tbuckley/cabot-search huggingface dataset:
Evaluating alopecia areata risk among patients with seasonal and food allergies: A multicenter cohort study
Authors: David Garate, Christopher J. Thang, Trevor L. Murphy, Divija Sharma, George Golovko, Michael G. Wilkerson, Emma Guttman‐Yassky, Nicholas Gulati, Benjamin Ungar
Journal: Allergy (2024)

Data sharing is not applicable to this article as no new data were created or analyzed in this study. Table S1. Table S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Thalamocortical architectures for flexible cognition and efficient learning
Authors: Daniel N. Scott, Arghya Mukherjee, Matthew R. Nassar, Michael M. Halassa
Journal: Trends in Cognitive Sciences (2024)

The brain exhibits a remarkable ability to learn and execute context-appropriate behaviors. How it achieves such flexibility, without sacrificing learning efficiency, is an important open question. Neuroscience, psychology, and engineering suggest that reusing and repurposing computations are part of the answer. Here, we review evidence that thalamocortical architectures may have evolved to facilitate these objectives of flexibility and efficiency by coordinating distributed computations. Recent work suggests that distributed prefrontal cortical networks compute with flexible codes, and that the mediodorsal thalamus provides regularization to promote efficient reuse. Thalamocortical interactions resemble hierarchical Bayesian computations, and their network implementation can be related to existing gating, synchronization, and hub theories of thalamic function. By reviewing recent findings and providing a novel synthesis, we highlight key research horizons integrating computation, cognition, and systems neuroscience.
Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer
Authors: Ha Rin Kim, Seong Jin Park, Young Seok Cho, Mudhibadhi Knowledge Moyo, Jeong Uk Choi, Na Kyeong Lee, Seung Woo Chung, Seho Kweon, Jooho Park, Byoungmo Kim, Yoon Gun Ko, Joo Hye Yeo, Jinu Lee, Sang Yoon Kim, Youngro Byun
Journal: Journal of Controlled Release (2024)
Comparison of craniotomy and decompressive craniectomy for acute subdural hematoma: a meta-analysis of comparative study
Authors: Hua Li, Yuqiang Yao, Wenyi Gan, Yibing Su, Hanbin Wang, Can Zhu, Yuwen Jiang
Journal: International Journal of Surgery (2024)

Background: Acute subdural hematoma (ASDH) necessitates urgent surgical intervention. Craniotomy (CO) and decompressive craniectomy (DC) are the two main surgical procedures for ASDH evacuation. This meta-analysis is to compare the clinical outcomes between the CO and DC procedures. Materials and Methods: We performed a meta-analysis according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, Supplemental Digital Content 1, http://links.lww.com/JS9/C513, Supplemental Digital Content 2, http://links.lww.com/JS9/C514) Statement protocol and AMSTAR, Supplemental Digital Content 3, http://links.lww.com/JS9/C515 (Assessing the methodological quality of systematic reviews) guideline. The PubMed, Embase, Web of Science and Cochrane Library databases were systematically searched. Comparative studies reporting the outcomes of the CO and DC procedures in patients with ASDH were included. Results: A total of 15 articles with 4853 patients (2531 [52.2%] receiving CO and 2322 [47.8%] receiving DC) were included in this meta-analysis. DC was associated with higher mortality (31.5% vs. 40.6%, odds ratio [OR]=0.58, 95% confidence interval [CI] 0.43 to 0.77) and rate of patients with poorer neurological outcomes (54.3% vs. 72.7%; OR=0.43, 95% CI 0.28 to 0.67) compared to CO. The meta-regression model identified the comparability of preoperative severity as the only potential source of heterogeneity. When the preoperative severity was comparable between the two procedures, the mortality (CO 35.5% vs. DC 38.1%, OR=0.80, 95% CI 0.62 to 1.02) and the proportion of patients with poorer neurological outcomes (CO 64.8% vs. DC 66.0%; OR=0.82, 95% CI 0.57 to 1.16) were both similar. Reoperation rates were similar between the two procedures (CO 16.1% vs. DC 16.0%; OR=0.95, 95% CI 0.61 to 1.48). Conclusion: Our meta-analysis reveals that DC is associated with higher mortality and poorer neurological outcomes in ASDH compared to CO. Notably, this difference in outcomes might be driven by baseline patient severity, as the significance of surgical choice diminishes after adjusting for this factor. Our findings challenge previous opinions regarding the superiority of CO over DC and underscore the importance of considering patient-specific characteristics when making surgical decisions. This insight offers guidance for surgeons in making decisions tailored to the specific conditions of their patients.
Utilizing extracellular vesicles as a drug delivery system in glaucoma and RGC degeneration
Authors: Esmahan Durmaz, Lujien Dribika, Matyas Kutnyanszky, Ben Mead
Journal: Journal of Controlled Release (2024)

