Effects of RANKL-Targeted Therapy in Immunity and Cancer.

The role of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK system is well characterized within bone, where RANKL/RANK signaling mediates osteoclastogenesis and bone resorption. However, this system has also been shown to influence biologic processes beyond the skeletal system, including in the immune system and in cancer. RANKL/RANK signaling is important in lymph-node development, lymphocyte differentiation, dendritic cell survival, T-cell activation, and tolerance induction. The RANKL/RANK axis may also have direct, osteoclast-independent effects on tumor cells. Indeed, activity of the RANKL/RANK pathway in cancer cells has been correlated with tumor progression and advanced disease. Denosumab, a fully human monoclonal antibody against RANKL, inhibits osteoclastogenesis and is widely used not just for the treatment of osteoporosis, but for the prevention of skeletal-related events from bone metastases in solid malignancies such as breast and prostate cancer. The potential effects of denosumab on the immune system have been largely ignored. Nevertheless, with the emergence of immunotherapies for cancer, denosumab may impact the effectiveness of these therapies, especially if they are given in combination. In this article, we review the role of RANKL/RANK in bone, immunity, and cancer. Examining the potential effects of routine treatment with denosumab beyond the bone represents an important area of investigation

Interoperability Optimization and Service Enhancement in Vehicle Onboard Infortainment Systems

This paper presents an overview on optimizing interoperability between different applications for enhanced return-on-investment through utilization of business intelligence in conjunction with prognostics and health management methodology. Such implementation is particularly suitable for deployment in mass-produced vehicle onboard diagnostics system

Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and confers a poor prognosis. Beyond standard systemic therapy with multikinase inhibitors, recent studies demonstrate the potential for robust and durable responses from immune checkpoint inhibition in subsets of HCC patients across disease etiologies. The majority of HCC arises in the context of chronic inflammation and from within a fibrotic liver, with many cases associated with hepatitis virus infections, toxins, and fatty liver disease. Many patients also have concomitant cirrhosis which is associated with both local and systemic immune deficiency. Furthermore, the liver is an immunologic organ in itself, which may enhance or suppress the immune response to cancer arising within it. Here, we explore the immunobiology of the liver from its native state to chronic inflammation, fibrosis, cirrhosis and then to cancer, and summarize how this unique microenvironment may affect the response to immunotherapy

ENHANCING DYNAMICS COURSES WITH MODEL ELICITING ACTIVITIES

Model eliciting activities are assignments which require students to develop models to describe realistic situations. Every MEA follows six principles: model-construction, reality, self-assessment, model documentation, generalizability, and effective prototype. The six principles provide a solid guideline in which instructors can develop more MEAs, which can then be shared and used among several participating universities. Under NSF CCLI Grant #0717595, Cal Poly is currently developing Model Eliciting Activities for the subject of Mechanical Engineering. This report documents the undertakings to implement and enhance two Model Eliciting Activities (MEAs) into the Cal Poly curriculum. Specifically, the development of the Vehicle Accident Reconstruction (VAR) MEA and the Catapult MEA will be covered in detail. The VAR MEA was a project assigned in ME212 “Engineering Dynamics,” which required students to apply momentum principles to a two-vehicle collision. Because of the heavy development time experienced by the MEA research team, a MatLab program which accepted user inputs via a graphical user interface (GUI) was developed. This GUI solved for initial velocities during two-vehicle collisions by applying appropriate momentum and work-energy principles. With this program, instructors can more easily develop crash scenarios, as well as check student work. The Catapult MEA was also a project assigned to ME212 students. It required them to analyze the launch trajectory of an actual scaled catapult using angular motion and work-energy principles. This scaled-catapult was instrumented with one ADXL278 dual-axis accelerometer and four CEA-06-240UZ-120 strain gages. This instrumentation allowed for the experimental data acquisition of the catapult angular velocity, acceleration, and strains. By postprocessing this experimental data using a MatLab program, the experimental results can then be compared to theoretical results. The overall goal for the VAR MEA GUI programming was to reduce instructor workload in order to promote usage the MEA through a broader range of universities. The goal of the Catapult instrumentation was to provide students with actual experimental data, which could then be used to confirm their theoretical model. The system was set up so that they could easily record their own experimental data for each catapult launch

Combination immunotherapy induces distinct T-cell repertoire responses when administered to patients with different malignancies.

BackgroundCTLA-4 blockade with ipilimumab is Food and Drug Administration-approved for melanoma as a monotherapy and has been shown to modulate the circulating T-cell repertoire. We have previously reported clinical trials combining CTLA-4 blockade with granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic melanoma patients and in metastatic castration resistant prostate cancer (mCRPC) patients. Here, we investigate the effect that cancer type has on circulating T cells in metastatic melanoma and mCRPC patients, treated with ipilimumab and GM-CSF.MethodsWe used next-generation sequencing of T-cell receptors (TCR) to compare the circulating T cells of melanoma and mCRPC patients receiving the same treatment with ipilimumab and GM-CSF by Wilcoxon rank sum test. Flow cytometry was utilized to investigate specific T-cell populations. TCR sequencing results were correlated with each T-cell subpopulation by Spearman's rank correlation coefficient. Of note, 14 metastatic melanoma patients had samples available for TCR sequencing and 21 had samples available for flow cytometry analysis; 37 mCRPC patients had samples available for sequencing of whom 22 have TCR data available at both timepoints; 20 of these patients had samples available for flow cytometry analysis and 16 had data available at both timepoints.ResultsWhile melanoma and mCRPC patients had similar pretreatment circulating T-cell counts, treatment induces greater expansion of circulating T cells in melanoma patients. Metastatic melanoma patients have a higher proportion of clones that increased more than fourfold after the treatment compared with mCRPC patients (18.9% vs 11.0%, p=0.017). Additionally, melanoma patients compared with mCRPC patients had a higher ratio of convergent frequency (1.22 vs 0.60, p=0.012). Decreases in clonality induced by treatment are associated with baseline CD8+ T-cell counts in both patient groups, but are more pronounced in the melanoma patients (r=-0.81, p<0.001 vs r=-0.59, p=0.02).Trial registration numbersNCT00064129; NCT01363206

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer.

