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training Physician‒scientists for Careers in Investigative Dermatology

JID Innovations 2022年第1期2卷 100061-100061页

作者： Li, Stephen Yancey, Kim B. Cruz, Ponciano D. Le, Lu Q. Department of Dermatology The University of Texas Southwestern Medical Center Dallas Texas United States Medical Scientist Training Program The University of Texas Southwestern Medical Center Dallas Texas United States Hamon Center for Regenerative Science and Medicine The University of Texas Southwestern Medical Center Dallas Texas United States Harold C. Simmons Comprehensive Cancer Center The University of Texas Southwestern Medical Center Dallas Texas United States Peter O'Donnell Jr. Brain Institute The University of Texas Southwestern Medical Center Dallas Texas United States

Physician‒scientists have made countless discoveries, and their dwindling numbers are a significant concern. Although dermatology has become an increasingly popular destination for physician‒scientist trainees, the proportion of trainees who pursue scientific research careers after training is among the lowest of all medical specialties. To investigate this problem, we surveyed a national cohort of dermatology educators, physician‒scientist track program directors, and National Institute of Arthritis and Musculoskeletal and Skin Diseases T32 directors for opinions regarding physician‒scientist training in dermatology. On the basis of these findings and to help address the issue, we propose a training practicum and provide a resource for funding opportunities to help guide trainees and institutions interested in supporting investigative dermatologists. We also discuss the important roles of department chairs and institutions in fashioning an environment conducive to physician‒scientist training. The information and recommendations provided in this paper may help to improve the recruitment, training, development, and retention of investigative dermatologists and future leaders in this field. © 2021 The Authors

关键词： ABD American Board of Dermatology ASCI American Society of Clinical Investigators CDA Career Development Award CV curriculum vitae LRP loan repayment program MD medical degree MSTP medical scientist training program NIGMS National Institute of General medical Sciences NIH National Institutes of Health NIAMS National Institute of Arthritis and Musculoskeletal and Skin Diseases PGY postgraduate year PSTP physician‒scientist training program PSW physician‒scientist workforce STAR Specialty training and Advanced Research URM under-represented minority

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EXTH-75. IMMUNOVIROTHERAPY WITH PP2A AND PD-1 INHIBITION IN PEDIATRIC HIGH-GRADE GLIOMA

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Neuro-Oncology 2024年第SUPPLEMENT_8期26卷 viii254–viii254页

作者： Kang, Kyung-Don Frederico, Stephen Fan, Aaron Gary, Sam Zhang, Zhuo Zhou, Li Markert, James Bernstock, Joshua Friedman, Gregory Division of Pediatrics The University of Texas MD Anderson Cancer Center Houston USA School of Medicine University of Pittsburgh Pittsburgh USA Department of Neurosurgery Brigham and Women’s Hospital Harvard Medical School Boston USA Medical Scientist Training Program The University of Alabama at Birmingham Birmingham USA Department of Neurosurgery The University of Alabama at Birmingham Birmingham USA

Pediatric high-grade gliomas (HGGs) represent a significant clinical challenge with poor survival rates. Engineered oncolytic herpes simplex virus (oHSV) has shown potential in several clinical trials at targeting HGGs through their direct lytic effect and induction of an immune response. We have learned from our clinical trial experience (NCT02457845) that a critical barrier to more durable response is augmenting and sustaining the anti-tumor immune response generated by oHSV. LB-100, a protein phosphatase 2A (PP2A) inhibitor, is known to enhance T-cell activity. We hypothesized that LB-100 with anti-PD-1 therapy would overcome the immunosuppressive barriers, enhancing the immunotherapeutic effects of oHSV and improve survival in an immunocompetent murine model. We investigated the therapeutic impact of clinically available, next-generation oHSV, M002, which expresses murine interleukin-12, combined with LB-100 and PD-1 inhibition compared to M002 with LB-100 or anti-PD-1 antibody, each therapy alone, or control by measuring median survival and changes in the tumor immune microenvironment. The triple combination of M002, LB-100, and anti-PD-1 antibody significantly extended median survival compared to control (45 days vs 22.5 days, P=0.001) or each treatment alone, and compared to M002 and LB-100 (44 days vs 28 days, P=0.017) or M002 and anti-PD-1 (45.5 days vs 41 days, P=0.023). This increase in survival was correlated with a robust increase in CD45+ immune cell infiltration and a reduction in T-regulatory cells. We will further investigate the changes in the tumor microenvironment to better understand the specific contributions of different immune cell populations. These data support the hypothesis that LB-100 enhances the efficacy of oHSV by amplifying T-cell-mediated immune responses against tumor cells. This combination therapy demonstrates a promising strategy that warrants further exploration and potential clinical application, emphasizing the critical role

