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1. Airway management in the paediatric difficult intubation registry: a propensity score matched analysis of outcomes over time

Author

Stein, Mary Lyn, primary, Sarmiento Argüello, Lina Andrea, additional, Staffa, Steven J., additional, Heunis, Julia, additional, Egbuta, Chinyere, additional, Flynn, Stephen G., additional, Khan, Sabina A., additional, Sabato, Stefano, additional, Taicher, Brad M., additional, Chiao, Franklin, additional, Bosenberg, Adrian, additional, Lee, Angela C., additional, Adams, H. Daniel, additional, von Ungern-Sternberg, Britta S., additional, Park, Raymond S., additional, Peyton, James M., additional, Olomu, Patrick N., additional, Hunyady, Agnes I., additional, Garcia-Marcinkiewicz, Annery, additional, Fiadjoe, John E., additional, Kovatsis, Pete G., additional, Bruins, Benjamin, additional, Stricker, Paul, additional, Laverriere, Elizabeth, additional, Lockman, Justin L., additional, Struyk, Brian, additional, Ward, Christopher, additional, Nishisaki, Akira, additional, Kodavatiganti, Ramesh, additional, Guris, Rodrigo Daly, additional, Sequera-Ramos, Luis, additional, Teen, Mark, additional, Oke, Ayodele, additional, Hsu, Grace, additional, Lingappan, Arul, additional, Battles, Rhae, additional, Bocanegra, Ashley, additional, Goldfarb, Tally, additional, Kiss, Edgar, additional, Szmuk, Peter, additional, Mireles, Sam, additional, Murray, Andrea, additional, Whyte, Simon, additional, Jain, Ranu, additional, Matuszczak, Maria, additional, Holmes, Christopher, additional, McCann, Alexander, additional, Matava, Clyde, additional, Dalesio, Nicholas, additional, Greenberg, Robert, additional, Lucero, Angela, additional, Desai, Sapna, additional, Rosander, Sondra, additional, Samba, Sindhu, additional, Schrock, Charles, additional, Nykiel-Bailey, Sydney, additional, Marsh, Jennifer, additional, Peterson, Melissa Brooks, additional, Lee, Amy, additional, Bhattacharya, Somaletha, additional, Burjek, Nicholas, additional, Jagannathan, Narasimhan, additional, Lardner, David, additional, Crockett, Christy, additional, Robetson, Sara, additional, Patel, Jasmine, additional, Sharma, Aarti, additional, Templeton, Thomas, additional, Marín, Piedad Echeverry, additional, Pérez-Pradilla, Carolina, additional, Singh, Neeta, additional, Sommerfield, David, additional, Hauser, Neil, additional, Hesselink, Emily, additional, Lewkowitz-Shpuntoff, Hilana, additional, Castro, Pilar, additional, Riveros Perez, N. Ricardo, additional, Vega, Eduardo, additional, González, Alejandro, additional, Ostermann, Paola, additional, Rubin, Kasia, additional, Meserve, Jonathan, additional, Lord, Charles, additional, Lee, Angela, additional, Valairucha, Songyos, additional, Dalal, Priti, additional, Tran, Thanh, additional, Anspach, Taylor, additional, Lee, Lisa K., additional, Ayad, Ihab, additional, Rehman, Mohamed, additional, Fernandez, Allison, additional, Zamora, Lillian, additional, Ravula, Niroop, additional, Shaik, Sadiq, additional, Szolnoki, Judit, additional, Mathew, Preethy, additional, Yaddanapudi, Sandhya, additional, Sen, Indu, additional, Gupta, Aakriti, additional, Handlogten, Kathryn, additional, Sroka, J. Michael, additional, Quintão, Vinícius Caldeira, additional, Carlos, Ricardo Vieira, additional, and Leite, Fernanda, additional

Published
2024
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2. A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma

Author

Pozniak, Joanna, primary, Pedri, Dennis, additional, Landeloos, Ewout, additional, Van Herck, Yannick, additional, Antoranz, Asier, additional, Vanwynsberghe, Lukas, additional, Nowosad, Ada, additional, Roda, Niccolò, additional, Makhzami, Samira, additional, Bervoets, Greet, additional, Maciel, Lucas Ferreira, additional, Pulido-Vicuña, Carlos Ariel, additional, Pollaris, Lotte, additional, Seurinck, Ruth, additional, Zhao, Fang, additional, Flem-Karlsen, Karine, additional, Damsky, William, additional, Chen, Limin, additional, Karagianni, Despoina, additional, Cinque, Sonia, additional, Kint, Sam, additional, Vandereyken, Katy, additional, Rombaut, Benjamin, additional, Voet, Thierry, additional, Vernaillen, Frank, additional, Annaert, Wim, additional, Lambrechts, Diether, additional, Boecxstaens, Veerle, additional, Saeys, Yvan, additional, van den Oord, Joost, additional, Bosisio, Francesca, additional, Karras, Panagiotis, additional, Shain, A. Hunter, additional, Bosenberg, Marcus, additional, Leucci, Eleonora, additional, Paschen, Annette, additional, Rambow, Florian, additional, Bechter, Oliver, additional, and Marine, Jean-Christophe, additional

Published
2024
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5. Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Author