Sipuleucel-T is the only FDA-approved immunotherapy for metastatic castration-resistant prostate cancer. The mechanism by which this treatment improves survival is not fully understood. We have previously shown that this treatment can induce the recruitment of CD4 and CD8 T cells to the tumor microenvironment. In this study, we examined the functional state of these T cells through gene expression profiling. We found that the magnitude of T cell signatures correlated with the frequency of T cells as measured by immunohistochemistry. Sipuleucel-T treatment was associated with increased expression of Th1-associated genes, but not Th2-, Th17 - or Treg-associated genes. Post-treatment tumor tissues with high CD8+T cell infiltration was associated with high levels of CXCL10 expression. On in situ hybridization, CXCL10+ cells colocalized with CD8+T cells in post-treatment prostatectomy tumor tissue. Neoadjuvant sipuleucel-T was also associated with upregulation of immune inhibitory checkpoints, including CTLA4 and TIGIT, and downregulation of the immune activation marker, dipeptidylpeptidase, DPP4. Treatment-associated declines in serum PSA were correlated with induction of Th1 response. In contrast, rises in serum PSA while on treatment were associated with the induction of multiple immune checkpoints, including CTLA4, CEACAM6 and TIGIT. This could represent adaptive immune resistance mechanisms induced by treatment. Taken together, neoadjuvant sipuleucel-T can induce both a Th1 response and negative immune regulation in the prostate cancer microenvironment

Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein.

Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer's disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons. We further demonstrate that manipulation of retromer complex levels within neurons affects pathogenic TAU phosphorylation in an amyloid-independent manner. Taken together, our work demonstrates that retromer stabilization is a promising candidate for therapeutic development in AD and highlights the advantages of testing novel compounds in a human-specific, neuronal system

TCR Convergence in Individuals Treated With Immune Checkpoint Inhibition for Cancer.

Tumor antigen-driven selection may expand T cells having T cell receptors (TCRs) of shared antigen specificity but different amino acid or nucleotide sequence in a process known as TCR convergence. Substitution sequencing errors introduced by TCRβ (TCRB) repertoire sequencing may create artifacts resembling TCR convergence. Given the anticipated differences in substitution error rates across different next-generation sequencing platforms, the choice of platform could be consequential. To test this, we performed TCRB sequencing on the same peripheral blood mononuclear cells (PBMC) from individuals with cancer receiving anti-CTLA-4 or anti-PD-1 using an Illumina-based approach (Sequenta) and an Ion Torrent-based approach (Oncomine TCRB-LR). While both approaches found similar TCR diversity, clonality, and clonal overlap, we found that Illumina-based sequencing resulted in higher TCR convergence than with the Ion Torrent approach. To build upon this initial observation we conducted a systematic comparison of Illumina-based TCRB sequencing assays, including those employing molecular barcodes, with the Oncomine assay, revealing differences in the frequency of convergent events, purportedly artifactual rearrangements, and sensitivity of detection. Finally, we applied the Ion Torrent-based approach to evaluate clonality and convergence in a cohort of individuals receiving anti-CTLA-4 blockade for cancer. We found that clonality and convergence independently predicted response and could be combined to improve the accuracy of a logistic regression classifier. These results demonstrate the importance of the sequencing platform in assessing TCRB convergence

Accuracy of binary black hole waveform models for aligned-spin binaries

Coalescing binary black holes are among the primary science targets for second generation ground-based gravitational wave (GW) detectors. Reliable GW models are central to detection of such systems and subsequent parameter estimation. This paper performs a comprehensive analysis of the accuracy of recent waveform models for binary black holes with aligned spins, utilizing a new set of $84$ high-accuracy numerical relativity simulations. Our analysis covers comparable mass binaries ($1\le m_1/m_2\le 3$), and samples independently both black hole spins up to dimensionless spin-magnitude of $0.9$ for equal-mass binaries and $0.85$ for unequal mass binaries. Furthermore, we focus on the high-mass regime (total mass $\gtrsim 50M_\odot$). The two most recent waveform models considered (PhenomD and SEOBNRv2) both perform very well for signal detection, losing less than 0.5\% of the recoverable signal-to-noise ratio $\rho$, except that SEOBNRv2's efficiency drops mildly for both black hole spins aligned with large magnitude. For parameter estimation, modeling inaccuracies of SEOBNRv2 are found to be smaller than systematic uncertainties for moderately strong GW events up to roughly $\rho\lesssim 15$. PhenomD's modeling errors are found to be smaller than SEOBNRv2's, and are generally irrelevant for $\rho\lesssim 20$. Both models' accuracy deteriorates with increased mass-ratio, and when at least one black hole spin is large and aligned. The SEOBNRv2 model shows a pronounced disagreement with the numerical relativity simulation in the merger phase, for unequal masses and simultaneously both black hole spins very large and aligned. Two older waveform models (PhenomC and SEOBNRv1) are found to be distinctly less accurate than the more recent PhenomD and SEOBNRv2 models. Finally, we quantify the bias expected from all GW models during parameter estimation for recovery of binary's masses and spins.Comment: 24 pages, 15 figures, minor change