Investigative Ophthalmology & Visual Science
Coble, M;Aranda, J;Demirs, JT;Esterberg, R;Hanks, S;Jose, S;Leehy, B;Liao, S;Niu, YZ;Qiu, Y;Yang, J;
METHODS : Gene expression of ABCA1 and ApoA1 on human donor tissue and iPSC-RPE were examined by qPCR (n=3). Bulk RNAseq examined transcript changes in key RCT genes on donor retinas across different stages of disease progression. RNAscope probes (ACDBio) were designed against abca1 transcripts with appropriate mismatch controls. Neutral lipid stain with oil-red O on 10um cryo-sections of abca1 KO and wild type (WT) eyes (N= 5). Two siRNAs knocked down abca1 in iPSC-RPE cells to assess abca1 contribution to cholesterol efflux (n=3). Samples were analyzed with the cholesterol efflux kit (ab196985) and compared to non-targeting control siRNAs. Histological analysis of ABCA1 protein using anti-ABCA1 (Invitrogen-MA516026) on human donor retinas (AMD1 vs AMD3).
Philipp, S;Landwehr, L;Justus, W;Altieri, B;Rodrigo, R;Tanja, M;Daniel, O;Kroiss, M;Sbiera, S;Michael, H;Fassnacht, M;
| DOI: 10.1530/endoabs.90.oc6.4
Background: Adrenocortical carcinoma (ACC) is a very rare and aggressive, endocrine malignancy with still limited treatment options. Approximately 60% of patients with ACC show endogenous glucocorticoid excess which could be one potential cause, why first clinical trials with immunotherapies, like immune checkpoint inhibitors, showed only modest results. Due to the lack of an ACC-specific antigen structure, other immunotherapeutic approaches, like specialized cancer treatments using chimeric antigen receptor (CAR) therapy in ACC, have not been tested so far. In this study, we evaluated the expression of a new enticing tumor antigen (TA*) structure and investigated the effect of TA-specific CAR-T cells _in vitro_.
Contemporary Clinical Neuroscience
Rahimi-Balaei, M;Ramirez, M;Gupta, I;Goldowitz, D;
| DOI: 10.1007/978-3-031-23104-9_6
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Paczkowska, J;Tang, M;Wright, K;Song, L;Shanmugam, V;Luu, K;Welsh, E;Cader, F;Mandato, E;Ouyang, J;Bai, G;Lawton, L;Rodig, S;Liu, X;Shipp, M;
| DOI: 10.1097/01.hs9.0000890680.82329.6b
The most abundant circulating CD3- population in patients with cHL was a newly identified monocyte subset with increased expression of multiple immunosuppressive and tumorigenic cytokines and chemokines, PD-L1 and SIRPa. This newly identified monocytic population was virtually absent from the blood of healthy donors. RNAscope analysis of the intact tumor microenvironment localized these tumor-infiltrating monocytes/macrophages to the immediate proximity of HRS cells. Monocytes from patients whose disease progressed following PD-1 blockade expressed significantly higher levels of immunosuppressive cytokine/chemokine signature which led to the development of a predictive transcriptional assay. We identified a comparable circulating monocyte population and transcriptional signature associated with unresponsiveness to PD-1 blockade in an additional solid tumor underscoring the broad-based significance of these findings.
Biomarkers of the Tumor Microenvironment
Wik, E;Ingebriktsen, L;Akslen, L;
| DOI: 10.1007/978-3-030-98950-7_23
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Molecular medicine (Cambridge, Mass.)
Chapoval, SP;Keegan, AD;
PMID: 34961486 | DOI: 10.1186/s10020-021-00423-y
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel type b coronavirus responsible for the COVID-19 pandemic. With over 224 million confirmed infections with this virus and more than 4.6 million people dead because of it, it is critically important to define the immunological processes occurring in the human response to this virus and pathogenetic mechanisms of its deadly manifestation. This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike-NRP1 interaction to combat virus infectivity and severe disease manifestations.