Lei, Yuanjiu, primary, VanPortfliet, Jordyn J., additional, Chen, Yi-Fan, additional, Bryant, Joshua D., additional, Li, Ying, additional, Fails, Danielle, additional, Torres-Odio, Sylvia, additional, Ragan, Katherine B., additional, Deng, Jingti, additional, Mohan, Armaan, additional, Wang, Bing, additional, Brahms, Olivia N., additional, Yates, Shawn D., additional, Spencer, Michael, additional, Tong, Carl W., additional, Bosenberg, Marcus W., additional, West, Laura Ciaccia, additional, Shadel, Gerald S., additional, Shutt, Timothy E., additional, Upton, Jason W., additional, Li, Pingwei, additional, and West, A. Phillip, additional

Published
2023
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6. Validation of the Prognostic Usefulness of the Gene Expression Profiling Test in Patients with Uveal Melanoma

Author

Miguez, Sofia, primary, Lee, Ryan Y., additional, Chan, Alison X., additional, Demkowicz, Patrick C., additional, Jones, Bailey S.C.L., additional, Long, Christopher P., additional, Abramson, David H., additional, Bosenberg, Marcus, additional, Sznol, Mario, additional, Kluger, Harriet, additional, Goldbaum, Michael H., additional, Francis, Jasmine H., additional, Pointdujour-Lim, Renelle, additional, and Bakhoum, Mathieu F., additional

Published
2023
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11. Difficult or impossible facemask ventilation in children with difficult tracheal intubation: a retrospective analysis of the PeDI registry

Author

Garcia-Marcinkiewicz, Annery G., primary, Lee, Lisa K., additional, Haydar, Bishr, additional, Fiadjoe, John E., additional, Matava, Clyde T., additional, Kovatsis, Pete G., additional, Peyton, James, additional, Stein, Mary L., additional, Park, Raymond, additional, Taicher, Brad M., additional, Templeton, Thomas W., additional, Bruins, Benjamin B., additional, Stricker, Paul, additional, Laverriere, Elizabeth K., additional, Lockman, Justin L., additional, Struyk, Brian, additional, Ward, Christopher, additional, Nishisaki, Akira, additional, Kodavatiganti, Ramesh, additional, Daly Guris, Rodrigo J., additional, Sequera-Ramos, Luis, additional, Teen, Mark S., additional, Oke, Ayodele, additional, Hsu, Grace, additional, Lingappan, Arul, additional, Egbuta, Chinyere, additional, Flynn, Stephen, additional, Sarmiento, Lina, additional, Goldfarb, Tally, additional, Kiss, Edgar E., additional, Olomu, Patrick N., additional, Szmuk, Peter, additional, Mireles, Sam, additional, Murray, Andrea, additional, Whyte, Simon, additional, Jain, Ranu, additional, Matuszczak, Maria, additional, Hunyady, Agnes, additional, Bosenberg, Adrian, additional, Tham, See, additional, Low, Daniel, additional, Holmes, Christopher, additional, Sabato, Stefan, additional, Dalesio, Nicholas, additional, Greenberg, Robert, additional, Lucero, Angela, additional, Reynolds, Paul, additional, Lewis, Ian, additional, Schrock, Charles, additional, Nykiel-Bailey, Sydney, additional, Starker, Elizabeth, additional, Szolnoki, Judit, additional, Brooks-Peterson, Melissa, additional, Bhattacharya, Somaletha, additional, Burjek, Nicholas E., additional, Jagannathan, Narasimhan, additional, Lardner, David, additional, Watkins, Scott, additional, Crockett, Christy, additional, Moore, John, additional, Robertson, Sara, additional, Sathyamoorthy, Madhankumar, additional, Chiao, Franklin, additional, Patel, Jasmine, additional, Sharma, Aarti, additional, Echeverry Marin, Piedad, additional, Pérez-Pradilla, Carolina, additional, Singh, Neeta, additional, von Ungern-Sternberg, Britta S., additional, Sommerfield, David, additional, Bilen-Rosas, Guelay, additional, Lewkowitz-Shpuntoff, Hilana, additional, Castro, Pilar, additional, Riveros Perez, N. Ricardo, additional, de Graaff, Jurgen C., additional, Vega, Eduardo, additional, González, Alejandro, additional, Ostermann, Paola, additional, and Rubin, Kasia, additional

Published
2023
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12. Difficult or impossible facemask ventilation in children with difficult tracheal intubation: a retrospective analysis of the PeDI registry

