Project description:The Piedmont study is a prospectively designed retrospective evaluation of a new 48-gene antifolate response signature (AF-PRS) in patients with locally advanced/metastatic NS-NSCLC treated with pemetrexed-containing platinum doublet chemotherapy (PMX-PDC). The study tested the hypothesis that the AF-PRS selects for patients with NS-NSCLC that preferentially respond to PMX-PDC, with a goal of providing clinical support for AF-PRS as potential diagnostic test. Overall, 53% of patients were AF-PRS(+), which was associated with extended PFS, but not OS, vs. AF-PRS(-) (16.6 vs. 6.6 mo; p = 0.025). In patients who were Stage I-III patients at time of treatment, PFS, but not OS, was further extended in AF-PRS(+) vs. AF-PRS(-) (36.2 vs. 9.3 mo; p = 0.03). A complete response (CR) to therapy was noted in 14 of 95 patients. AF-PRS(+) preferentially selected a majority (79%) of CRs, which were evenly split between patients Stage I-III (6 of 7) and Stage IV (5 of 7) at time of treatment. AF-PRS identified a significant population of patients with extended survival and/or clinical response following PMX-PDC treatment. AF-PRS may be a useful diagnostic test for patients indicated for systemic chemotherapy, especially when determining the optimal PDC regimen for locally advanced disease.
Project description:Plasmacytoid dendritic cells (pDC) are the main source of type I interferon (IFN) during viral infections. Their other functions are debated, due to a lack of tools to identify and target them in vivo without affecting pDC-like cells and transitional DC (tDC), which harbor overlapping phenotypes and transcriptomes but a higher efficacy for T cell activation. To overcome this bottleneck, we designed, generated and validated a pDC-Tomato reporter mouse. We bred pDC-Tomato with Zbtb46 GFP mice to yield the he ZeST mouse strain that enabled transcriptomic profiling of all splenic DC types, by single cell RNA sequencing, both at steady state and during the course of the infection with mouse cytomegalovirus (MCMV). Analyses of the transcriptomic dataset unraveled diverging activation of pDC-like cells vs tDC during the infection. This dataset and the associated specific gene modules will be useful to delineate the physiological functions of pDC versus other DC types.
Project description:This paper presents a teleoperation system of robot grasping for undefined objects based on a real-time EEG (Electroencephalography) measurement and shared autonomy. When grasping an undefined object in an unstructured environment, real-time human decision is necessary since fully autonomous grasping may not handle uncertain situations. The proposed system allows involvement of a wide range of human decisions throughout the entire grasping procedure, including 3D movement of the gripper, selecting proper grasping posture, and adjusting the amount of grip force. These multiple decision-making procedures of the human operator have been implemented with six flickering blocks for steady-state visually evoked potentials (SSVEP) by dividing the grasping task into predefined substeps. Each substep consists of approaching the object, selecting posture and grip force, grasping, transporting to the desired position, and releasing. The graphical user interface (GUI) displays the current substep and simple symbols beside each flickering block for quick understanding. The tele-grasping of various objects by using real-time human decisions of selecting among four possible postures and three levels of grip force has been demonstrated. This system can be adapted to other sequential EEG-controlled teleoperation tasks that require complex human decisions.
Project description:The healthy intestine mounts immune responses to microbiota to maintain homeostasis, which includes basal production of interferon cytokines. Previous work showed that Type III Interferon (IFN-λ) stimulates localized pockets of interferon-stimulated genes (ISGs) in the adult mouse intestinal epithelium at homeostasis that provide preemptive protection from viral pathogens. Here, we demonstrate that a major source of homeostatic IFN-λ production in the intestine is a population of epithelium-associated plasmacytoid dendritic cells (pDC). These pDC are recruited to the intestine by bacterial microbiota colonization, and pDC depletion or bone marrow reconstitution with IFN-λ-deficient pDC results in reduced homeostatic ISGs in the intestinal epithelium. Notably, intestinal pDC preferentially produce IFN-λ over Type I IFNs whereas splenic pDC produce more Type I IFNs. Comparison of splenic and intestinal pDC reveal tissue-specific changes in gene expression and genomic accessibility, including evidence of response to transforming growth factor beta (TGF-β) in the intestine. Isolated gut pDC produce more IFN-λ that splenic pDC upon stimulation, and pre-treatment of a human pDC cell line with TGF-β results in enhanced production of IFN-λ upon stimulation. This study implicates pDC as important sources of homeostatic IFN-λ in the intestine and defines the role of barrier cytokine TGF-β in regulating IFN types produced by pDC upon stimulation. Reprogramming of recruited pDC by tissue cytokines may have important implications for balancing effective antimicrobial responses with damaging inflammation at barrier tissues.
Project description:Here we confirm an essential requirement for the BCL11A transcription factor in fetal pDC development, and for the first time demonstrate this lineage specific requirement in the adult organism. Genome-wide analyses of BCL11A DNA binding and expression revealed that BCL11A regulates transcription of E2-2 and other pDC differentiation modulators including ID2 and MTG16. Our results identify BCL11A as an essential, lineage-specific factor that regulates pDC development. ChIP sequenicng was performed for a transcription factor of BCL11A in Cal1 cell line. Input was sequenced and used as a control.
Project description:Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells in bone marrow by successive steps of lineage commitment and differentiation. Different DC subsets were identified based on phenotype, localisation and function: (i) classical DC (cDC) and plasmacytoid DC (pDC) are found in lymphoid organs and (ii) migratory tissue DC are spread throughout peripheral organs, including Langerhans cells, the cutaneous contingent of DC. We have developed a two-step culture system that recapitulates DC development in vitro (Felker et al., J. Immunol. 185, 5326-5335, 2010). In this system multipotent hematopoietic progenitors (MPP) progress into DC-restricted common DC progenitors (CDP) and further into the two major DC subsets cDC and pDC. We employed chromatin immunoprecipitation (ChIP) with deep sequencing (ChIP-seq) to determine the dynamics of H3K27ac occupancy in MPP, CMP, cDC and pDC. Histone modification H3K27ac and RNA-Seq in MPP, CDP, cDC and pDC