Can we really predict risk of cancer?

Background: Growing awareness of the potential to predict a person's future risk of cancer has resulted in the development of numerous algorithms. Such algorithms aim to improve the ability of policy makers, doctors and patients to make rational decisions about behaviour modification or surveillance, with the expectation that this activity will lead to overall benefit. There remains debate however, about whether accurate risk prediction is achievable for most cancers. Methods: We conducted a brief narrative review of the literature regarding the history and challenges of risk prediction, highlighting our own recent experiences in developing tools for oesophageal adenocarcinoma. Results and conclusions: While tools for predicting future risk of cardiovascular outcomes have been translated successfully to clinical practice, the experience with cancer risk prediction has been mixed. Models have now been developed and validated for predicting risk of melanoma and cancers of the breast, colo-rectum, lung, liver, oesophagus and prostate, and while several of these have adequate performance at the population-level, none to date have adequate discrimination for predicting risk in individual patients. Challenges of individual risk prediction for cancer are many, and include long latency, multiple risk factors of mostly small effect, and incomplete knowledge of the causal pathways.     

Leptin-Induced Endothelium-Dependent Vasorelaxation of Peripheral Arteries in Lean and Obese Rats: Role of Nitric Oxide and Hydrogen Sulfide

Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF). Previously it has been demonstrated that in short-term obesity the NO-dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1) control, (2) treated with exogenous leptin for 1 week to induce hyperleptinemia, (3) obese, fed highly-palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA) for 1 week, (5) fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine γ-lyase, propargylglycine, or a hydrogen sulfide (H₂S) scavenger, bismuth (III) subsalicylate. The results indicate that NO deficiency is compensated by the up-regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H₂S.     

Ecological differences between hamlet (Hypoplectrus: Serranidae) colour morphs: between-morph variation in diet

Dietary differences between hamlet Hypoplectrus spp. colour morphs were examined in fishes from Puerto Rico, U.S. Virgin Islands, Curacao, Honduras and Belize. Hamlet diet across all countries was characterized by large overlap between most colour morphs in both the proportion and numbers of dietary items consumed, although some differences between morphs were apparent. Indigo hamlets Hypoplectrus indigo were the only morph to consume fishes (blue chromis Chromis cyanea and sunshinefish Chromis insolata ) almost exclusively. The sympatric occurrence of other ecologically indistinguishable colour morphs, however, suggests that divergent ecological selection alone cannot explain population divergence in hamlets. Geographical variation in diet was also observed within black Hypoplectrus nigricans and yellowtail Hypoplectrus chlorurus hamlets which may reflect geographical differences in prey availability or differences in prey choice.     

Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage

In this report, we describe the synthesis of a panel of disulfide-linked huC242 (anti-CanAg) antibody maytansinoid conjugates (AMCs), which have varying levels of steric hindrance around the disulfide bond, in order to investigate the relationship between stability to reduction of the disulfide linker and antitumor activity of the conjugate in vivo. The conjugates were first tested for stability to reduction by dithiothreitol in vitro and for plasma stability in CD1 mice. It was found that the conjugates having the more sterically hindered disulfide linkages were more stable to reductive cleavage of the maytansinoid in both settings. When the panel of conjugates was tested for in vivo efficacy in two human colon cancer xenograft models in SCID mice, it was found that the conjugate with intermediate disulfide bond stability having two methyl groups on the maytansinoid side of the disulfide bond and no methyl groups on the linker side of the disulfide bond (huC242-SPDB-DM4) displayed the best efficacy. The ranking of in vivo efficacies of the conjugates was not predicted by their in vitro potencies, since all conjugates were highly active in vitro, including a huC242-SMCC-DM1 conjugate with a noncleavable linkage which showed only marginal activity in vivo. These data suggest that factors in addition to intrinsic conjugate potency and conjugate half-life in plasma influence the magnitude of antitumor activity observed for an AMC in vivo. We provide evidence that bystander killing of neighboring nontargeted tumor cells by diffusible cytotoxic metabolites produced from target cell processing of disulfide-linked antibody-maytansinoid conjugates may be one additional factor contributing to the activity of these conjugates in vivo.     