Author

Annery G. Garcia-Marcinkiewicz, Lisa K. Lee, Bishr Haydar, John E. Fiadjoe, Clyde T. Matava, Pete G. Kovatsis, James Peyton, Mary L. Stein, Raymond Park, Brad M. Taicher, Thomas W. Templeton, Benjamin B. Bruins, Paul Stricker, Elizabeth K. Laverriere, Justin L. Lockman, Brian Struyk, Christopher Ward, Akira Nishisaki, Ramesh Kodavatiganti, Rodrigo J. Daly Guris, Luis Sequera-Ramos, Mark S. Teen, Ayodele Oke, Grace Hsu, Arul Lingappan, Chinyere Egbuta, Stephen Flynn, Lina Sarmiento, Tally Goldfarb, Edgar E. Kiss, Patrick N. Olomu, Peter Szmuk, Sam Mireles, Andrea Murray, Simon Whyte, Ranu Jain, Maria Matuszczak, Agnes Hunyady, Adrian Bosenberg, See Tham, Daniel Low, Christopher Holmes, Stefan Sabato, Nicholas Dalesio, Robert Greenberg, Angela Lucero, Paul Reynolds, Ian Lewis, Charles Schrock, Sydney Nykiel-Bailey, Elizabeth Starker, Judit Szolnoki, Melissa Brooks-Peterson, Somaletha Bhattacharya, Nicholas E. Burjek, Narasimhan Jagannathan, David Lardner, Scott Watkins, Christy Crockett, John Moore, Sara Robertson, Madhankumar Sathyamoorthy, Franklin Chiao, Jasmine Patel, Aarti Sharma, Piedad Echeverry Marin, Carolina Pérez-Pradilla, Neeta Singh, Britta S. von Ungern-Sternberg, David Sommerfield, Guelay Bilen-Rosas, Hilana Lewkowitz-Shpuntoff, Pilar Castro, N. Ricardo Riveros Perez, Jurgen C. de Graaff, Eduardo Vega, Alejandro González, Paola Ostermann, Kasia Rubin, Charles (Ted) Lord, Angela Lee, Eugenie Heitmiller, Songyos Valairucha, Priti Dalal, Thanh Tran, Ihab Ayad, Mohamed Rehman, Allison Fernandez, Lillian Zamora, Niroop Ravula, Sadiq Shaik, and Anesthesiology

Subjects
Anesthesiology and Pain Medicine
Abstract

Background: Difficult facemask ventilation is perilous in children whose tracheas are difficult to intubate. We hypothesised that certain physical characteristics and anaesthetic factors are associated with difficult mask ventilation in paediatric patients who also had difficult tracheal intubation. Methods: We queried a multicentre registry for children who experienced “difficult” or “impossible” facemask ventilation. Patient and case factors known before mask ventilation attempt were included for consideration in this regularised multivariable regression analysis. Incidence of complications, and frequency and efficacy of rescue placement of a supraglottic airway device were also tabulated. Changes in quality of mask ventilation after injection of a neuromuscular blocking agent were assessed. Results: The incidence of difficult mask ventilation was 9% (483 of 5453 patients). Infants and patients having increased weight, being less than 5th percentile in weight for age, or having Treacher-Collins syndrome, glossoptosis, or limited mouth opening were more likely to have difficult mask ventilation. Anaesthetic induction using facemask and opioids was associated with decreased risk of difficult mask ventilation. The incidence of complications was significantly higher in patients with “difficult” mask ventilation than in patients without. Rescue placement of a supraglottic airway improved ventilation in 71% (96 of 135) of cases. Administration of neuromuscular blocking agents was more frequently associated with improvement or no change in quality of ventilation than with worsening. Conclusions: Certain abnormalities on physical examination should increase suspicion of possible difficult facemask ventilation. Rescue use of a supraglottic airway device in children with difficult or impossible mask ventilation should be strongly considered.

Published
2023
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15. Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib

Author

Alice Wang, Richard A. Flavell, Brett A. King, William Damsky, Meaghan K. McGeary, Marcus Bosenberg, Danielle Peterson, Michael J. Murphy, Austin McHenry, and Nur-Taz Rahman

Subjects
CD4-Positive T-Lymphocytes, medicine.medical_treatment, Immunology, Inflammation, Proinflammatory cytokine, Granuloma Annulare, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Piperidines, medicine, Humans, Janus Kinase Inhibitors, Immunology and Allergy, Aged, Skin, Tofacitinib, biology, Janus kinase 1, Sequence Analysis, RNA, business.industry, Macrophages, Oncostatin M, Fibroblasts, Middle Aged, Pyrimidines, Cytokine, 030220 oncology & carcinogenesis, Cancer research, biology.protein, STAT protein, Cytokines, medicine.symptom, Janus kinase, business
Abstract

Background Granuloma annulare (GA) is a common cutaneous inflammatory disorder characterized by macrophage accumulation and activation in skin. Its pathogenesis is poorly understood, and there are no effective treatments. The potential health implications of severe GA are unknown. Objective We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease. Methods We used single-cell RNA sequencing to study the immunopathogenesis of GA and also evaluated the efficacy of tofacitinib (a Janus kinase 1/3 inhibitor) in 5 patients with severe, long-standing GA in an open-label clinical trial. Results Using single-cell RNA sequencing, we found that in GA lesions IFN-γ production by CD4+ T cells is upregulated and is associated with inflammatory polarization of macrophages and fibroblasts. In particular, macrophages upregulate oncostatin M, an IL-6 family cytokine, which appears to act on fibroblasts to alter extracellular matrix production, a hallmark of GA. IL-15 and IL-21 production appears to feed back on CD4+ T cells to sustain inflammation. Treatment of 5 patients with recalcitrant GA with tofacitinib inhibited IFN-γ and oncostatin M, as well as IL-15 and IL-21, activity and resulted in clinical and histologic disease remission in 3 patients and marked improvement in the other 2. Inhibition of these effects at the molecular level paralleled the clinical improvement. Evidence of systemic inflammation is also present in some patients with severe GA and is mitigated by tofacitinib. Conclusions The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, likely in part through the activity of IFN-γ and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.

