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4. Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

Author

Koenecke, Allison, Powell, Michael, Xiong, Ruoxuan, Shen, Zhu, Fischer, Nicole, Huq, Sakibul, Khalafallah, Adham M., Trevisan, Marco, Sparen, Pär, Carrero, Juan J, Nishimura, Akihiko, Caffo, Brian, Stuart, Elizabeth A., Bai, Renyuan, Staedtke, Verena, Thomas, David L., Papadopoulos, Nickolas, Kinzler, Kenneth W., Vogelstein, Bert, Zhou, Shibin, Bettegowda, Chetan, Konig, Maximilian F., Mensh, Brett, Vogelstein, Joshua T., and Athey, Susan

Subjects
Quantitative Biology - Tissues and Organs, Quantitative Biology - Quantitative Methods
Abstract

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor ($\alpha_1$-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n=18,547) and three cohorts with pneumonia (n=400,907). Federated across two ARD cohorts, we find that patients exposed to $\alpha_1$-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR=0.70, p=0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of $\alpha_1$-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19., Comment: 31 pages, 10 figures

Published
2020
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5. Barriers to T Cell Functionality in the Glioblastoma Microenvironment.

Author

Nader, Noor E., Frederico, Stephen C., Miller, Tracy, Huq, Sakibul, Zhang, Xiaoran, Kohanbash, Gary, and Hadjipanayis, Constantinos G.

Subjects
GLIOMAS, T cells, CELL physiology, CENTRAL nervous system, VACCINE immunogenicity
Abstract

Simple Summary: Malignant brain tumors, such as glioblastoma (GBM), are devastating diagnoses for patients and their families, as these tumors are difficult to fully remove with surgery and respond poorly to chemotherapy and radiation. Immunotherapy is a novel approach to treating cancer, as these therapies are intended to initiate robust antitumor immune responses. However, immunotherapy for GBM has largely been unsuccessful. It is hypothesized that one of the major contributors to immunotherapy failure in GBM patients is the number of immunosuppressive blockades present in these patients. Often, the GBM microenvironment is characterized as highly immunosuppressive due to GBM recruiting anti-inflammatory immune cells to the microenvironment and releasing immunosuppressive factors such as PD-L1. Additionally, treatment given to GBM patients, such as corticosteroids, is immunosuppressive. In this review, we outline potential blockades to immunotherapy success in GBM patients to highlight where new approaches to combatting this malignancy should be considered. Glioblastoma (GBM) is an aggressive primary brain tumor depicted by a cold tumor microenvironment, low immunogenicity, and limited effective therapeutic interventions. Its location in the brain, a highly immune-selective organ, acts as a barrier, limiting immune access and promoting GBM dissemination, despite therapeutic interventions. Currently, chemotherapy and radiation combined with surgical resection are the standard of care for GBM treatment. Although immune checkpoint blockade has revolutionized the treatment of solid tumors, its observed success in extracranial tumors has not translated into a significant survival benefit for GBM patients. To develop effective immunotherapies for GBM, it is vital to tailor treatments to overcome the numerous immunosuppressive barriers that inhibit T cell responses to these tumors. In this review, we address the unique physical and immunological barriers that make GBM challenging to treat. Additionally, we explore potential therapeutic mechanisms, studied in central nervous system (CNS) and non-CNS cancers, that may overcome these barriers. Furthermore, we examine current and promising immunotherapy clinical trials and immunotherapeutic interventions for GBM. By highlighting the array of challenges T cell-based therapies face in GBM, we hope this review can guide investigators as they develop future immunotherapies for this highly aggressive malignancy. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Transcriptomic observations of intra and extracellular immunotherapy targets for pediatric brain tumors.

Author

Frederico, Stephen C., Raphael, Itay, Nisnboym, Michal, Huq, Sakibul, Schlegel, Brent T., Sneiderman, Chaim T., Jackson, Sydney A., Jain, Anya, Olin, Michael R., Rood, Brian R., Pollack, Ian F., Hwang, Eugene I., Rajasundaram, Dhivyaa, and Kohanbash, Gary

Subjects
TREATMENT effectiveness, INTERFERON gamma, CHILD mortality, ANTIGEN presentation, ANTIGEN processing, BRAIN tumors
Abstract

