Cigarette smoke metabolically promotes cancer,via autophagy and premature aging in the host stromal microenvironment

Cigarette smoke has been directly implicated in the disease pathogenesis of a plethora of different human cancer subtypes, including breast cancers. The prevailing view is that cigarette smoke acts as a mutagen and DNA damaging agent in normal epithelial cells, driving tumor initiation. However, its potential negative metabolic effects on the normal stromal microenvironment have been largely ignored. Here, we propose a new mechanism by which carcinogen-rich cigarette smoke may promote cancer growth, by metabolically “fertilizing” the host microenvironment. More specifically, we show that cigarette smoke exposure is indeed sufficient to drive the onset of the cancer-associated fibroblast phenotype via the induction of DNA damage, autophagy and mitophagy in the tumor stroma. In turn, cigarette smoke exposure induces premature aging and mitochondrial dysfunction in stromal fibroblasts, leading to the secretion of high-energy mitochondrial fuels, such as L-lactate and ketone bodies. Hence, cigarette smoke induces catabolism in the local microenvironment, directly fueling oxidative mitochondrial metabolism (OXPHOS) in neighboring epithelial cancer cells, actively promoting anabolic tumor growth. Remarkably, these autophagic-senescent fibroblasts increased breast cancer tumor growth in vivo by up to 4-fold. Importantly, we show that cigarette smoke-induced metabolic reprogramming of the fibroblastic stroma occurs independently of tumor neo-angiogenesis. We discuss the possible implications of our current findings for the prevention of aging-associated human diseases and, especially, common epithelial cancers, as we show that cigarette smoke can systemically accelerate aging in the host microenvironment. Finally, our current findings are consistent with the idea that cigarette smoke induces the “reverse Warburg effect,” thereby fueling “two-compartment tumor metabolism” and oxidative mitochondrial metabolism in epithelial cancer cells.     

Recent advances in ecological stoichiometry: insights for population and community ecology

Conventional theories of population and community dynamics are based on a single currency such as number of individuals, biomass, carbon or energy. However, organisms are constructed of multiple elements and often require them (in particular carbon, phosphorus and nitrogen) in different ratios than provided by their resources; this mismatch may constrain the net transfer of energy and elements through trophic levels. Ecological stoichiometry, the study of the balance of elements in ecological processes, offers a framework for exploring ecological effects of such constraints. We review recent theoretical and empirical studies that have considered how stoichiometry may affect population and community dynamics. These studies show that stoichiometric constraints can affect several properties of populations (e.g. stability, oscillations, consumer extinction) and communities (e.g. coexistence of competitors, competitive interactions between different guilds). We highlight gaps in general knowledge and focus on areas of population and community ecology where incorporation of stoichiometric constraints may be particularly fruitful, such as studies of demographic bottlenecks, spatial processes, and multi-species interactions. Finally, we suggest promising directions for new research by recommending potential study systems (terrestrial insects, detritivory-based webs, soil communities) to improve our understanding of populations and communities. Our conclusion is that a better integration of stoichiometric principles and other theoretical approaches in ecology may allow for a richer understanding of both population and community structure and dynamics.     

Comparative studies on physiological and biochemical adaptation of Taxodium distichum and Taxodium ascendens seedlings to different soil water regimes

Responses of baldcypress (Taxodium distichum) and pondcypress (Taxodium ascendens) seedlings in leaf gas exchange and root metabolism to a wide range of hydrological regimes were studied. Four water treatments included control (C), mild drought (MD), wet soil (WS) and flooding (FL). Both species showed no significant change in net photosynthetic rate (Pn) in response to flooding in contrast to significant reduction in Pn under mild drought conditions. In baldcypress, Pn was also maintained at control level compared to significant increase of Pn in pondcypress when subjected to the wet soil treatment. In flooding, both species showed significant increase in contents of malate and shikimate in their lateral roots and further in total roots, as compared to control. However, different adaptation to flooding was demonstrated in their taproots in contents of malate and shikimate. Furthermore, baldcypress seedlings showed significant reductions in lateral and total root biomass, in contrast with no significant change in that of pondcypress seedlings in response to flooding. In wet soil, no significant effects were revealed in contents of malate and shikimate in roots (including different root portions) of baldcypress seedlings in contrast to significant increase of their contents in lateral roots of pondcypress seedlings. No significant effects on root biomass were detected in either baldcypress or pondcypress seedlings in response to wet soil. When subjected to mild drought, baldcypress seedlings displayed no significant change in contents of malate and shikimate in roots, whereas pondcypress seedlings exhibited significant reduction in content of shikimate in lateral roots and total roots. In addition, root biomass of baldcypress seedlings showed no significant change, while lateral and total root biomass of pondcypress seedlings demonstrated significant increase when mild drought was imposed. These findings indicate that baldcypress and pondcypress appear to be promising candidates for reforestation in the Three Gorges Reservoir region due to their characteristics of water-tolerance and mild drought endurance. However, pondcypress is more resilient than baldcypress to the continuum of water availability conditions expected in the Three Gorges Reservoir region.     