Published
2021
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16. Melanoma models for the next generation of therapies

Author

Ze'ev Ronai, Leonard I. Zon, Carmit Levy, Meenhard Herlyn, Marcus Bosenberg, Amanda W. Lund, David B. Lombard, Jean-Christophe Marine, Richard M. White, Yardena Samuels, Charles K. Kaufman, Christin E. Burd, Shaheen Khan, Marc Hurlbert, Kristen L. Mueller, Eleonora Leucci, Andrew E. Aplin, Sheri L. Holmen, Iwei Yeh, Ashani T. Weeraratna, David J. Adams, Martin McMahon, Corine Bertolotto, Florian A. Karreth, Sebastian Kobold, Glenn Merlino, Carla Daniela Robles-Espinoza, Ping Chi, Jessie Villanueva, Niroshana Anandasabapathy, Kerrie L. Marie, Maria S. Soengas, Jiyue Zhu, Richard Marais, Craig J. Ceol, and E. Elizabeth Patton

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Skin Neoplasms, medicine.medical_treatment, Drug resistance, Article, Targeted therapy, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Skin Neoplasms/drug therapy, Tumor Microenvironment, medicine, Tumor Microenvironment/immunology, Animals, Humans, Melanoma/drug therapy, Melanoma, neoplasms, Immunity/immunology, Tumor microenvironment, business.industry, Immunity, Cell Biology, Immunotherapy, medicine.disease, 3. Good health, Clinical trial, Disease Models, Animal, 030104 developmental biology, 030220 oncology & carcinogenesis, Genetically Engineered Mouse, Immunotherapy/methods, business
Abstract

Summary There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.

Published
2021
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22. Corrigendum to “Physachenolide C induces complete regression of established murine melanoma tumors via apoptosis and cell cycle arrest”

Author

Adams, Anngela C., primary, Macy, Anne M., additional, Kang, Paul, additional, Castro-Ochoa, Karla F., additional, Wijeratne, E. M. Kithsiri, additional, Xu, Ya-Ming, additional, Liu, Manping X., additional, Charos, Alexandra, additional, Bosenberg, Marcus W., additional, Gunatilaka, A.A. Leslie, additional, Sertil, Aparna R., additional, and Hastings, K. Taraszka, additional

Published
2022
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23. Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations

Author

Hong Yan, Ronan Talty, Abhishek Jain, Yuping Cai, Jie Zheng, Xinyi Shen, Engjel Muca, Philip B. Paty, Marcus W. Bosenberg, Sajid A. Khan, and Caroline H. Johnson

Subjects
Organic Chemistry, Clinical Biochemistry, Biochemistry
Abstract

Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that tumors from male patients with KRAS mutations only, had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression ofGPX4, FTH1, FTL, which suppressed ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Low compared to high expression ofACSL4was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.

Published
2023
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26. Inhibition of renalase drives tumour rejection by promoting T cell activation

Author

Guo, Xiaojia, primary, Jessel, Shlomit, additional, Qu, Rihao, additional, Kluger, Yuval, additional, Chen, Tian-Min, additional, Hollander, Lindsay, additional, Safirstein, Robert, additional, Nelson, Bryce, additional, Cha, Charles, additional, Bosenberg, Marcus, additional, Jilaveanu, Lucia B., additional, Rimm, David, additional, Rothlin, Carla V., additional, Kluger, Harriet M., additional, and Desir, Gary V., additional

Published
2022
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27. Comparison of Continuous Adductor Canal and Femoral Nerve Blocks for Analgesia and Return of Quadriceps Function After Anterior Cruciate Ligament Reconstruction in Adolescent Patients

Author

Erica L. Holland, Gregory A. Schmale, Robin E. Robbins, Viviana Bompadre, Adrian T. Bosenberg, and Daniel Low

Subjects
Demographics, Anterior cruciate ligament reconstruction, business.industry, Adductor canal, medicine.medical_treatment, Rehabilitation, Analgesic, Public Health, Environmental and Occupational Health, Pain relief, Physical Therapy, Sports Therapy and Rehabilitation, medicine.anatomical_structure, Femoral nerve, Opioid, Anesthesia, Sports medicine, Medicine, Original Article, Orthopedics and Sports Medicine, business, RC1200-1245, Hamstring, medicine.drug
Abstract

