Breast cancer is one of the most frequent cancers among women. Extensive studies into the molecular heterogeneity of breast cancer have produced a plethora of molecular subtype classification and ...prognosis prediction algorithms, as well as numerous gene expression signatures. However, reimplementation of these algorithms is a tedious but important task to enable comparison of existing signatures and classification models between each other and with new models. Here, we present the genefu R/Bioconductor package, a multi-tiered compendium of bioinformatics algorithms and gene signatures for molecular subtyping and prognostication in breast cancer.
The genefu package is available from Bioconductor. http://www.bioconductor.org/packages/devel/bioc/html/genefu.html Source code is also available on Github https://github.com/bhklab/genefu
bhaibeka@uhnresearch.ca
Supplementary data are available at Bioinformatics online.
Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both ...account for clinical manifestations.
We provided 198 healthy men 20 to 50 years of age with goserelin acetate (to suppress endogenous testosterone and estradiol) and randomly assigned them to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Changes in the percentage of body fat and in lean mass were the primary outcomes. Subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function were also assessed.
The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced.
The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00114114.).
Sports specialization is becoming the norm in youth sports for a variety of reasons. When sports specialization occurs too early, detrimental effects may occur, both physically and psychologically. ...If the timing is correct and sports specialization is performed under the correct conditions, the athlete may be successful in reaching specific goals. Young athletes who train intensively, whether specialized or not, can also be at risk of adverse effects on the mind and body. The purpose of this clinical report is to assist pediatricians in counseling their young athlete patients and their parents regarding sports specialization and intensive training. This report supports the American Academy of Pediatrics clinical report "Overuse Injuries, Overtraining, and Burnout in Child and Adolescent Athletes."
Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent ...that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d
+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d
+/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.
Immune infiltration of the tumor microenvironment has been associated with improved survival for some patients with solid tumors. The precise makeup and prognostic relevance of immune infiltrates ...across a broad spectrum of tumors remain unclear.
Using mRNA sequencing data from The Cancer Genome Atlas (TCGA) from 11 tumor types representing 3485 tumors, we evaluated lymphocyte and macrophage gene expression by tissue type and by genomic subtypes defined within and across tumor tissue of origin (Cox proportional hazards, Pearson correlation). We investigated clonal diversity of B-cell infiltrates through calculating B-cell receptor (BCR) repertoire sequence diversity. All statistical tests were two-sided.
High expression of T-cell and B-cell signatures predicted improved overall survival across many tumor types including breast, lung, and melanoma (breast CD8_T_Cells hazard ratio HR = 0.36, 95% confidence interval CI = 0.16 to 0.81, P = .01; lung adenocarcinoma B_Cell_60gene HR = 0.71, 95% CI = 0.58 to 0.87, P = 7.80E-04; melanoma LCK HR = 0.86, 95% CI = 0.79 to 0.94, P = 6.75E-04). Macrophage signatures predicted worse survival in GBM, as did B-cell signatures in renal tumors (Glioblastoma Multiforme GBM: macrophages HR = 1.62, 95% CI = 1.17 to 2.26, P = .004; renal: B_Cell_60gene HR = 1.17, 95% CI = 1.04 to 1.32, P = .009). BCR diversity was associated with survival beyond gene segment expression in melanoma (HR = 2.67, 95% CI = 1.32 to 5.40, P = .02) and renal cell carcinoma (HR = 0.36, 95% CI = 0.15 to 0.87, P = .006).
These data support existing studies suggesting that in diverse tissue types, heterogeneous immune infiltrates are present and typically portend an improved prognosis. In some tumor types, BCR diversity was also associated with survival. Quantitative genomic signatures of immune cells warrant further testing as prognostic markers and potential biomarkers of response to cancer immunotherapy.
BACKGROUNDThe KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently ...bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed, they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance.METHODSHere, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep-RNA and whole-exome sequencing comparing pretreatment, posttreatment, and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition.RESULTSIn addition to decreased KRAS G12C-mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell-intrinsic and non-cell autonomous mechanisms included increased complement activation, coagulation, and tumor angiogenesis, and several lines of evidence of immunologic evasion.CONCLUSIONTogether, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling, and diverse remodeling of the tumor microenvironment.FUNDINGRichard and Fran Duley, Jimmy and Kay Mann, the NIH, and the North Carolina Biotechnology Center.
This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor ...mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.
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•New TNBC murine models with high mutation burden and immune cell activity•A genomics resource of immune checkpoint treated tumors from TNBC murine models•Immune checkpoint blockade activates Tfh and B cells in the anti-tumor response•B cells impact immunotherapy response by secreting antibody and activating T cells
Mouse models of triple-negative breast cancer provide insights into how T follicular helper cell activation of B cells facilitates the effects of immune checkpoint inhibitors.
Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically ...connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.
We demonstrate ultrahigh speed swept source/Fourier domain ophthalmic OCT imaging using a short cavity swept laser at 100,000 - 400,000 axial scan rates. Several design configurations illustrate ...tradeoffs in imaging speed, sensitivity, axial resolution, and imaging depth. Variable rate A/D optical clocking is used to acquire linear-in-k OCT fringe data at 100 kHz axial scan rate with 5.3 um axial resolution in tissue. Fixed rate sampling at 1 GSPS achieves a 7.5mm imaging range in tissue with 6.0 um axial resolution at 100 kHz axial scan rate. A 200 kHz axial scan rate with 5.3 um axial resolution over 4mm imaging range is achieved by buffering the laser sweep. Dual spot OCT using two parallel interferometers achieves 400 kHz axial scan rate, almost 2X faster than previous 1050 nm ophthalmic results and 20X faster than current commercial instruments. Superior sensitivity roll-off performance is shown. Imaging is demonstrated in the human retina and anterior segment. Wide field 12x12 mm data sets include the macula and optic nerve head. Small area, high density imaging shows individual cone photoreceptors. The 7.5 mm imaging range configuration can show the cornea, iris, and anterior lens in a single image. These improvements in imaging speed and depth range provide important advantages for ophthalmic imaging. The ability to rapidly acquire 3D-OCT data over a wide field of view promises to simplify examination protocols. The ability to image fine structures can provide detailed information on focal pathologies. The large imaging range and improved image penetration at 1050 m wavelengths promises to improve performance for instrumentation which images both the retina and anterior eye. These advantages suggest that swept source OCT at 1050 nm wavelengths will play an important role in future ophthalmic instrumentation.
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