المؤلفون: Lakhani, Nehal, Johnson, Melissa, Groisberg, Roman, Han, Hyunsil, Casey, Kerry, Li, Siyu, Skokos, Dimitris, Seebach, Frank, Lowy, Israel, Fury, Matthew, Mathias, Melissa

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2021-sitc2021.535Test

المؤلفون: Segal, Neil Howard, Girda, Eugenia, Sohal, Davendra, Lakhani, Nehal J., Olszanski, Anthony J., Fong, Lawrence, Han, Hyunsil, Casey, Kerry A., Li, Siyu, Ganguly, Samit, Seebach, Frank A., Mathias, Melissa Divya, Pelster, Meredith

المصدر: Journal of Clinical Oncology; 2024 Supplement 3, Vol. 42, pTPS239-TPS239, 235p

المؤلفون: Gross, Neil D, Miller, David M, Khushalani, Nikhil I, Divi, Vasu, Ruiz, Emily S, Lipson, Evan J, Meier, Friedegund, Su, Yungpo Bernard, Swiecicki, Paul L, Atlas, Jennifer, Geiger, Jessica L, Hauschild, Axel, Choe, Jennifer H, Hughes, Brett G, Schadendorf, Dirk, Patel, Vishal A, Homsi, Jade, Taube, Janis M, Lim, Annette M, Ferrarotto, Renata, Yoo, Suk-Young, Mathias, Melissa, Han, Hyunsil, Seebach, Frank, Lowy, Israel, Fury, Matthew G, Rischin, Danny

المصدر: GW Authored Works

الوصف: BACKGROUND: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. METHODS: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. FINDINGS: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received ...

العلاقة: https://hsrc.himmelfarb.gwu.edu/gwhpubs/3878Test; https://doi.org/10.1016/S1470-2045Test(23)00459-X

الإتاحة: https://doi.org/10.1016/S1470-2045Test(23)00459-X
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3878Test

المؤلفون: Johnson, Melissa, Lakhani, Nehal, Girda, Eugenia, Olszanski, Anthony, Fong, Lawrence, Han, Hyunsil, Casey, Kerry, Li, Siyu, Visich, Jennifer, Skokos, Dmitris, Seebach, Frank, Lowy, Israel, Fury, Matthew, Mathias, Melissa, Segal, Neil

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2022-sitc2022.0735Test

المؤلفون: Gross, Neil D, Miller, David M, Khushalani, Nikhil I, Divi, Vasu, Ruiz, Emily S, Lipson, Evan J, Meier, Friedegund, Su, Yungpo B, Swiecicki, Paul L, Atlas, Jennifer, Geiger, Jessica L, Hauschild, Axel, Choe, Jennifer H, Hughes, Brett G, Schadendorf, Dirk, Patel, Vishal A, Homsi, Jade, Taube, Janis M, Lim, Annette M, Ferrarotto, Renata, Kaufman, Howard L, Seebach, Frank, Lowy, Israel, Yoo, Suk-Young, Mathias, Melissa, Fenech, Keilah, Han, Hyunsil, Fury, Matthew G, Rischin, Danny

المصدر: GW Authored Works

الوصف: BACKGROUND: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS: Neoadjuvant therapy with ...

العلاقة: https://hsrc.himmelfarb.gwu.edu/gwhpubs/1728Test; https://doi.org/10.1056/NEJMoa2209813Test

الإتاحة: https://doi.org/10.1056/NEJMoa2209813Test
https://hsrc.himmelfarb.gwu.edu/gwhpubs/1728Test

المؤلفون: Wang, Yanming, Li, Ming, Stadler, Sonja, Correll, Sarah, Li, Pingxin, Wang, Danchen, Hayama, Ryo, Leonelli, Lauriebeth, Han, Hyunsil, Grigoryev, Sergei A., Allis, C. David, Coonrod, Scott A.

المصدر: The Journal of Cell Biology, 2009 Jan . 184(2), 205-213.