Purpose To compare early pain relief and late quadriceps function after anterior cruciate ligament reconstruction (ACLR) with hamstring autograft in adolescent patients treated with either a continuous femoral nerve block (cFNB) or continuous adductor canal block (cACB). Methods We retrospectively reviewed a consecutive series of adolescent patients who underwent ACLR and received either a cACB or cFNB for postoperative pain management. Over a 1-year period, all patients underwent ACLR with cFNBs. Over the subsequent 9 months, all patients underwent their ACLR with cACBs. Patient demographics, postoperative pain scores, opioid consumption, satisfaction and complications, and dates and results of quadriceps function derived at the Return to Sports evaluation were compared. Results Ninety-one patients (53 cFNB, 38 cACB) were reviewed. There were no differences in the demographics of the 2 groups. There were no statistically significant differences between groups in variations in postoperative pain scores (P = .21), or satisfaction with the blocks (P = .93). Patients in the cFNB group consumed a greater number of opioid doses on postoperative day 3 (2.2 ± 2.1 doses cFNB, 1.1 ± 1.6 doses cACB, P = .03) and a greater number of opioid doses overall for postoperative days 1 to 3 (mean 6.8 ± 5.3 doses cFNB, 3.8 ± 2.1 doses cACB, P = .03). There was no difference in time to return of acceptable quadriceps strength and function when comparing the 2 groups (30.9 ± 7.7 weeks cFNB, 28.9 ± 6.6 weeks cACB, P = .087). Conclusions We found few differences in postoperative analgesic requirements when comparing patients who underwent ACLR with hamstring autograft with a cACB to those who underwent a similar procedure with a cFNB. Return of quadriceps strength and function by six months did not appear to vary with regional technique, either cACB or cFNB, employed at surgery. Level of Evidence III, Retrospective comparative study.

Published
2020
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29. Physachenolide C induces complete regression of established murine melanoma tumors via apoptosis and cell cycle arrest

Author

Adams, Anngela C., primary, Macy, Anne M., additional, Kang, Paul, additional, Castro-Ochoa, Karla F., additional, Wijeratne, E.M. Kithsiri, additional, Xu, Ya-Ming, additional, Liu, Manping X., additional, Charos, Alexandra, additional, Bosenberg, Marcus W., additional, Gunatilaka, A.A. Leslie, additional, Sertil, Aparna R., additional, and Hastings, K. Taraszka, additional

Published
2022
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30. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

Author

Wang, Yujue, primary, Liu, Sixue, additional, Yang, Zhentao, additional, Algazi, Alain P., additional, Lomeli, Shirley H., additional, Wang, Yan, additional, Othus, Megan, additional, Hong, Aayoung, additional, Wang, Xiaoyan, additional, Randolph, Chris E., additional, Jones, Alexis M., additional, Bosenberg, Marcus W., additional, Byrum, Stephanie D., additional, Tackett, Alan J., additional, Lopez, Henry, additional, Yates, Clayton, additional, Solit, David B., additional, Ribas, Antoni, additional, Piva, Marco, additional, Moriceau, Gatien, additional, and Lo, Roger S., additional

Published
2021
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34. Practice advisory on the prevention and management of complications of pediatric regional anesthesia

Author

C, Ecoffey, A, Bosenberg, P A, Lonnqvist, S, Suresh, A, Delbos, G, Ivani, Hôpital Pontchaillou, University of Washington [Seattle], Karolinska Institutet [Stockholm], Northwestern University [Evanston], and Regina Margherita University Children's Hospital [Turin, Italy]

Subjects
Local anesthetic systemic toxicity, Coagulation, Complications, [SDV]Life Sciences [q-bio], Anticoagulants, Pain, Venous Thromboembolism, Pediatric regional anesthesia, United States, Anesthesiology and Pain Medicine, Anesthesia, Conduction, Humans, Anesthetics, Local, Child, Infection
Abstract

International audience; STUDY OBJECTIVES: To develop evidence-based recommendations for prevention and management of infections, bleeding, and local anesthetic toxicity in children undergoing regional anesthesia. DESIGN: A joint committee of the European Society of Regional Anesthesia and Pain Therapy (ESRA) and the American Society of Regional Anesthesia and Pain Medicine (ASRA) studied electronic literature databases of pediatric regional anesthesia to construct evidence-based recommendations. MAIN RESULTS: For epidural anesthesia lumbar or thoracic placement is preferred. Skin preparation prior to block placement with chlorhexidine is preferred to povidone iodine. A tunneled catheter technique is suggested when using the caudal route or if the epidural catheter placement is kept in situ for more than 3 days. Inspection of the epidural catheter insertion site should be performed at least once a day as part of the postoperative management. When medical and physical examination is normal, coagulation tests are usually unnecessary but if coagulation tests are abnormal, neuraxial and deep peripheral nerve blocks are contraindicated. For patients receiving Low Molecular Weight Heparin thromboprophylaxis, a safety interval of two half-lives plus the time required for heparin to reach maximal levels is considered an adequate compromise between bleeding risk and thrombosis risk when removing epidural catheters. Ultrasound-guided peripheral nerve blocks reduce the risk of vascular puncture and thus the risk of local anesthetic toxicity is reduced. CONCLUSIONS: In children undergoing regional anesthesia the incidence of infection, hematoma, and local anesthetic toxicity is low. The ASRA/ESRA joint committee proposes a practice advisory to prevent and treat these complications.

