Epigenetic Regulation of Tumor Cell Phenotype

The Transforming Growth Factor-β (TGFβ)/SMAD signaling pathway can function as either a tumor suppressor or metastasis promoter during tumor progression. In normal epithelial cells and early stages of epithelial tumorigenesis TGFβ functions as a tumor suppressor to decrease cell proliferation or induce apoptosis. However, during malignant progression tumor cells no longer respond to the anti-proliferative effects of TGFβ, but instead undergo an epithelial-to-mesenchymal transition (EMT) whereby cells acquire a migratory and invasive phenotype which promotes tumor metastasis. Resolution of the dichotomy in TGFβ function and a further understanding of its tumor suppressor and metastasis promoting functions may uncover new strategies for the treatment of epithelial cancers. Previous studies have demonstrated an important role of the TGFβ-Inducible Early Gene-1 (TIEG1)/Krüppel-like Factor-10 (KLF10) as a central regulator of TGFβ/SMAD signaling and the anti-proliferative functions of TGFβ. In this study we examined the role of KLF10 in controlling the TGFβ-induced EMT and show that depletion of KLF10 results in a more pronounced induction of EMT. Moreover, chromatin immunoprecipitation (ChIP) and chromatin immunoprecipitation- sequencing (ChIP-seq) analysis shows that KLF10 directly binds to GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2 to repress its transcription. Consistent with these findings, an analysis of KLF10 in lung cancer revealed that KLF10 levels are decreased in lung cancer vs. normal samples. Furthermore, in vivo study revealed a significantly increased tumor incidence and tumor size in Klf10-/- mice compared to the wild type mice. Additional ChIP studies showed that KLF10 recruits HDAC1 to the SNAI2 promoter and is required for the removal of activating histone acetylation marks. These findings reveal a previously unknown function of KLF10 in suppressing TGFβ-induced EMT and Abstract x represent a significant advancement in the understanding the molecular dichotomy of TGFβ function during tumor progression. In a more global approach, we have utilized a dual LSD1/HDAC inhibitor 4SC-202 to study the effect on tumor cell phenotype. We have shown that combined inhibition of LSD1 and HDACs significantly block the TGFβ-induced EMT. Immunohistochemical staining of LSD1 in pancreatic cancer samples revealed that LSD1 is highly expressed in a subset of tumors. Consistent with this finding, in our xenograft study we have shown that 4SC-202 significantly decreases the tumor size. Together these findings revealed the potential role of small molecule inhibitors against epigenetic modifiers in targeted anticancer therapy

Modification of collector of Electro spinning Machine for the fabrication of 3-D nanofibrous scaffold for Tissue Engineering applications

The present work deals with the modification of collector system of the existing Free liquid surface type electrospinning machine to prepare 3-D Nanofibrous scaffold. Initially the trial has been given to prepare 2-D electrospun nanofibers using PVA polymer solution. To make 3-D nanofibrous scaffold, a cylindrical pipe made up of plastic material with required diameter was introduced as the collector. A motor attached to the collector to rotate at its horizontal axis thus acting as a guide to the charged polymer jet to let it deposit around its curved surface area. The cylindrical-shaped nanofibrous PVA scaffolds were then prepared that can be useful for tissue engineering application especially in the development of vascular blood vessels implant

Optimizing Multimodal Transportation Access to Support Commuting Among Low-Income Transit Riders with Social Distancing

During the COVID-19 pandemic, LA Metro has encouraged social distancing among passengers—especially at stations of high-demand routes—and has increased fixed-route transit (FRT) services. However, potential impacts of social distancing on the performance of FRT services remain mostly unknown. This research evaluates the accessibility of FRT buses with social distancing using the ridership data collected on four FRT routes: 105, 108, 111, and 115 of the LA Metro\u27s A Line stations located in low-income neighborhoods. This research shows that social distancing of six feet can impact FRT\u27s accessibility to destination stations, and maximum accessibility is achieved only for a certain number of stops served—which is less than the current number of stops served. The FRT routes 105, 108, 111 and 115 have maximum accessibility with social distancing for the number of stops served equal to 65, 52, 52 and 50, respectively. The methodology used in this research can help decision-makers understand how FRT bus frequencies are impacted by social distancing measures, and the results can guide the transit authorities developing FRT service among low-income commuters during and after the pandemic