tbuckley/cabot-search huggingface dataset:
CNSC-43. NEUROTRANSMITTER DEPENDENCY UNDERLIES TUMOR GROWTH IN HUMANIZED PEDIATRIC LOW-GRADE GLIOMA MODELS
Authors: Corina Anastasaki, Rasha Barakat, Rui Mu, Joshua P Koleske, Chloe M Kernan, Yunqing Gao, Olivia M Cobb, Corrine Gardner, Hongjin Shu, Lakshmi Ramachandran Nair, Sonika Dahiya, Charles G Eberhart, Joanna J Phillips, Steven J Mennerick, Jennifer M Strahle, Fausto J Rodriguez, David H Gutmann
Journal: Neuro-Oncology (2024)

Abstract Brain tumors arise in close association with neurons, suggesting that these non-neoplastic cells may be critical stromal drivers of brain tumor initiation and growth. Previously, we have shown that murine low-grade optic glioma formation and progression in the setting of Neurofibromatosis type 1 (NF1) is dictated by neurons and neuronal activity. In these studies, these neuronal dependencies reflected neuronal activity-driven enzymatic cleavage of a growth factor (neuroligin-3) from oligodendrocyte precursors cells (tumor initiation) or neuronal production of a paracrine factor to stimulate T cell support of optic glioma growth (tumor progression). Since neurons typically communicate with other neurons through neurotransmitters, we sought to explore the possibility that neurotransmitters operate to modulate low-grade glioma growth using humanized mouse models of pilocytic astrocytoma (PA). Leveraging single cell RNA sequencing of three independent sets of pediatric PAs, we identified neurotransmitter pathway enrichment in the tumor cells. This neurotransmitter pathway enrichment reflected aberrant expression of specific neurotransmitter receptors, which we confirmed in three independently generated PA tissue microarrays and in five distinct primary PA cell lines grown in vitro. Moreover, this aberrant neurotransmitter receptor expression established differential neurotransmitter PA growth dependencies in vitro. Importantly, interruption of neurotransmitter signaling in human PA xenografts attenuated tumor growth and ERK activation in Rag1-/- mice in vivo. Finally, we discovered crosstalk between neurotransmitter receptor and receptor tyrosine kinase signaling that revealed another target for therapeutic inhibition. Taken together, these findings elucidate a previously unknown neurotransmitter PA growth dependency amenable to therapeutic targeting.
NCOG-15. CONNECTOME-BASED APPROACHES FOR PRESERVING COGNITIVE FUNCTION AND MINIMIZING DELIRIUM DURING GLIOMA RESECTION: A PILOT STUDY
Authors: Melike Mut, Kathleen Fuchs, Jordan Rosen, Joseph Donahue, Nadia Lunardi, Brian Reon, Ifrah Zawar, David Schiff
Journal: Neuro-Oncology (2024)