Published
2022
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36. Endogenous Glucocorticoid Signaling Regulates CD8+ T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment

Author

Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology), Howard Hughes Medical Institute, Acharya, Nandini, Madi, Asaf, Zhang, Huiyuan, Klapholz, Max, Escobar, Giulia, Dulberg, Shai, Christian, Elena, Ferreira, Michelle, Dixon, Karen O, Fell, Geoffrey, Tooley, Katherine, Mangani, Davide, Xia, Junrong, Singer, Meromit, Bosenberg, Marcus, Neuberg, Donna, Rozenblatt-Rosen, Orit, Regev, Aviv, Kuchroo, Vijay K, Anderson, Ana C, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology), Howard Hughes Medical Institute, Acharya, Nandini, Madi, Asaf, Zhang, Huiyuan, Klapholz, Max, Escobar, Giulia, Dulberg, Shai, Christian, Elena, Ferreira, Michelle, Dixon, Karen O, Fell, Geoffrey, Tooley, Katherine, Mangani, Davide, Xia, Junrong, Singer, Meromit, Bosenberg, Marcus, Neuberg, Donna, Rozenblatt-Rosen, Orit, Regev, Aviv, Kuchroo, Vijay K, and Anderson, Ana C

Abstract

© 2020 Elsevier Inc. Acharya et al. uncover a gradient of increasing glucocorticoid signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes. This gradient regulates effector transition and development of dysfunction. Glucocorticoid is produced locally by tumor-associated monocyte-macrophage lineage cells, and presence of active glucocorticoid signaling associates with poor response to immune checkpoint blockade.

Published
2021

37. Cytokine RNA In Situ Hybridization Permits Individualized Molecular Phenotyping in Biopsies of Psoriasis and Atopic Dermatitis

Author

Wang, Alice, primary, Fogel, Alexander L., additional, Murphy, Michael J., additional, Panse, Gauri, additional, McGeary, Meaghan K., additional, McNiff, Jennifer M., additional, Bosenberg, Marcus, additional, Vesely, Matthew D., additional, Cohen, Jeffrey M., additional, Ko, Christine J., additional, King, Brett A., additional, and Damsky, William, additional

Published
2021
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39. Melanoma models for the next generation of therapies

Author

Patton, E. Elizabeth, primary, Mueller, Kristen L., additional, Adams, David J., additional, Anandasabapathy, Niroshana, additional, Aplin, Andrew E., additional, Bertolotto, Corine, additional, Bosenberg, Marcus, additional, Ceol, Craig J., additional, Burd, Christin E., additional, Chi, Ping, additional, Herlyn, Meenhard, additional, Holmen, Sheri L., additional, Karreth, Florian A., additional, Kaufman, Charles K., additional, Khan, Shaheen, additional, Kobold, Sebastian, additional, Leucci, Eleonora, additional, Levy, Carmit, additional, Lombard, David B., additional, Lund, Amanda W., additional, Marie, Kerrie L., additional, Marine, Jean-Christophe, additional, Marais, Richard, additional, McMahon, Martin, additional, Robles-Espinoza, Carla Daniela, additional, Ronai, Ze'ev A., additional, Samuels, Yardena, additional, Soengas, Maria S., additional, Villanueva, Jessie, additional, Weeraratna, Ashani T., additional, White, Richard M., additional, Yeh, Iwei, additional, Zhu, Jiyue, additional, Zon, Leonard I., additional, Hurlbert, Marc S., additional, and Merlino, Glenn, additional

Published
2021
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40. Endogenous Glucocorticoid Signaling Regulates CD8+ T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment

Author

Giulia Escobar, Nandini Acharya, Meromit Singer, Huiyuan Zhang, Marcus Bosenberg, Vijay K. Kuchroo, Karen O. Dixon, Davide Mangani, Aviv Regev, Geoffrey Fell, Elena Christian, Junrong Xia, Donna Neuberg, Orit Rozenblatt-Rosen, Michelle Ferreira, Asaf Madi, Shai Dulberg, Katherine Tooley, Max Klapholz, and Ana C. Anderson

Subjects
0301 basic medicine, Tumor microenvironment, medicine.medical_treatment, Immunology, Biology, 03 medical and health sciences, Steroid hormone, 030104 developmental biology, 0302 clinical medicine, Infectious Diseases, Glucocorticoid receptor, Cancer immunotherapy, 030220 oncology & carcinogenesis, medicine, Cancer research, Immunology and Allergy, Cytotoxic T cell, Receptor, Transcription factor, Glucocorticoid, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract

Summary Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naive to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy.

Published
2020

41. Increased Serine Synthesis Provides an Advantage for Tumors Arising in Tissues Where Serine Levels Are Limiting

Author

Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Sullivan, Mark Robert, Mattaini, Katherine Ruth, Dennstedt, Emily A, Nguyen, Anna, Sivanand, Sharanya, Reilly, Montana F., Meeth, Katrina, Muir, Alexander, Darnell, Alicia, Bosenberg, Marcus W., Lewis, Caroline A., Vander Heiden, Matthew G., Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Sullivan, Mark Robert, Mattaini, Katherine Ruth, Dennstedt, Emily A, Nguyen, Anna, Sivanand, Sharanya, Reilly, Montana F., Meeth, Katrina, Muir, Alexander, Darnell, Alicia, Bosenberg, Marcus W., Lewis, Caroline A., and Vander Heiden, Matthew G.

