All Publications

  • Child Neurology: Remarkable Recovery From Severe Acute Necrotizing Encephalopathy. Neurology Silverman, A., Sasaki, M., Espindola Lima, J. E., Cheronis, C., Lin, G. L., Johnson, A., Dahmoush, H., Archer, E., Grekov, K., LaRocca, T. J., Van Haren, K. 2024; 103 (8): e209877

    Abstract

    A previously healthy 6-year-old girl presented with several days of fever before a generalized seizure. Laboratory investigation revealed elevated liver enzymes, normal ammonia, and positive influenza A through respiratory PCR. Brain MRI demonstrated extensive, bilateral lesions in the cerebral and cerebellar white matter, thalami, basal ganglia, and brainstem. She was diagnosed with acute necrotizing encephalopathy, a rare parainfectious encephalitis commonly associated with influenza. Genetic variants have been implicated (e.g., RANBP2 and RNH1), but our patient's rapid genome was nondiagnostic. Her 1-month hospitalization was complicated by prolonged encephalopathy and intracranial pressure crises requiring hyperosmolar therapy, sedation, intermittent paralysis, and hypothermia. Concomitantly, she received pulse corticosteroids, plasmapheresis, and oseltamivir. Three months after illness onset, she achieved a remarkable recovery with a normal neurologic examination. Although prognosis may comprise considerable morbidity and mortality, prompt recognition, immunotherapy, and intensive care can achieve positive neurodevelopmental outcomes. Our discussion concludes with a focus on the intrinsic uncertainties of neuroprognostication in the pediatric intensive care unit.

    View details for DOI 10.1212/WNL.0000000000209877

    View details for PubMedID 39298704

  • Benign Ocular Flutter. The Journal of pediatrics Silverman, A., Maran, K., Lin, G. L., Johnson, A., Cheronis, C., Beres, S. 2024: 114229

    View details for DOI 10.1016/j.jpeds.2024.114229

    View details for PubMedID 39178940

  • Contextualizing the Resurgence of U.S. Housestaff Union Activity. Academic medicine : journal of the Association of American Medical Colleges Lin, G. L., Priest, K. C., Sossenheimer, P. H., Pal, R. 2024

    Abstract

    There is a growing trend of resident and fellow physician unionization in the United States, with 14 new housestaff unions formed at private employers since 2022. This resurgence of housestaff union organizing parallels the last era of housestaff activism in the 1960s. Today's housestaff organizing takes place within the context of longstanding challenges in medicine, including the burnout and systemic inequities highlighted by the COVID-19 pandemic, and an increase in national activism and labor organizing. Housestaff unions offer opportunities for residents and fellows to negotiate for improvements across multiple issues.In this Commentary, the authors focus on common bargaining topics: poor working conditions, undercompensation, and inadequate representation in an increasingly corporatized health care landscape. The authors also discuss the role of collective bargaining for improving the housestaff experience and address common concerns about unionization. Finally, the authors explore the limited evidence of the impact of unions in health care settings and outline key considerations for future scholarship.The current generation of housestaff started their medical careers with an awareness of systemic challenges to the profession and have responded through collective organizing. While the short- and long-term ramifications of housestaff organizing need further study, the authors express optimism that unionization will lead to improved working conditions and thus improved health care delivery.

    View details for DOI 10.1097/ACM.0000000000005816

    View details for PubMedID 39018433

  • Resident and Fellow Unions: Collective Activism to Promote Well-being for Physicians in Training. JAMA Lin, G. L., Ge, T. J., Pal, R. 2022

    View details for DOI 10.1001/jama.2022.12838

    View details for PubMedID 35900751

  • UGRC 2021 recommendations on GME transition: pros and cons, opportunities and limitations. Journal of osteopathic medicine Gimpel, J. R., Swails, J. L., Bienstock, J. L., Lin, G. L., Roett, M. A., Patel, J. K., Giang, D. W. 2022