Objectives: Despite surgical resection, chemoradiation, and targeted therapy, brain tumors remain a leading cause of cancer-related death in children. Immunotherapy has shown some promise and is actively being investigated for treating childhood brain tumors. However, a critical step in advancing immunotherapy for these patients is to uncover targets that can be effectively translated into therapeutic interventions. Methods: In this study, our team performed a transcriptomic analysis across pediatric brain tumor types to identify potential targets for immunotherapy. Additionally, we assessed components that may impact patient response to immunotherapy, including the expression of genes essential for antigen processing and presentation, inhibitory ligands and receptors, interferon signature, and overall predicted T cell infiltration. Results: We observed distinct expression patterns across tumor types. These included elevated expression of antigen genes and antigen processing machinery in some tumor types while other tumors had elevated inhibitory checkpoint receptors, known to be associated with response to checkpoint inhibitor immunotherapy. Conclusion: These findings suggest that pediatric brain tumors exhibit distinct potential for specific immunotherapies. We believe our findings can guide investigators in their assessment of appropriate immunotherapy classes and targets in pediatric brain tumors. [ABSTRACT FROM AUTHOR]

Published
2024
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20. Magnetic Hyperthermia Therapy for High-Grade Glioma: A State-of-the-Art Review.

Author

Rodriguez, Benjamin, Rivera, Daniel, Zhang, Jack Y., Brown, Cole, Young, Tirone, Williams, Tyree, Huq, Sakibul, Mattioli, Milena, Bouras, Alexandros, and Hadjpanayis, Constantinos G.

Subjects
MAGNETOTHERAPY, THERMOTHERAPY, MAGNETIC particle imaging, GLIOMAS, BRAIN tumors, FEVER, TRANSCRANIAL magnetic stimulation
Abstract

Magnetic hyperthermia therapy (MHT) is a re-emerging treatment modality for brain tumors where magnetic nanoparticles (MNPs) are locally delivered to the brain and then activated with an external alternating magnetic field (AMF) to generate localized heat at a site of interest. Due to the recent advancements in technology and theory surrounding the intervention, clinical and pre-clinical trials have demonstrated that MHT may enhance the effectiveness of chemotherapy and radiation therapy (RT) for the treatment of brain tumors. The future clinical success of MHT relies heavily on designing MNPs optimized for both heating and imaging, developing reliable methods for the local delivery of MNPs, and designing AMF systems with integrated magnetic particle imaging (MPI) for use in humans. However, despite the progression of technological development, the clinical progress of MHT has been underwhelming. This review aims to summarize the current state-of-the-art of MHT and offers insight into the current barriers and potential solutions for moving MHT forward. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Preventing cytokine storm syndrome in COVID-19 using [alpha]-1 adrenergic receptor antagonists

Author

Konig, Maximilian F., Staedtke, Mike Powell Verena, Bai, Ren-Yuan, Thomas, David L., Fischer, Nicole, Huq, Sakibul, Khalafallah, Adham M., Koenecke, Allison, Xiong, Ruoxuan, Mensh, Brett, Papadopoulos, Nickolas, Kinzler, Kenneth W., Vogelstein, Bert, Vogelstein, Joshua T., Athey, Susan, Zhou, Shibin, and Bettegowda, Chetan

Subjects
Mortality -- China -- United Kingdom -- Maryland, Sarilumab -- Health aspects, Severe acute respiratory syndrome -- Prevention, Coronaviruses -- Health aspects, Cytokines -- Health aspects, Pneumonia -- Prevention, Siltuximab -- Health aspects, Adult respiratory distress syndrome -- Prevention, COVID-19 -- Prevention, Medical schools -- Health aspects, T cells -- Health aspects, Health care industry, Johns Hopkins University. School of Medicine
Abstract

Dysregulated host immune responses drive mortality in pneumonia and acute respiratory distress syndrome (ARDS) caused by a wide range of infections. In coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome [...]

