Two Poems: Economy Class Particulate View and Daynotes on Fields & Forms (Flittings)

Poetry by Linda Russo

Improving Treatments for Peritoneal Metastasis Originating from Colorectal Cancer

Peritoneal metastasis (PM) is a terminal disease that often arises from colorectal cancer (CRC). PM Patients are treated either with systemic chemotherapies or with the combination of cytoreductive surgery (CRS) and local hyperthermic intraperitoneal chemotherapy (HIPEC). Studies suggest that compared to systemic chemotherapy CRS/HIPEC enhances survival of patients, but frequent recurrence of the disease limits overall 5-years survival. Therefore, new effective treatments are needed to improve survival of PM patients. To do so, we assessed protective immune-related mechanisms of chemotherapeutics and further combined them with other drugs in order to improve treatment outcome. Different drug combinations were tested in vitro on human colorectal cancer cell lines and patient-derived PM organoids to assess cell viability and the potential to induce immunogenic changes. For in vivo experiments, C57BL/6 mice were injected i.p with murine colorectal cancer cell lines MC-38 and treated with Oxaliplatin and ATRi. To identify potential drug combinations to treat PM, we treated human colorectal cancer cells with either Oxaliplatin alone or in combination with DNA damage inhibitors, cell proliferation inhibitors or multi-kinase inhibitors. We noticed enhanced cytotoxicity as well as the expression and release of immune stimulatory molecules when cells were treated with Oxaliplatin + ATRi (ataxia telangiectasia and Rad3-related). Using our PM mouse model, we showed that the combination of Oxaliplatin + ATRi significantly reduced growth of PM lesions, which was due to immunogenic changes occurring within the lesions like reduced PD-L1 expression and regulatory T-cell frequency as well as increased CD8+ T-cell effector functions. Furthermore, depletion of CD8+ T cells abrogated the protective effects of the combination therapy suggesting that CD8+ T cells are crucial to control tumor growth. Moreover, addition of PD-1 blocking antibody enhanced PM lesion control. Overall, these results suggest that optimal priming of the immune system with novel drug combinations may provide long-term control of PM lesions

3D Extracellular Matrix Mimics: Fundamental Concepts and Role of Materials Chemistry to Influence Stem Cell Fate

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Simulation of solute transport in a heterogeneous vadose zone describing the hydraulic properties using a multistep stochastic approach

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95612/1/wrcr10619.pd

Spatial proteomics finds CD155 and Endophilin-A1 as mediators of growth and invasion in medulloblastoma

The composition of the plasma membrane (PM)-associated proteome of tumor cells determines cell-cell and cell-matrix interactions and the response to environmental cues. Whether the PM-associated proteome impacts the phenotype of Medulloblastoma (MB) tumor cells and how it adapts in response to growth factor cues is poorly understood. Using a spatial proteomics approach, we observed that hepatocyte growth factor (HGF)-induced activation of the receptor tyrosine kinase c-MET in MB cells changes the abundance of transmembrane and membrane-associated proteins. The depletion of MAP4K4, a pro-migratory effector kinase downstream of c-MET, leads to a specific decrease of the adhesion and immunomodulatory receptor CD155 and of components of the fast-endophilin-mediated endocytosis (FEME) machinery in the PM-associated proteome of HGF-activated MB cells. The decreased surface expression of CD155 or of the fast-endophilin-mediated endocytosis effector endophilin-A1 reduces growth and invasiveness of MB tumor cells in the tissue context. These data thus describe a novel function of MAP4K4 in the control of the PM-associated proteome of tumor cells and identified two downstream effector mechanisms controlling proliferation and invasiveness of MB cells

Local structure of semicrystalline P3HT films probed by nanofocused coherent x-rays

We present results of an x-ray study of structural properties of semicrystalline polymer films using nanofocused x-ray beam. We applied the x-ray cross-correlation analysis (XCCA) to scattering data from blends of poly(3-hexylthiophene) (P3HT) embedded with gold nanoparticles (AuNPs). Spatially resolved maps of orientational distribution of crystalline domains allow us to distinguish sample regions of predominant face-on morphology,with a continuous transition to edge-on morphology. The average size of crystalline domains was determined to be of the order of 10 nm. As compared to pristine P3HT film, the P3HT/AuNPs blend is characterized by substantial ordering of crystalline domains, which can be induced by Au nanoparticles. The inhomogeneous structure of the polymer film is clearly visualized on the spatially resolved nanoscale 2D maps obtained using XCCA. Our results suggest that the observed changes of the polymer matrix within crystalline regions can be attributed to nanoconfinement in the presence of gold nanoparticles.Comment: 10 pages, 6 figures, 53 reference

Integration of Pharmacogenetics and Pharmacogenomics in Drug Development: Implications for Regulatory and Medical Decision Making in Pediatric Diseases

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Maternal Dioxin Exposure Combined with a Diet High in Fat Increases Mammary Cancer Incidence in Mice

BackgroundRESULTS from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk.ObjectivesBecause both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility.MethodsWe exposed pregnant female FVB/NJ mice (12.5 days postcoitus) to 1 microg/kg TCDD or vehicle; at parturition, the dams were randomly assigned to a low-fat diet (LFD) or a high-fat diet (HFD). Female offspring were maintained on the same diets after weaning and were exposed to 7,12-dimethylbenz[a]anthracene on postnatal days (PNDs) 35, 49, and 63 to initiate mammary tumors. A second cohort of females was treated identically until PND35 or PND49, when mammary gland morphology was examined, or PND50, when mammary gland mRNA was analyzed.ResultsWe found that maternal TCDD exposure doubled mammary tumor incidence only in mice fed the HFD. Among HFD-fed mice, maternal TCDD exposure caused rapid mammary development with increased Cyp1b1 (cytochrome P450 1B1) expression and decreased Comt (catechol-O-methyltransferase) expression in mammary tissue. Maternal TCDD exposure also increased mammary tumor Cyp1b1 expression.ConclusionsOur data suggest that the HFD increases sensitivity to maternal TCDD exposure, resulting in increased breast cancer incidence, by changing metabolism capability. These results provide a mechanism to explain epidemiological data linking early-life TCDD exposure and diets high in fat to increased risk for breast cancer in humans