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POS0348 ACTIVATING STAT3 MUTATIONS IN CD8+ T CELLS CORRELATE TO SEROLOGICAL POSITIVITY IN RHEUMATOID ARTHRITIS PATIENTS

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Annals of the Rheumatic Diseases 2023年 82卷 423-424页

作者： K. Moosic T. Olson M. Freijat S. Khalique C. Hamele B. Shemo J. Boodoo W. Baker M. Schmachtenberg A. Ratan E. Darrah F. Andrade K. Olson D. Feith T. Loughran D. Kimpel University of Virginia School of Medicine Department of Pathology Charlottesville United States of America University of Virginia School of Medicine Department of Medicine Division of Hematology/Oncology Charlottesville United States of America University of Virginia School of Medicine Cancer Center Charlottesville United States of America University of Virginia School of Medicine Department of Medicine Division of Rheumatology Charlottesville United States of America University of Virginia School of Medicine Department of Public Health Sciences Charlottesville United States of America University of Virginia School of Medicine Medical Scientist Training Program Charlottesville United States of America The Johns Hopkins University School of Medicine Division of Rheumatology Baltimore United States of America

Background Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that leads to inflammation and bone erosion of synovial joints. Serological markers such as rheumatoid factor (RF) and anti-CCP antibodies are commonly elevated, and cytotoxic CD8+ T-cell expansions have been implicated in disease pathogenesis. Large granular lymphocyte (LGL) leukemia is a rare hematologic malignancy characterized by clonal expansion of CD8+ cytotoxic T-cells. A major hallmark of all LGL leukemia is increased STAT3 activation. About 50% of patients have somatic activating mutations in STAT3 , the most common being Y640F and D661Y. Additionally, STAT3 mutations correlate with numerous clinical features in LGL leukemia. LGL leukemia patients with STAT3 mutations are more likely to respond to methotrexate treatment, tend to have low neutrophil counts, and clinical features can differ between mutation types (e.g. Y640F vs D661Y). Approximately one third of LGL leukemia patients also suffer from RA, and those with STAT3 mutations are more likely to exhibit concomitant RA. Those patients with both diseases also tend to have increased positivity for serological markers like RF and anti-CCP antibodies than patients with either disease alone[1]. Objectives Based on disease overlap between LGL leukemia and RA, and a putative role for CD8+ T-cells in RA, we hypothesized that STAT3 mutations may be detected in the CD8+ T cells of RA patients without LGL leukemia and correlate with RA clinical characteristics. Methods Blood samples, clinical parameters, and demographic data were collected from RA patients (n=96), many of whom were on immunosuppressives such as methotrexate, and healthy controls (n=9). CD8+ cell DNA was isolated and analyzed via droplet digital (dd)PCR to detect common STAT3 mutations in LGL leukemia: Y640F, D661Y, and mutations in the S614 to G618 region. RA samples were divided into wild-type (WT) vs. STAT3 -mutant groups using a variant allele frequency (VAF) cutoff

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How public health policy can be informed by neuroscience

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Behavioural Public Policy 2019年第1期3卷 37-46页

作者： Andrew B. Wolf Felsen, Gidon Department of Physiology and Biophysics University of Colorado School of Medicine United States Medical Scientist Training Program University of Colorado School of Medicine United States Center for Bioethics and Humanities University of Colorado Anschutz Medical Campus United States

Many public policies are designed to counteract commonly made decisions that result in poor health. These policies have primarily been informed by the behavioural economics of decision making. Underappreciated in this conversation has been the perspective from neuroscience, despite its recent success - and the likelihood of future progress - in advancing our understanding of the neural basis for health-related decisions. Using tobacco control as an example, we provide a concise overview of how public health policies can and should be informed by neuroscience. We propose that such input can improve policies by increasing their effectiveness, improving screening efficiency and informing relevant ethical considerations. Finally, we recognise limitations and highlight roles that key stakeholders can play in incorporating neuroscientific evidence for the benefit of public policy. Copyright © Cambridge University Press 2018 .