Retinal diseases are the leading cause of blindness, resulting in irreversible degeneration and death of retinal neurons. One such cell type, the retinal ganglion cell (RGC), is responsible for connecting the retina to the rest of the brain through its axons that make up the optic nerve and is the primary cell lost in glaucoma and traumatic optic neuropathy. To date, different therapeutic strategies have been investigated to protect RGCs from death and preserve vision, yet currently available strategies are restricted to treating neuron loss by reducing intraocular pressure. A major barrier identified by these studies is drug delivery to RGCs, which is in large part due to drug stability, short duration time at target, low delivery efficiency, and undesired off-target effects. Therefore, a delivery system to deal with these problems is needed to ensure maximum benefit from the candidate therapeutic material. Extracellular vesicles (EV), nanocarriers released by all cells, are lipid membranes encapsulating RNAs, proteins, and lipids. As they naturally shuttle these encapsulated compounds between cells for communicative purposes, they may be exploitable and offer opportunities to overcome hurdles in retinal drug delivery, including drug stability, drug molecular weight, barriers in the retina, and drug adverse effects. Here, we summarize the potential of an EV drug delivery system, discussing their superiorities and potential application to target RGCs.
Rewiring the Sex-Determination Pathway During the Evolution of Self-Fertility
Authors: Yongquan Shen, Shin-Yi Lin, Jonathan Harbin, Richa Amin, Allison Vassalotti, Joseph Romanowski, Emily Schmidt, Alexis Tierney, Ronald E Ellis
Journal: Molecular Biology and Evolution (2024)

Although evolution is driven by changes in how regulatory pathways control development, we know little about the molecular details underlying these transitions. The TRA-2 domain that mediates contact with TRA-1 is conserved in Caenorhabditis. By comparing the interaction of these proteins in two species, we identified a striking change in how sexual development is controlled. Identical mutations in this domain promote oogenesis in Caenorhabditis elegans but promote spermatogenesis in Caenorhabditis briggsae. Furthermore, the effects of these mutations involve the male-promoting gene fem-3 in C. elegans but are independent of fem-3 in C. briggsae. Finally, reciprocal mutations in these genes show that C. briggsae TRA-2 binds TRA-1 to prevent expression of spermatogenesis regulators. By contrast, in C. elegans TRA-1 sequesters TRA-2 in the germ line, allowing FEM-3 to initiate spermatogenesis. Thus, we propose that the flow of information within the sex determination pathway has switched directions during evolution. This result has important implications for how evolutionary change can occur.
Increased Protein Kinase A Activity Induces Fibrolamellar Hepatocellular Carcinoma Features Independent of DNAJB1
Authors: Mahsa Shirani, Solomon Levin, Bassem Shebl, David Requena, Tova M. Finkelstein, Daniel S. Johnson, Denise Ng, Gadi Lalazar, Søren Heissel, Peter Hojrup, Henrik Molina, Ype P. de Jong, Charles M. Rice, Aatur D. Singhi, Michael S. Torbenson, Philip Coffino, Barbara Lyons, Sanford M. Simon
Journal: Cancer Research (2024)