Abstract

Tumors exhibit altered metabolism compared to normal tissues. Many cancers upregulate expression of serine synthesis pathway enzymes, and some tumors exhibit copy-number gain of the gene encoding the first enzyme in the pathway, phosphoglycerate dehydrogenase (PHGDH). However, whether increased serine synthesis promotes tumor growth and how serine synthesis benefits tumors is controversial. Here, we demonstrate that increased PHGDH expression promotes tumor progression in mouse models of melanoma and breast cancer, human tumor types that exhibit PHGDH copy-number gain. We measure circulating serine levels and find that PHGDH expression is necessary to support cell proliferation at lower physiological serine concentrations. Increased dietary serine or high PHGDH expression is sufficient to increase intracellular serine levels and support faster tumor growth. Together, these data suggest that physiological serine availability restrains tumor growth and argue that tumors arising in serine-limited environments acquire a fitness advantage by upregulating serine synthesis pathway enzymes. Nutrient availability can constrain tumor growth. Sullivan et al. demonstrate that in some cancers, physiological levels of the amino acid serine are insufficient to support maximal tumor growth and that melanoma and breast tumors derive a growth advantage by upregulating serine biosynthesis., National Science Foundation (Grant DGE-1122374), National Science Foundation (Grant T32-GM007287), National Science Foundation (Grant F32CA213810), National Science Foundation (Grant R21CA198028), National Science Foundation (Grant R01CA168653)

Published
2020

42. A comparison of videolaryngoscopy using standard blades or non-standard blades in children in the Paediatric Difficult Intubation Registry

Author

Peyton, James, primary, Park, Raymond, additional, Staffa, Steven J., additional, Sabato, Stefano, additional, Templeton, Thomas W., additional, Stein, Mary Lyn, additional, Garcia-Marcinkiewicz, Annery G., additional, Kiss, Edgar, additional, Fiadjoe, John Edem, additional, von Ungern-Sternberg, Britta, additional, Chiao, Franklin, additional, Olomu, Patrick, additional, Zurakowski, David, additional, Kovatsis, Pete G., additional, Sommerfield, David, additional, Holmes, Chris, additional, Ravula, Niroop, additional, Jette, Christine, additional, Mireles, Sam, additional, Matava, Clyde, additional, Whyte, Simon, additional, Vega, Eduardo, additional, Yang, Lei, additional, Echeverry-Marin, Piedad, additional, Perez-Pradilla, Carolina, additional, Starker, Elizabeth, additional, Zieg, Jennifer, additional, Szolnoki, Judit, additional, Lee, Angela, additional, Heitmiller, Eugenie, additional, Rehman, Mohamed, additional, Zamora, Lillian, additional, Fernandez, Allison, additional, Meserve, Jonathan, additional, Bhattacharya, Solmaletha, additional, Reynolds, Paul, additional, Lewis, Ian, additional, Haydar, Bishr, additional, Therrian, Megan, additional, Sarmiento, Linare, additional, Richtsfeld, Martina, additional, Belani, Kumar, additional, Robertson, Sara, additional, Sathyamoorthy, Kumar, additional, Schrock, Charles, additional, de Graaff, Jurgen, additional, Soneru, Codruta, additional, Singh, Neeta, additional, Taicher, Brad, additional, Castro, Pilar, additional, Riveros Perez, N.R., additional, Stricker, Paul, additional, Lockman, Justin L., additional, Galvez, Jorge, additional, Isserman, Rebecca, additional, Struyk, Brian, additional, Ward, Christopher, additional, Hsu, Grace, additional, Nishisaki, Akira, additional, Kodavatiganti, Ramesh, additional, Ramos, Luis S., additional, Scheu, Eric, additional, Bruins, Benjamin, additional, Goldfarb, Tally, additional, Szmuk, Peter, additional, Jain, Ranu, additional, Matuszczak, Maria, additional, Polaner, David, additional, Hunyady, Agnes, additional, Bosenberg, Adrian, additional, Tham, See, additional, Low, Daniel, additional, Rosas, Guelay B., additional, Lee, Lisa K., additional, Iyah, Ihab, additional, Dalesio, Nicholas, additional, and Greenberg, Rob, additional

Published
2021
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43. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

Author

Gatien Moriceau, Marcus Bosenberg, Shirley H. Lomeli, Alan J. Tackett, David B. Solit, Clayton Yates, Stephanie D. Byrum, Aayoung Hong, Alain Algazi, Yujue Wang, Roger S. Lo, Megan Othus, Zhentao Yang, Xiaoyan Wang, Chris E. Randolph, Sixue Liu, Alexis Jones, Marco Piva, Yan Wang, Henry Lopez, and Antoni Ribas

Subjects
MAPK/ERK pathway, Neuroblastoma RAS viral oncogene homolog, Cancer Research, Colorectal cancer, Oncology and Carcinogenesis, pancreatic ductal adenocarcinoma, Article, Mice, Rare Diseases, colorectal carcinoma, Neoplasms, MAPK/BRAF/MEK inhibitor resistance, melanoma, Animals, Humans, Medicine, Cytotoxic T cell, brain metastasis, Oncology & Carcinogenesis, Immune Checkpoint Inhibitors, Cancer, Mitogen-Activated Protein Kinase Kinases, tumor immune microenvironment, BRAF/NRAS/KRAS/NF1, business.industry, Melanoma, Neurosciences, medicine.disease, Immune checkpoint, sequential-combination therapy, Good Health and Well Being, Oncology, 5.1 Pharmaceuticals, anti-CTLA-4, Cancer research, Immunotherapy, anti-PD-1/L1, Development of treatments and therapeutic interventions, Digestive Diseases, business, CD8, Brain metastasis
Abstract

Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) Tcells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust Tcell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

