Discovery Analysis of TCGA Data Reveals Association between Germline Genotype and Survival in Ovarian Cancer Patients

Background

Ovarian cancer remains a significant public health burden, with the highest mortality rate of all the gynecological cancers. This is attributable to the late stage at which the majority of ovarian cancers are diagnosed, coupled with the low and variable response of advanced tumors to standard chemotherapies. To date, clinically useful predictors of treatment response remain lacking. Identifying the genetic determinants of ovarian cancer survival and treatment response is crucial to the development of prognostic biomarkers and personalized therapies that may improve outcomes for the late-stage patients who comprise the majority of cases.

Methods

To identify constitutional genetic variations contributing to ovarian cancer mortality, we systematically investigated associations between germline polymorphisms and ovarian cancer survival using data from The Cancer Genome Atlas Project (TCGA). Using stage-stratified Cox proportional hazards regression, we examined 650,000 SNP loci for association with survival. We additionally examined whether the association of significant SNPs with survival was modified by somatic alterations.

Results

Germline polymorphisms at rs4934282 (AGAP11/C10orf116) and rs1857623 (DNAH14) were associated with stage-adjusted survival ( = 1.12e-07 and 1.80e-07, FDR  = 1.2e-04 and 2.4e-04, respectively). A third SNP, rs4869 (C10orf116), was additionally identified as significant in the exome sequencing data; it is in near-perfect LD with rs4934282. The associations with survival remained significant when somatic alterations.

Conclusions

Discovery analysis of TCGA data reveals germline genetic variations that may play a role in ovarian cancer survival even among late-stage cases. The significant loci are located near genes previously reported as having a possible relationship to platinum and taxol response. Because the variant alleles at the significant loci are common (frequencies for rs4934282 A/C alleles = 0.54/0.46, respectively; rs1857623 A/G alleles = 0.55/0.45, respectively) and germline variants can be assayed noninvasively, our findings provide potential targets for further exploration as prognostic biomarkers and individualized therapies.     

Earliest Stone-Tipped Projectiles from the Ethiopian Rift Date to >279,000 Years Ago

Projectile weapons (i.e. those delivered from a distance) enhanced prehistoric hunting efficiency by enabling higher impact delivery and hunting of a broader range of animals while reducing confrontations with dangerous prey species. Projectiles therefore provided a significant advantage over thrusting spears. Composite projectile technologies are considered indicative of complex behavior and pivotal to the successful spread of Homo sapiens. Direct evidence for such projectiles is thus far unknown from >80,000 years ago. Data from velocity-dependent microfracture features, diagnostic damage patterns, and artifact shape reported here indicate that pointed stone artifacts from Ethiopia were used as projectile weapons (in the form of hafted javelin tips) as early as >279,000 years ago. In combination with the existing archaeological, fossil and genetic evidence, these data isolate eastern Africa as a source of modern cultures and biology.     

Impaired Excitatory Drive to Spinal Gabaergic Neurons of Neuropathic Mice

Adequate pain sensitivity requires a delicate balance between excitation and inhibition in the dorsal horn of the spinal cord. This balance is severely impaired in neuropathy leading to enhanced pain sensations (hyperalgesia). The underlying mechanisms remain elusive. Here we explored the hypothesis that the excitatory drive to spinal GABAergic neurons might be impaired in neuropathic animals. Transgenic adult mice expressing EGFP under the promoter for GAD67 underwent either chronic constriction injury of the sciatic nerve or sham surgery. In transverse slices from lumbar spinal cord we performed whole-cell patch-clamp recordings from identified GABAergic neurons in lamina II. In neuropathic animals rates of mEPSC were reduced indicating diminished global excitatory input. This downregulation of excitatory drive required a rise in postsynaptic Ca²⁺. Neither the density and morphology of dendritic spines on GABAergic neurons nor the number of excitatory synapses contacting GABAergic neurons were affected by neuropathy. In contrast, paired-pulse ratio of Aδ- or C-fiber-evoked monosynaptic EPSCs following dorsal root stimulation was increased in neuropathic animals suggesting reduced neurotransmitter release from primary afferents. Our data indicate that peripheral neuropathy triggers Ca²⁺-dependent signaling pathways in spinal GABAergic neurons. This leads to a global downregulation of the excitatory drive to GABAergic neurons. The downregulation involves a presynaptic mechanism and also applies to the excitation of GABAergic neurons by presumably nociceptive Aδ- and C-fibers. This then leads to an inadequately low recruitment of inhibitory interneurons during nociception. We suggest that this previously unrecognized mechanism of impaired spinal inhibition contributes to hyperalgesia in neuropathy.     

