line L-14, deprived of IL 2, becomes quiescent and expresses comparable numbers of high affinity IL 2R (HA-IL 2R) and LA-IL 2R. After activation by recombinant IL 2, this cell line preferentially expresses LA-IL 2R. The IL 2 responsiveness of the L-14 cell line was found to vary according to the ratio of LA-IL 2R to HA-IL 2R: the relative predominance of the LA-IL 2R coincides with a hyporeactivity of cells to IL 2. In contrast, a predominance of HA-IL 2R is accompanied by an increase in cellular IL 2 reactivity. Treatment of three IL 2-dependent T cell lines (L-14, HT-2, and C30.1) with limited amounts of recombinant IL 2 and moderate concentrations of anti-IL 2R monoclonal antibodies stimulates T cell growth. This treatment was shown to selectively diminish the expression of membrane LA-IL 2R. The stimulation was attributed to the decrease of expression of LA-IL 2R.     

Ajoene prevents fat digestion by human gastric lipase in vitro

Human gastric lipase (HGL) is a sulfhydryl enzyme which has been shown by Gargouri et al. (Gargouri, Y., Moreau, H., Piéroni, G. and Verger, R. (1988) J. Biol. Chem. 263, 2159-2162) to be inhibited by hydrophobic disulfides. Since HGL is involved in the digestion and absorption of dietary fats we have investigated in vitro the ability of ajoene, a natural disulfide to inactivate HGL. Ajoene is derived from ethanolic garlic extracts. The finding that ajoene inactivates HGL is consistent with the fact that it is reactive towards sulfhydryl compounds and also corroborates previous reports on the ability of garlic to lower triacylglycerol blood levels. These data may explain the age-old Mediterranean and Oriental belief in the 'blood-thinning' effects of garlic on a molecular and physiological basis.     

Perspectives of scintigraphic diagnosis of malignant lymphoma using a new radiopharmaceutical

In the sequence of our studies on radiopharmaceuticals for malignant melanoma detection the results were most promising for the possible use of 125I or 123I-N-(2-diethyl amino ethyl)4-iodobenzamide. The biodistribution in mice bearing melanoma either human or animal from 4 to 24 hrs. post i.v. injection showed high uptake in tumor tissue together with relatively low uptake in muscle, brain, lung and liver. Scintigraphic images of the tumor obtained at the same times confirmed that melanoma detection was very promising.     

Overproduction of single-stranded-DNA-binding protein specifically inhibits recombination of UV-irradiated bacteriophage DNA in Escherichia coli.

Overproduction of single-stranded DNA (ssDNA)-binding protein (SSB) in uvr Escherichia coli mutants results in a wide range of altered phenotypes. (i) Cell survival after UV irradiation is decreased; (ii) expression of the recA-lexA regulon is slightly reduced after UV irradiation, whereas it is increased without irradiation; and (iii) recombination of UV-damaged lambda DNA is inhibited, whereas recombination of nonirradiated DNA is unaffected. These results are consistent with the idea that in UV-damaged bacteria, SSB is first required to allow the formation of short complexes of RecA protein and ssDNA that mediate cleavage of the LexA protein. However, in a second stage, SSB should be displaced from ssDNA to permit the production of longer RecA-ssDNA nucleoprotein filaments that are required for strand pairing and, hence, recombinational repair. Since bacteria overproducing SSB appear identical in physiological respects to recF mutant bacteria, it is suggested that the RecF protein (alone or with other proteins of the RecF pathway) may help RecA protein to release SSB from ssDNA.     

In vitro and in vivo inhibition of human small cell lung carcinoma (NCI-H69) growth by a somatostatin analogue

An endocrinologically-potent octapeptide analogue of somatostatin (SRIF), 3-(2-naphthyl)-D-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (BIM-23014 C), was examined for its ability to inhibit the in vitro and in vivo growth of the human small cell lung carcinoma (SCLC) line, NCI-H69. When cultured cells were implanted into athymic nude mice, treatment (500 micrograms/injection, twice daily) resulted in a prolongation of lag time for the appearance of measurable tumors, and there was a marked inhibition of the growth rate. Indeed, peptide injection in the region of the tumor resulted in a complete regression of the NCI-H69 tumors. Withdrawal of BIM-23014 C treatment resulted in an acceleration of tumor growth indicating an antiproliferative rather the oncolytic action. A similar inhibition of tumor growth was also observed when solid tumors obtained from the first implantation were used as the donor tissues. In cell culture, the proliferation in the presence of a low concentration (10nM) of BIM-23104 C was also significantly retarded suggesting a direct mechanism of action.     

Structural analysis of the specific capsular polysaccharide of Streptococcus pneumoniae type 45 (American type 72)

The specific capsular polysaccharide of Streptococcus pneumoniae type 45 (American type 72) was found to be a high molecular weight polymer composed of D-galactose, 2-acetamido-2-deoxy-D-galactose, 2-acetamido-2-deoxy-D-glucose, 2-acetamido-2-deoxy-L-fucose, L-rhamnose, glycerol, and phosphate (2:1:1:1:1:1:1). Partial hydrolysis, dephosphorylation, methylation analysis, periodate oxidation studies, and one- and two-dimensional 1H and 13C high-field nuclear magnetic resonance experiments showed the polysaccharide to be a branched polymer of a 1-phosphoglycerol-substituted hexasaccharide repeating unit having the structure: (formula; see text).