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Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and degradation of (p)ppGpp by RelA and SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Here, we show that human MESH1 is an efficient cytosolic NADPH phosphatase that facilitates ferroptosis. Visualization of the MESH1-NADPH crystal structure revealed a bona fide affinity for the NADPH substrate. Ferroptosis-inducing erastin or cystine deprivation elevates MESH1, whose overexpression depletes NADPH and sensitizes cells to ferroptosis, whereas MESH1 depletion promotes ferroptosis survival by sustaining the levels of NADPH and GSH and by reducing lipid peroxidation. The ferroptotic protection by MESH1 depletion is ablated by suppression of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. Collectively, these data shed light on the importance of cytosolic NADPH levels and their regulation under ferroptosis-inducing conditions in mammalian cells.

Low-grade glioma (LGG) is a malignancy of the central nervous system that is often treatable with surgical resection and chemoradiation. However, despite an initial positive response to standard therapy, most LGG eventually progress to high-grade gliomas which are nearly uniformly fatal. There is a pressing need for more clinical trials and greater clinical trial accessibility to improve the standard of care of LGG to delay or prevent its progression. In this study, we systematically examined the scope and inclusion of clinical trials for LGG based in the United States. This cross-sectional study analyzes trends in trial design and reported demographic data from completed LGG trials registered on ClinicalTrials.gov between 2010 to 2023. Inclusion criteria, investigational therapies, primary outcomes, and preliminary results were compared and summarized. A total of 14 trials with 1067 participants were included in the study. Most of the trials were not exclusive to LGGs and 14% had mutation-specific inclusion criteria. To date, two of the trials have led to new FDA-approved treatments. All trials reported age and sex, while only 57% reported race and 43% reported ethnicity. Individuals identifying as Black or African American and Asian or Pacific Islander were statistically underrepresented. Lastly, we investigated the geographic distributions of trial sites across the United States, which demonstrated several coverage gaps in the Rocky Mountain and Southeast regions. These findings suggest specific areas for improvement in LGG clinical trial reporting and accessibility. [ABSTRACT FROM AUTHOR]

Stargardt atrophy and geographic atrophy (GA) represent pivotal endpoints in FDA-approved clinical trials. Predicting atrophy progression is crucial for evaluating drug efficacy. Fundus autofluorescence (FAF), the standard 2D imaging modality in these trials, has limitations in patient comfort. In contrast, spectral-domain optical coherence tomography (SD-OCT), a 3D imaging modality, is more patient friendly but suffers from lower image quality. This study has two primary objectives: (1) develop an efficient predictive modeling for the generation of future FAF images and prediction of future Stargardt atrophic (as well as GA) regions and (2) develop an efficient predictive modeling with advanced 3D OCT features at ellipsoid zone (EZ) for the comparative performance in the generation of future enface EZ maps and prediction of future Stargardt atrophic regions on OCT as on FAF. To achieve these goals, we propose two deep neural networks (termed ReConNet and ReConNet-Ensemble) with recurrent learning units (long short-term memory, LSTM) integrating with a convolutional neural network (CNN) encoder–decoder architecture and concurrent learning units integrated by ensemble/multiple recurrent learning channels. The ReConNet, which incorporates LSTM connections with CNN, is developed for the first goal on longitudinal FAF. The ReConNet-Ensemble, which incorporates multiple recurrent learning channels based on enhanced EZ enface maps to capture higher-order inherent OCT EZ features, is developed for the second goal on longitudinal OCT. Using FAF images at months 0, 6, and 12 to predict atrophy at month 18, the ReConNet achieved mean (±standard deviation, SD) and median Dice coefficients of 0.895 (±0.086) and 0.922 for Stargardt atrophy and 0.864 (±0.113) and 0.893 for GA. Using SD-OCT images at months 0 and 6 to predict atrophy at month 12, the ReConNet-Ensemble achieved mean and median Dice coefficients of 0.882 (±0.101) and 0.906 for Stargardt atrophy. The prediction performance on OCT images is comparably good to that on FAF. These results underscore the potential of SD-OCT for efficient and practical assessment of atrophy progression in clinical trials and retina clinics, complementing or surpassing the widely used FAF imaging technique. [ABSTRACT FROM AUTHOR]

High-grade glioma is the most frequent and lethal primary tumor of the central nervous system. Despite advances in surgical, pharmacological, and cell-directed therapies, there have been no updates to the standard of care in over a decade. This cross-sectional study analyzes patient and trial data from 201 interventional trials completed between 2010 and 2023, encompassing 18,563 participants. Although we found that all trials reported participant age and sex, only 52% of trials reported participant demographics, resulting in 51% of total participant demographics being unreported. The majority of studies did not report ethnicity, with approximately 60% of participants unreported. Additionally, males were significantly underrepresented in trials, comprising 60% of participants despite representing 75% of glioblastoma patients. Improved demographic reporting has been observed since 2011; however, it is inconsistent. Furthermore, we cataloged the geographic diversity of trials across the United States and found significant coverage deserts in relatively rural, but highly affected, areas such as Montana and Maine. We found a wider distribution of trials in both urban and wealthier regions, which indicates extensive coverage gaps and decreased access to participation for patients of a lower socioeconomic status. [ABSTRACT FROM AUTHOR]