Abstract Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that is driven by the fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA activity is controlled through regulatory proteins that both inhibit catalytic activity and control localization, and an excess of regulatory subunits ensures PRKACA activity is inhibited. Here, we found an increase in the ratio of catalytic to regulatory units in FLC patient tumors driven by DNAJB1::PRKACA using mass spectrometry, biochemistry, and immunofluorescence, with increased nuclear localization of the kinase. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA, or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes in primary human hepatocytes, recapitulating the changes observed in FLC. Consistently, tumors in patients missing a regulatory subunit or harboring an ATP1B1::PRKACA fusion were indistinguishable from FLC based on the histopathological, transcriptomic, and drug–response profiles. Together, these findings indicate that the DNAJB1 domain of DNAJB1::PRKACA is not required for FLC. Instead, changes in PKA activity and localization determine the FLC phenotype. Significance: Alterations leading to unconstrained protein kinase A signaling, regardless of the presence or absence of PRKACA fusions, drive the phenotypes of fibrolamellar hepatocellular carcinoma, reshaping understanding of the pathogenesis of this rare liver cancer.
Predicting prostate cancer grade reclassification on active surveillance using a deep learning–based grading algorithm
Authors: Chien-Kuang C Ding, Zhuo Tony Su, Erik Erak, Lia De Paula Oliveira, Daniela C Salles, Yuezhou Jing, Pranab Samanta, Saikiran Bonthu, Uttara Joshi, Chaith Kondragunta, Nitin Singhal, Angelo M De Marzo, Bruce J Trock, Christian P Pavlovich, Claire M de la Calle, Tamara L Lotan
Journal: JNCI Journal of the National Cancer Institute (2024)

Deep learning (DL)-based algorithms to determine prostate cancer (PCa) Grade Group (GG) on biopsy slides have not been validated by comparison to clinical outcomes. We used a DL-based algorithm, AIRAProstate, to regrade initial prostate biopsies in 2 independent PCa active surveillance (AS) cohorts. In a cohort initially diagnosed with GG1 PCa using only systematic biopsies (n = 138), upgrading of the initial biopsy to ≥GG2 by AIRAProstate was associated with rapid or extreme grade reclassification on AS (odds ratio = 3.3, P = .04), whereas upgrading of the initial biopsy by contemporary uropathologist reviews was not associated with this outcome. In a contemporary validation cohort that underwent prostate magnetic resonance imaging before initial biopsy (n = 169), upgrading of the initial biopsy (all contemporary GG1 by uropathologist grading) by AIRAProstate was associated with grade reclassification on AS (hazard ratio = 1.7, P = .03). These results demonstrate the utility of a DL-based grading algorithm in PCa risk stratification for AS.
Decoding the hallmarks of allograft dysfunction with a comprehensive pan-organ transcriptomic atlas
Authors: Harry Robertson, Hani Jieun Kim, Jennifer Li, Nicholas Robertson, Paul Robertson, Elvira Jimenez-Vera, Farhan Ameen, Andy Tran, Katie Trinh, Philip J. O’Connell, Jean Y. H. Yang, Natasha M. Rogers, Ellis Patrick
Journal: Nature Medicine (2024)