Abstract AIM The surgical treatment of gliomas poses significant challenges due to the involvement of complex neural networks critical for cognitive functions. This study reviews the application of connectome-based approaches to minimize cognitive impairments and delirium during glioma resection, focusing on networks related to cognitive functions: the Default Mode Network (DMN), Dorsal Attention Network (DAN), Salience Network (SN), and Central Executive Network (CEN). METHODS Ten patients underwent surgery utilizing cloud-based connectomics software (Quicktome®), which maps the brain’s structural and functional connectivity. Preoperative MRIs with structural and functional connectome were performed for preoperative planning and intraoperative navigation. Preoperative neuropsychological assessments were conducted for elective cases. Only one patient was able to undergo awake craniotomy due to various medical, neurological and psychological limitations. Intraoperatively, with connectome-navigation guidance, a connectomics-based approach was conducted to preserve the networks. A semiquantitative analysis was performed as described (https://pubmed.ncbi.nlm.nih.gov/36719613). Pre- and postoperative (inpatient and 2 week follow up) RASS and NuDESC delirium screenings were performed, with long-term cognitive evaluations and repeat connectomics imaging planned. RESULTS Three out of ten patients presented with rapid functional deterioration and needed urgent surgical decompression had postoperative delirium. Connectome analysis showed involvement of cognition-related networks in these patients. Two out of 3 patients showed improvement in delirium scores at a two-week follow-up after tumor resection. CONCLUSION This pilot study suggests that factors such as acute presentation, emergency surgery, and tumor location involving and disrupting the DMN, SN, DAN, and CEN networks may contribute to early postoperative delirium. The study may pave the way for the efficacy of connectomics in preserving cognitive functions post-operatively, particularly when awake craniotomy is not possible. This approach holds promise for improving surgical outcomes, survival, and the quality of life for patients with gliomas by mitigating the cognitive impacts of tumor resection and postoperative complications.
CTNI-58. A PHASE 0/2 TRIAL OF ABEMACICLIB PLUS LY3214996 IN RECURRENT GLIOBLASTOMA
Authors: Nader Sanai, Yoshie Umemura, Yu-Wei Chang, Tigran Margaryan, Anita DeSantis, Mackenna Elliott, Jennifer Molloy, Dylan Huttenlocher, Garry Hook, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND This Phase 0/2 study (NCT04391595) evaluates tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and clinical efficacy of abemaciclib, a CDK4 and 6 inhibitor, plus LY3214996, an ERK 1/2 inhibitor, in recurrent glioblastoma (rGBM). METHODS Adult rGBM patients (n=42) with intact RB, &amp;gt;30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib plus LY3214996 prior to a planned resection. Time-escalation cohorts (3-5 and 7-9 hour intervals from last dose to tumor resection) identified the optimal time interval (OTI). Subsequent Phase 0 patients had tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma collected at the OTI. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD was compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration &amp;gt; 5 x IC50) was set for each drug. Gd-nonenhancing tumor demonstrating PK response to both drugs qualified patients for the Phase 2 component of the study. RESULTS Forty two patients were accrued to Phase 0 and no dose-limiting toxicities were observed. Median unbound concentrations in Gd-nonenhancing tumor regions were 31 nM and 10 nM for abemaciclib and LY3214996, respectively. Tumor RB, RSK phosphorylation, and tumor proliferation (MIB-1) decreased in (47.5%), (25%) and (72.5%) patients, respectively. Nine of the 40 (22.5%) patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), qualifying them for Phase 2. Here, median PFS and median OS were 2.4 and 7.2 months, respectively. CONCLUSION Abemaciclib and LY3214996 achieved pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue in 80% and 30% of the patients, respectively. Suppression of the RB pathway and tumor proliferation, but not ERK pathway was observed. Inadequate CNS penetration and tumor PD modulation by LY3214996 contributed to the unremarkable clinical efficacy profile of this drug combination. Targeted ERK inhibition remains an unmet need in experimental GBM therapy.
BIOM-57. PERITUMORAL EDEMA AS A PREDICTOR OF PD-1 EXPRESSION IN BRAIN METASTASES
Authors: Anthony Elengickal, Gerald Wallace, Juhi Bansal, Ambur Reddy, Girindra Raval
Journal: Neuro-Oncology (2024)

Abstract Brain metastases represent a significant problem in oncology with associated high morbidity and mortality. They have been associated with increased peritumoral edema which can worsen neurological symptoms and patient outcomes. Peritumoral cerebral edema may be an important metric of interest as some MRI studies have suggested an association between molecular factors and peritumoral edema. We hypothesized that an association exists between PD-1 expression in brain mets from NSCLC and the radiographic peritumoral edema to enhancing tumor ratio (ETR). A retrospective analysis of tumor characteristics was conducted to identify patients with brain metastases from non-small cell lung cancer. Patients were stratified into three groups based on their tumor PD-1 expression levels: 0%, 1-49%, and 50% or higher. Tumor and edema volumes were measured in these patients using MRIs at the time of diagnosis and converted into edema to tumor ratios. Radiographic analysis has been completed for 19 patients with 9 having no PD-1 expression, 5 having low PD-1 expression, and 5 having high PD-1 expression. The no expression group had an average ETR of 3.02 while the low expression group had an average of 15.85 and the high expression group had an average of 9.12. These initial results show increased peritumoral edema in tumors with PD-1 expression when compared to tumors with no PD-1 expression, with a non-significant trend in favor of increased edema to tumor ratio (p = 0.055). The current project is ongoing with plans to expand patient cohorts to affirm or rule out significant ETR association by MRI.
Reply: Prevalence of subclinical hypothyroidism and longitudinal thyroid stimulating hormone changes in youth with metabolic dysfunction-associated steatotic liver disease: an observational study
Authors: Vidhu V. Thaker, Nancy Crimmins, Katherine P. Yates, Ali Mencin, Stavra Xanthakos
Journal: Hepatology (2024)