Published
2021
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44. Endogenous Glucocorticoid Signaling Regulates CD8+ T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment

Author

Acharya, Nandini, primary, Madi, Asaf, additional, Zhang, Huiyuan, additional, Klapholz, Max, additional, Escobar, Giulia, additional, Dulberg, Shai, additional, Christian, Elena, additional, Ferreira, Michelle, additional, Dixon, Karen O., additional, Fell, Geoffrey, additional, Tooley, Katherine, additional, Mangani, Davide, additional, Xia, Junrong, additional, Singer, Meromit, additional, Bosenberg, Marcus, additional, Neuberg, Donna, additional, Rozenblatt-Rosen, Orit, additional, Regev, Aviv, additional, Kuchroo, Vijay K., additional, and Anderson, Ana C., additional

Published
2020
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47. The efficacy of GlideScope® videolaryngoscopy compared with direct laryngoscopy in children who are difficult to intubate: an analysis from the paediatric difficult intubation registry

Author

Kumar G. Belani, B. Haydar, C. Glover, Sam Mireles, Pete G. Kovatsis, P. Hopkins, J. Zieg, A. Nishisaki, John E. Fiadjoe, S. Khalil, Nicholas E. Burjek, Mdm Rehman, Jorge A. Gálvez, Justin L. Lockman, Peter Szmuk, Brad M. Taicher, S. Watkins, Patrick Olomu, Paul A. Stricker, David Zurakowski, T. Kimball, M. Matuszczak, Vidya T. Raman, R. Jain, S. Bhattacharya, David Sommerfield, James Peyton, J. Szolnoki, M. Sathyamoorthy, Narasimhan Jagannathan, Tarun Bhalla, O. Olutoye, Raymond Park, D. Polaner, F. Chiao, Codruta Soneru, Martina Richtsfeld, Agnes Hunyady, L. Sarmiento, G. B. Rosas, A. Bosenberg, P. Reynolds, and B. S. von Ungern-Sternberg

Subjects
Male, medicine.medical_treatment, Laryngoscopy, Video Recording, Pediatrics, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Intratracheal intubation, Intubation, Intratracheal, Humans, Medicine, Registries, Airway Management, Child, Difficult intubation, medicine.diagnostic_test, business.industry, Tracheal intubation, Infant, 030208 emergency & critical care medicine, Equipment Design, Anesthesiology and Pain Medicine, Increased risk, Child, Preschool, Anesthesia, Female, Airway management, business
Abstract

We analysed data from the Paediatric Difficult Intubation Registry examining the use of direct laryngoscopy and GlideScope® videolaryngoscopy.Data collected by a multicentre, paediatric difficult intubation registry from 1295 patients were analysed. Rates of success and complications between direct laryngoscopy and GlideScope videolaryngoscopy were analysed.Initial (464/877 = 53% vs 33/828 = 4%, Z-test = 22.2, P 0.001) and eventual (720/877 = 82% vs. 174/828 = 21%, Z-test = 25.2, P 0.001) success rates for GlideScope were significantly higher than direct laryngoscopy. Children weighing10 kg had lower success rates with the GlideScope than the group as a whole. There were no differences in complication rates per attempt between direct laryngoscopy and GlideScope. The direct laryngoscopy group had more complications associated with the greater number of attempts needed to intubate. There were no increased risks of hypoxia or trauma with GlideScope use. Each additional attempt at intubation with either device resulted in a two-fold increase in complications (odds ratio: 2.0, 95% confidence interval: 1.5-2.5, P 0.001).During difficult tracheal intubation in children, direct laryngoscopy is an overly used technique with a low chance of success. GlideScope use was associated with a higher chance of success with no increased risk of complications. GlideScope use in children with difficult tracheal intubation has a lower success rate than in adults with difficult tracheal intubation. Children weighing less than 10 kilograms had lower success rates with either device. Attempts should be minimized with either device to decrease complications.

Published
2017
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48. Expansion and Activation of CD103+ Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition

Author

Brian D. Brown, Romain Remark, Florent Ginhoux, Sacha Gnjatic, Judith Agudo, Marcus Bosenberg, Juliana Idoyaga, Anna Karolina Palucka, Daigo Hashimoto, Stefan Jordan, Maria Casanova-Acebes, Nina Bhardwaj, Marylene Leboeuf, Christina Rivera, Adeeb Rahman, Svetoslav Chakarov, Joshua Brody, Makhzuna Khudoynazarova, Miriam Merad, Navpreet Tung, Hélène Salmon, and Brandon Hogstad

Subjects
Proto-Oncogene Proteins B-raf, 0301 basic medicine, Immunology, Melanoma, Experimental, Priming (immunology), chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Cell Line, Tumor, PD-L1, medicine, Animals, Immunology and Allergy, Progenitor cell, Mice, Knockout, Antigen Presentation, biology, Melanoma, hemic and immune systems, Dendritic Cells, Dendritic cell, medicine.disease, 3. Good health, Blockade, Mice, Inbred C57BL, Poly I-C, 030104 developmental biology, Infectious Diseases, fms-Like Tyrosine Kinase 3, 030220 oncology & carcinogenesis, biology.protein, Systemic administration, Cancer research, Integrin alpha Chains, CD8
Abstract

Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.

Published
2016
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