A multi-modal data resource for investigating topographic heterogeneity in patient-derived xenograft tumors.

Patient-derived xenografts (PDXs) are an essential pre-clinical resource for investigating tumor biology. However, cellular heterogeneity within and across PDX tumors can strongly impact the interpretation of PDX studies. Here, we generated a multi-modal, large-scale dataset to investigate PDX heterogeneity in metastatic colorectal cancer (CRC) across tumor models, spatial scales and genomic, transcriptomic, proteomic and imaging assay modalities. To showcase this dataset, we present analysis to assess sources of PDX variation, including anatomical orientation within the implanted tumor, mouse contribution, and differences between replicate PDX tumors. A unique aspect of our dataset is deep characterization of intra-tumor heterogeneity via immunofluorescence imaging, which enables investigation of variation across multiple spatial scales, from subcellular to whole tumor levels. Our study provides a benchmark data resource to investigate PDX models of metastatic CRC and serves as a template for future, quantitative investigations of spatial heterogeneity within and across PDX tumor models

Proteomics reveals multiple routes to the osteogenic phenotype in mesenchymal stem cells

<p>Abstract</p> <p>Background</p> <p>Recently, we demonstrated that human mesenchymal stem cells (hMSC) stimulated with dexamethazone undergo gene focusing during osteogenic differentiation (<it>Stem Cells Dev </it>14(6): 1608–20, 2005). Here, we examine the protein expression profiles of three additional populations of hMSC stimulated to undergo osteogenic differentiation via either contact with pro-osteogenic extracellular matrix (ECM) proteins (collagen I, vitronectin, or laminin-5) or osteogenic media supplements (OS media). Specifically, we annotate these four protein expression profiles, as well as profiles from naïve hMSC and differentiated human osteoblasts (hOST), with known gene ontologies and analyze them as a tensor with modes for the expressed proteins, gene ontologies, and stimulants.</p> <p>Results</p> <p>Direct component analysis in the gene ontology space identifies three components that account for 90% of the variance between hMSC, osteoblasts, and the four stimulated hMSC populations. The directed component maps the differentiation stages of the stimulated stem cell populations along the differentiation axis created by the difference in the expression profiles of hMSC and hOST. Surprisingly, hMSC treated with ECM proteins lie closer to osteoblasts than do hMSC treated with OS media. Additionally, the second component demonstrates that proteomic profiles of collagen I- and vitronectin-stimulated hMSC are distinct from those of OS-stimulated cells. A three-mode tensor analysis reveals additional focus proteins critical for characterizing the phenotypic variations between naïve hMSC, partially differentiated hMSC, and hOST.</p> <p>Conclusion</p> <p>The differences between the proteomic profiles of OS-stimulated hMSC and ECM-hMSC characterize different transitional phenotypes en route to becoming osteoblasts. This conclusion is arrived at via a three-mode tensor analysis validated using hMSC plated on laminin-5.</p

Accretion of gas by globular cluster stars

Some recent observations of the abundances of s-process, r-process, and alpha elements in metal-poor stars have led to a new scenario for their formation. According to this scenario, these stars were born in a globular cluster and accreted the s-process enriched gas expelled by cluster stars of higher-mass, thereby modifying their surface abundances. Later on, these polluted stars evaporated from the globular cluster to constitute an important fraction of the current halo population. In addition, there are now many direct observations of abundance anomalies not only in globular cluster giant stars but also in subgiant and main-sequence stars. Accretion provides again a plausible explanation for (at least some of) these peculiarities. Here we investigate further the efficiency of the accretion scenario. We find that in concentrated clusters with large escape velocities, accretion is very efficient and can indeed lead to major modifications of the stellar surface abundances.Comment: 11 pages; accepted for publication in Astronomy and Astrophysic

Identifying olanzapine induced liver injury in the setting of acute hepatitis C: A case report

Olanzapine is linked to asymptomatic, transient elevations of liver aminotransferases but is historically thought to rarely cause significant hepatotoxicity. Underlying liver disease is a risk factor for drug-induced liver injury and may complicate the differential diagnosis of acute transaminitis in patients taking medications associated with hepatotoxicity. Ms L presented with 2 months of new psychotic symptoms resulting in hospitalizations. Although psychosis previously improved with haloperidol, she reported symptoms concerning for akathisia. Restlessness improved and psychotic symptoms resolved after initiation of olanzapine. Concurrently, her alanine aminotransferase (ALT) was elevated, prompting further workup and new diagnosis of acute hepatitis C. Over the course of hospitalization, her ALT increased exponentially. Initially attributed solely to acute hepatitis C infection, ALT rapidly decreased after holding olanzapine, implying it was contributing to her liver injury. Subsequently, given her prior response, haloperidol was retrialed with close monitoring for adverse effects. Her subjective restlessness was treated with additional agents, and she was then transitioned to monthly haloperidol decanoate injections to further assist her adherence. Prior to discharge, she had resolution of psychosis and transaminitis. Olanzapine may contribute to hepatotoxicity with concurrent viral hepatitis, and clarity can be obtained by a trial of stopping the suspected medication. Furthermore, olanzapine, when combined with underlying liver disease, may have an additive effect on liver injury, resulting in accelerated elevations in liver aminotransferases

HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and Invasion

SummaryDevelopment of hypoxic regions is an indicator of poor prognosis in many tumors. Here, we demonstrate that HIF1α, the direct effector of hypoxia, partly through increases in SDF1α, induces recruitment of bone marrow-derived CD45+ myeloid cells containing Tie2+, VEGFR1+, CD11b+, and F4/80+ subpopulations, as well as endothelial and pericyte progenitor cells to promote neovascularization in glioblastoma. MMP-9 activity of bone marrow-derived CD45+ cells is essential and sufficient to initiate angiogenesis by increasing VEGF bioavailability. In the absence of HIF1α, SDF1α levels decrease, and fewer BM-derived cells are recruited to the tumors, decreasing MMP-9 and mobilization of VEGF. VEGF also directly regulates tumor cell invasiveness. When VEGF activity is impaired, tumor cells invade deep into the brain in the perivascular compartment