Published
2020
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25. Contributors

Author

Al Enazy, Sanaalarab, primary, Anthony, Casey, additional, Aubert, Isabelle, additional, Bankiewicz, Krystof, additional, Bell, Susan D., additional, Belov, Vasily, additional, Boulis, Nicholas M., additional, Brem, Henry, additional, Campbell, Matthew, additional, Caruso, Hillary, additional, Casaos, Joshua, additional, Chaudhuri, Tista Roy, additional, Dadas, Aaron, additional, Davidson, Beverly L., additional, Deer, Timothy R., additional, Di, Long, additional, Doolittle, Nancy D., additional, Elder, James B., additional, Elmghirbi, Rasha, additional, Ewing, James R., additional, Fiandaca, Massimo, additional, Grant, Gerald, additional, Greene, Chris, additional, Gupta, Kunal, additional, Hardcastle, Nathan, additional, Heimberger, Amy B., additional, Hoang, Nguyen, additional, Huang, Yuhao, additional, Huntoon, Kristin, additional, Huq, Sakibul, additional, Hwang, Lee S., additional, Iadarola, Michael J., additional, Janigro, Damir, additional, Kassab, Cynthia, additional, Parker Kerrigan, Brittany, additional, Kim, Philip S., additional, Krivosheya, Daria, additional, Larson, Paul, additional, Lim, Daniel A., additional, Lipsman, Nir, additional, Lonser, Russell R., additional, Mannes, Andrew J., additional, Marchi, Nicola, additional, Martin, Bryn A., additional, McGregor, John M., additional, Meng, Ying, additional, Mithani, Karim, additional, Morrison, Paul, additional, Nagaraja, Tavarekere, additional, Naidoo, Jerusha, additional, Neuwelt, Edward A., additional, Nimjee, Shahid M., additional, O’Connor, Claire, additional, Pahlavian, Soroush Heidari, additional, Pan, James, additional, Papisov, Mikhail, additional, Poth, Kelly M., additional, Ramanath, Nirmala, additional, Richardson, R. Mark, additional, Sandor, Kaitlin, additional, Sarntinoranont, Malisa, additional, Selden, Nathan R., additional, Serra, Riccardo, additional, Simpson, Bryan P., additional, Staats, Peter S., additional, Straubinger, Robert M., additional, Tora, Muhibullah S., additional, Tyler, Betty, additional, Vecchio, Laura, additional, Vogelbaum, Michael A., additional, Washington, Jolewis, additional, Winkler, Ethan A., additional, and Youngers, Emily, additional

Published
2019
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26. Supplementary Data from Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma

Author

Huq, Sakibul, primary, Casaos, Joshua, primary, Serra, Riccardo, primary, Peters, Michael, primary, Xia, Yuanxuan, primary, Ding, Andy S., primary, Ehresman, Jeff, primary, Kedda, Jayanidhi N., primary, Morales, Manuel, primary, Gorelick, Noah L., primary, Zhao, Tianna, primary, Ishida, Wataru, primary, Perdomo-Pantoja, Alexander, primary, Cecia, Arba, primary, Ji, Chenchen, primary, Suk, Ian, primary, Sidransky, David, primary, Brait, Mariana, primary, Brem, Henry, primary, Skuli, Nicolas, primary, and Tyler, Betty, primary

Published
2023
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27. The Neurosurgery Research & Education Foundation-Young Neurosurgeons Committee Webinar Series: Providing Education and Inspiration During the Covid-19 Pandemic

Author

Rodriguez-Armendariz, Ana G., primary, Saint-Germain, Max Andy, additional, Khalafallah, Adham M., additional, Huq, Sakibul, additional, Almeida, Neil D., additional, Dornbos III, David L., additional, Graffeo, Christopher S., additional, Sivakumar, Walavan, additional, Mukherjee, Debraj, additional, and Johnson, Jeremiah N., additional

Published
2023
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30. Predictors and Impact of Postoperative 30-Day Readmission in Glioblastoma

Author

Botros, David, primary, Khalafallah, Adham M., additional, Huq, Sakibul, additional, Dux, Hayden, additional, Oliveira, Leonardo A. P., additional, Pellegrino, Richard, additional, Jackson, Christopher, additional, Gallia, Gary L., additional, Bettegowda, Chetan, additional, Lim, Michael, additional, Weingart, Jon, additional, Brem, Henry, additional, and Mukherjee, Debraj, additional

Published
2022
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31. Synergy between glutamate modulation and anti–programmed cell death protein 1 immunotherapy for glioblastoma

Author

Medikonda, Ravi, primary, Choi, John, additional, Pant, Ayush, additional, Saleh, Laura, additional, Routkevitch, Denis, additional, Tong, Luqing, additional, Belcaid, Zineb, additional, Kim, Young Hoon, additional, Jackson, Christopher M., additional, Jackson, Christina, additional, Mathios, Dimitrios, additional, Xia, Yuanxuan, additional, Shah, Pavan P., additional, Patel, Kisha, additional, Kim, Timothy, additional, Srivastava, Siddhartha, additional, Huq, Sakibul, additional, Ehresman, Jeff, additional, Pennington, Zach, additional, Tyler, Betty, additional, Brem, Henry, additional, and Lim, Michael, additional

