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At least 289 records · Page 16Linked to original sources
PubMed2002

Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6.

Interleukin-6 (IL-6) is a prominent tumor growth factor for malignant multiple myeloma cells. In addition to its known activation of the Janus tyrosine kinase-STAT and RAS-MEK-ERK pathways, recent work suggests that IL-6 can also activate the phosphatidylinositol 3-kinase (PI3-K)/AKT kinase pathway in myeloma cells. Because activation of the PI3-K/AKT as well as RAS-MEK-ERK pathways may result in downstream stimulation of the p70(S6K) (p70) and phosphorylation of the 4E-BP1 translational repressor, we assessed these potential molecular targets in IL-6-treated myeloma cells. IL-6 rapidly activated p70 kinase activity and p70 phosphorylation. Activation was inhibited by wortmannin, rapamycin, and the ERK inhibitors PD98059 and UO126, as well as by a dominant negative mutant of AKT. The concurrent requirements for both ERK and PI3-K/AKT appeared to be a result of their ability to phosphorylate p70 on different residues. In contrast, IL-6-induced phosphorylation of 4E-BP1 was inhibited by rapamycin, wortmannin, and dominant negative AKT but ERK inhibitors had no effect, indicating ERK function was dispensable. In keeping with these data, a dominant active AKT mutant was sufficient to induce 4E-BP1 phosphorylation but could not by itself activate p70 kinase activity. Prevention of IL-6-induced p70 activation and 4E-BP1 phosphorylation by the mammalian target of rapamycin inhibitors rapamycin and CCI-779 resulted in inhibition of IL-6-induced myeloma cell growth. These results indicate that both ERK and PI3-K/AKT pathways are required for optimal IL-6-induced p70 activity, but PI3-K/AKT is sufficient for 4E-BP1 phosphorylation. Both effects are mediated via mammalian target of rapamycin function, and, furthermore, these effects are critical for IL-6-induced tumor cell growth.

Adaptor Proteins, Signal Transducing↗
PubMed2006

In vivo membrane topology of Escherichia coli SecA ATPase reveals extensive periplasmic exposure of multiple functionally important domains clustering on one face of SecA.

The Sec-dependent protein translocation pathway promotes the transport of proteins into or across the bacterial plasma membrane. SecA ATPase has been shown to be a nanomotor that associates with its protein cargo as well as the SecYEG channel complex and to undergo ATP-driven cycles of membrane insertion and retraction that promote stepwise protein translocation. Previous studies have shown that both the 65-kDa N-domain and 30-kDa C-domain of SecA appear to undergo such membrane cycling. In the present study we performed in vivo sulfhydryl labeling of an extensive collection of monocysteine secA mutants under topologically specific conditions to identify regions of SecA that are accessible to the trans side of the membrane in its membrane-integrated state. Our results show that distinct regions of five of six SecA domains were labeled under these conditions, and such labeling clusters to a single face of the SecA structure. Our results demarcate an extensive face of SecA that interacts with SecYEG and is in fluid contact with the protein-conducting channel. The observed domain-specific labeling patterns should also provide important constraints on model building efforts in this dynamic system.

Adenosine Triphosphatases↗
PubMed1999

Bloodborne exposures at a United States Army Medical Center.

With the ultimate goal of minimizing exposures, we conducted a hazard analysis on bloodborne disease transmission at our hospital to identify appropriate control interventions. We utilized basic principles of occupational epidemiology to gather information on the severity and extent of exposures. Because we suspected inadequate reporting of needlestick injuries, we collected 339 reported exposures of health care workers; we conducted a survey of all workers requiring universal precautions training for bloodborne pathogens. The annual incidence of exposures reported was 93.7 per 1000 workers who required this training. Sharps accounted for 83.5 percent of these exposures. Exposure sources demonstrated 4.3 percent positive for HIV, 4.4 percent positive for hepatitis B, and 7.1 percent positive for hepatitis C. The survey indicated that blood/body fluid exposures were underreported by at least fourfold. House officers were most at risk. At-risk behaviors were identified by the significant differences in knowledge of HIV transmission and work practices between groups reporting no or single exposures versus groups reporting multiple exposures. Increased emphasis should be placed on education, reporting exposures, and training house officers in procedures requiring the use of hollow bore needles. This study shows how the use of occupational epidemiology principles and methods were utilized in conducting a thorough hazard analysis and in identifying appropriate control methods.