    Abstract

    The Coalition for Physician Accountability's Undergraduate Medical Education-Graduate Medical Education (UME-GME) Review Committee (UGRC): Recommendations for Comprehensive Improvement of the UME-GME Transition final report includes a total of 34 recommendations and outlines opportunities to transform the current processes of learner transition from a US-based MD- or DO-granting medical school or international medical education pathway into residency training in the United States. This review provides a reflection on the recommendations from the authors, all members ofthe UGRC, describing the pros and cons and the opportunities and limitations, in the hopes that they might inspire readers to dig deeper into the report and contribute to meaningful improvements to the current transition. The UGRC Recommendations highlight the many opportunities for improvement in the UME-to-GME transition. They are built on the connection to the system of education and formation of physicians to a more just healthcare system, with attention to diversity, equity, andinclusion to improve health disparities and to the quality of care that patients receive. However, there are justifiable concerns about changes that are not fully understood orthat could potentially lead to unintentional consequences. This analysis, reached through author consensus, considers the pros and cons in the potential application of the UGRC Recommendations to improve the UME-to-GME transition. Further debate and discussion are warranted, without undue delay, all with the intention to continue to improve the education of tomorrow's physicians and the care for the patients who we have the privilege to serve.

    View details for DOI 10.1515/jom-2021-0285

    View details for PubMedID 35545609

  • Reimagining the Transition to Residency: A Trainee Call to Accelerated Action. Academic medicine : journal of the Association of American Medical Colleges Lin, G. L., Guerra, S., Patel, J., Burk-Rafel, J. 2022

    Abstract

    The transition from medical student to resident is a pivotal step in the medical education continuum. For applicants, successfully obtaining a residency position is the actualization of a dream after years of training and has life-changing professional and financial implications. These high stakes contribute to a residency application and Match process in the United States that is increasingly complex and dysfunctional, and that does not effectively serve applicants, residency programs, or the public good. In July 2020, the Coalition for Physician Accountability (Coalition) formed the Undergraduate Medical Education-Graduate Medical Education Review Committee (UGRC) to critically assess the overall transition to residency and offer recommendations to solve the growing challenges in the system. In this Invited Commentary, the authors reflect on their experience as the trainee representatives on the UGRC. They emphasize the importance of trainee advocacy in medical education change efforts; reflect on opportunities, concerns, and tensions with the final UGRC recommendations (released in August 2021); discuss factors that may constrain implementation; and call for the medical education community-and the Coalition member organizations in particular-to accelerate fully implementing the UGRC recommendations. By seizing the momentum created by the UGRC, the medical education community can create a reimagined transition to residency that reshapes its approach to training a more diverse, competent, and growth-oriented physician workforce.

    View details for DOI 10.1097/ACM.0000000000004646

    View details for PubMedID 35263298

  • How the Quadruple Aim Widens the Lens on the Transition to Residency. Journal of graduate medical education Barone, M. A., Bienstock, J. L., Lovell, E., Gimpel, J. R., Lin, G. L., Swails, J., Mejicano, G. C. 2022; 14 (6): 634-638

    View details for DOI 10.4300/JGME-D-22-00026.1

    View details for PubMedID 36591427

  • Fostering Medical Students' Curiosity Through Early Clinical Experiences. Academic medicine : journal of the Association of American Medical Colleges Lin, G. L., Basaviah, P. n. 2021; 96 (3): 321

    View details for DOI 10.1097/ACM.0000000000003878

    View details for PubMedID 33661844

  • Pass/Fail Score Reporting for USMLE Step 1: An Opportunity to Redefine the Transition to Residency Together. Academic medicine : journal of the Association of American Medical Colleges Lin, G. L., Nwora, C., Warton, L. 2020

    Abstract

    The upcoming transition of the United States Medical Licensing Examination Step 1 to pass/fail score reporting has wide-ranging implications for the medical education community. The decision to discontinue 3-digit numeric score reporting comes following advocacy to change the exam because of its disproportionate importance in the residency match process, the negative impact the exam has on student well-being, and the prominent influence the exam has on medical school curricula. Shifting to pass/fail score reporting for Step 1 creates significant uncertainties to be addressed by the stakeholders in the transition from undergraduate medical education to graduate medical education. In this Invited Commentary, the authors reflect on the positive implications of this scoring change, potential negative ramifications that need to be proactively addressed, and future ways that the transition to residency can be optimized. The transition to pass/fail score reporting for Step 1 creates an opportunity to redefine the residency match process, to support applicant decision making, and to encourage a holistic review of applicants. These changes to the review process will require grace and trust among stakeholders, including students, as well as active support for students who might be negatively impacted during a complex implementation phase. By removing the dominance of Step 1 numeric scores from the residency selection process, the change to pass/fail scoring provides a unique opportunity for all stakeholders to work together and redefine the transition to residency while protecting students from unintended negative consequences.