Thaker, Vidhu V.; Crimmins, Nancy; Yates, Katherine P.; Mencin, Ali; Xanthakos, Stavra Author Information
Utilizing of viral RNA fragment to limit acute inflammation
Authors: Chunyuan Zhao, Wei Zhao
Journal: Hepatology (2024)

1Department of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China 2Department of Cell Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China Correspondence Wei Zhao, Shandong University, Department of Pathogenic Biology. Email: [email protected]
Telehealth Brief Cognitive Behavioral Therapy for Suicide Prevention
Authors: Justin C. Baker, Austin Starkey, Ennio Ammendola, Christina Rose Bauder, Samantha E. Daruwala, Jaryd Hiser, Lauren R. Khazem, Keelin Rademacher, Jarrod Hay, AnnaBelle O. Bryan, Craig J. Bryan
Journal: JAMA Network Open (2024)

Suicide rates continue to increase in the US. Evidence-based treatments for suicide risk exist, but their effectiveness when delivered via telehealth remains unknown.
Income-Related Disparities in Mortality Among Young Adults With Type 2 Diabetes
Authors: Ji Yoon Kim, Sojeong Park, Minae Park, Nam Hoon Kim, Sin Gon Kim
Journal: JAMA Network Open (2024)

Previous studies have indicated an inverse association between income and mortality. However, differences in health outcomes according to the income level of young adults with type 2 diabetes (T2D) compared with older adults with T2D have not been elucidated.
Patient-Reported Discussions on Fertility Preservation Before Early-Onset Cancer Treatment
Authors: Samantha R. Keller, Allison Rosen, Mark A. Lewis, Hyo K. Park, Rebecca Babyak, Jill Feldman, Fei Ye, Rajiv Agarwal, Kristen K. Ciombor, Timothy M. Geiger, Cathy Eng, Katherine J. Hunzinger, Richard H. Viskochil, Michelle K. Roach, Digna R. Velez Edwards, Michele L. Cote, Andreana N. Holowatyj
Journal: JAMA Network Open (2024)

This cross-sectional study evaluates discussion patterns about fertility preservation options reported by patients with early-onset cancer to better understand the patient experience.
Culturally Tailored Messages and Trial Registry Enrollment
Authors: Kevin B. Johnson, Stacy L. Iannone, Susan L. Furth, Lynne Taylor, Andy S. L. Tan
Journal: JAMA Network Open (2024)