Published
2022
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36. Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model

Author

Serra, Riccardo, primary, Zhao, Tianna, additional, Huq, Sakibul, additional, Gorelick, Noah Leviton, additional, Casaos, Joshua, additional, Cecia, Arba, additional, Mangraviti, Antonella, additional, Eberhart, Charles, additional, Bai, Renyuan, additional, Olivi, Alessandro, additional, Brem, Henry, additional, Jackson, Eric M., additional, and Tyler, Betty, additional

Published
2021
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38. Patient-Specific Factors Drive Intensive Care Unit and Total Hospital Length of Stay in Operative Patients with Brain Tumor

Author

Jimenez, Adrian E., primary, Shah, Pavan P., additional, Khalafallah, Adham M., additional, Huq, Sakibul, additional, Porras, Jose L., additional, Jackson, Christopher M., additional, Gallia, Gary, additional, Bettegowda, Chetan, additional, Weingart, Jon, additional, Suarez, Jose Ignacio, additional, Brem, Henry, additional, and Mukherjee, Debraj, additional

Published
2021
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39. Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

Author

Koenecke, Allison, primary, Powell, Michael, primary, Xiong, Ruoxuan, additional, Shen, Zhu, additional, Fischer, Nicole, additional, Huq, Sakibul, additional, Khalafallah, Adham M, additional, Trevisan, Marco, additional, Sparen, Pär, additional, Carrero, Juan J, additional, Nishimura, Akihiko, additional, Caffo, Brian, additional, Stuart, Elizabeth A, additional, Bai, Renyuan, additional, Staedtke, Verena, additional, Thomas, David L, additional, Papadopoulos, Nickolas, additional, Kinzler, Ken W, additional, Vogelstein, Bert, additional, Zhou, Shibin, additional, Bettegowda, Chetan, additional, Konig, Maximilian F, additional, Mensh, Brett D, additional, Vogelstein, Joshua T, additional, and Athey, Susan, additional

Published
2021
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40. Scoring System to Triage Patients for Spine Surgery in the Setting of Limited Resources

Author

Sciubba, Daniel M, Ehresman, Jeffrey S, Pennington, Zach, Lubelski, Daniel, Feghali, James, Bydon, Ali, Chou, Dean, Elder, Benjamin D, Elsamadicy, Aladine A, Goodwin, Matthew, Goodwin, C. Rory, Harrop, James S, Huq, Sakibul, Klineberg, Eric, Laufer, Ilya, Lo, Sheng-fu L, Neumaan, Brian J, Passias, Peter G, Protopsaltis, Themistocles, Shin, John H, Theodore, Nicholas, Witham, Timothy F, and Benzel, Edward C

Subjects
CNS ACCEPTED ABSTRACTS, AcademicSubjects/MED00930, Surgery, Neurology (clinical), CNS Best Clinical Research Award
Abstract

INTRODUCTION As of May 04, 2020, the COVID-19 pandemic has affected over 3.5 million people and touched every inhabited continent. Accordingly, it has stressed health systems the world over leading to the cancellation of elective surgical cases and discussions regarding healthcare resource rationing. It is expected that rationing of surgical resources will continue even after the pandemic peak, and may recur with future pandemics, creating a need for a means of triaging emergent and elective spine surgery patients. METHODS Using a modified Delphi technique, a cohort of 16 fellowship-trained spine surgeons from 10 academic medical centers constructed a scoring system for the triage and prioritization of emergent and elective spine surgeries. Three separate rounds of videoconferencing and written correspondence were used to reach a final scoring system. Sixteen test cases were used to optimize the scoring system so that it could categorize cases as requiring emergent, urgent, high-priority elective, or low-priority elective scheduling. RESULTS The devised scoring system included 8 independent components: neurological status, underlying spine stability, presentation of a highrisk post-operative complication, patient medical comorbidities, expected hospital course, expected discharge disposition, facility resource limitations, and local disease burden. The resultant calculator was deployed as a freely-available web-based calculator: https://jhuspine3.shinyapps.io/SpineUrgencyCalculator/ CONCLUSION Here we present the first quantitative urgency scoring system for the triage and prioritizing of spine surgery cases in resource-limited settings. We believe that our scoring system, while not all-encompassing, has potential value as a guide for triaging spine surgical cases during the COVID pandemic and post-COVID period.