Functional reconstitution of a maltose ATP-binding cassette transporter from the thermoacidophilic gram-positive bacterium Alicyclobacillus acidocaldarius

The thermoacidophilic gram-positive bacterium Alicyclobacillus acidocaldarius grows at 60 degrees C and pH 2-3. The organism can utilize maltose and maltodextrins as energy source that are taken up by an ATP-binding cassette (ABC) import system. Genes encoding a maltose binding protein, MalE, and two membrane-integral subunits, MalF and MalG, are clustered on the chromosome but a malK gene translating into a cognate ATPase subunit is lacking. Here we report the cloning of malK from genomic DNA by using the msiK gene of Streptomyces lividans as a probe. Purified MalK exhibited a spontaneous ATPase activity with a Vmax of 0.13 micromol Pi/min/mg and a Km of 330 microM that was optimal at the growth temperature of the organism. Coexpression of malK, malF and malG in Escherichia coli resulted in the formation of a complex that could be coeluted from an affinity matrix after solubilization of membranes with dodecylmaltoside. Proteoliposomes prepared from the MalFGK complex and preformed phospholipid vesicles of A. acidocaldarius displayed a low intrinsic ATPase activity that was stimulated sevenfold by maltose-loaded MalE, thereby indicating coupling of ATP hydrolysis to substrate translocation. These results provide evidence for MalK being the physiological ATPase subunit of the A. acidocaldarius maltose transporter. Moreover, to our knowledge, this is the first report on the functional reconstitution of an ABC transport system from a thermophilic microorganism.     

Mutations affecting retina development in Medaka

In a large scale mutagenesis screen of Medaka we identified 60 recessive zygotic mutations that affect retina development. Based on the onset and type of phenotypic abnormalities, the mutants were grouped into five categories: the first includes 11 mutants that are affected in neural plate and optic vesicle formation. The second group comprises 15 mutants that are impaired in optic vesicle growth. The third group includes 18 mutants that are affected in optic cup development. The fourth group contains 13 mutants with defects in retinal differentiation. 12 of these have smaller eyes, whereas one mutation results in enlarged eyes. The fifth group consists of three mutants with defects in retinal pigmentation. The collection of mutants will be used to address the molecular genetic mechanisms underlying vertebrate eye formation.     

Blooms of Pseudo-nitzschia and domoic acid in the San Pedro Channel and Los Angeles harbor areas of the Southern California Bight, 2003–2004

Abundances of Pseudo-nitzschia spp. and concentrations of particulate domoic acid (DA) were determined in the Southern California Bight (SCB) along the coasts of Los Angeles and Orange Counties during spring and summer of 2003 and 2004. At least 1500 km² were affected by a toxic event in May/June of 2003 when some of the highest particulate DA concentrations reported for US coastal waters were measured inside the Los Angeles harbor (12.7 μg DA L⁻¹). Particulate DA levels were an order of magnitude lower in spring of 2004 (February and March), but DA concentrations per cell at several sampling stations during 2004 exceeded previously reported maxima for natural populations of Pseudo-nitzschia (mean = 24 pg DA cell⁻¹, range = 0–117 pg DA cell⁻¹). Pseudo-nitzschia australis dominated the Pseudo-nitzschia assemblage in spring 2004. Overall, DA-poisoning was implicated in >1400 mammal stranding incidents within the SCB during 2003 and 2004. Ancillary physical and chemical data obtained during our regional surveys in 2004 revealed that Pseudo-nitzschia abundances, particulate DA and cellular DA concentrations were inversely correlated with concentrations of silicic acid, nitrogen and phosphate, and to specific nutrient ratios. Particulate DA was detected in sediment traps deployed at 550 and 800 m depth during spring of 2004 (0.29–7.6 μg DA (g sediment dry weight)⁻¹). The highest DA concentration in the traps was measured within 1 week of dramatic decreases in the abundances of Pseudo-nitzschia in surface waters. To our knowledge these are the deepest sediment trap collections from which DA has been detected. Sinking of the spring Pseudo-nitzschia bloom may constitute a potentially important link between DA production in surface waters and benthic communities in the coastal ocean near Los Angeles. Our study indicates that toxic blooms of Pseudo-nitzschia are a recurring phenomenon along one of the most densely populated coastal stretches of the SCB and that the severity and magnitude of these events can be comparable to or greater than these events in other geographical regions affected by domoic acid.     