Importance Marginalized populations have lower levels of clinical trial representation than other populations. Tailoring recruitment materials and providing incentives may improve representation. Objective To determine whether culturally tailored video improves parents’ decision to enroll (DTE) Black children in a research registry. Design, Setting, and Participants A randomized clinical trial, using mixed methods and consecutive sampling, was conducted in an urban primary care pediatric clinic. A post hoc study assessed the association of a monetary incentive with DTE. Ninety-three parents were recruited before their child’s scheduled clinic visit. Participants completed a survey during which they were randomly assigned to review a paragraph (control group), generic video, or tailored video and received a gift card. Video watchers completed questions about its effectiveness. All participants were invited to join the registry. In the post hoc study, consenting participants followed the control group protocol and the coordinator promised them an ink pen for participating. The study was conducted between November 15, 2022, and August 29, 2023. Intervention A survey regarding the importance of being included in research studies was administered after participants watched a culturally tailored video. Main Outcome and Measures The primary outcome was DTE. Covariates were message effectiveness, clinical trial knowledge, and trust. Intention-to-treat analysis was performed. Results A total of 125 individuals were included. All groups had similar mean (SD) parent age (overall, 32.6 [7.35] years), gender (110 [88.0%] women), and race (116 [92.8%] Black or African American). There was no significant difference in the odds of DTE between the appeal video and control (odds ratio [OR], 1.19; 95% CI, 0.38-3.72) or between the generic video and control (OR, 1.91; 95% CI, 0.54-6.71). However, DTE was higher for all 3 gift card groups vs the ink pen incentive group (eg, control vs ink pen incentive: OR, 5.01; 95% CI, 1.68-14.95). After adjusting for trust, monetary incentives were associated with higher odds of DTE (adjusted OR, 5.92; 95% CI, 2.44-14.39). Conclusions and Relevance In this randomized clinical trial, targeted messaging was not associated with a higher decision to enroll in a pediatric clinical trial registry. There may be a role for combining holistic messaging with monetary incentives to improve enrollment. Trial Registration ClinicalTrials.gov Identifier: NCT06138145
Stroke Risk Following Nonarteritic Anterior Ischemic Optic Neuropathy
Authors: Yung-Yu Chu, Chung-Han Ho, Yi-Chen Chen, Shu-Chun Kuo
Journal: JAMA Network Open (2024)

Importance The association between nonarteritic anterior ischemic optic neuropathy (NAION) and an increased risk of stroke has been a subject of debate. However, multinational studies on this topic are scarce. Objective To evaluate the short-term and long-term stroke risk after NAION compared with a matched control group. Design, Setting, and Participants This global, retrospective, population-based cohort study used aggregated electronic health records from January 1, 2004, through March 19, 2024, sourced from the Global Collaborative Network of TriNetX, which includes data from over 152 million patients across 17 countries. Patients in the study were followed up for a maximum duration of 10 years. Patients with NAION and age-related cataract were included in the analysis. Those with stroke before the diagnosis of NAION and age-related cataract were excluded. Propensity score matching was applied to balance age, sex, race, ethnicity, comorbidities, and medication use. Exposure International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis code for NAION or age-related cataract. Main Outcomes and Measures The primary outcome was the relative risk (RR) of stroke ( ICD-10 code I60-63) in the NAION cohort vs the matched controls. Multivariable logistic regression analyses were applied to identify potential clinical factors associated with stroke within the NAION cohort. Results A total of 89 811 patients were identified in both the NAION (mean [SD] age, 57.2 [18.5] years; 38 678 men [43.1%]) and control (mean [SD] age, 57.0 [17.9] years; 40 014 men [44.6%]) cohorts after matching. The NAION cohort demonstrated a significantly higher all-stroke risk at all time points: 1 month (RR, 5.04; 95% CI, 4.41-5.78), 3 months (RR, 3.79; 95% CI, 3.40-4.21), 1 year (RR, 2.50; 95% CI, 2.32-2.70), 5 years (RR, 1.54; 95% CI, 1.45-1.63), and 10 years (RR, 1.33; 95% CI, 1.23-1.43). Sensitivity analysis in patients without comorbidities similarly revealed a significantly increased all-stroke risk across all intervals: 1 month (RR, 7.55; 95% CI, 4.74-12.03), 3 months (RR, 6.70; 95% CI, 4.48-10.04), 1 year (RR, 3.96; 95% CI, 2.94-5.34), 5 years (RR, 2.85; 95% CI, 2.18-3.72), and 10 years (RR, 1.68; 95% CI, 1.25-2.26). Among all the clinical factors of interest, only hypertension was consistently associated with all subtypes of stroke following NAION. Conclusions and Relevance This cohort study of patients with NAION found a significantly elevated risk of stroke compared with matched controls, independently of comorbidities. These findings underscore the importance of regular stroke workups following the onset of NAION.
State Medical Board Sanctions for Misinformation Should Be Rare
Authors: Megan L. Ranney, Lawrence O. Gostin
Journal: JAMA Network Open (2024)