Cytochrome bc(1) regulates the mitochondrial permeability transition by two distinct pathways

The mitochondrial permeability transition (MPT) pore is a calcium-sensitive channel in the mitochondrial inner membrane that plays a crucial role in cell death. Here we show that cytochrome bc(1) regulates the MPT in isolated rat liver mitochondria and in CEM and HL60 cells by two independent pathways. Glutathione depletion activated the MPT via increased production of reactive oxygen species (ROS) generated by cytochrome bc(1). The ROS producing mechanism in cytochrome bc(1) involves movement of the "Rieske" iron-sulfur protein subunit of the enzyme complex, because inhibition of cytochrome bc(1) by pharmacologically blocking iron-sulfur protein movement completely abolished ROS production, MPT activation, and cell death. The classical inhibitor of the MPT, cyclosporine A, had no protective effect against MPT activation. In contrast, the calcium-activated, cyclosporine A-regulated MPT in rat liver mitochondria was also blocked with inhibitors of cytochrome bc(1). These results indicate that electron flux through cytochrome bc(1) regulates two distinct pathways to the MPT, one unregulated and involving mitochondrial ROS and the other regulated and activated by calcium.     

Nitric oxide and peroxynitrite. The ugly,the uglier and the not so good

Nitric oxide, a gaseous free radical, is poorly reactive with most biomolecules but highly reactive with other free radicals. Its ability to scavenge peroxyl and other damaging radicals may make it an important antioxidant in vivo, particular in the cardiovascular system, although this ability has been somewhat eclipsed in the literature by a focus on the toxicity of peroxynitrite, generated by reaction of O^·-₂ with NO^· (or of NO^- with O₂). On balance, experimental and theoretical data support the view that ONOO^- can lead to hydroxyl radical (OH^·) generation at pH 7.4, but it seems unlikely that OH^· contributes much to the cytotoxicity of ONOO^-. The cytotoxicity of ONOO^- may have been over-emphasized: its formation and rapid reaction with antioxidants may provide a mechanism of using NO^· to dispose of excess O^·-₂, or even of using O^·-₂ to dispose of excess NO^·, in order to maintain the correct balance between these radicals in vivo. Injection or instillation of “bolus” ONOO^- into animals has produced tissue injury, however, although more experiments generating ONOO^- at steady rates in vivo are required. The presence of 3-nitrotyrosine in tissues is still frequently taken as evidence of ONOO^- generation in vivo, but abundant evidence now exists to support the view that it is a biomarker of several “reactive nitrogen species”. Another under-addressed problem is the reliability of assays used to detect and measure 3-nitrotyrosine in tissues and body fluids: immunostaining results vary between laboratories and simple HPLC methods are susceptible to artefacts. Exposure of biological material to low pH (e.g. during acidic hydrolysis to liberate nitrotyrosine from proteins) or to H₂O₂ might cause artefactual generation of nitrotyrosine from NO^-₂ in the samples. This may be the origin of some of the very large values for tissue nitrotyrosine levels quoted in the literature. Nitrous acid causes not only tyrosine nitration but also DNA base deamination at low pH: these events are relevant to the human stomach since saliva and many foods are rich in nitrite. Several plant phenolics inhibit nitration and deamination in vitro, an effect that could conceivably contribute to their protective effects against gastric cancer development.     

The role of heterogenous environmental conditions in shaping the spatiotemporal distribution of competing Aedes mosquitoes in Panama: implications for the landscape of arboviral disease transmission

Monitoring the invasion process of the Asian tiger mosquito Aedes albopictus and its interaction with the contender Aedes aegypti, is critical to prevent and control the arthropod-borne viruses (i.e., Arboviruses) they transmit to humans. Generally, the superior ecological competitor Ae. albopictus displaces Ae. aegypti from most geographic areas, with the combining factors of biology and environment influencing the competitive outcome. Nonetheless, detailed studies asserting displacement come largely from sub-tropical areas, with relatively less effort being made in tropical environments, including no comprehensive research about Aedes biological interactions in Mesoamerica. Here, we examine contemporary and historical mosquito surveillance data to assess the role of shifting abiotic conditions in shaping the spatiotemporal distribution of competing Aedes species in the Republic of Panama. In accordance with prior studies, we show that Ae. albopictus has displaced Ae. aegypti under suboptimal wet tropical climate conditions and more vegetated environments within the southwestern Azuero Peninsula. Conversely, in the eastern Azuero Peninsula, Ae. aegypti persists with Ae. albopictus under optimal niche conditions in a dry and more seasonal tropical climate. While species displacement was stable over the course of two years, the presence of both species generally appears to fluctuate in tandem in areas of coexistence. Aedes albopictus was always more frequently found and abundant regardless of location and climatic season. The heterogenous environmental conditions of Panama shape the competitive outcome and micro-geographic distribution of Aedes mosquitoes, with potential consequences for the transmission dynamics of urban and sylvatic zoonotic diseases.

