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Supplementary Figures 1-3 from Cancer Resistance in Transgenic Mice Expressing the SAC Module of Par-4

Supplementary Figure Legends 1-3 from Cancer Resistance in Transgenic Mice Expressing the SAC Module of Par-4

Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal/immortalized cells. The cancer-specific proapoptotic action of Par-4 is encoded in its centrally located SAC domain. We report here the characterization of a novel mouse model with ubiquitous expression of the SAC domain. Although SAC transgenic mice displayed normal development and life span, they were resistant to the growth of spontaneous, as well as oncogene-induced, autochthonous tumors. Resistance to tumorigenesis was linked to inhibition of nuclear factor-κB activity and induction of apoptosis by the SAC domain. Collectively, our findings provide genetic evidence that the SAC domain of Par-4 confers cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance. [Cancer Res 2007;67(19):9276–85]

The overarching goalsof the University of Kentucky (UK) IMERS workshops, supported by an IPERT grant, are to empower faculty at minority-serving institutions (MSIs) to develop and submit competitive research proposals through intensive grant-writing skills training;to build research-related individual and institutional capacity through training on mentorship of student researchers;and to sustain workshop momentum by embedding multiple levels of mentored proposal development support during and after each workshop. We hypothesize that this targeted training will enhance the research environment at MSI's, increase the diversity of NIH-funded investigators and improve the training of underrepresented students in biomedical research, thus providing a feed-forward mechanism to expand the diversity of the US biomedical workforce in future years. A hallmark of IMERS is to engage participants in hands-on, active-learning style grant-writing training for faculty who are poised to submit NIH proposals ranging from development/exploratory to R01s. This training is provided by UK faculty and experienced research development professionals. The IMERS model incorporates guided writing, participatory training, and active learning. Training is comprised of several modalities. First, IMERS offers two 3-day grant-writing retreats/year on the UK campus. These workshops are designed for highly motivated investigators who have submitted proposals to NIH without success and those who have been actively planning NIH submission;~25 faculty are selected for each workshop via an on-line application. On-site workshops include consultation with actively funded UK investigators and staff from the UK Proposal Development Office;we strive to maintain post-workshop interactions between participants and UK faculty/staff. Three 2-day off-site workshops/year are also offered. The IMERS staff will work with off-site institutions to tailor the workshops to specific needs. In-person workshops have been postponed due to COVID-19 restrictions, but will resume when safe to do so. However, we have developed an active series of virtual workshops and seminars during this time, and we anticipate that these and additional on-line activities will continue as a third arm of training even after restriction are lifted. Travel and lodging expenses for faculty to attend UK workshops, for the IMERS team to travel, are covered by the grant. Workshop sessions cover numerous topics, including: using NIH resources for program/funding information, budget issues, the proposal review process, writing a high-impact specific aims page and an effective research strategy, rigor and reproducibility, responsible conduct of research, NIH Biosketch, navigating the NIH resubmission process, and mentoring student researchers. Program evaluation, based in part on participant survey data, communication email and an active ListServ and subsequent submission rate and success, validates that program participants have increased confidence in their grant-writing abilities and are succeeding in obtaining NIH funding.

The aim of this study is to find synergistic effect using FH535 and sorafenib by targeting the RAS/RAF/MAPK and WNT/β-catenin pathways.3H-Thymidine incorporation assays were performed to address Huh7 and liver cancer stem cell (LCSC) inhibition using FH535 and sorafenib, alone and in combination. Calcusyn analysis was used to calculate the combination index (CI). A western blot assay was performed to check for potential targets.FH535 and sorafenib caused inhibition of Huh7 and LCSC. Combination therapy was significantly better than monotherapy in inhibition of HuH7. Combination with sorafenib and FH535 was found to be synergistic in inhibition of LCSC with a CI of less than 1. The western blot assay demonstrated enhanced cleaved poly (ADP-ribose) polymerase (PARP) and inhibition of cyclin D1, B-cell lymphoma 2 (Bcl2), survivin and cellular myelocytomatosis oncogene (c-MYC).FH535 and sorafenib combination produced synergistic effect on inhibition of HCC and LCSC. Our study demonstrated that FH535 can induce apoptosis in these two different hepatocellular carcinoma (HCC) cell lines.

Two-dimensional gel electrophoresis was used to compare immunoprecipitated, radiolabeled HLA-DR molecules synthesized by alveolar macrophages (AM) and blood monocytes (BM) of the same healthy, nonsmoking volunteers. No charge differences were noted by isoelectric focusing. Molecular weight analysis of HLA-DR from AM revealed a complex pattern of radioactive spots differing slightly in molecular weight. This pattern was apparent in both the alpha and the beta chains. In contrast, a simpler pattern without the slight molecular weight differences was noted in HLA-DR from BM. The differences were eliminated by labeling AM and BM in the presence of tunicamycin, a specific inhibitor of protein-carbohydrate linkages of the N-glycosidic type. Thus, it appears that neutral, N-linked carbohydrate moieties account for the differences in HLA-DR molecules between AM and BM. The differential glycosylation of HLA-DR molecules in AM and BM may relate to mononuclear phagocyte development as well as antigen-presenting function.