Age-Related Differences in Susceptibility to Carcinogenesis. II. Approaches for Application and Uncertainty Analyses for Individual Genetically Acting Carcinogens

In an earlier report we developed a quantitative likelihood-based analysis of the differences in sensitivity of rodents to mutagenic carcinogens across three life stages (fetal, birth to weaning, and weaning to 60 days) relative to exposures in adult life. Here we draw implications for assessing human risks for full lifetime exposures, taking into account three types of uncertainties in making projections from the rodent data: uncertainty in the central estimates of the life-stage–specific sensitivity factors estimated earlier, uncertainty from chemical-to-chemical differences in life-stage–specific sensitivities for carcinogenesis, and uncertainty in the mapping of rodent life stages to human ages/exposure periods. Among the uncertainties analyzed, the mapping of rodent life stages to human ages/exposure periods is most important quantitatively (a range of several-fold in estimates of the duration of the human equivalent of the highest sensitivity “birth to weaning” period in rodents). The combined effects of these uncertainties are estimated with Monte Carlo analyses. Overall, the estimated population arithmetic mean risk from lifetime exposures at a constant milligrams per kilogram body weight level to a generic mutagenic carcinogen is about 2.8-fold larger than expected from adult-only exposure with 5–95% confidence limits of 1.5-to 6-fold. The mean estimates for the 0- to 2-year and 2- to 15-year periods are about 35–55% larger than the 10- and 3-fold sensitivity factor adjustments recently proposed by the U.S. Environmental Protection Agency. The present results are based on data for only nine chemicals, including five mutagens. Risk inferences will be altered as data become available for other chemicals

Characteristic Relations for Quantum Matrices

General algebraic properties of the algebras of vector fields over quantum linear groups $GL_q(N)$ and $SL_q(N)$ are studied. These quantum algebras appears to be quite similar to the classical matrix algebra. In particular, quantum analogues of the characteristic polynomial and characteristic identity are obtained for them. The $q$-analogues of the Newton relations connecting two different generating sets of central elements of these algebras (the determinant-like and the trace-like ones) are derived. This allows one to express the $q$-determinant of quantized vector fields in terms of their $q$-traces.Comment: 11 pages, latex, an important reference [16] added

Interaction between Thymidylate Synthase and Its Cognate mRNA in Zebrafish Embryos

Thymidylate synthase (TS), which catalyzes the de novo synthesis of dUMP, is an important target for cancer therapy. In this report, the effects of 5-fluorouracil (5-FU) and ZD1694 on the regulation of TS gene expression were evaluated in zebrafish embryos. Our results revealed that the expression of TS was increased by about six-fold when embryos were treated with 1.0 µM 5-FU and there was a greater than 10-fold increase in the TS protein level after treatment with 0.4 µM ZD1694. Northern blot analysis confirmed that expression of TS mRNA was identical in treated or untreated embryos. Gel shift and immunoprecipitation assays revealed that zebrafish TS was specifically bound with its cognate mRNA in vitro and in vivo. We identified a 20 nt RNA sequence, TS:N20, localized to the 5′-UTR of TS mRNA, which corresponded to nt 13–32; TS:N20 bound to the TS protein with an affinity similar to that of the full-length TS mRNA. The MFold program predicted that TS:N20 formed a stable stem-loop structure similar to that of the cis-acting element found in human TS mRNA. Variant RNAs with either a deletion or mutation in the core motif of TS:N20 were unable to bind to the TS protein. In vitro translation experiments, using the rabbit lysate system, confirmed that zebrafish TS mRNA translation was significantly repressed when an excess amount of TS protein was included in the system. Additionally, a TS stability experiment confirmed that treatment of zebrafish embryos with 5-FU could increase the TS stability significantly, and the half life of TS protein was about 2.7 times longer than in untreated embryos. Our study revealed a structural requirement for the interaction of TS RNA with TS protein. These findings also demonstrated that the increase in TS protein induced by 5-FU occurs at the post-transcriptional level and that increased stability and translation efficiency both contributed to the increase in TS protein levels induced by TS inhibitors