Recently, we have shown that coexpression of hMet and mutant-β-catenin using sleeping beauty transposon/transposase leads to hepatocellular carcinoma (HCC) in mice that corresponds to around 10% of human HCC. In the current study, we investigate whether Ras activation, which can occur downstream of Met signaling, is sufficient to cause HCC in association with mutant-β-catenin. We also tested therapeutic efficacy of targeting β-catenin in an HCC model. We show that mutant-K-Ras (G12D), which leads to Ras activation, cooperates with β-catenin mutants (S33Y, S45Y) to yield HCC in mice. Affymetrix microarray showed > 90% similarity in gene expression in mutant-K-Ras-β-catenin and Met-β-catenin HCC. K-Ras-β-catenin tumors showed up-regulation of β-catenin targets like glutamine synthetase (GS), leukocyte cell-derived chemotaxin 2, Regucalcin, and Cyclin-D1 and of K-Ras effectors, including phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phosphorylated mammalian target of rapamycin, phosphorylated eukaryotic translation initiation factor 4E, phosphorylated 4E-binding protein 1, and p-S6 ribosomal protein. Inclusion of dominant-negative transcription factor 4 at the time of K-Ras-β-catenin injection prevented HCC and downstream β-catenin and Ras signaling. To address whether targeting β-catenin has any benefit postestablishment of HCC, we administered K-Ras-β-catenin mice with EnCore lipid nanoparticles (LNP) loaded with a Dicer substrate small interfering RNA targeting catenin beta 1 (CTNNB1; CTNNB1-LNP), scrambled sequence (Scr-LNP), or phosphate-buffered saline for multiple cycles. A significant decrease in tumor burden was evident in the CTNNB1-LNP group versus all controls, which was associated with dramatic decreases in β-catenin targets and some K-Ras effectors, leading to reduced tumor cell proliferation and viability. Intriguingly, in relatively few mice, non-GS-positive tumors, which were evident as a small subset of overall tumor burden, were not affected by β-catenin suppression.ConclusionRas activation downstream of c-Met is sufficient to induce clinically relevant HCC in cooperation with mutant β-catenin. β-catenin suppression by a clinically relevant modality is effective in treatment of β-catenin-positive, GS-positive HCCs. (Hepatology 2017;65:1581-1599).

Previous studies on crosslinguistic influence (CLI) on third language (L3) morphosyntactic acquisition have provided support for competing theories about the source(s) of CLI. The present study aimed to test if both L1 and L2 can be the source of CLI, and whether they influence L3 learning in similar or different ways. In particular, we aimed to add to our knowledge of the neural correlates of CLI by conducting an exploratory EEG study to investigate how L1 and L2 CLI affect L3 neural processing. Predictions based on the D/P model, which posited different memory systems sustaining L1 and L2, were tested. The findings confirmed both L1-sourced and L2-sourced facilitation on L3 morphosyntactic acquisition. Specifically, we suggest that L1-similarity showed a consolidating effect on L3 implicit knowledge and neurocognitive internalization, whereas L2-similarity contributed to enhanced L3 metalinguistic knowledge. This preliminary study is the first to investigate the neurocognitive mechanisms underlying CLI in L3 learning by natural language learners. [ABSTRACT FROM AUTHOR]

Hepatocellular cancer (HCC) remains a significant therapeutic challenge due to its poorly understood molecular basis. In the current study, we investigated two independent cohorts of 249 and 194 HCC cases for any combinatorial molecular aberrations. Specifically we assessed for simultaneous HMET expression or hMet activation and catenin β1 gene (CTNNB1) mutations to address any concomitant Met and Wnt signaling. To investigate cooperation in tumorigenesis, we coexpressed hMet and β-catenin point mutants (S33Y or S45Y) in hepatocytes using sleeping beauty transposon/transposase and hydrodynamic tail vein injection and characterized tumors for growth, signaling, gene signatures, and similarity to human HCC. Missense mutations in exon 3 of CTNNB1 were identified in subsets of HCC patients. Irrespective of amino acid affected, all exon 3 mutations induced similar changes in gene expression. Concomitant HMET overexpression or hMet activation and CTNNB1 mutations were evident in 9%-12.5% of HCCs. Coexpression of hMet and mutant-β-catenin led to notable HCC in mice. Tumors showed active Wnt and hMet signaling with evidence of glutamine synthetase and cyclin D1 positivity and mitogen-activated protein kinase/extracellular signal-regulated kinase, AKT/Ras/mammalian target of rapamycin activation. Introduction of dominant-negative T-cell factor 4 prevented tumorigenesis. The gene expression of mouse tumors in hMet-mutant β-catenin showed high correlation, with subsets of human HCC displaying concomitant hMet activation signature and CTNNB1 mutations.ConclusionWe have identified cooperation of hMet and β-catenin activation in a subset of HCC patients and modeled this human disease in mice with a significant transcriptomic intersection; this model will provide novel insight into the biology of this tumor and allow us to evaluate novel therapies as a step toward precision medicine. (Hepatology 2016;64:1587-1605).