     

Evolution of Olfactory Receptors Tuned to Mustard Oils in Herbivorous Drosophilidae

The diversity of herbivorous insects is attributed to their propensity to specialize on toxic plants. In an evolutionary twist, toxins betray the identity of their bearers when herbivores coopt them as cues for host-plant finding, but the evolutionary mechanisms underlying this phenomenon are poorly understood. We focused on Scaptomyza flava, an herbivorous drosophilid specialized on isothiocyanate (ITC)-producing (Brassicales) plants, and identified Or67b paralogs that were triplicated as mustard-specific herbivory evolved. Using in vivo heterologous systems for the expression of olfactory receptors, we found that S. flava Or67bs, but not the homologs from microbe-feeding relatives, responded selectively to ITCs, each paralog detecting different ITC subsets. Consistent with this, S. flava was attracted to ITCs, as was Drosophila melanogaster expressing S. flava Or67b3 in the homologous Or67b olfactory circuit. ITCs were likely coopted as olfactory attractants through gene duplication and functional specialization (neofunctionalization and subfunctionalization) in S. flava, a recently derived herbivore.     

No barriers to fertilization between sympatric colour morphs in the marine species flock Hypoplectrus (Serranidae)

Assortative mate choice is, so far, the only demonstrated isolating barrier between colour morphs in fish species flocks, such as freshwater cichlids and marine hamlets, suggesting an important role for sexual selection in speciation. However, there has been little consideration of post-copulatory mechanisms that are known to influence reproductive isolation in other taxa. Selective pressures through a cost to hybrid matings, or genetic drift, may lead to the evolution of fertilization barriers through gamete incompatability. In cases of incipient speciation, such as the hamlets, complete fertilization blocks may not have evolved. Instead, differential fertilization between species may reduce the success of interspecific fertilizations. We examined the fertilization dynamics of sympatric Hypoplectrus nigricans (black hamlet) and Hypoplectrus puella (barred hamlet). Experimental crosses were performed to score fertilization success in within-morph and between-morph crosses. Fertilization success did not differ between self-fertilized, within-morph or between-morph crosses. We therefore found no evidence of post-mating barriers through sperm:egg incompatibilities and potential for self-fertilization. Our results are consistent with a mechanism of colour morph divergence based on sexually selected morph mating preferences.     

Microsporidia Are Natural Intracellular Parasites of the Nematode Caenorhabditis elegans

For decades the soil nematode Caenorhabditis elegans has been an important model system for biology, but little is known about its natural ecology. Recently, C. elegans has become the focus of studies of innate immunity and several pathogens have been shown to cause lethal intestinal infections in C. elegans. However none of these pathogens has been shown to invade nematode intestinal cells, and no pathogen has been isolated from wild-caught C. elegans. Here we describe an intracellular pathogen isolated from wild-caught C. elegans that we show is a new species of microsporidia. Microsporidia comprise a large class of eukaryotic intracellular parasites that are medically and agriculturally important, but poorly understood. We show that microsporidian infection of the C. elegans intestine proceeds through distinct stages and is transmitted horizontally. Disruption of a conserved cytoskeletal structure in the intestine called the terminal web correlates with the release of microsporidian spores from infected cells, and appears to be part of a novel mechanism by which intracellular pathogens exit from infected cells. Unlike in bacterial intestinal infections, the p38 MAPK and insulin/insulin-like growth factor (IGF) signaling pathways do not appear to play substantial roles in resistance to microsporidian infection in C. elegans. We found microsporidia in multiple wild-caught isolates of Caenorhabditis nematodes from diverse geographic locations. These results indicate that microsporidia are common parasites of C. elegans in the wild. In addition, the interaction between C. elegans and its natural microsporidian parasites provides a system in which to dissect intracellular intestinal infection in vivo and insight into the diversity of pathogenic mechanisms used by intracellular microbes.