Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Dissolution Enhancement in Cocoa Extract, Combining Hydrophilic Polymers through Hot-Melt Extrusion

The aim of this study was to improve the physicochemical properties of cocoa extract (CE) using hot-melt extrusion (HME) for pharmaceutical proposes. A mixture design was applied using three distinct hydrophilic polymeric matrices (Soluplus, Plasdone S630, and Eudragit E). Systems obtained by HME were evaluated using morphologic, chromatographic, thermic, spectroscopic, and diffractometric assays. The flow, wettability, and dissolution rate of HME powders were also assessed. Both CE and its marker theobromine proved to be stable under heating according to thermal analysis and Arrhenius plot under isothermal conditions. Physicochemical analysis confirmed the stability of CE HME preparations and provided evidence of drug&ndash;polymer interactions. Improvements in the functional characteristics of CE were observed after the extrusion process, particularly in dissolution and flow properties. In addition, the use of a mixture design allowed the identification of synergic effects by excipient combination. The optimized combination of polymers obtained considering four different aspects showed that a mixture of the Soluplus, Plasdone S630, and Eudragit E in equal proportions produced the best results (flowability index 88%; contact angle 47&deg;; dispersibility 7.5%; and dissolution efficiency 87%), therefore making the pharmaceutical use of CE more feasible

Hot-Melt Extrusion as an Advantageous Technology to Obtain Effervescent Drug Products

Here, we assessed the feasibility of hot-melt extrusion (HME) to obtain effervescent drug products for the first time. For this, a combined mixture design was employed using paracetamol as a model drug. Extrudates were obtained under reduced torque (up to 0.3 Nm) at 100 &deg;C to preserve the stability of the effervescent salts. Formulations showed vigorous and rapid effervescent disintegration (&lt;3 min), adequate flow characteristics, and complete solubilization of paracetamol instantly after the effervescent reaction. Formulations containing PVPVA in the concentration range of 15&ndash;20% m/m were demonstrated to be sensitive to accelerated aging conditions, undergoing marked microstructural changes, since the capture of water led to the agglomeration and loss of their functional characteristics. HPMC matrices, in contrast, proved to be resistant to storage conditions in high relative humidity, showing superior performance to controls, including the commercial product. Moreover, the combined mixture design allowed us to identify significant interactions between the polymeric materials and the disintegrating agents, showing the formulation regions in which the responses are kept within the required levels. In conclusion, this study demonstrates that HME can bring important benefits to the elaboration of effervescent drug products, simplifying the production process and obtaining formulations with improved characteristics, such as faster disintegration, higher drug solubilization, and better stability

Application of hot-melt extrusion in the complexation of naringenin with cyclodextrin using hydrophilic polymers

The complexation of cyclodextrin ranks among the best methods of overcoming the unfavorable pharma cokinetic properties of naringenin (NAR). This work proposes obtaining NAR complexes with hydroxypropyl-b-cyclodextrin (HPbCD) using hot-melt extrusion (HME), a solvent-free, continuous man ufacturing process. To that end, the miscibility and stability of NAR in different hydrophilic polymeric matrices were tested using thermal, morphological, and spectroscopic assays, after which inclusion com plexes were prepared via HME using different plasticizers. While the cellulosic polymers showed a lim ited ability to dissolve NAR, Plasdone! S-630 was chemically incompatible with the drug under shearing and heating. By contrast, polyvinyl alcohol and Soluplus! demonstrated compatibility and a high capacity to interact with NAR. The polyvinyl alcohol extrudates accelerated NAR’s dissolution, especially in sys tems containing HPbCD, which suggests high levels of the inclusion complex’s formation and nearly instantaneous dissolution (28 mg/mL in 15 min) superior to other technological approaches described in the literature. Meanwhile, samples extruded with Soluplus! delayed NAR’s dissolution, with rates modulated according to the drug–cyclodextrin interaction. Thus, HME proved to be a valuable, versatile method of producing cyclodextrin complexes of NAR able to support immediate and prolonged drug delivery systems depending on the formulation parameters. Many industrial advantages, including being eco-friendly and easy to scale up, make HME a promising method for exploring NAR’s remarkable medical potential

Sex differences in oncogenic mutational processes

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Peer reviewe

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research