    View details for DOI 10.1097/ACM.0000000000003495

    View details for PubMedID 32379144

  • Understanding the Deadly Silence of Posterior Fossa A Ependymoma. Molecular cell Lin, G. L., Monje, M. n. 2020; 78 (6): 999–1001

    Abstract

    In a breakthrough study in a recent issue of Cell, Michealraj et al. (2020) demonstrate that posterior fossa A ependymoma, a lethal pediatric brain tumor with a silent genome, is dependent upon metabolic changes associated with hypoxia that drive the tumor's characteristic epigenetic dysregulation.

    View details for DOI 10.1016/j.molcel.2020.05.020

    View details for PubMedID 32559429

  • Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Science translational medicine Lin, G. L., Wilson, K. M., Ceribelli, M. n., Stanton, B. Z., Woo, P. J., Kreimer, S. n., Qin, E. Y., Zhang, X. n., Lennon, J. n., Nagaraja, S. n., Morris, P. J., Quezada, M. n., Gillespie, S. M., Duveau, D. Y., Michalowski, A. M., Shinn, P. n., Guha, R. n., Ferrer, M. n., Klumpp-Thomas, C. n., Michael, S. n., McKnight, C. n., Minhas, P. n., Itkin, Z. n., Raabe, E. H., Chen, L. n., Ghanem, R. n., Geraghty, A. C., Ni, L. n., Andreasson, K. I., Vitanza, N. A., Warren, K. E., Thomas, C. J., Monje, M. n. 2019; 11 (519)

    Abstract

    Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.

    View details for DOI 10.1126/scitranslmed.aaw0064

    View details for PubMedID 31748226

  • Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma. Acta neuropathologica communications Lin, G. L., Nagaraja, S., Filbin, M. G., Suva, M. L., Vogel, H., Monje, M. 2018; 6 (1): 51

    Abstract

    Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9-11months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult high-grade gliomas. Thus, we directly compared inflammatory characteristics of DIPG and adult glioblastoma (GBM). We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b+macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments.

    View details for PubMedID 29954445

  • Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma ACTA NEUROPATHOLOGICA COMMUNICATIONS Lin, G. L., Nagaraja, S., Filbin, M. G., Suva, M. L., Vogel, H., Monje, M. 2018; 6

    View details for DOI 10.1186/s40478-018-0553-x

    View details for Web of Science ID 000436975700001

  • HDAC INHIBITION IN THALAMIC AND SPINAL CORD H3K27M+DIFFUSE MIDLINE GLIOMA Kreimer, S., Lin, G., Woo, P., Monje-Deisseroth, M. OXFORD UNIV PRESS INC. 2018: 50

    View details for Web of Science ID 000438339000104

  • NON-INFLAMMATORY EFFECT OF DIPG ON TUMOR-ASSOCIATED MICROGLIA Lin, G., Arnold, E., Mount, C., Monje-Deisseroth, M. OXFORD UNIV PRESS INC. 2017: 119

    View details for Web of Science ID 000415152502100

  • A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma (DIPG) JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Lin, G. L., Monje, M. 2017

    Abstract

    Diffuse Intrinsic Pontine Glioma (DIPG) is a childhood brainstem tumor that carries a universally fatal prognosis. Because surgical resection is not a viable treatment strategy and biopsy is not routinely performed, the availability of patient samples for research is limited. Consequently, efforts to study this disease have been challenged by a paucity of faithful disease models. To address this need, we describe here a protocol for the rapid processing of post-mortem autopsy tissue samples in order to generate durable patient-derived cell culture models that can be used in in vitro assays or in vivo orthotopic xenograft experiments. These models can be used to screen for potential drug targets and to study fundamental pathobiological processes within DIPG. This protocol can further be extended to analyze and isolate tumor and microenvironmental cells using Fluorescence-activated Cell Sorting (FACS), which enables subsequent analysis of gene expression, protein expression, or epigenetic modifications of DNA at the bulk cell or single cell level. Finally, this protocol can also be adapted to generate patient-derived cultures for other central nervous system tumors.

    View details for DOI 10.3791/55360

    View details for Web of Science ID 000397848300065

    View details for PubMedID 28362421

  • Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science Gibson, E. M., Purger, D., Mount, C. W., Goldstein, A. K., Lin, G. L., Wood, L. S., Inema, I., Miller, S. E., Bieri, G., Zuchero, J. B., Barres, B. A., Woo, P. J., Vogel, H., Monje, M. 2014; 344 (6183): 1252304-?

    Abstract

    Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.

    View details for DOI 10.1126/science.1252304

    View details for PubMedID 24727982