Hyperspectral Remote Sensing of Canopy Biodiversity in Hawaiian Lowland Rainforests

Mapping biological diversity is a high priority for conservation research, management and policy development, but few studies have provided diversity data at high spatial resolution from remote sensing. We used airborne imaging spectroscopy to map woody vascular plant species richness in lowland tropical forest ecosystems in Hawai’i. Hyperspectral signatures spanning the 400–2,500 nm wavelength range acquired by the NASA Airborne Visible and Infrared Imaging Spectrometer (AVIRIS) were analyzed at 17 forest sites with species richness values ranging from 1 to 17 species per 0.1–0.3 ha. Spatial variation (range) in the shape of the AVIRIS spectra (derivative reflectance) in wavelength regions associated with upper-canopy pigments, water, and nitrogen content were well correlated with species richness across field sites. An analysis of leaf chlorophyll, water, and nitrogen content within and across species suggested that increasing spectral diversity was linked to increasing species richness by way of increasing biochemical diversity. A linear regression analysis showed that species richness was predicted by a combination of four biochemically-distinct wavelength observations centered at 530, 720, 1,201, and 1,523 nm (r ² = 0.85, p < 0.01). This relationship was used to map species richness at approximately 0.1 ha resolution in lowland forest reserves throughout the study region. Future remote sensing studies of biodiversity will benefit from explicitly connecting chemical and physical properties of the organisms to remotely sensed data.     

Mortality Risk among Children Admitted in a Large-Scale Nutritional Program in Niger, 2006

Background

In 2006, the Médecins sans Frontières nutritional program in the region of Maradi (Niger) included 68,001 children 6–59 months of age with either moderate or severe malnutrition, according to the NCHS reference (weight-for-height<80% of the NCHS median, and/or mid-upper arm circumference<110 mm for children taller than 65 cm and/or presence of bipedal edema). Our objective was to identify baseline risk factors for death among children diagnosed with severe malnutrition using the newly introduced WHO growth standards. As the release of WHO growth standards changed the definition of severe malnutrition, which now includes many children formerly identified as moderately malnourished with the NCHS reference, studying this new category of children is crucial.

Methodology

Program monitoring data were collected from the medical records of all children admitted in the program. Data included age, sex, height, weight, MUAC, clinical signs on admission including edema, and type of discharge (recovery, death, and default/loss to follow up). Additional data included results of a malaria rapid diagnostic test due to Plasmodium falciparum (Paracheck®) and whether the child was a resident of the region of Maradi or came from bordering Nigeria to seek treatment. Multivariate logistic regression was performed on a subset of 27,687 children meeting the new WHO growth standards criteria for severe malnutrition (weight-for-height<−3 Z score, mid-upper arm circumference<110 mm for children taller than 65 cm or presence of bipedal edema). We explored two different models: one with only basic anthropometric data and a second model that included perfunctory clinical signs.

Principal Findings

In the first model including only weight, height, sex and presence of edema, the risk factors retained were the weight/height^1.84 ratio (OR: 5,774; 95% CI: [2,284; 14,594]) and presence of edema (7.51 [5.12; 11.0]). A second model, taking into account supplementary data from perfunctory clinical examination, identified other risk factors for death: apathy (9.71 [6.92; 13.6]), pallor (2.25 [1.25; 4.05]), anorexia (1.89 [1.35; 2.66]), fever>38.5°C (1.83 [1.25; 2.69]), and age below 1 year (1.42 [1.01; 1.99]).

Conclusions

Although clinicians will continue to perform screening using clinical signs and anthropometry, these risk indicators may provide additional criteria for the assessment of absolute and relative risk of death. Better appraisal of the child''s risk of death may help orientate the child towards either hospitalization or ambulatory care. As the transition from the NCHS growth reference to the WHO standards will increase the number of children classified as severely malnourished, further studies should explore means to identify children at highest risk of death within this group using simple and standardized indicators.