Adult↗
PubMedDate not supplied

Human Exposures to N,N-diethyl-m-toluamide insect repellents reported to the American Association of Poison Control Centers 1993-1997.

This study analyzed 20,764 exposures involving insect repellants containing N,N-diethyl-m-toluamide (DEET) that were reported to poison control centers from 1993 to 1997. Nearly 70% of the cases reported no symptoms related to the exposure. The occurrence of symptoms was related to the route of exposure, with the highest rates associated with ocular exposures, followed by inhalation, multiple exposure routes, dermal, and ingestion. Two deaths were reported, one in a 26-year-old male and one in a 34-year-old female, both following a dermal exposure. Twenty-six subjects experienced major effects. The greatest number of reported exposures involved infants and children, but this group experienced lower rates of adverse effects than teens or adults. There was no clear relationship between DEET concentration and presence or severity of clinical effects. For the cases reported to poison control centers and included in this analysis, the risk of serious medical effects for labeled use of insect repellants containing N,N-diethyl-m-toluamide appears to be low.

Adolescent↗
PubMed1994

Hierarchical regression analysis applied to a study of multiple dietary exposures and breast cancer.

Hierarchical regression attempts to improve standard regression estimates by adding a second-stage "prior" regression to an ordinary model. Here, we use hierarchical regression to analyze case-control data on diet and breast cancer. This regression yields semi-Bayes relative risk estimates for dietary items by using a second-stage model to pull estimates toward each other when the corresponding variables have similar levels of nutrients. Unlike classical Bayesian analysis, however, no use is made of previous studies on nutrient effects. Compared with results obtained with one-stage conditional maximum-likelihood logistic regression, our hierarchical regression model gives more stable and plausible estimates. In particular, certain effects with implausible maximum-likelihood estimates have more reasonable semi-Bayes estimates.

Bayes Theorem↗
PubMed2001

Epithelial damage thresholds for multiple-pulse exposures to 80 ns pulses of CO2 laser radiation.

Corneal epithelial damage thresholds for exposures to 80 ns pulses of 10.6 microm infrared radiation produced by a CO2-TEA laser were investigated. Thresholds were determined for sequences of 1, 2, 8, 32, 128, and 1,024 pulses at pulse repetition frequencies of 10 and 16 Hz. Threshold damage is correlated by an empirical power law of the form EDth = CN(-alpha) in which EDth, is the threshold radiant exposure per pulse, and N is the number of pulses. The constants C and alpha are similar for the two pulse repetition frequencies. For the combined data set, C = 2,955 J m(-2) pulse(-1) (295.5 mJ cm(-2) pulse(-1) and alpha = 0.178. This value of the constant C is within 5% of the measured damage threshold for a single 80 ns pulse exposure. Temperature calculations reveal that the maximum temperature increase on the beam axis, 10 microm beneath the anterior tear surface, resulting from the different threshold exposures is constant to within +/-10% of the mean values. This result is consistent with a critical temperature damage model. Damage threshold measurements on cooled corneas indicate that the damage mechanism indeed has a substantial thermal component.

Animals↗
PubMed2002

Preadult stage parasites and multiple timed exposure to infective larvae are involved in development of limb edema in Brugia malayi-infected Indian leaf monkeys (Presbytis entellus).

The pathogenesis of filarial limb edema is not known. The role of parasitological variables and parasite-mediated phenomena in the development of limb edema was investigated in the Presbytis entellus-Brugia malayi model. Infection was initiated with subcutaneous inoculation of infective third-stage larvae (L(3)), and the animals were reexposed to different doses of L(3) at the prepatent, patent, and diminishing microfilaremia (0 to 5% of peak microfilaremia count) stages of infection. A large L(3) inoculum size and repeated inoculation in the ankle region during the prepatent, patent, and diminishing microfilaremia stages of infection were found to be necessary for reproducible induction of limb edema. The preadult stage of the parasite was found to be the most potent inducer of limb edema, followed by L(5) and L(4). The presence of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 in edema fluid in the leg receiving the parasite challenge indicated that the limb edema development was due to parasite-mediated cytokine responses. The absence of bacterial infection or anti-streptolysin O titer in the edema fluid and blood indicated that bacterial infection is not necessary for the development of limb edema.

