Browsing by Author "Giroux, Nicholas"
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Item Open Access DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists.(Biomaterials, 2022-04) Naqvi, Ibtehaj; Giroux, Nicholas; Olson, Lyra; Morrison, Sarah Ahn; Llanga, Telmo; Akinade, Tolu O; Zhu, Yuefei; Zhong, Yiling; Bose, Shree; Arvai, Stephanie; Abramson, Karen; Chen, Lingye; Que, Loretta; Kraft, Bryan; Shen, Xiling; Lee, Jaewoo; Leong, Kam W; Nair, Smita K; Sullenger, BruceMillions of COVID-19 patients have succumbed to respiratory and systemic inflammation. Hyperstimulation of toll-like receptor (TLR) signaling is a key driver of immunopathology following infection by viruses. We found that severely ill COVID-19 patients in the Intensive Care Unit (ICU) display hallmarks of such hyper-stimulation with abundant agonists of nucleic acid-sensing TLRs present in their blood and lungs. These nucleic acid-containing Damage and Pathogen Associated Molecular Patterns (DAMPs/PAMPs) can be depleted using nucleic acid-binding microfibers to limit the patient samples' ability to hyperactivate such innate immune receptors. Single-cell RNA-sequencing revealed that CD16+ monocytes from deceased but not recovered ICU patients exhibit a TLR-tolerant phenotype and a deficient anti-viral response after ex vivo TLR stimulation. Plasma proteomics confirmed such myeloid hyperactivation and revealed DAMP/PAMP carrier consumption in deceased patients. Treatment of these COVID-19 patient samples with MnO nanoparticles effectively neutralizes TLR activation by the abundant nucleic acid-containing DAMPs/PAMPs present in their lungs and blood. Finally, MnO nanoscavenger treatment limits the ability of DAMPs/PAMPs to induce TLR tolerance in monocytes. Thus, treatment with microfiber- or nanoparticle-based DAMP/PAMP scavengers may prove useful for limiting SARS-CoV-2 induced hyperinflammation, preventing monocytic TLR tolerance, and improving outcomes in severely ill COVID-19 patients.Item Open Access Patient-derived micro-organospheres enable clinical precision oncology.(Cell stem cell, 2022-06) Ding, Shengli; Hsu, Carolyn; Wang, Zhaohui; Natesh, Naveen R; Millen, Rosemary; Negrete, Marcos; Giroux, Nicholas; Rivera, Grecia O; Dohlman, Anders; Bose, Shree; Rotstein, Tomer; Spiller, Kassandra; Yeung, Athena; Sun, Zhiguo; Jiang, Chongming; Xi, Rui; Wilkin, Benjamin; Randon, Peggy M; Williamson, Ian; Nelson, Daniel A; Delubac, Daniel; Oh, Sehwa; Rupprecht, Gabrielle; Isaacs, James; Jia, Jingquan; Chen, Chao; Shen, John Paul; Kopetz, Scott; McCall, Shannon; Smith, Amber; Gjorevski, Nikolche; Walz, Antje-Christine; Antonia, Scott; Marrer-Berger, Estelle; Clevers, Hans; Hsu, David; Shen, XilingPatient-derived xenografts (PDXs) and patient-derived organoids (PDOs) have been shown to model clinical response to cancer therapy. However, it remains challenging to use these models to guide timely clinical decisions for cancer patients. Here, we used droplet emulsion microfluidics with temperature control and dead-volume minimization to rapidly generate thousands of micro-organospheres (MOSs) from low-volume patient tissues, which serve as an ideal patient-derived model for clinical precision oncology. A clinical study of recently diagnosed metastatic colorectal cancer (CRC) patients using an MOS-based precision oncology pipeline reliably assessed tumor drug response within 14 days, a timeline suitable for guiding treatment decisions in the clinic. Furthermore, MOSs capture original stromal cells and allow T cell penetration, providing a clinical assay for testing immuno-oncology (IO) therapies such as PD-1 blockade, bispecific antibodies, and T cell therapies on patient tumors.