Hospital Authority audit of the outcome of endoscopic resection of superficial upper gastro-intestinal lesions in Hong Kong

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A phase II trial of ixabepilone in Asian patients with advanced gastric cancer previously treated with fluoropyrimidine-based chemotherapy

PURPOSE: The highest rates of gastric cancer occur in Eastern Asia. Fluoropyrimidine-based therapy is used initially in unresectable and metastatic disease, but no single standard of care exists following disease progression. Ixabepilone, an epothilone B analog, is a non-taxane microtubule-stabilizing agent with clinical activity across multiple tumor types approved by the United States Food and Drug Administration for treatment of metastatic breast cancer. METHODS: Asian patients with unresectable or metastatic gastric adenocarcinoma who had failed fluoropyrimidine-based chemotherapy received ixabepilone 40 mg/m(2) by 3-h intravenous infusion every 3 weeks. The primary endpoint was objective response rate (ORR). RESULTS: Fifty-two patients were treated (65.4 % men; median age: 56.5 years). The ORR was 15.4 % (95 % confidence interval [CI] 6.9-28.1); 8 patients achieved partial responses for a median duration of 3.1 months (95 % CI 2.6-4.1 months) and 26 patients (50.0 %) had stable disease. Median progression-free survival was 2.8 months (95 % CI 2.1-3.5 months). The most common grade 3 non-hematological toxicities were fatigue (9.6 %), decreased appetite (7.7 %), sensory neuropathy (5.8 %), and diarrhea (5.8 %). Grade 3/4 neutropenia occurred in 46.2 % of patients. CONCLUSIONS: Ixabepilone is active in Asian patients with advanced gastric cancer and shows a toxicity profile similar to those previously reported in other tumor types.published_or_final_versio

Planar and Nonplanar Konishi Anomalies and Effective Superpotential for Noncommutative N=1 Supersymmetric U(1)

The Konishi anomalies for noncommutative N=1 supersymmetric U(1) gauge theory arising from planar and nonplanar diagrams are calculated. Whereas planar Konishi anomaly is the expected \star-deformation of the commutative anomaly, nonplanar anomaly reflects the important features of nonplanar diagrams of noncommutative gauge theories, such as UV/IR mixing and the appearance of nonlocal open Wilson lines. We use the planar and nonplanar Konishi anomalies to calculate the effective superpotential of the theory. In the limit of vanishing |\Theta p|, with \Theta the noncommutativity parameter, the noncommutative effective superpotential depends on a gauge invariant superfield, which includes supersymmetric Wilson lines, and has nontrivial dependence on the gauge field supermultiplet.Comment: LaTeX, 36 pages. Version 2: Typos Corrected. Version 3: Extensively revised version, 42 pages, to be published in Int. J. Mod. Phys. A. (2005

On the Bohr inequality

The Bohr inequality, first introduced by Harald Bohr in 1914, deals with finding the largest radius $r$, $0<r<1$, such that $\sum_{n=0}^\infty |a_n|r^n \leq 1$ holds whenever $|\sum_{n=0}^\infty a_nz^n|\leq 1$ in the unit disk $\mathbb{D}$ of the complex plane. The exact value of this largest radius, known as the \emph{Bohr radius}, has been established to be $1/3.$ This paper surveys recent advances and generalizations on the Bohr inequality. It discusses the Bohr radius for certain power series in $\mathbb{D},$ as well as for analytic functions from $\mathbb{D}$ into particular domains. These domains include the punctured unit disk, the exterior of the closed unit disk, and concave wedge-domains. The analogous Bohr radius is also studied for harmonic and starlike logharmonic mappings in $\mathbb{D}.$ The Bohr phenomenon which is described in terms of the Euclidean distance is further investigated using the spherical chordal metric and the hyperbolic metric. The exposition concludes with a discussion on the $n$-dimensional Bohr radius