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Engineered Invariant Natural Killer T Cells (iNKT cells) Targeting CD 117 As a Novel Treatment for Acute Myeloid Leukemia.

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Transplantation and Cellular Therapy 2025年第2期31卷 S201-S202页

作者： Boonchalermvichian, Chaiyaporn, MD, PhD Yan, Hao, PhD Baker, Jeanette Bubb, Quenton Rashawn, MPhil, PhD Gupta, Biki, PhD Czechowicz, Agnieszka, MD, PhD Negrin, Robert S., MD Division of Blood and Marrow Transplantation & Cellular Therapy Stanford University School of Medicine Stanford CA Department of Medicine Division of Blood and Marrow Transplantation Stanford University School of Medicine Stanford CA Stem Cell Biology and Regenerative Medicine Graduate Program Medical Scientist Training Program Stanford University Stanford CA Department of Pediatrics； Division of Hematology Oncology Stem Cell Transplantation and Regenerative Medicine Stanford University School of Medicine Stanford CA

BackgroundOur research aims to develop a CAR based therapy for the treatment of acute myeloid leukemia (AML) using engineered invariant natural killer T (iNKT) cells targeting the CD117 molecule. iNKT cells are specialized subset of innate T cells with an invariant T-cell receptor that have demonstrated cytotoxicity against cancer cells, making them a promising candidate for adoptive cell therapy. Moreover, their ability to suppress or prevent graft-versus-host disease (GVHD) while maintaining potent antitumor activity makes iNKT cells a possible " off-the-shelf" product for treating various hematologic and solid tumor malignancies. MethodsPeripheral blood mononuclear cells were isolated by gradient centrifugation from buffy coats using Ficoll Pague Plus Media, followed by enrichment using anti-iNKT microbeads. Stimulation of iNKT cells with irradiated allogeneic PBMC, α-Galcer, and key cytokines (IL2, IL15, IL21) on days 0 and 10 facilitated expansion. After 14 days of expansion (67-80-fold expansion), the iNKT cells were transduced with an MSGV1 gamma-retroviral vector that was modified to include a CAR sequence. CAR constructs consist of single chain variable fragment (scFv) binding to CD117. The fibronectin enhanced retroviral transduction of human iNKT cells achieved transfection efficacies ranging from 72% – 91.2%, depending on donors. In vitro cytotoxicity assay was done by co-culturing either CD117- CAR-iNKT cells or CD117- CAR-T cells (effector cells) with luciferase-transduced CD117 leukemia cell lines (target cells) for 24 hours. To study the impact of CD117 CAR iNKT cells in vivo(Figure 1), NSG mice (6 mice per group) were irradiated (250 cGy/ mouse) on D0 and engrafted with luc-transduced CD117 leukemia cell lines (Kasumi-1) on D4. Mice were treated with either 1.5 × 10 7 CD117- CAR-iNKT cells or untransduced iNKT cells, 3 days after the engraftment of leukemia cell lines to compare efficacy and mortality. Animals also received IL2 intraperitoneally (1,

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Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models

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SCIENCE 2022年第6606期377卷 618-+页