Abstract The pathogenesis of allograft (dys)function has been increasingly studied using ‘omics’-based technologies, but the focus on individual organs has created knowledge gaps that neither unify nor distinguish pathological mechanisms across allografts. Here we present a comprehensive study of human pan-organ allograft dysfunction, analyzing 150 datasets with more than 12,000 samples across four commonly transplanted solid organs (heart, lung, liver and kidney, n = 1,160, 1,241, 1,216 and 8,853 samples, respectively) that we leveraged to explore transcriptomic differences among allograft dysfunction (delayed graft function, acute rejection and fibrosis), tolerance and stable graft function. We identified genes that correlated robustly with allograft dysfunction across heart, lung, liver and kidney transplantation. Furthermore, we developed a transfer learning omics prediction framework that, by borrowing information across organs, demonstrated superior classifications compared to models trained on single organs. These findings were validated using a single-center prospective kidney transplant cohort study (a collective 329 samples across two timepoints), providing insights supporting the potential clinical utility of our approach. Our study establishes the capacity for machine learning models to learn across organs and presents a transcriptomic transplant resource that can be employed to develop pan-organ biomarkers of allograft dysfunction.
MODL-07. BUILDING BETTER MODELS OF BRAIN TUMOURS TO ADVANCE PATIENT TREATMENT WITH MINIMAL SIDE EFFECTS
Authors: Danai Stella Gkotsi, Isabelle Forder-Denham, Timothy A Ritzmann, Judith Ramage, Ian D Kerr, Andrew Jackson, Alvaro Mata, Beth Coyle
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Paediatric brain tumours pose a formidable challenge in oncology, necessitating innovative approaches to bridge the gap between molecular understanding and therapeutic efficacy. Current preclinical models lack fidelity in capturing the dynamic interplay between tumour cells and their microenvironment, hindering translation of research findings into clinical practice. METHODS We are developing advanced three-dimensional (3D) models of paediatric brain tumours, integrating crucial components of the tumour microenvironment. Leveraging self-assembling peptide amphiphiles (PAs), we are constructing subgroup-specific PA-ECM-Immuno models mimicking brain stiffness, ECM composition, immune cell interactions, and oxygen levels. Spatial transcriptomics and multiplex immunohistochemistry are being employed to elucidate tumour-microenvironment interactions. RESULTS Building upon our successes in modelling brain tumour growth and behaviour, as well as other types of tumours (the Mata lab has previously successfully established PA-ECM models of prostate and ovarian cancer), our approach demonstrates feasibi lity in incorporating immune cells and subgroup-specific ECM components into PA-ECM matrices. These models provide insight into dynamic interactions driving tumour progression, facilitating identification of key pathways and potential therapeutic targets. CONCLUSIONS Our approach represents a novel paradigm in paediatric neuro-oncology research, aiming to establish clinically relevant 3D models faithfully recapitulating intricate tumour-microenvironment interactions. By elucidating mechanisms of tumour progression and employing spatial transcriptomics and multiplex immunohistochemistry, our tailored models will enable the identification of precision therapies with enhanced efficacy and reduced off-target effects. Collaborative efforts through our multidisciplinary approach are poised to advance the field towards personalised treatments and improved outcomes for paediatric brain tumour patients.
LGG-06. THREE PRACTICAL CHALLENGES IN IMPLEMENTING RAPNO RESPONSE ASSESSMENT FOR PEDIATRIC LOW-GRADE GLIOMAS
Authors: Asim Kumar Bag, Giles W Robinson
Journal: Neuro-Oncology (2024)

Abstract The RAPNO criteria for pediatric low-grade gliomas (pLGGs), designed to improve upon the RANO criteria, are increasingly being employed to assess treatment responses. However, the adoption of the RAPNO guidelines in our clinical trials has revealed some notable challenges that stymie their practical implementation. These challenges should be addressed to render the guidelines more comprehensive and facilitate their widespread adoption. Definition of tumor burden should be modified: The current guidelines define tumor burden as the sum of the products of the longest tumor diameter and its longest perpendicular diameter. While this approach generally works, implementing it in optic pathway gliomas involving the nerve and subtotally resected pLGGs where the longest diameter is often disproportionally larger than the perpendicular diameter creates a challenge. The result is an inaccurate measure of tumor burden as well as poor reproducibility. Progressive disease should be confirmed with follow-up imaging. Unlike response confirmation, guidelines do not recommend confirmation of progression. Since pLGGs grow slowly, the change in diameters between two consecutive scans is often so small that it can be indistinguishable from measurement error. This is particularly problematic in smaller tumors and in diffusely infiltrating tumors, in which minor measurement change can erroneously shift response to progressive disease. Definition of target lesion should be more specific: pLGGs can recur focally without involving the entire previously treated residual tumor. Based on RAPNO guidelines, the target lesion includes both the growing and the stable residual components. This poses a challenge and can result in a serious underestimate of efficacy, particularly with biologic therapy, when the response of the recurrent focal tumor is major or complete but, by the current criteria, only registers as stable disease or minor response. Our discussion will show real-world examples of these challenges and propose recommendations to enhance the practical application of RAPNO criteria.
LGG-13. UNRAVELING THE SPATIAL TUMOR MICROENVIRONMENT OF PEDIATRIC LOW-GRADE GLIOMAS USING IMAGING MASS CYTOMETRY
Authors: Augusto Faria Andrade*, Romain Sigaud*, Evan Puligandla*, Bridget Liu, Elham Karimi, Simone Schmid, Florian Selt, Pablo Hernáiz Driever, Arend Koch, Felix Sahm, Philipp Sievers, Stefan M Pfister, Olaf Witt, David T W Jones, David Capper, Logan Walsh*, Nada Jabado*, Till Milde*
Journal: Neuro-Oncology (2024)