Most patients trust their physicians to provide high-quality, evidence-based health information. 1fortunately, misinformation and disinformation are problems as old as medicine and have been recognized as a public health threat for millenia. 2Today, the rise of social media and artificial intelligence, together with a world-wide pandemic, have combined to create an unprecedented "infodemic" of false and misleading health information.
Diagnostic Test Accuracy of the Fungitell Serum (1→3)-β-D-Glucan Assay for the Diagnosis of Pneumocystis jirovecii Pneumonia: A Systematic Review and Meta-Analysis
Authors: Connor Prosty, Owen Dan Luo, Roy Khalaf, Olivier Del Corpo, Emily G McDonald, Todd C Lee
Journal: Clinical Microbiology and Infection (2024)
Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging
Authors: Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E. Jacot, Thibaut Desgeorges, José-Luis Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G. Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N. Feige
Journal: Journal of Clinical Investigation (2024)

Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.
Misprocessing of Alpha-Galactosidase A, Endoplasmic Reticulum Stress, and the Unfolded Protein Response
Authors: Martina Živná, Gabriela Dostálová, Veronika Barešová, Dita Mušálková, Klára Svojšová, Doria Meiseles, Sara Kinstlinger, Ladislav Kuchař, Befekadu Asfaw, Helena Poupětová, Hana Vlášková, Tereza Kmochová, Petr Vyleťal, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Lenka Steiner-Mrázová, Aleš Hnízda, Jan Živný, Martin Radina, Miroslav Votruba, Jana Sovová, Helena Trešlová, Larisa Stolnaja, Petra Reková, Lenka Roblová, Eva Honsová, Ivan Rychlík, Moran Dvela-Levitt, Anthony J. Bleyer, Aleš Linhart, Jakub Sikora, Stanislav Kmoch
Journal: Journal of the American Society of Nephrology (2024)

Key Points The clinical significance of a number of missense variants of α -galactosidase A is often ambiguous. Defective proteostasis of some missense α -galactosidase A variants induced chronic endoplasmic reticulum stress and the unfolded protein response. Endoplasmic reticulum stress and the unfolded protein response may explain clinical manifestations of non-classic Fabry disease. Background Classic Fabry disease is caused by GLA mutations that result in loss of enzymatic activity of α -galactosidase A, lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic Fabry disease, patients have some preserved α -galactosidase A activity and a milder disease course. Heterozygous female patients may also be affected. While Fabry disease pathogenesis has been mostly attributed to catalytic deficiency of mutated α -galactosidase A, lysosomal storage, and impairment of lysosomal functions, other pathogenic factors may contribute, especially in nonclassic Fabry disease. Methods We characterized the genetic, clinical, biochemical, molecular, cellular, and organ pathology correlates of the p.L394P α -galactosidase A variant that was identified initially in six individuals with kidney failure by the Czech national screening program for Fabry disease and by further screening in an additional 24 family members. Results Clinical findings in affected male patients revealed a milder clinical course, with approximately 15% residual α -galactosidase A activity with normal plasma lyso-globotriaosylceramide levels and abnormally low ratio of these values. None of the four available kidney biopsies showed lysosomal storage. Laboratory investigations documented intracellular retention of mutated α -galactosidase A with resulting endoplasmic reticulum stress and the unfolded protein response, which were alleviated with BRD4780, a small molecule clearing misfolded proteins from the early secretory compartment. We observed similar findings of endoplasmic reticulum stress and unfolded protein response in five kidney biopsies with several other classic and non-classic Fabry disease missense α -galactosidase A variants. Conclusions We identified defective proteostasis of mutated α -galactosidase A resulting in chronic endoplasmic reticulum stress and unfolded protein response of α -galactosidase A expressing cells as a contributor to Fabry disease pathogenesis.