Assessing the contribution of tumor mutational phenotypes to cancer progression risk

Cancer occurs via an accumulation of somatic genomic alterations in a process of clonal evolution. There has been intensive study of potential causal mutations driving cancer development and progression. However, much recent evidence suggests that tumor evolution is normally driven by a variety of mechanisms of somatic hypermutability, which act in different combinations or degrees in different cancers. These variations in mutability phenotypes are predictive of progression outcomes independent of the specific mutations they have produced to date. Here we explore the question of how and to what degree these differences in mutational phenotypes act in a cancer to predict its future progression. We develop a computational paradigm using evolutionary tree inference (tumor phylogeny) algorithms to derive features quantifying single-tumor mutational phenotypes, followed by a machine learning framework to identify key features predictive of progression. Analyses of breast invasive carcinoma and lung carcinoma demonstrate that a large fraction of the risk of future clinical outcomes of cancer progression—overall survival and disease-free survival—can be explained solely from mutational phenotype features derived from the phylogenetic analysis. We further show that mutational phenotypes have additional predictive power even after accounting for traditional clinical and driver gene-centric genomic predictors of progression. These results confirm the importance of mutational phenotypes in contributing to cancer progression risk and suggest strategies for enhancing the predictive power of conventional clinical data or driver-centric biomarkers.     

Rhesus macaques build new social connections after a natural disaster

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Complexome profile of Toxoplasma gondii mitochondria identifies divergent subunits of respiratory chain complexes including new subunits of cytochrome bc1 complex

The mitochondrial electron transport chain (mETC) and F₁F_o-ATP synthase are of central importance for energy and metabolism in eukaryotic cells. The Apicomplexa, important pathogens of humans causing diseases such as toxoplasmosis and malaria, depend on their mETC in every known stage of their complicated life cycles. Here, using a complexome profiling proteomic approach, we have characterised the Toxoplasma mETC complexes and F₁F_o-ATP synthase. We identified and assigned 60 proteins to complexes II, IV and F₁F_o-ATP synthase of Toxoplasma, of which 16 have not been identified previously. Notably, our complexome profile elucidates the composition of the Toxoplasma complex III, the target of clinically used drugs such as atovaquone. We identified two new homologous subunits and two new parasite-specific subunits, one of which is broadly conserved in myzozoans. We demonstrate all four proteins are essential for complex III stability and parasite growth, and show their depletion leads to decreased mitochondrial potential, supporting their assignment as complex III subunits. Our study highlights the divergent subunit composition of the apicomplexan mETC and F₁F_o-ATP synthase complexes and sets the stage for future structural and drug discovery studies.     

Avian Community Responses to Variability in River Hydrology

River flow is a major driver of morphological structure and community dynamics in riverine-floodplain ecosystems. Flow influences in-stream communities through changes in water velocity, depth, temperature, turbidity and nutrient fluxes, and perturbations in the organisation of lower trophic levels are cascaded through the food web, resulting in shifts in food availability for consumer species. River birds are sensitive to spatial and phenological mismatches with aquatic prey following flow disturbances; however, the role of flow as a determinant of riparian ecological structure remains poorly known. This knowledge is crucial to help to predict if, and how, riparian communities will be influenced by climate-induced changes in river flow characterised by more extreme high (i.e. flood) and/or low (i.e. drought) flow events. Here, we combine national-scale datasets of river bird surveys and river flow archives to understand how hydrological disturbance has affected the distribution of riparian species at higher trophic levels. Data were analysed for 71 river locations using a Generalized Additive Model framework and a model averaging procedure. Species had complex but biologically interpretable associations with hydrological indices, with species’ responses consistent with their ecology, indicating that hydrological-disturbance has implications for higher trophic levels in riparian food webs. Our quantitative analysis of river flow-bird relationships demonstrates the potential vulnerability of riparian species to the impacts of changing flow variability and represents an important contribution in helping to understand how bird communities might respond to a climate change-induced increase in the intensity of floods and droughts. Moreover, the success in relating parameters of river flow variability to species’ distributions highlights the need to include river flow data in climate change impact models of species’ distributions.     

A Generator-Produced Gallium-68 Radiopharmaceutical for PET Imaging of Myocardial Perfusion

Lipophilic cationic technetium-99m-complexes are widely used for myocardial perfusion imaging (MPI). However, inherent uncertainties in the supply chain of molybdenum-99, the parent isotope required for manufacturing ⁹⁹Mo/^99mTc generators, intensifies the need for discovery of novel MPI agents incorporating alternative radionuclides. Recently, germanium/gallium (Ge/Ga) generators capable of producing high quality ⁶⁸Ga, an isotope with excellent emission characteristics for clinical PET imaging, have emerged. Herein, we report a novel ⁶⁸Ga-complex identified through mechanism-based cell screening that holds promise as a generator-produced radiopharmaceutical for PET MPI.     

Purification and partial characterization of a bovine epidermal growth factor-like polypeptide

A heterologous radioreceptor assay was developed to follow the purification of an EGF-like polypeptide from bovine kidney. Purification of the growth factor was facilitated by the use of a novel affinity column using fixed A431 cells attached to sephadex beads. The mol. wt. of the purified EGF-LP was estimated to be 5480 from the amino acid composition. The purified EGF-like polypeptide stimulated the proliferation of bovine mammary epithelial cells and appeared to be equipotent to mouse EGF. Available evidence suggests that the purified molecule is distinct from bovine TGF-alpha.     

In Vitro and Sensory Evaluation of Capsaicin-Loaded Nanoformulations

Capsaicin has known health beneficial and therapeutic properties. It is also able to enhance the permeability of drugs across epithelial tissues. Unfortunately, due to its pungency the oral administration of capsaicin is limited. To this end, we assessed the effect of nanoencapsulation of capsaicin, under the hypothesis that this would reduce its pungency. Core-shell nanocapsules with an oily core and stabilized with phospholipids were used. This system was used with or without chitosan coating. In this work, we investigated the in vitro release behavior of capsaicin-loaded formulations in different physiological media (including simulated saliva fluid). We also evaluated the influence of encapsulation of capsaicin on the cell viability of buccal cells (TR146). To study the changes in pungency after encapsulation we carried out a sensory analysis with a trained panel of 24 students. The in vitro release study showed that the systems discharged capsaicin slowly in a monotonic manner and that the chitosan coating had an effect on the release profile. The cytotoxic response of TR146 cells to capsaicin at a concentration of 500 μM, which was evident for the free compound, was reduced following its encapsulation. The sensory study revealed that a chitosan coating results in a lower threshold of perception of the formulation. The nanoencapsulation of capsaicin resulted in attenuation of the sensation of pungency significantly. However, the presence of a chitosan shell around the nanoformulations did not mask the pungency, when compared with uncoated systems.