作者： Cohen, Alexander A. van Doremalen, Neeltje Greaney, Allison J. Andersen, Hanne Sharma, Ankur Starr, Tyler N. Keeffe, Jennifer R. Fan, Chengcheng Schulz, Jonathan E. Gnanapragasam, Priyanthi N. P. Kakutani, Leesa M. West, Anthony P., Jr. Saturday, Greg Lee, Yu E. Gao, Han Jette, Claudia A. Lewis, Mark G. Tan, Tiong K. Townsend, Alain R. Bloom, Jesse D. Munster, Vincent J. Bjorkman, Pamela J. Division of Biology and Biological Engineering California Institute of Technology Pasadena CA 91125 USA Laboratory of Virology National Institute of Allergy and Infectious Diseases National Institutes of Health Hamilton MT 59840 USA Basic Sciences Division and Computational Biology Program Fred Hutchinson Cancer Research Center Seattle WA 98109 USA Department of Genome Sciences and Medical Scientist Training Program University of Washington Seattle WA 98195 USA BIOQUAL Rockville MD USA MRC Human Immunology Unit MRC Weatherall Institute of Molecular Medicine John Radcliffe Hospital University of Oxford Oxford OX3 9DS UK Chinese Academy of Medical Sciences Oxford Institute University of Oxford Oxford OX3 9DS UK Howard Hughes Medical Institute Seattle WA 98109 USA.

To combat future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles that present randomly arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded rather than variable, immunodominant, and exposed. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD nanoparticles in mice and macaques and observed stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains, including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants, including Omicrons, and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest that mosaic-8 RBD nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

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CSIG-20. LIPOCALIN-2 DRIVES CELL-INTRINSIC FUNCTIONS IN GLIOBLASTOMA

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Neuro-Oncology 2024年第SUPPLEMENT_8期26卷 viii68–viii68页

作者： Wang, Sabrina Timken, J Bishop, Christopher Deleyrolle, Loic Lathia, Justin Lerner Research Institute Cleveland Clinic Cleveland USA Medical Scientist Training Program Case Western Reserve University Cleveland USA Lillian S. Wells Department of Neurosurgery University of Florida Gainesville USA Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center Cleveland Clinic Cleveland USA

Glioblastoma (GBM) continues to persist despite aggressive therapies, many of which are cytotoxic, and therapeutic failure is driven, in part, by the tumor cell’s ability to evade multiple forms of cell death, including ferroptosis. Lipocalin-2 (LCN2) functions to sequester iron and is considered an inflammatory marker through its function of limiting iron for bacterial usage; it has also been described to have pro and anti-tumorigenic effects depending on environmental iron status. In previously published studies in brain metastases, LCN2 promotes tumor cell proliferation by sequestering iron for cancer cells growth and survival, but the mechanisms of how LCN2 contributes to GBM progression is unknown. LCN2 expression in patient data revealed that high LCN2 expression is associated with reduced survival in GBM patients. A survey of mouse glioma models demonstrated a range of LCN2 secretion across models with KR158 and CPA being high and medium LCN2 secretors. LCN2 short hairpin knockdown of KR158 and CPA and decreased tumor cell viability and proliferation. Furthermore, when both KR158 and CPA control versus LCN2 knockdown cells were orthotopically implanted into mice, survival was increased. To understand if LCN2 impacted cell death dynamics, we investigated various cell death mechanisms and found that LCN2 knockdown increases tumor susceptibility to ferroptotic death by sensitizing cells to lipid peroxidation as well as reducing key anti-ferroptotic proteins GPX4 and xCT. To elucidate downstream mechanisms, we performed a phosphorylation array and discovered that phosphorylation of AXL, which has recently been linked to ferroptosis, is decreased with LCN2 knockdown. Moreover, AXL phosphorylation was localized to the nucleus, indicating that LCN2 knockdown attenuates AXL processing and downstream signaling. Overall, these findings indicate that LCN2 in GBM promotes tumor cell growth through AXL signaling and evasion of ferroptotic death, ultimately revealing a nov

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SURG-38. SAFETY AND EFFICACY OF COMBINATORIAL IMMUNE CHECKPOINT BLOCKADE AND LASER INTERSTITIAL THERMAL THERAPY

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Neuro-Oncology 2023年第SUPPLEMENT_5期25卷 v270–v270页

作者： Haskell-Mendoza, Aden Wachsmuth, Lucas Srinivasan, Ethan Jackson, Joshua Zaidi, Saif Gonzalez, Ariel Reason, Elle Lerner, Emily Fecci, Peter Duke University School of Medicine Durham NC USA Duke University Medical Scientist Training Program Durham NC USA Johns Hopkins Department of Neurosurgery Baltimore MD USA Duke University Medical Center Durham NC USA Duke University Department of Neurosurgery Durham NC USA

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Auditory Understanding of Speech and Non-speech. 1

Auditory Understanding of Speech and Non-speech. 1

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作者： Uddin, Sophia.0(orcid)0000-0002-7285-42620 The University of Chicago.bInterdisciplinary Scientist Training Program: Computational Neuroscience.0

学位级别：Ph.D.

