Age-Related Differences in Susceptibility to Carcinogenesis: A Quantitative Analysis of Empirical Animal Bioassay Data

In revising cancer risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) analyzed animal cancer bioassay data over different periods of life. In this article, we report an improved analysis of these data (supplemented with some chemical carcinogenesis observations not included in the U.S. EPA’s original analysis) and animal bioassay studies of ionizing radiation. We use likelihood methods to avoid excluding cases where no tumors were observed in specific groups. We express dosage for animals of different weights on a metabolically consistent basis (concentration in air or food, or per unit body weight to the three-quarters power). Finally, we use a system of dummy variables to represent exposures during fetal, preweaning, and weaning–60-day postnatal periods, yielding separate estimates of relative sensitivity per day of dosing in these intervals. Central estimate results indicate a 5- to 60-fold increased carcinogenic sensitivity in the birth–weaning period per dose ÷ (body weight(0.75)-day) for mutagenic carcinogens and a somewhat smaller increase—centered about 5-fold—for radiation carcinogenesis per gray. Effects were greater in males than in females. We found a similar increased sensitivity in the fetal period for direct-acting nitrosoureas, but no such increased fetal sensitivity was detected for carcinogens requiring metabolic activation. For the birth–weaning period, we found an increased sensitivity for direct administration to the pups similar to that found for indirect exposure via lactation. Radiation experiments indicated that carcinogenic sensitivity is not constant through the “adult” period, but the dosage delivered in 12- to 21-month-old animals appears a few-fold less effective than the comparable dosage delivered in young adults (90–105 days of age)

Supersymmetry in the shadow of photini

Additional neutral gauge fermions -- "photini" -- arise in string compactifications as superpartners of U(1) gauge fields. Unlike their vector counterparts, the photini can acquire weak-scale masses from soft SUSY breaking and lead to observable signatures at the LHC through mass mixing with the bino. In this work we investigate the collider consequences of adding photini to the neutralino sector of the MSSM. Relatively large mixing of one or more photini with the bino can lead to prompt decays of the lightest ordinary supersymmetric particle; these extra cascades transfer most of the energy of SUSY decay chains into Standard Model particles, diminishing the power of missing energy as an experimental handle for signal discrimination. We demonstrate that the missing energy in SUSY events with photini is reduced dramatically for supersymmetric spectra with MSSM neutralinos near the weak scale, and study the effects on limits set by the leading hadronic SUSY searches at ATLAS and CMS. We find that in the presence of even one light photino the limits on squark masses from hadronic searches can be reduced by 400 GeV, with comparable (though more modest) reduction of gluino mass limits. We also consider potential discovery channels such as dilepton and multilepton searches, which remain sensitive to SUSY spectra with photini and can provide an unexpected route to the discovery of supersymmetry. Although presented in the context of photini, our results apply in general to theories in which additional light neutral fermions mix with MSSM gauginos.Comment: 23 pages, 8 figures, references adde

Tethered cord: natural history, surgical outcome and risk for Chiari malformation 1 (CM1): A review of 110 detethering

The surgical results of this series of occult spina bifida seem better than the natural history registered in the long pre-operative period in terms of neurological deterioration. The major contribution to this result is attributed to neurophysiological monitoring that lowers the risks of permanent damage and increases the percentage of effective detethering. The present series of TCS, due to conus and filar lipoma, documents that CM1 is a really rare association occurring in less than 6% of the patients, despite the low position of conus. The detethering procedure did not influence the tonsillar position, thus excluding the correlation between the tethering and the tonsillar descent. The genetic alteration documented in a girl reinforces the hypothesis of a rare complex polymaformative picture deserving multiple procedures according to the prevailing clinical symptoms

The Schro¨\ddot{o}dinger-Poisson equations as the large-N limit of the Newtonian N-body system: applications to the large scale dark matter dynamics

In this paper it is argued how the dynamics of the classical Newtonian N-body system can be described in terms of the Schr$\ddot{o}$dinger-Poisson equations in the large $N$ limit. This result is based on the stochastic quantization introduced by Nelson, and on the Calogero conjecture. According to the Calogero conjecture, the emerging effective Planck constant is computed in terms of the parameters of the N-body system as $\hbar \sim M^{5/3} G^{1/2} (N/)^{1/6}$, where is $G$ the gravitational constant, $N$ and $M$ are the number and the mass of the bodies, and $$ is their average density. The relevance of this result in the context of large scale structure formation is discussed. In particular, this finding gives a further argument in support of the validity of the Schr$\ddot{o}$dinger method as numerical double of the N-body simulations of dark matter dynamics at large cosmological scales.Comment: Accepted for publication in the Euro. Phys. J.

Human newborn bacille Calmette–Guérin vaccination and risk of tuberculosis disease: a case-control study

: An incomplete understanding of the immunological mechanisms underlying protection against tuberculosis (TB) hampers the development of new vaccines against TB. We aimed to define host correlates of prospective risk of TB disease following bacille Calmette-Guérin (BCG) vaccination. : In this study, 5,726 infants vaccinated with BCG at birth were enrolled. Host responses in blood collected at 10 weeks of age were compared between infants who developed pulmonary TB disease during 2 years of follow-up (cases) and those who remained healthy (controls). : Comprehensive gene expression and cellular and soluble marker analysis failed to identify a correlate of risk. We showed that distinct host responses after BCG vaccination may be the reason: two major clusters of gene expression, with different myeloid and lymphoid activation and inflammatory patterns, were evident when all infants were examined together. Cases from each cluster demonstrated distinct patterns of gene expression, which were confirmed by cellular assays. : Distinct patterns of host responses to Mycobacterium bovis BCG suggest that novel TB vaccines may also elicit distinct patterns of host responses. This diversity should be considered in future TB vaccine development

Retroviral Integration Process in the Human Genome: Is It Really Non-Random? A New Statistical Approach

Retroviral vectors are widely used in gene therapy to introduce therapeutic genes into patients' cells, since, once delivered to the nucleus, the genes of interest are stably inserted (integrated) into the target cell genome. There is now compelling evidence that integration of retroviral vectors follows non-random patterns in mammalian genome, with a preference for active genes and regulatory regions. In particular, Moloney Leukemia Virus (MLV)–derived vectors show a tendency to integrate in the proximity of the transcription start site (TSS) of genes, occasionally resulting in the deregulation of gene expression and, where proto-oncogenes are targeted, in tumor initiation. This has drawn the attention of the scientific community to the molecular determinants of the retroviral integration process as well as to statistical methods to evaluate the genome-wide distribution of integration sites. In recent approaches, the observed distribution of MLV integration distances (IDs) from the TSS of the nearest gene is assumed to be non-random by empirical comparison with a random distribution generated by computational simulation procedures. To provide a statistical procedure to test the randomness of the retroviral insertion pattern, we propose a probability model (Beta distribution) based on IDs between two consecutive genes. We apply the procedure to a set of 595 unique MLV insertion sites retrieved from human hematopoietic stem/progenitor cells. The statistical goodness of fit test shows the suitability of this distribution to the observed data. Our statistical analysis confirms the preference of MLV-based vectors to integrate in promoter-proximal regions