The Therapeutic Implications of Plasticity of the Cancer Stem Cell Phenotype

The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer

Two Coregulated Efflux Transporters Modulate Intracellular Heme and Protoporphyrin IX Availability in Streptococcus agalactiae

Streptococcus agalactiae is a major neonatal pathogen whose infectious route involves septicemia. This pathogen does not synthesize heme, but scavenges it from blood to activate a respiration metabolism, which increases bacterial cell density and is required for full virulence. Factors that regulate heme pools in S. agalactiae are unknown. Here we report that one main strategy of heme and protoporphyrin IX (PPIX) homeostasis in S. agalactiae is based on a regulated system of efflux using two newly characterized operons, gbs1753 gbs1752 (called pefA pefB), and gbs1402 gbs1401 gbs1400 (called pefR pefC pefD), where pef stands for ‘porphyrin-regulated efflux’. In vitro and in vivo data show that PefR, a MarR-superfamily protein, is a repressor of both operons. Heme or PPIX both alleviate PefR-mediated repression. We show that bacteria inactivated for both Pef efflux systems display accrued sensitivity to these porphyrins, and give evidence that they accumulate intracellularly. The ΔpefR mutant, in which both pef operons are up-regulated, is defective for heme-dependent respiration, and attenuated for virulence. We conclude that this new efflux regulon controls intracellular heme and PPIX availability in S. agalactiae, and is needed for its capacity to undergo respiration metabolism, and to infect the host

Effects of two oil dispersants on phototaxis and swimming behaviour of barnacle larvae

The effects of two oil dispersants (Vecom B-1425 GL and Norchem OSD-570) mixed with diesel oil on the survival and behaviour of the stage II nauplii of the barnacle Balanus amphitrite were investigated. The 24 and 48-hour LC50 values for Vecom B-1425 GL:diesel mixture were 514 and 48 mg 1-1 respectively, while respective values for Norchem OSD-570:diesel mixture were 505 and 71 mg 1-1. Under sublethal concentrations, increased levels of the dispersant:diesel mixtures caused a reduction in phototactic responses. Balanus amphitrite nauplii failed to exhibit phototactic responses when exposed to Vecom B-1425 GL:diesel mixtures of 400 mg 1-1 and higher for 24 hours. A longer exposure time of 48 hours further reduced the Lowest Observable Effect Concentrations (LOECs) to 60 mg 1-1. The LOECs for Norchem OSD-570:diesel mixtures under exposure periods of 24 and 48 hours were 400 and 80 mg 1-1 respectively. The curvilinear velocities (VCL) and straight-line velocities (VSL) of the stage II nauplii ranged from 0.7-1.1 and 0.2-0.4 mm s-1 respectively. Increased concentrations of dispersant:diesel mixtures caused a significant change in the curvilinear and straight-line velocities. Both oil dispersants, dispersant:diesel mixtures of 20 to 40 mg 1-1 caused significant increases in VCL, but no significant change in VSL. Dispersant:diesel mixtures of 100 mg 1-1 and higher resulted in a reduction in VSL for both dispersants. ©1997 Kluwer Academic Publishers.link_to_subscribed_fulltex

Four monuments and a funeral:established pathological mourning and collective memory in contemporary Hungary

In this chapter, I suggest that the rhetoric of the Hungarian far right largely resembles what Vamik Volkan has called Established Pathological Mourning. In such circumstances, mourning becomes extended, whereby an individual – or in the present case, a collective – cannot adaptively work through the loss of a loved object. Mourning rituals are extended, whereby the repetition of mourning is an attempt to ‘keep alive’ the lost object. Rather than being a recognition of loss, these complicated mourning rituals forestall the work of living on without the lost object. I suggest that, similar to the re-grief therapy that Volkan promotes, collective cultural mourning may offer an adaptive way forward in working through the issues of loss and control for a larger segment of a society

A critical appraisal of prognostic and predictive factors for common lung cancers.

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