Elemental Concentration in Mealworm Beetle (Tenebrio molitor L.) During Metamorphosis

Mealworm beetles have been used in numerous experiments as bioindicators. The aim of our experiment was to study the elemental composition in three larvae, pupae and first and second generation adult stages during their life cycle. We selected 180 larvae from a genetically similar population and put them in three groups, in two boxes (60 larvae in each box). Larvae were fed with mashed potato made of the same quality and quantity of potato powder. Then, we selected 10 individuals from each stage to the elemental analysis, using the ICP-OES method. The following elements were analysed in the studied stages: Ca, Cu, Fe, K, Mg, Mn, Na, P, S, Sr and Zn. The results of principal component analysis demonstrated that based on elemental composition, different stages were separated with each other, but in the cases of the three larvae stages, high overlap was found. The results of the GLM ANOVA showed significant differences between the different stages of metamorphosis-based elemental composition. Our results show that the calcium and magnesium were found in a relatively high concentration, while the iron and zinc may be essential elements during the metamorphosis. Our results also show that in insect, the concentration of sodium was higher than in the pupa which may cause by hemolymph. We also demonstrated that the metamorphosis has an effect on the concentration of elements. Our study shows that in the different stages of insects, there are significant changes in the elemental composition of different stages of insects during their metamorphosis.     

Binding to G-quadruplex RNA activates the mitochondrial GTPase NOA1

NOA1 is an evolutionary conserved, nuclear encoded GTPase essential for mitochondrial function and cellular survival. The function of NOA1 for assembly of mitochondrial ribosomes and regulation of OXPHOS activity depends on its GTPase activity, but so far no ligands have been identified that regulate the GTPase activity of NOA1. To identify nucleic acids that bind to the RNA-binding domain of NOA1 we employed SELEX (Systemic Evolution of Ligands by EXponential Enrichment) using recombinant mouse wildtype NOA1 and the GTPase mutant NOA1-K353R. We found that NOA1 binds specifically to oligonucleotides that fold into guanine tetrads (G-quadruplexes). Binding of G-quadruplex oligonucleotides stimulated the GTPase activity of NOA1 suggesting a regulatory link between G-quadruplex containing RNAs, NOA1 function and assembly of mitochondrial ribosomes.     

Effects of surfactin on membrane models displaying lipid phase separation

Surfactin, a bacterial amphiphilic lipopeptide is attracting more and more attention in view of its bioactive properties which are in relation with its ability to interact with lipids of biological membranes. In this work, we investigated the effect of surfactin on membrane structure using model of membranes, vesicles as well as supported bilayers, presenting coexistence of fluid-disordered (DOPC) and gel (DPPC) phases. A range of complementary methods was used including AFM, ellipsometry, dynamic light scattering, fluorescence measurements of Laurdan, DPH, calcein release, and octadecylrhodamine B dequenching. Our findings demonstrated that surfactin concentration is critical for its effect on the membrane. The results suggest that the presence of rigid domains can play an essential role in the first step of surfactin insertion and that surfactin interacts both with the membrane polar heads and the acyl chain region. A mechanism for the surfactin lipid membrane interaction, consisting of three sequential structural and morphological changes, is proposed. At concentrations below the CMC, surfactin inserted at the boundary between gel and fluid lipid domains, inhibited phase separation and stiffened the bilayer without global morphological change of liposomes. At concentrations close to CMC, surfactin solubilized the fluid phospholipid phase and increased order in the remainder of the lipid bilayer. At higher surfactin concentrations, both the fluid and the rigid bilayer structures were dissolved into mixed micelles and other structures presenting a wide size distribution.     

Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm² chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s⁻¹), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037 or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implant''s power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.     

Monthly stem increment in relation to climatic variables during 7 years in an East African rainforest

Monthly stem increment of 766 trees was assessed for 7 years in Kakamega Forest, Kenya and related to monthly climatic variables. Mean stem increment of all tree individuals correlated negatively with maximum temperature but not with mean and minimum temperatures. For the precipitation variables sum of precipitation and number of rainy days we found positive correlations. Stem increment of the trees in the early-, mid-, and late-successional groups correlated positively with the number of rainy days. For late-successional trees increment correlated negatively with mean and maximum temperature and positively with all other precipitation variables. For mid-successional trees we found a negative correlation with mean temperature. In addition, the stem increment of most species related positively to precipitation variables and negatively to mean and maximum temperature. In view of the expected increasing temperatures and fewer but heavier rain events, our results suggest that climate change will lead to a reduction in stem increment. The results appertaining to the successional groups imply that early and mid-successional species are better equipped to perform well under the expected future climatic conditions than the late-successional species. This could reduce the role of this East African forest as a carbon store. As the responses to climatic variables were highly group- and species-specific it is likely that climate change will result in a species composition shift, presumably in favour of drought-resistant and heat-tolerating species.     

p53 DNA Binding Cooperativity Is Essential for Apoptosis and Tumor Suppression In Vivo

1. Download : Download full-size image