Loss of heterozygosity and microsatellite instability in de novo versus ex-adenoma carcinomas of the colorectum

Small adenocarcinomas of the colorectum showing no evidence of origin from an adenoma have been called de novo carcinomas, a name that implies an origin via a different molecular genetic mechanism than the usual colorectal carcinoma which develops from an adenoma. Using microsatellite analysis, 35 early (pT1) de novo and 36 pT1 ex-adenoma carcinomas were compared using 8 microsatellite loci at 6 different chromosomal loci (1p, 2p, 8p, 5q, 17p, and 18q) known or hypothesized to be important for colorectal carcinogenesis. The rate of loss of heterozygosity (LOH) at the 17p locus (near the p53 gene) was significantly higher in the de novo than in the ex-adenoma group (73 vs. 37%, P = 0.004). The rates of LOH at the other loci (including the APC and DCC genes) and the rate of MSI were not significantly different in the two groups. These results indicate that de novo carcinomas of the colorectum develop via a similar carcinogenetic pathway as conventional ex-adenoma carcinomas; however, their higher rate of LOH at 17p is evidence for a biologically more advanced lesion with more frequent p53 mutations, consistent with clinicopathological data indicating that de novo carcinomas are more aggressive than ex-adenoma carcinomas.     

Regulated nucleo/cytoplasmic exchange of HOG1 MAPK requires the importin beta homologs NMD5 and XPO1

MAP kinase signaling modules serve to transduce extracellular signals to the nucleus of eukaryotic cells, but little is known about how signals cross the nuclear envelope. Exposure of yeast cells to increases in extracellular osmolarity activates the HOG1 MAP kinase cascade, which is composed of three tiers of protein kinases, namely the SSK2, SSK22 and STE11 MAPKKKs, the PBS2 MAPKK, and the HOG1 MAPK. Using green fluorescent protein (GFP) fusions of these kinases, we found that HOG1, PBS2 and STE11 localize to the cytoplasm of unstressed cells. Following osmotic stress, HOG1, but neither PBS2 nor STE11, translocates into the nucleus. HOG1 translocation occurs very rapidly, is transient, and correlates with the phosphorylation and activation of the MAP kinase by its MAPKK. HOG1 phosphorylation is necessary and sufficient for nuclear translocation, because a catalytically inactive kinase when phosphorylated is translocated to the nucleus as efficiently as the wild-type. Nuclear import of the MAPK under stress conditions requires the activity of the small GTP binding protein Ran-GSP1, but not the NLS-binding importin alpha/beta heterodimer. Rather, HOG1 import requires the activity of a gene, NMD5, that encodes a novel importin beta homolog. Similarly, export of dephosphorylated HOG1 from the nucleus requires the activity of the NES receptor XPO1/CRM1. Our findings define the requirements for the regulated nuclear transport of a stress-activated MAP kinase.     

Magnetic field dependence of the cyclotron effective mass in the organic superconductor κ-(BEDT-TTF)2I3

κ-(BEDT-TTF)₂I₃ is an electronically extreme two-dimensional (2d) organic metal with a superconducting transition at around 4K. In magnetic fields above 12T the effective mass, as obtained from the temperature dependence of the amplitudes of Shubnikov-de Haas (SdH) oscillations, is magnetic field dependent as long as the magnetic field is arranged perpendicular to the conducting planes. In contrast to this by turning the magnetic field 27° or even only by 9° the observed effective mass (as obtained from SdH- and de Haas-van Alphen (dHvA)-measurements) is field independent. We suppose that the occurrence of anyons at temperatures below 1K and in fields above 12T is the reason for the observed field dependence of the effective mass.     

Using focus groups to identify psychosocial issues of urban black individuals with diabetes

BACKGROUND: Human serum represents an important barrier to the entry of most mucosal organisms into tissues and to the systemic circulation. If at all present, Helicobacter pylori within gastric tissue is rare, and bacteremia for this organism has been described only once. METHODS: To assess the susceptibility of H. pylori to the bactericidal activity present in normal human serum (NHS), we examined 13 H. pylori isolates. To assess the contributions of the classical and alternative complement pathways to killing, we added either C2-deficient or factor B-deficient serum, respectively, to heat-inactivated NHS. Also we assessed the ability of the strains to bind 125I-C3. RESULTS: After incubation for 60 minutes at 37 degrees C, all 13 H. pylori strains were killed by NHS; heating to 56 degrees C for 30 minutes ablated killing, indicating complement dependence for this phenomenon. In the absence of an antibody source, there was no killing when either an alternative or classical complement pathway source was used. Adding B-deficient serum to heat-inactivated normal human serum did not restore killing, but adding C2-deficient serum permitted partial killing. All of the 13 strains bound 125I-C3. Although the kinetics varied from strain to strain, C3 bound was significantly correlated (r = 0.61, p = 0.03) with serum susceptibility. CONCLUSIONS: H. pylori are susceptible to complement, alternative pathway activation appears critical, and C3 binding is a major locus of variability.     

