Antifungal interactions within the triple combination of amphotericin B, caspofungin and voriconazole against Aspergillus species.

OBJECTIVES: The in vitro effects of caspofungin combined with voriconazole and amphotericin B were tested in triplicate experiments against nine clinical isolates of Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus. METHODS: The isolates were tested against a range of concentrations of voriconazole (0.015-1.0 mg/L), caspofungin (0.125-256 mg/L) and five concentrations of amphotericin B (0.1-0.5 mg/L) with a microdilution chequerboard method based on the CLSI M38-A reference method and the results were analysed with the fractional inhibitory concentration (FIC) index. The effect of individual drugs on the FIC index of each of the double combinations was also evaluated. RESULTS: The triple combination of voriconazole, caspofungin and amphotericin B against all Aspergillus spp. was synergistic (FIC index 0.49-0.57) at low median concentrations of amphotericin B (0.10-0.22 mg/L) and voriconazole (0.07-0.15 mg/L) over a wide range of caspofungin concentrations (4.32-17.28 mg/L). Antagonistic interactions (FIC index 1.65-2.15) were found at higher median concentrations of amphotericin B (0.3-0.5 mg/L) and voriconazole (0.23-0.68 mg/L) over a similarly wide range of caspofungin concentrations (1.47-32 mg/L). CONCLUSIONS: These concentration-dependent interactions may have important clinical implications, which require further evaluation in animal models of invasive aspergillosis

A novel approach to high-quality postmortem tissue procurement: The GTEx Project

The Genotype-Tissue Expression (GTEx) project, sponsored by the NIH Common Fund, was established to study the correlation between human genetic variation and tissue-specific gene expression in non-diseased individuals. A significant challenge was the collection of high-quality biospecimens for extensive genomic analyses. Here we describe how a successful infrastructure for biospecimen procurement was developed and implemented by multiple research partners to support the prospective collection, annotation, and distribution of blood, tissues, and cell lines for the GTEx project. Other research projects can follow this model and form beneficial partnerships with rapid autopsy and organ procurement organizations to collect high quality biospecimens and associated clinical data for genomic studies. Biospecimens, clinical and genomic data, and Standard Operating Procedures guiding biospecimen collection for the GTEx project are available to the research community.This work was supported by the National Institutes of Health (HHSN261200800001E (Leidos Prime contract with NCI); 10XS170 (NDRI), 10XS171 (Roswell Park Cancer Institute), 10X172 (Science Care Inc.), 12ST1039 (IDOX); 10ST1035 (Van Andel Institute); HHSN268201000029C (Broad Institute); and R01 DA006227-17 (U Miami Brain Bank)

The Genotype-Tissue Expression (GTEx) project

Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues

Comprehensive genomic characterization of squamous cell lung cancers

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.National Institutes of Health (U.S.) (Grant U24 CA126561)National Institutes of Health (U.S.) (Grant U24 CA126551)National Institutes of Health (U.S.) (Grant U24 CA126554)National Institutes of Health (U.S.) (Grant U24 CA126543)National Institutes of Health (U.S.) (Grant U24 CA126546)National Institutes of Health (U.S.) (Grant U24 CA126563)National Institutes of Health (U.S.) (Grant U24 CA126544)National Institutes of Health (U.S.) (Grant U24 CA143845)National Institutes of Health (U.S.) (Grant U24 CA143858)National Institutes of Health (U.S.) (Grant U24 CA144025)National Institutes of Health (U.S.) (Grant U24 CA143882)National Institutes of Health (U.S.) (Grant U24 CA143866)National Institutes of Health (U.S.) (Grant U24 CA143867)National Institutes of Health (U.S.) (Grant U24 CA143848)National Institutes of Health (U.S.) (Grant U24 CA143840)National Institutes of Health (U.S.) (Grant U24 CA143835)National Institutes of Health (U.S.) (Grant U24 CA143799)National Institutes of Health (U.S.) (Grant U24 CA143883)National Institutes of Health (U.S.) (Grant U24 CA143843)National Institutes of Health (U.S.) (Grant U54 HG003067)National Institutes of Health (U.S.) (Grant U54 HG003079)National Institutes of Health (U.S.) (Grant U54 HG003273