Cancer from the perspective of stem cells and misappropriated tissue regeneration mechanisms

Tumorigenesis can be considered as pathologically misappropriated tissue regeneration. In this review we will address some unresolved issues that support this concept. First, we will address the issue of the identity of cancer-initiating cells and the presence of cancer stem cells in growing tumors. We will also ask are there rare and distinct populations of cancer stem cells in established tumor cell lines, or are all of the cells cancer stem cells? Second, the most important clinical problem with cancer is its metastasis, and here a challenging question arises: by employing radio-chemotherapy for tumor treatment, do we unintentionally create a prometastatic microenvironment in collateral organs? Specifically, many factors upregulated in response to radio-chemotherapy-induced injury may attract highly migratory cancer cells that survived initial treatment. Third, what is the contribution of normal circulating stem cells to the growing malignancy? Do circulating normal stem cells recognize a tumor as a hypoxia-damaged tissue that needs vascular and stromal support and thereby contribute to tumor expansion? Fourth, is it reasonable to inhibit only one prometastatic ligand-receptor axis when cancer stem cells express several receptors for several chemotactic factors that may compensate for inhibition of the targeted receptor? Fifth, since most aggressive cancer cells mimic early-development stem cells, which properties of embryonic stem cells are retained in cancer cells? Would it be reasonable to inhibit cancer cell signaling pathways involved in the migration and proliferation of embryonic stem cells? We will also briefly address some new players in cancerogenesis, including extracellular microvesicles, bioactive phospholipids, and extracellular nucleotides.

Outcomes of modified-eam conditioned autologous non-cryopreserved hematopoietic sct for lymphoma. A retrospective single-centre study

The murine lung as a factory to produce secreted intrapulmonary and circulatory proteins

We have shown that a lentiviral vector (rSIV.F/HN) pseudotyped with the F and HN proteins from Sendai virus generates high levels of intracellular proteins after lung transduction. Here, we evaluate the use of rSIV.F/HN for production of secreted proteins. We assessed whether rSIV.F/HN transduction of the lung generates therapeutically relevant levels of secreted proteins in the lung and systemic circulation using human α1-anti-trypsin (hAAT) and factor VIII (hFVIII) as exemplars. Sedated mice were transduced with rSIV.F/HN carrying either the secreted reporter gene Gaussia luciferase or the hAAT or hFVIII cDNAs by nasal sniffing. rSIV.F/HN-hAAT transduction lead to therapeutically relevant hAAT levels (70 μg/ml) in epithelial lining fluid, with stable expression persisting for at least 19 months from a single application. Secreted proteins produced in the lung were released into the circulation and stable expression was detectable in blood. The levels of hFVIII in murine blood approached therapeutically relevant targets. rSIV.F/HN was also able to produce secreted hAAT and hFVIII in transduced human primary airway cells. rSIV.F/HN transduction of the murine lungs leads to long-lasting and therapeutically relevant levels of secreted proteins in the lung and systemic circulation. These data broaden the use of this vector platform for a large range of disease indications.

PreDicta chip-based high resolution diagnosis of rhinovirus-induced wheeze

Rhinovirus (RV) infections are major triggers of acute exacerbations of severe respiratory diseases such as pre-school wheeze, asthma and chronic obstructive pulmonary disease (COPD). The occurrence of numerous RV types is a major challenge for the identification of the culprit virus types and for the improvement of virus type-specific treatment strategies. Here, we develop a chip containing 130 different micro-arrayed RV proteins and peptides and demonstrate in a cohort of 120 pre-school children, most of whom had been hospitalized due to acute wheeze, that it is possible to determine the culprit RV species with a minute blood sample by serology. Importantly, we identify RV-A and RV-C species as giving rise to most severe respiratory symptoms. Thus, we have generated a chip for the serological identification of RV-induced respiratory illness which should be useful for the rational development of preventive and therapeutic strategies targeting the most important RV types.

Mouse MRI shows brain areas relatively larger in males emerge before those larger in females

Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI’s ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.

Higher activation barriers can lift exothermic rate restrictions in electron transfer and enable faster reactions

Electron transfer reactions are arguably the simplest chemical reactions but they have not yet ceased to intrigue chemists. Charge-separation and charge-recombination reactions are at the core of life-sustaining processes, molecular electronics and solar cells. Intramolecular electron donor-acceptor systems capture the essential features of these reactions and enable their fundamental understanding. Here, we report intramolecular electron transfers covering a range of 100 kcal mol −1 in exothermicities that show an increase, then a decrease, and finally an increase in rates with the driving force of the reactions. Concomitantly, apparent activation energies change from positive, to negative and finally to positive. Reactions with positive activation energies are found to be faster than analogous reactions with negative effective activation energies. The increase of the reorganization energy with the driving force of the reactions can explain the peculiar free-energy relationship observed in this work.

Identification of nine new susceptibility loci for endometrial cancer

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins ( SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Native iron reduces CO2 to intermediates and end-products of the acetyl-CoA pathway

Autotrophic theories for the origin of life propose that CO 2 was the carbon source for primordial biosynthesis. Among the six known CO 2 fixation pathways in nature, the acetyl-CoA (AcCoA; or Wood-Ljungdahl) pathway is the most ancient, and relies on transition metals for catalysis. Modern microbes that use the AcCoA pathway typically fix CO 2 with electrons from H 2 , which requires complex flavin-based electron bifurcation. This presents a paradox: how could primitive metabolic systems have fixed CO 2 before the origin of proteins? Here, we show that native transition metals (Fe 0 , Ni 0 and Co 0 ) selectively reduce CO 2 to acetate and pyruvate-the intermediates and end-products of the AcCoA pathway-in near millimolar concentrations in water over hours to days using 1-40 bar CO 2 and at temperatures from 30 to 100 °C. Geochemical CO 2 fixation from native metals could have supplied critical C 2 and C 3 metabolites before the emergence of enzymes.

Niobium tungsten oxides for high-rate lithium-ion energy storage

The maximum power output and minimum charging time of a lithium-ion battery depend on both ionic and electronic transport. Ionic diffusion within the electrochemically active particles generally represents a fundamental limitation to the rate at which a battery can be charged and discharged. To compensate for the relatively slow solid-state ionic diffusion and to enable high power and rapid charging, the active particles are frequently reduced to nanometre dimensions, to the detriment of volumetric packing density, cost, stability and sustainability. As an alternative to nanoscaling, here we show that two complex niobium tungsten oxides-Nb 16 W 5 O 55 and Nb 18 W 16 O 93 , which adopt crystallographic shear and bronze-like structures, respectively-can intercalate large quantities of lithium at high rates, even when the sizes of the niobium tungsten oxide particles are of the order of micrometres. Measurements of lithium-ion diffusion coefficients in both structures reveal room-temperature values that are several orders of magnitude higher than those in typical electrode materials such as Li 4 Ti 5 O 12 and LiMn 2 O 4 . Multielectron redox, buffered volume expansion, topologically frustrated niobium/tungsten polyhedral arrangements and rapid solid-state lithium transport lead to extremely high volumetric capacities and rate performance. Unconventional materials and mechanisms that enable lithiation of micrometre-sized particles in minutes have implications for high-power applications, fast-charging devices, all-solid-state energy storage systems, electrode design and material discovery.

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.