الوصول الحر: https://www.jstor.org/stable/20537133Test

مستخلص: The present invention relates to a method of treating an inflammatory disorder in a subject with an effective amount of compound having the general formula (I) as described in the present application, under conditions effective to treat the inflammatory disorder. The present invention also relates to a method of inhibiting respiratory burst in neutrophils without inhibiting degranulation in or bacterial killing by the neutrophils by contacting neutrophils with the compounds described above. [chemical expression included]

المؤلفون: Han, Hyunsil, Stessin, Alexander, Roberts, Julia, Hess, Kenneth, Gautam, Narinder, Kamenetsky, Margarita, Lou, Olivia, Hyde, Edward, Nathan, Noah, Muller, William A., Buck, Jochen, Levin, Lonny R., Nathan, Carl

المصدر: The Journal of Experimental Medicine ; volume 202, issue 3, page 353-361 ; ISSN 1540-9538 0022-1007

الوصف: Through chemical screening, we identified a pyrazolone that reversibly blocked the activation of phagocyte oxidase (phox) in human neutrophils in response to tumor necrosis factor (TNF) or formylated peptide. The pyrazolone spared activation of phox by phorbol ester or bacteria, bacterial killing, TNF-induced granule exocytosis and phox assembly, and endothelial transmigration. We traced the pyrazolone's mechanism of action to inhibition of TNF-induced intracellular Ca2+ elevations, and identified a nontransmembrane (“soluble”) adenylyl cyclase (sAC) in neutrophils as a Ca2+-sensing source of cAMP. A sAC inhibitor mimicked the pyrazolone's effect on phox. Both compounds blocked TNF-induced activation of Rap1A, a phox-associated guanosine triphosphatase that is regulated by cAMP. Thus, TNF turns on phox through a Ca2+-triggered, sAC-dependent process that may involve activation of Rap1A. This pathway may offer opportunities to suppress oxidative damage during inflammation without blocking antimicrobial function.

الإتاحة: https://doi.org/10.1084/jem.20050778Test
https://rupress.org/jem/article-pdf/202/3/353/1718739/jem2023353.pdfTest

المؤلفون: Han, Hyunsil, Roberts, Julia, Lou, Olivia, Muller, Willam A, Nathan, Noah, Nathan, Carl

المساهمون: National Institutes of Health, Cancer Research Institute, Department of Microbiology and Immunology

المصدر: Journal of Leukocyte Biology ; volume 79, issue 1, page 147-154 ; ISSN 1938-3673 0741-5400

مصطلحات موضوعية: Cell Biology, Immunology, Immunology and Allergy

الوصف: Chemical screening identified three small compounds that selectively inhibited activation of the respiratory burst (RB) of human neutrophils in response to tumor necrosis factor (TNF) and formylated peptide but not phorbol ester and spared the ability of neutrophils to kill bacteria. These compounds partially inhibited TNF-triggered cytoskeletal rearrangements without blocking adhesion or transmigation of polymorphonuclear neutrophils through TNF-activated monolayers of endothelial cells. The compounds were nontoxic to neutrophils and endothelial cells. They had no direct inhibitory effect on the tyrosine kinases Src, Syk, or Pyk2. However, their differential effects on cell spreading, bacteria-induced RB, TNF-induced degranulation, TNF-induced protein tyrosine phosphorylation, and TNF-induced Syk activation suggested that each may act on different elements of neutrophil signaling pathways.

الإتاحة: https://doi.org/10.1189/jlb.0605308Test
https://academic.oup.com/jleukbio/article-pdf/79/1/147/49643836/jlb0147.pdfTest

المؤلفون: Han, Hyunsil, Fuortes, Michele, Nathan, Carl

المصدر: The Journal of Experimental Medicine ; volume 197, issue 1, page 63-75 ; ISSN 1540-9538 0022-1007

الوصف: Transduction of Tat-tagged fusion proteins confirmed a hypothesis based on pharmacologic inhibitors (Fuortes, M., M. Melchior, H. Han, G.J. Lyon, and C. Nathan. 1999. J. Clin. Invest. 104:327–335) that proline-rich tyrosine kinase (Pyk2) plays a critical role in the activation of adherent human neutrophils, and allowed an analysis of individual Pyk2 domains not possible with chemical inhibitors. Acting as a dominant negative, the COOH terminus of Pyk2 fused to a Tat peptide (Tat-CT), but not other regions of Pyk2, specifically inhibited the respiratory burst of cells responding to tumor necrosis factor (TNF), Salmonella, or Listeria, while sparing responses induced by phorbol ester. Tat-CT suppressed TNF-triggered cell spreading and the phosphorylation of endogenous Pyk2 and the associated tyrosine kinase Syk without blocking the ability of neutrophils to degranulate and kill bacteria. Thus, separate signals control the respiratory burst and degranulation, and a normal rate of killing of some bacteria can be sustained by granule products in conjunction with a minimal residual respiratory burst. Inhibition of select inflammatory functions without impairment of antibacterial activity may commend the Pyk2 pathway as a potential target for antiinflammatory therapy.

الإتاحة: https://doi.org/10.1084/jem.20021638Test
https://rupress.org/jem/article-pdf/197/1/63/1708724/jem197163.pdfTest