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We recommend upgrading to the latest version of Internet Explorer , Google Chrome , or Firefox × Issue published May 8, 2024 Volume 9, Issue 9 Previous Issue Go to section: Research Articles Technical Advance Physician-Scientist Development Corrigendum Cross-species single-cell analysis uncovers the immunopathological mechanisms associated with IgA nephropathy progression Chen et al. report single-cell transcriptomic characteristics of IgA nephropathy across species and identify key cell types and molecular pathways associated with disease progression. The cover art sho ws the recruitment of bone marrow–derived immune cells, especially macrophages, that infiltrate into kidney tissue through blood vessels and secrete immune factors to activate mesangial cells, thereby promoting IgA nephropathy immune injury. Image credit: Yiyao Deng. Technical Advance Tumor treating fields suppress tumor cell growth and neurologic decline in models of spinal metastases Daniel Ledbetter, … , Claudio Tatsui, Christopher Alvarez-Breckenridge Daniel Ledbetter, … , Claudio Tatsui, Christopher Alvarez-Breckenridge Published March 21, 2024 Citation Information: JCI Insight. 2024; 9(9) :e176962. https://doi.org/10.1172/jci.insight.176962 . View: Text | PDF Tumor treating fields suppress tumor cell growth and neurologic decline in models of spinal metastases Text PDF Abstract Spinal metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel therapies. Tumor treating fields (TTFields) impair tumor cell replication and are influenced by properties of surrounding tissue. We hypothesized that bone’s dielectric properties will enhance TTFields-mediated suppression of tumor growth in spinal metastasis models. Computational modeling of TTFields intensity was performed following surgical resection of a spinal metastasis and demonstrated enhanced TTFields intensity within the resected vertebral body. Additionally, luciferase-tagged human KRIB osteosarcoma and A549 lung adenocarcinoma cell lines were cultured in demineralized bone grafts and exposed to TTFields. Following TTFields exposure, the bioluminescence imaging (BLI) signal decreased to 10%–80% of baseline, while control cultures displayed a 4.48- to 9.36-fold increase in signal. Lastly, TTFields were applied in an orthotopic murine model of spinal metastasis. After 21 days of treatment, control mice demonstrated a 5-fold increase in BLI signal compared with TTFields-treated mice. TTFields similarly prevented tumor invasion into the spinal canal and development of neurologic symptoms. Our data suggest that TTFields can be leveraged as a local therapy within minimally conductive bone of spinal metastases. This provides the groundwork for future studies investigating TTFields for patients with treatment-refractory spinal metastases. Authors Daniel Ledbetter, Romulo Augusto Andrade de Almeida, Xizi Wu, Ariel Naveh, Chirag B. Patel, Queena Gonzalez, Thomas H. Beckham, Robert North, Laurence Rhines, Jing Li, Amol Ghia, David Aten, Claudio Tatsui, Christopher Alvarez-Breckenridge × Physician-Scientist Development The National MD-PhD Program Outcomes Study: career paths followed by Black and Hispanic graduates Myles H. Akabas, Lawrence F. Brass Myles H. Akabas, Lawrence F. Brass Published May 8, 2024 Citation Information: JCI Insight. 2024; 9(9) :e178248. https://doi.org/10.1172/jci.insight.178248 . View: Text | PDF The National MD-PhD Program Outcomes Study: career paths followed by Black and Hispanic graduates Text PDF Abstract Previous studies on attrition from MD-PhD programs have shown that students who self-identify as Black are more likely to withdraw before graduating than Hispanic students and students not from groups underrepresented in medicine (non-UIM). Here, we analyzed data collected for the National MD-PhD Program Outcomes Study, a national effort to track the careers of over 10,000 individuals who have graduated from MD-PhD programs over the past 60 years. On average, Black trainees took slightly longer to graduate, were less likely to choose careers in academia, and were more likely to enter nonacademic clinical practice; although, none of these differences were large. Black graduates were also more likely to choose careers in surgery or internal medicine, or entirely forego residency, and less likely to choose pediatrics, pathology, or neurology. Among those in academia, average research effort rates self-reported by Black, Hispanic, and non-UIM alumni were indistinguishable, as were rates of obtaining research grants and mentored training awards. However, the proportion of Black and Hispanic alumni who reported having NIH research grants was lower than that of non-UIM alumni, and the NIH career development to research project grant (K-to-R) conversion rate was lower for Black alumni. We propose that the reasons for these differences reflect experiences before, during, and after training and, therefore, conclude with action items that address each of these stages. Authors Myles H. Akabas, Lawrence F. Brass × Research Articles Minnelide suppresses GVHD and enhances survival while maintaining GVT responses Sabrina N. Copsel, … , Ashok K. Saluja, Robert B. Levy Sabrina N. Copsel, … , Ashok K. Saluja, Robert B. Levy Published April 11, 2024 Citation Information: JCI Insight. 2024; 9(9) :e165936. https://doi.org/10.1172/jci.insight.165936 . View: Text | PDF Minnelide suppresses GVHD and enhances survival while maintaining GVT responses Text PDF Abstract Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent antiinflammatory and antitumor activity in several preclinical models and has proven both safe and efficacious in clinical trials for advanced gastrointestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared with posttransplant cyclophosphamide (PTCy). Strikingly, we found Minnelide improved survival, weight loss, and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC–matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score, and colonic length. Notably, in addition to decreased donor T cell infiltration early after aHSCT, several regulatory cell populations, including Tregs, ILC2s, and myeloid-derived stem cells in the colon were increased, which together may account for Minnelide’s GVHD suppression after aHSCT. Importantly, Minnelide’s GVHD prevention was accompanied by preservation of graft-versus-tumor activity. As Minnelide possesses anti–acute myeloid leukemia (anti-AML) activity and is being applied in clinical trials, together with the present findings, we conclude that this...