Evidence map›Paper›PMID 38187773›Full record

ArticlebioRxiv : the preprint server for biology2023

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease.

Mariam Lotfy Khaled, Yuan Ren, Ronak Kundalia, Hasan Alhaddad, Zhihua Chen, Gerald C Wallace, Brittany Evernden, Oscar E Ospina, MacLean Hall, Min Liu and 12 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed, 1 citations in OpenAlex.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors at 4 institutions in 2 countries.

Mariam Lotfy KhaledThe Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Yuan RenThe Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Ronak KundaliaThe Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Hasan AlhaddadThe Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Zhihua ChenDepartment of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Gerald C WallaceDepartment of Hematology/Oncology, Georgia Cancer Center at Medical College of Georgia, Augusta, GA, USA.
Brittany EverndenDepartment of Neuro Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Oscar E OspinaDepartment of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
MacLean HallDepartment of Immunology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Min LiuThe Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Lancia N F DarvilleThe Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Victoria IzumiThe Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Y Ann ChenDepartment of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Shari Pilon-ThomasDepartment of Immunology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Paul A StewartDepartment of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
John M KoomenThe Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Salvatore A CoralloDepartment of Blood and Marrow Transplant and Cellular Immunotherapy, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Michael D JainDepartment of Blood and Marrow Transplant and Cellular Immunotherapy, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Timothy J RobinsonTherapeutic Radiology, Smilow Cancer Hospital at Yale New Haven, 35 Park Street, New Haven, CT, USA.
Fredrick L LockeDepartment of Blood and Marrow Transplant and Cellular Immunotherapy, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Peter A ForsythDepartment of Neuro Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Inna SmalleyThe Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.ORCID 0000-0002-6796-9145
Moffitt Cancer Center · USAugusta University · USCairo University · EGSmilow Cancer Hospital · US

Funding

TRANSLATIONAL RESEARCHP30CA076292 · NCI · UNIVERSITY OF SOUTH FLORIDA · PI John L. Cleveland · 1998 to 2026
$93.5M
Neurocognitive and Patient-Reported Outcomes after Chimeric Antigen Receptor T-Cell Therapy: A Controlled ComparisonR01CA244328 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI HEATHER S.L. JIM, Frederick Locke · 2022 to 2026
$3.8M
Defining the Role of Metabolic Heterogeneity in Melanoma Dissemination and Therapy EscapeR00CA226679 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI SMALLEY, INNA · 2020 to 2022
$747k
Defining and targeting the immune-suppressive metabolic microenvironment of leptomeningeal melanoma metastasesR21CA274060 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI SMALLEY, INNA · 2022 to 2023
$429k
NCI NIH HHS P30 CA076292NCI NIH HHS R00 CA226679NCI NIH HHS R01 CA244328NCI NIH HHS R21 CA274060
6 · The paper itself

Abstract

Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.

Indexed as

BrainBranched-chain keto acidsCSFLeptomeninges

Identifiers

PMID38187773
PMCPMC10769272
OpenAlexW4389954717

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.