Matern, M;Milon, B;Elkon, R;Hertzano, R;
| DOI: 10.1007/978-1-0716-2022-9_8
We use cookies to make sure that our website works properly, as well as some ‘optional’ cookies to personalise content and advertising, provide social media features and analyse how people use our site. By accepting some or all optional cookies you give consent to the processing of your personal data, including transfer to third parties, some in countries outside of the European Economic Area that do not offer the same data protection standards as the country where you live. You can decide which optional cookies to accept by clicking on ‘Manage Settings’, where you can also find more information about how your personal data is processed. Further information can be found in our privacy policy [https://link.springer.com/privacystatement].
A hidden threshold in motor neuron gene networks revealed by modulation of miR-218 dose
Amin, ND;Senturk, G;Costaguta, G;Driscoll, S;O'Leary, B;Bonanomi, D;Pfaff, SL;
PMID: 34450025 | DOI: 10.1016/j.neuron.2021.07.028
Disruption of homeostatic microRNA (miRNA) expression levels is known to cause human neuropathology. However, the gene regulatory and phenotypic effects of altering a miRNA's in vivo abundance (rather than its binary gain or loss) are not well understood. By genetic combination, we generated an allelic series of mice expressing varying levels of miR-218, a motor neuron-selective gene regulator associated with motor neuron disease. Titration of miR-218 cellular dose unexpectedly revealed complex, non-ratiometric target mRNA dose responses and distinct gene network outputs. A non-linearly responsive regulon exhibited a steep miR-218 dose-dependent threshold in repression that, when crossed, resulted in severe motor neuron synaptic failure and death. This work demonstrates that a miRNA can govern distinct gene network outputs at different expression levels and that miRNA-dependent phenotypes emerge at particular dose ranges because of hidden regulatory inflection points of their underlying gene networks.
Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma
Hara, T;Chanoch-Myers, R;Mathewson, ND;Myskiw, C;Atta, L;Bussema, L;Eichhorn, SW;Greenwald, AC;Kinker, GS;Rodman, C;Gonzalez Castro, LN;Wakimoto, H;Rozenblatt-Rosen, O;Zhuang, X;Fan, J;Hunter, T;Verma, IM;Wucherpfennig, KW;Regev, A;Suvà, ML;Tirosh, I;
PMID: 34087162 | DOI: 10.1016/j.ccell.2021.05.002
The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.
Bridging scales: From cell biology to physiology using in situ single-cell technologies
Nagle, MP;Tam, GS;Maltz, E;Hemminger, Z;Wollman, R;
PMID: 34015260 | DOI: 10.1016/j.cels.2021.03.002
Biological organization crosses multiple spatial scales: from molecular, cellular, to tissues and organs. The proliferation of molecular profiling technologies enables increasingly detailed cataloging of the components at each scale. However, the scarcity of spatial profiling has made it challenging to bridge across these scales. Emerging technologies based on highly multiplexed in situ profiling are paving the way to study the spatial organization of cells and tissues in greater detail. These new technologies provide the data needed to cross the scale from cell biology to physiology and identify the fundamental principles that govern tissue organization. Here, we provide an overview of these key technologies and discuss the current and future insights these powerful techniques enable.
Novel Tyrosine Kinase Targets in Urothelial Carcinoma
International journal of molecular sciences
Torres-Jiménez, J;Albarrán-Fernández, V;Pozas, J;Román-Gil, MS;Esteban-Villarrubia, J;Carrato, A;Rosero, A;Grande, E;Alonso-Gordoa, T;Molina-Cerrillo, J;
PMID: 33451055 | DOI: 10.3390/ijms22020747
Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.
Coordination between Transport and Local Translation in Neurons
Broix, L;Turchetto, S;Nguyen, L;
| DOI: 10.1016/j.tcb.2021.01.001
The axonal microtubules (MTs) support long-distance transport of cargoes that are dispatched to distinct cellular subcompartments. Among them, mRNAs are directly transported in membraneless ribonucleoprotein (RNP) granules that, together with ribosomes, can also hitchhike on fast-moving membrane-bound organelles for accurate transport along MTs. These organelles serve as platforms for mRNA translation, thus generating axonal foci of newly synthesized proteins. Local translation along axons not only supports MT network integrity but also modulates the processivity and function of molecular motors to allow proper trafficking of cargoes along MTs. Thus, identifying the mechanisms that coordinate axonal transport with local protein synthesis will shed new light on the processes underlying axon development and maintenance, whose deregulation often contribute to neurological disorders.