There is a longstanding debate about the specificity and encapsulation of the mechanisms behind humans' ability to understand speech. Some scholars argue that these abilities arise from evolutionarily specialized language modules, while others hold that they are a result of the interaction between cognitive-general mechanisms and extensive experience. In the present work, we use meaningful non-speech sounds, e.g. dog barks and train whistles, in the context of spoken sentences, to probe the extent to which language understanding mechanisms can quickly and easily adapt to non-speech. We find that behaviorally, listeners can recognize and understand non-speech sounds in sentence context quickly and easily, with processing costs much smaller than those that would be expected from a "translation" or covert naming process. Moreover, neurally, the N400 and P600 potentials are remarkably similar between non-speech sounds and matched spoken words, suggesting similar processing that is, in both cases, equally sensitive to sentential constraint and congruency with the preceding sentence context. These results closely mirrored the results from a final study in which we examined neural responses to spoken words said by a different talker. Analysis of relationships between working memory and scalp topography, as well as source analysis, indicated that both the comprehension of a different talker and the comprehension of an environmental sound involve early recruitment of working memory in the N1 and P2 time windows. These processes are mediated by parietal and temporal speech areas that have previously been identified in studies of talker normalization. Though the degree of recruitment of these resources may be greater and/or last longer for non-speech sounds than for a changing talker, the underlying mechanisms appear to be qualitatively the same. These results are discussed in light of a new model of auditory understanding, in which working memory, attention, and experience in

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Peripheral vestibular system: Age-related vestibular loss and associated deficits

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Journal of Otology 2021年第4期16卷 258-265页

作者： Jennifer Coto Carmen L.Alvarez Ivette Cejas Brett M.Colbert Bonnie E.Levin Joshua Huppert Tatjana Rundek Carey Balaban Susan H.Blanton David J.Lee David Loewenstein Michael Hoffer Xue Zhong Liu University of Miami Miller School of Medicine Department of OtolaryngologyMiamiFLUSA San Juan Bautista Medical School CaguasPRUSA Medical Scientist Training Program University of Miami Miller School of MedicineMiamiFLUSA University of Miami Miller School of Medicine Department of Neurology and the Evelyn F.McKnight Brain InstituteMiamiFLUSA University of Pittsburgh Departments of OtolaryngologyNeurobiologyCommunication Sciences&Disordersand BioengineeringPittsburghPAUSA University of Miami Miller School of Medicine Dr.John T.Macdonald Department of Human GeneticsMiamiFLUSA University of Miami Miller School of Medicine Department of Public Health SciencesMiamiFLUSA University of Miami Miller School of Medicine Department of Psychiatry and Behavioral SciencesMiamiFLUSA

Given the interdependence of multiple factors in age-related vestibular loss (e.g., balance, vision,cognition), it is important to examine the individual contributions of these factors with ARVL. While therelationship between the vestibular and visual systems has been well studied (Bronstein et al., 2015),little is known about the association of the peripheral vestibular system with neurodegenerative disorders (Cronin et al., 2017). Further, emerging research developments implicate the vestibular system asan opportunity for examining brain function beyond balance, and into other areas, such as cognition andpsychological functioning. Additionally, the bidirectional impact of psychological functioning is understudied in ARVL. Recognition of ARVL as part of a multifaceted aging process will help guide thedevelopment of integrated interventions for patients who remain at risk for decline. In this review, wewill discuss a wide variety of characteristics of the peripheral vestibular system and ARVL, how it relatesto neurodegenerative diseases, and correlations between ARVL and balance, vision, cognitive, and psychological dysfunction. We also discuss clinical implications as well as future directions for research, withan emphasis on improving care for patients with ARVL.

关键词： Peripheral vestibular system Age-related vestibular loss Balance Vision Cognitive Psychological

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