Formalization of Transform Methods using HOL Light

Transform methods, like Laplace and Fourier, are frequently used for analyzing the dynamical behaviour of engineering and physical systems, based on their transfer function, and frequency response or the solutions of their corresponding differential equations. In this paper, we present an ongoing project, which focuses on the higher-order logic formalization of transform methods using HOL Light theorem prover. In particular, we present the motivation of the formalization, which is followed by the related work. Next, we present the task completed so far while highlighting some of the challenges faced during the formalization. Finally, we present a roadmap to achieve our objectives, the current status and the future goals for this project.Comment: 15 Pages, CICM 201

The number of intestinal bacteria is not critical for the enhancement of antitumor activity and reduction of intestinal toxicity of irinotecan by the Chinese herbal medicine PHY906 (KD018)

Background: The four-herb Chinese medicine PHY906(KD018) has been shown to both enhance the in vivo antitumor activity of irinotecan (CPT-11) against colon cancer tumor allografts and alleviate intestinal toxicity caused by CPT-11. Methods: Since intestinal bacteria can metabolize CPT-11 and PHY906, we investigated whether intestinal bacteria play a critical role in the in vivo activity of PHY906 in murine Colon-38 tumor-bearing mice. Intestinal bacteria were depleted using streptomycin/neomycin for 10 days before and during treatment with PHY906 and/or CPT-11. qPCR using 16S DNA group-specific primers was used to quantify the levels of the major intestinal bacteria. Results: Both PHY906 and antibiotic treatment changed the profile of intestinal bacteria species: Lactobacillus/Enterococcus, Bacteroides, Clostridium leptum, and E. rectale/C. coccoides. Antibiotic treatment did not alter the ability of PHY906 to enhance the antitumor activity of CPT-11. Antibiotic treatment alone partially reduced animal body weight loss in CPT-11-treated mice. However, PHY906 treatment was able to protect against the body weight loss in the CPT-11/antibiotic treatment group. H&E and PCNA staining of intestine showed that antibiotic treatment partially reduced the intestinal damage caused by CPT-11 but not as effectively as PHY906 treatment. Antibiotic treatment plus PHY906 conferred the most effective protection of intestine histological structure against damage by CPT-11. Both PHY906 and antibiotic treatment inhibited CPT-11-associated inflammatory processes, including infiltration of the intestine by neutrophils, MCP1 and TNF-alpha mRNA expression in the intestine, and expression of pro-inflammatory cytokines G-CSF and MCP1 proteins in the plasma. However, whereas antibiotic treatment suppressed the mRNA expression of two important intestinal progenitor/stem cell markers, Olfm4 and Lgr5, PHY906 treatment resulted in enhanced expression of these two stem cell markers. Conclusions: Alterations in the population of intestinal bacteria did not affect the abilities of PHY906 to enhance CPT-11 antitumor activity or reduce the intestinal toxicity associated with CPT-11 treatment. The major species of intestinal bacteria do not appear to play a role in PHY906's enhancement of the therapeutic index of CPT-11 in tumor-bearing mice. Thus, patients with different intestinal bacterial profiles may still benefit from PHY906 treatment alongside CPT-11

3D human skin bioprinting: a view from the bio side

Based on the 3D printing technologies and the concepts developed in tissue engineering during the last decades, 3D bioprinting is emerging as the most innovative and promising technology for the generation of human tissues and organs. In the case of skin bioprinting, thanks to the research process carried out during the last years, interfollicular skin has been printed with a structural and functional quality that paves the way for clinical and industrial applications. This review analyzes the present achievements and the future improvements that this area must bring about if bioprinted skin is to become widely used. We have made an effort to integrate the technological and the biological/biomedical sides of the subject.We thank the Spanish Fundación Ramón Areces for its continuous support. This work was partially supported by grant DPI2014-61887-EXP from the Spanish Ministerio de Economía y Competitividad