Animals↗
PubMed2005

Generalization of motor learning based on multiple field exposures and local adaptation.

Previous studies have used transfer of learning over workspace locations as a means to determine whether subjects code information about dynamics in extrinsic or intrinsic coordinates. Transfer has been observed when the torque associated with joint displacement is similar between workspace locations-rather than when the mapping between hand displacement and force is preserved-which is consistent with muscle- or joint-based encoding. In the present study, we address the generality of an intrinsic coding of dynamics and examine how generalization occurs when the pattern of torques varies over the workspace. In two initial experiments, we examined transfer of learning when the direction of a force field was fixed relative to an external frame of reference. While there were no beneficial effects of transfer after training at a single location (experiments 1 and 2), excellent performance was observed at the center of the workspace after training at two lateral locations (experiment 2). Experiment 3 and associated simulations assessed the characteristics of this generalization. In these studies, we examined the patterns of transfer observed after adaptation to force fields that were composed of two subfields that acted in opposite directions. The experimental and simulated data are consistent with the idea that information about dynamics is encoded in intrinsic coordinates. The nervous system generalizes dynamics learning by interpolating between sets of control signals, each locally adapted to different patterns of torques.

Adaptation, Physiological↗
PubMed2003

Using multiple drug exposure levels to optimize power in pharmacogenetic trials.

Large-scale pharmacogenetic trials testing tens to hundreds of thousands of single-nucleotide polymorphisms (SNPs) will become possible in the near future given rapidly decreasing costs of genotyping. Devising optimal designs for these trials will be a significant challenge. The author demonstrates how the level of drug exposure may strongly affect the power to detect true associations between genetic polymorphisms and drug response. An analytic model of drug response is described that is used to simulate pharmacogenetic trials. Analytical and numerical sensitivity analyses are performed on the model to demonstrate possible exposure-sensitivity behaviors. This model shows that the power to detect an association can be a nonlinear, nonmonotonic function of drug exposure. This model is further investigated using two clinical trial designs. The conclusion is that trial designs that use more than one drug exposure or dose will have an increased likelihood of discovering statistically significant pharmacogenetic associations.

Computer Simulation↗
PubMed2003

Enhanced anterior pituitary mitotic response to adrenalectomy after multiple glucocorticoid exposures.

OBJECTIVES: Glucocorticoid withdrawal in man is associated with transient but sometimes prolonged impairment of hypothalamo-pituitary-adrenal axis secretory responsiveness. This has led to continued concern in the clinical arena. The acute anterior pituitary response to glucocorticoids in the rat includes apoptosis-mediated deletion of a cell population. Whilst continued cell turnover following glucocorticoid withdrawal and the potential for differentiation of uncommitted precursor cells and transdifferentiation of other secretory cell types predicts that, given sufficient time, complete anterior pituitary trophic recovery is likely, this hypothesis has not previously been tested. DESIGN AND METHODS: We have quantified pituitary mitotic and apoptotic rate, as well as corticotroph number and pro-opiomelanocortin transcript prevalence, together with hypothalamic corticotrophin-releasing hormone and vasopressin transcript prevalence 5 weeks after three short dexamethasone treatments each separated by a week. Bilateral adrenalectomy was then carried out as a maximal secretory and trophic stimulus, and the response to a fourth dexamethasone treatment assessed 1 week later. RESULTS: Anterior pituitary mitotic index was significantly higher in rats previously exposed to dexamethasone compared with age-matched controls exposed to dexamethasone for the first time. No differences were found in the subsequent apoptotic response to a fourth dexamethasone treatment or in the levels of paraventricular corticotrophin-releasing hormone or vasopressin transcripts or pituitary pro-opiomelanocortin transcripts. CONCLUSIONS: These data indicate that full recovery of pituitary mitotic activity takes longer than the recovery of secretory parameters, and suggest that, for several weeks after glucocorticoid exposure, the ability of the pituitary to meet fresh demands placed on it may be suboptimal.

Adrenalectomy↗