Theoretical Feasibility of Vasodilator-enhanced Local Tumor Heating

Normal arterioles, in contrast to the abnormal microvasculature of many solid tumors, provide a target for selective drug action that can enhance local heat treatment of the tumors. Measurements of tissue blood flow with radioactive microspheres and estimates of changes in blood flow with thermal clearance methods revealed that vasodilator drugs either decreased or did not alter blood flow in hamster melanoma, rat hepatoma, and canine transmissible venereal tumor, while increasing perfusion in adjacent normal tissues 2 to 4-fold. Solutions of the bio-heat transfer equation, which take into account such selective effects of vasodilators on blood flow in normal tissues, clearly demonstrate improved selective heating for spheroidal tumors over 2 cm in diameter. In the presence of vasodilator drug effect, steady-state center tumor temperatures of 45-50°C can be achieved by increased power input, while surrounding normal tissues remain below 42°C

On-Road Development of John Deere 6081 Natural Gas Engine: Final Technical Report, July 1999 - January 2001

Report that discusses John Deere's field development of a heavy-duty natural gas engine. As part of the field development project, Waste Management of Orange County, California refitted four existing trash packers with John Deere's prototype spark ignited 280-hp 8.1 L CNG engines. This report describes the project and also contains information about engine performance, emissions, and driveability

Sustained low-dose treatment with the histone deacetylase inhibitor LBH589 induces terminal differentation of osteosarcoma cells

Histone deacetylase inhibitors (HDACi) were identified nearly four decades ago based on their ability to induce cellular differentiation. However, the clinical development of these compounds as cancer therapies has focused on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents. In many cases, HDACi doses necessary to induce these effects result in significant toxicity. Since osteosarcoma cells express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we reasoned that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit. Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat) over a three-week period induces terminal osteoblast differentiation and irreversible senescence without inducing cell death. Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers. In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by induction of mature osteoblast gene expression. These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing systemic toxicity

A Call for Responsible Estimation of Global Health

Peer reviewedPublisher PD

Large-scale machine learning-based phenotyping significantly improves genomic discovery for optic nerve head morphology.

Genome-wide association studies (GWASs) require accurate cohort phenotyping, but expert labeling can be costly, time intensive, and variable. Here, we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; p ≤ 5 × 10-8) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 93 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR: select loci near genes involved in neuronal and synaptic biology or harboring variants are known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort