Investigating the Anti-tumorigenic Properties of Synthetic Inhibitors of B7-H3 in Group 3 Medulloblastoma

Medulloblastomas (MB) are devastating brain tumors originating in the cerebellum most commonly in children. There are four distinct subgroups of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. The most malignant tumors possess an aggressive phenotype characterized by c-Myc amplification and deletions to chromosome 17p; they belong to group 3. Prior investigations into the significance of genes on 17p revealed that miR-1253, which is found on locus 17p13.3, is significantly downregulated in medulloblastoma and has important tumor suppressive properties. Amongst its oncogenic targets is B7-H3 (CD276), a highly deregulated oncoprotein that attenuates the immune response to MB tumors. We chose to elucidate the oncogenic properties of B7-H3 in group 3 MB using synthetic inhibitors. After screening 100,000 different compounds for: 1) docking ability, 2) oral bioavailability, 3) potential CNS activity, and 4) number of metabolic side reactions, we selected two N-terminal inhibitors: B7-H3-Ni1 and B7-H3-Ni3. In HDMB03 cells (with c-Myc amplification and i17q), we found an IC50 of 3.7 M for B7-H3-Ni1 and no discernible effect of B7-H3-Ni3. We confirmed CD276 expression inhibition using B7-H3-Ni1 via Western blotting and concurrently noted elevations in cleaved PARP (apoptosis) and reduction in p-Akt (proliferation marker), providing us preliminary insights into the mechanism of inhibition. Notably, a remarkable decline in migration and wound healing and abrogation of colony formation were observed with B7-H3-Ni1. Collectively, our findings substantiate the inhibitory properties of B7-H3-Ni1 in vitro, potentially serving as a therapeutic agent for in vivo group 3 MB tumors.https://digitalcommons.unmc.edu/surp2021/1049/thumbnail.jp

Overexpression of Map3k7 activates sinoatrial node-like differentiation in mouse ES-derived cardiomyocytes

In vivo, cardiomyocytes comprise a heterogeneous population of contractile cells defined by unique electrophysiologies, molecular markers and morphologies. The mechanisms directing myocardial cells to specific sub-lineages remain poorly understood. Here we report that overexpression of TGFβ-Activated Kinase (TAK1/Map3k7) in mouse embryonic stem (ES) cells faithfully directs myocardial differentiation of embryoid body (EB)-derived cardiac cells toward the sinoatrial node (SAN) lineage. Most cardiac cells in Map3k7-overexpressing EBs adopt markers, cellular morphologies, and electrophysiological behaviors characteristic of the SAN. These data, in addition to the fact that Map3k7 is upregulated in the sinus venous—the source of cells for the SAN—suggest that Map3k7 may be an endogenous regulator of the SAN fate

Collective Flow from the Intranuclear Cascade Model

The phenomenon of collective flow in relativistic heavy ion collisions is studied using the hadronic cascade model ARC. Direct comparison is made to data gathered at the Bevalac, for Au+Au at $p=1-2$ GeV/c. In contrast to the standard lore about the cascade model, collective flow is well described quantitatively without the need for explicit mean field terms to simulate the nuclear equation of state. Pion collective flow is in the opposite direction to nucleon flow as is that of anti-nucleons and other produced particles. Pion and nucleon flow are predicted at AGS energies also, where, in light of the higher baryon densities achieved, we speculate that equation of state effects may be observable.Comment: 9 pages, 2 figures include

Systematics of Stopping and Flow in Au+Au Collisions

Excitation functions of flow and stopping observables for the Au+Au system at energies from 40 to 1500 MeV per nucleon are presented. The systematics were obtained by merging the results of the INDRA and FOPI experiments, both performed at the GSI facility. The connection to the nuclear equation of state is discussed.Comment: Contribution to the WCI book "Dynamics and Thermodynamics with Nucleonic Degrees of Freedom

Cosmological Distance Measurement of 12 Nearby Supernovae IIP with ROTSE-IIIB

We present cosmological analysis of 12 nearby ($z<0.06$) Type IIP supernovae (SNe IIP) observed with the ROTSE-IIIb telescope. To achieve precise photometry, we present a new image differencing technique that is implemented for the first time on the ROTSE SN photometry pipeline. With this method, we find up to a 20\% increase in the detection efficiency and significant reduction in residual RMS scatter of the SN lightcurves when compared to the previous pipeline performance. We use the published optical spectra and broadband photometry of well studied SNe IIP to establish temporal models for ejecta velocity and photospheric temperature evolution for our SNe IIP population. This study yields measurements that are competitive to other methods even when the data are limited to a single epoch during the photospheric phase of SNe IIP. Using the fully reduced ROTSE photometry and optical spectra, we apply these models to the respective photometric epochs for each SN in the ROTSE IIP sample. This facilitates the use of the Expanding Photosphere Method (EPM) to obtain distance estimates to their respective host galaxies. We then perform cosmological parameter fitting using these EPM distances from which we measure the Hubble constant to be $72.9^{+5.7}_{-4.3}~{\rm kms^{-1}~Mpc^{-1}}$, which is consistent with the standard $\Lambda CDM$ model values derived using other independent techniques.Comment: 19 pages, 13 figure

Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis

Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by ‘genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2′-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex diseas

Women bargaining with patriarchy in coastal Kenya:contradictions, creative agency and food provisioning

Gender analysts have long recognised that challenging existing patriarchal structures involves risks for women, who may lose both long-term support and protection from kin. However, understanding the specific ways in which they ‘bargain with patriarchy’ in particular contexts is relatively poorly understood. We focus on a Mijikenda fishing community in coastal Kenya to explore contradictions in gendered power relations and how women deploy these to reinterpret gendered practices without directly challenging local patriarchal structures. We argue that a more complex understanding of women’s creative agency can reveal both the value to women of culturally-specific gendered roles and responsibilities and the importance of subtle changes that they are able to negotiate in these. With reference to food provisioning, the analysis contributes to more nuanced understandings of gendered household food security and women’s creative approaches to maintaining long-term security in their lives