Novel algorithm for time division multiple access in broadband ISDN passive optical networks

For shared access to a broadband communication network using the asynchronous transfer mode (ATM) a passive optical network (PON) has previously been proposed. A novel algorithm to evaluate the time division multiple access (TDMA) protocol which controls the traffic from the various subscribers towards the shared access equipment (upstream direction) is proposed. It uses counters to estimate the moment of a data packet arrival at the subscriber side. By this ‘look-ahead’ technique no extra upstream channels are needed to initiate the polling by the subscriber. The algorithm guarantees fair access for all subscribers and minimizes the necessary overhead. Both the maximum access delay and overhead may be readily calculated, and the obtained results were supported by numerical simulation. Applicability in the standard broadband network environment has been proved by hardware design simulation.     

Association of MSX1 and TGFB3 with nonsyndromic clefting in humans

Nonsyndromic cleft lip with or without cleft palate (CL/P) and nonsyndromic cleft palate only (CPO) are common congenital anomalies with significant medical, psychological, social, and economic ramifications. Both CL/P and CPO are examples of complex genetic traits. There exists sufficient evidence to hypothesize that disease loci for CL/P and CPO can be identified by a candidate-gene linkage-disequilibrium (LD) strategy. Candidate genes for clefting, including TGFA, BCL3, DLX2, MSX1, and TGFB3, were screened for LD with either CL/P or CPO in a predominantly Caucasian population, with both case-control- and nuclear-family-based approaches. Previously reported LD for TGFA with both CL/P and CPO could not be confirmed, except in CL/P patients with a positive family history. Also, in contrast to previous studies, no LD was found between BCL3 and either CL/P or CPO. Significant LD was found between CL/P and both MSX1 and TGFB3 and between CPO and MSX1, suggesting that these genes are involved in the pathogenesis of clefting. In addition, a mutation search in the genes DLX2, MSX1, and TGFB3 was performed in 69 CPO patients and in a subset of the CL/P patients. No common mutations were found in the coding regions of these genes; however, several rare variants of MSX1 and TGFB3 were found that may alter the latters' normal function. These results form the basis for future research, including (a) mutation searches in the MSX1 and TGFB3 genes in Caucasian CL/P patients and (b) extension of the search for MSX1 mutations in CPO patients to the noncoding regions.     

Mechanism of triazolo-benzodiazepine and benzodiazepine action in anxiety and depression: behavioral studies with concomitant in vivo CA1 hippocampal norepinephrine and serotonin release detection in the behaving animal

1. Real time, in vivo microvoltammetric studies were performed, using miniature carbon-based sensors, to concurrently detect norepinephrine (NE) release and serotonin (5-HT) release, in 2 separate electrochemical signals, within CA1 region of hippocampus in the freely moving and behaving, male, Sprague Dawley laboratory rat. 2. Concurrently, four parameters of open-field behavior, i.e. Ambulations, Rearing, Fine Movements and Central Ambulatory behavior (a measure of anxiety reduction behavior), were assayed by infrared photobeam detection. 3. Time course studies showed that the mechanism of action of the triazolobenzodiazepine (TBZD), adinazolam, (Deracyn) is dramatically different from that of the classical benzodiazepine (BZD), diazepam (Valium, i.e., adinazolam increased, whereas diazepam decreased, 5-HT release within CA1 region of hippocampus in the freely moving and behaving rat. 4. Adinazolam initially increased NE release and then decreased NE release in CA1 region of hippocampus in the freely moving and behaving rat whereas diazepam only decreased the electrochemical signal for NE; the decrease in NE produced by adinazolam was greater than the decrease in NE release produced by diazepam. 5. The Behavioral Activity Patterns, derived from same animal controls, simultaneously with detection of in vivo microvoltammetric signals for NE release and 5-HT release, showed that the BZD, diazepam, exhibited more potent sedative properties than did the TBZD adinazolam. 6. Hippocampal 5-HT and NE release effects of the TBZD, adinazolam, concomitant with behavioral effects lends explanation to the dual anxiolytic/antidepressant properties of the TBZDs.