Published
2020

41. Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma

Author

Huq, Sakibul, primary, Kannapadi, Nivedha V., additional, Casaos, Joshua, additional, Lott, Tarik, additional, Felder, Raphael, additional, Serra, Riccardo, additional, Gorelick, Noah L., additional, Ruiz-Cardozo, Miguel A., additional, Ding, Andy S., additional, Cecia, Arba, additional, Medikonda, Ravi, additional, Ehresman, Jeff, additional, Brem, Henry, additional, Skuli, Nicolas, additional, and Tyler, Betty M., additional

Published
2021
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42. Author response: Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

Author

Koenecke, Allison, primary, Powell, Michael, additional, Xiong, Ruoxuan, additional, Shen, Zhu, additional, Fischer, Nicole, additional, Huq, Sakibul, additional, Khalafallah, Adham M, additional, Trevisan, Marco, additional, Sparen, Pär, additional, Carrero, Juan J, additional, Nishimura, Akihiko, additional, Caffo, Brian, additional, Stuart, Elizabeth A, additional, Bai, Renyuan, additional, Staedtke, Verena, additional, Thomas, David L, additional, Papadopoulos, Nickolas, additional, Kinzler, Ken W, additional, Vogelstein, Bert, additional, Zhou, Shibin, additional, Bettegowda, Chetan, additional, Konig, Maximilian F, additional, Mensh, Brett D, additional, Vogelstein, Joshua T, additional, and Athey, Susan, additional

Published
2021
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43. Alpha-1 adrenergic receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome

Author

Vogelstein, Joshua T., Powell, Michael, Koenecke, Allison, Xiong, Ruoxuan, Fischer, Nicole, Huq, Sakibul, Khalafallah, Adham M., Caffo, Brian, Stuart, Elizabeth A., Papadopoulos, Nickolas, Kinzler, Kenneth W., Vogelstein, Bert, Zhou, Shibin, Bettegowda, Chetan, Konig, Maximilian F., Mensh, Brett, and Athey, Susan

Subjects
TISSUES AND ORGANS, COVID-19, SARS-COV-2, SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2, QUANTITATIVE METHODS
Abstract

In severe viral pneumonias, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by a hyperinflammatory reaction (‘cytokine storm syndrome’) that leads to acute respiratory distress syndrome and death, despite maximal supportive care. Preventing hyperinflammation is key to avoiding these outcomes. We previously demonstrated that alpha-1 adrenergic receptor antagonists ( ⍺ -blockers) can prevent cytokine storm syndrome and death in mice. Here, we conduct a retrospective analysis of patients with acute respiratory distress or pneumonia (n = 13,125 and n = 108,956, respectively) from all causes; patients who were incidentally taking ⍺ -blockers had a reduced risk of requiring ventilation (by 35% and 16%, respectively), and a reduced risk of being ventilated and dying (by 56% and 20%, respectively), compared to non-users. Beta-adrenergic receptor antagonists had no significant effects. These results highlight the urgent need for prospective trials testing whether prophylactic ⍺ -blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19.

Published
2020
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45. Disulfiram and Copper Combination Therapy Targets NPL4, Cancer Stem Cells and Prolongs Survival in Group 3 Medulloblastoma

Author

Serra, Riccardo, primary, Zhao, Tianna, additional, Huq, Sakibul, additional, Gorelick, Noah L, additional, Casaos, Joshua, additional, Cecia, Arba, additional, Mangraviti, Antonella, additional, Bai, Renyuan, additional, Olivi, Alessandro, additional, Brem, Henry, additional, Jackson, Eric M, additional, and Tyler, Betty, additional

Published
2020
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47. Preclinical Efficacy of the Antiviral Drug Ribavirin in SHH and Group 3 Medulloblastoma

Author

Huq, Sakibul, primary, Kannapadi, Nivedha, additional, Casaos, Joshua, additional, Lott, Tarik, additional, Felder, Raphael, additional, Serra, Riccardo, additional, Gorelick, Noah L, additional, Ruiz-Cardozo, Miguel, additional, Ding, Andy, additional, Cecia, Arba, additional, Medikonda, Ravi, additional, Ehresman, Jeff, additional, Brem, Henry, additional, Skuli, Nicolas, additional, and Tyler, Betty, additional

Published
2020
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