Abstract Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children and are associated with significant morbidity. Therefore, there is an urgent need for novel therapeutic strategies. While some studies have described pLGG’s tumor microenvironment (TME) from bulk RNAseq and scRNAseq, little is known about the spatial architecture of pLGG and its association with clinico-molecular features. Our study utilized imaging mass cytometry and a panel of 35 metal-labelled antibodies to unravel the spatial organization of key TME cell populations in 120 primary pLGG samples from the LOGGIC Core BioClinical DataBank. Cellular neighborhood analysis was performed to map the spatial organization of pLGG TME. Several clinic-molecular features (entity, tumor location, genetic driver alteration, disease progression status, age and sex) were used to measure their putative association with the enrichment of key cell populations and cellular structures to identify diagnosis and prognosis markers. Here, we identified a predominant presence of myeloid cells in the TME, particularly notable in optic pathway tumors, which exhibited unique immune profiles. Optic pathway tumors demonstrated elevated immune subsets, delineating distinct architectural features in the TME of this brain region. Spatial analysis defined cellular neighborhoods and specific interactions thereof, including myeloid interaction and macrophage-abundant regions. Clinically, these myeloid cell populations, associated with an increased expression of the immune checkpoint protein TIM3, suggesting the presence of an immuno-suppressive environment, were associated with inferior survival outcomes. Importantly, we identified an immunophenotype signature based on the presence of 4 myeloid cell populations significantly associated with progression free survival in our cohort. Our study underscored the need for accurate identification of immune cell populations influencing tumor progression, offering valuable insights for the identification of prognostic markers, and for the development of effective therapeutic strategies, such as immune checkpoint inhibitors, for the treatment of pLGG.
LGG-08. DIFFUSE ASTROCYTOMA IN A PATIENT WITH POSSIBLE MBD4-ASSOCIATED NEOPLASIA SYNDROME (MANS)- EXPANDING THE SPECTRUM OF MANS-ASSOCIATED NEOPLASM
Authors: Hamza Gorsi, Jonathan Finlay, Maxim Yankelevich
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND MBD4-associated neoplasia syndrome (MANS) is a recently identified genetic syndrome characterized by the development of colorectal polyps, acute myeloid leukemia, and uveal melanoma, with an elevated mutation burden. MANS is attributed to bi-allelic germline variations in the MBD4 gene. METHOD We present a case of a pediatric patient with diffuse astrocytoma WHO-grade II and bi-allelic germline variations in the MBD4 gene. CASE REPORT A previously healthy 10-year-old female with a significant family history of high-grade IDH wild type-glioma in the deceased older brother presented with vague symptoms and was found to have abnormal brain MRI with multiple foci of subcortical FLAIR/T2 hyperintensity involving the right frontotemporal lobe, left frontal lobe, and left thalamus. She had intact neurologic exam findings and was followed with serial brain MRIs. Over the next 2 years, she continued to be asymptomatic, but her MRI showed an increase in the size of her brain lesions. Following a stereotactic biopsy of the right temporal lesion, a diagnosis of diffuse astrocytoma (WHO-grade II) was confirmed. Molecular analysis showed point mutations in IDH1, TP53, and PTEN genes, along with LOH at 17p (including TP53 gene), and outline gene expressions for NTRK2, OLIG2, GRM3, FGF1, SOX8, MBP, MGMT genes. Given the low grade of the tumor and the absence of tumor-related symptoms, a decision was made to continue monitoring with serial MRIs. Whole exome sequencing identified germline bi-allelic missense variations in the MBD4 gene, specifically C.1405A&amp;gt;G and C.1573A&amp;gt;C. Both parents were found to be heterozygous for one of these mutations. CONCLUSION The significance of MBD4 mutation remains unknown in our patient, but bi-allelic variations coupled with the presence of a brain tumor and positive family history raise concerns about MANS in our patient. Additional studies are needed to elucidate the potential association between brain tumors and MANS.