bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic glycogenolysis and hypometabolism induced by chemogenetic stimulation of C1 neurons
Authors: Abe Chikara , Katayama Chikako , Bazek Murat , Ohbayashi Kento , Horii Kazuhiro , Tanida Mamoru , Nin Fumiaki , Iwasaki Yusaku 
Published: May 2023

AbstractThe precise regulation of blood glucose levels is indispensable for maintaining physiological functions. C1 neurons determine the outflow of the autonomic nervous and endocrine systems to maintain blood glucose levels in the body. In contrast, activation of C1 neurons induces a decrease in activity, suggesting that hypoactivity also participates in maintaining blood glucose levels. To examine this, we evaluated both glycogenolysis and hypometabolism induced by the selective activation of C1 neurons. We used DbhCre/0 mice expressing receptors for chemogenetic tools in C1 neurons, resulting from microinjection of the viral vector. C1 neurons were activated by intraperitoneal injection of clozapine N‐oxide (CNO). The chemogenetic activation of C1 neurons significantly decreased body temperature, oxygen consumption and carbon dioxide production. On the other hand, blood glucose levels were increased by activation of C1 neurons 2 h after CNO administration, even in the fasting state. In this situation, an increase in glucagon and corticosterone levels was observed, while hepatic glycogen content decreased significantly. Plasma insulin levels were not changed by the activation of C1 neurons despite the increase in blood glucose level. Furthermore, adrenal sympathetic nerve activity was significantly increased by the activation of C1 neurons, and plasma catecholamine levels increased significantly. In conclusion, the selective activation of C1 neurons using chemogenetic tools induced an increase in blood glucose levels, probably as a result of hepatic glycogenolysis and hypometabolism.
imageKey points
Chemogenetic activation of C1 neurons in medulla oblongata decreased body temperature.
Oxygen consumption and carbon dioxide production were decreased by chemogenetic activation of C1 neurons in medulla oblongata.
Blood glucose levels were increased by chemogenetic activation of C1 neurons in medulla oblongata.
Chemogenetic activation of C1 neurons in medulla oblongata increased glucagon, corticosterone and catecholamine levels in plasma.
An increase in blood glucose levels by activation of C1 neurons occurred due to the combined effect of hepatic glycogenolysis and hypometabolism.
Crustal eduction and slab-failure magmatism in an Orosirian (2.05–1.80 Ga) postcollisional cratonic foredeep: geochronology of Seton volcanics and Compton laccoliths, Tu Cho (Great Slave Lake), NWT, Canada
Authors: Hoffman Paul F. , Macdonald Francis A. , Bowring Samuel A. , Ramezani Jahandar , Buchwaldt Robert , Hildebrand Robert S. , Whalen Joseph B. 
Published: May 2023

Three Orosirian basins and associated foreland thrust-fold belts are preserved on the margins of the Slave craton. All three are related to orogenic belts where oceans opened and later closed, uniting new crustal partners. The Great Slave basin differs from the Kilhigok and Coronation basins in ways that have defied explanation. It lacks a passive margin sequence and hosts two discrete igneous suites, separated by large-scale thrusting, that occurred well after the adjacent paleocean had closed. Here we report U–Pb zircon geochronology by chemical abrasion isotope dilution thermal ionization mass spectrometry for a member of each suite to constrain the age and origin of postcollisional thrusting. A widespread pulse of mainly phreatic alkaline volcanism, coeval with renewed foredeep flexure, occurred at 1889.0 ± 0.7 Ma (2 σ internal error). A quartz-monzodiorite body, one of a belt-parallel chain of laccoliths that postdate thrusting, was emplaced at 1866.9 ± 0.9 Ma. These ages bracket renewed foredeep sedimentation and thrusting that telescoped major facies zones and was rooted within the basin. The older age is 70 and 30−60 Myr younger than collision in the Thelon and Taltson orogens, respectively. We attribute postcollisional thrusting and foredeep subsidence to “eduction”—the upward and outward ejection of partly subducted crust—and postulate that the top of the ejected wedge was a normal-sense detachment fault projecting beneath the Nonacho basin. We infer that eduction was triggered by slab failure, producing alkaline volcanism, and ended with delamination and laccolith emplacement. Eduction was facilitated by tradewind-driven erosion. Delamination was enabled by crustal transfer to the educted wedge, reducing footwall buoyancy. Slab failure and/or delamination removed the passive margin.
The Imperative for Population-based Cancer Registration of All Metastatic Cancers
Authors: Stopsack Konrad H. , Plym Anna , Mucci Lorelei A. 
Published: May 2023

AbstractMetastases are the main cause of morbidity and mortality from solid tumors. Surprisingly, population-based cancer registries in various countries, including the National Cancer Institute's Surveillance, Epidemiology, and End Results program in the United States, only capture data on individuals diagnosed with cancers that are metastatic at diagnosis (M1). Metastatic recurrences of previously diagnosed, initially nonmetastatic tumors are missed. Devasia and colleagues specify an illness-death model for chronic disease and estimate that in prostate cancer, which has a large pool of primary disease that may or may not progress to metastases, about half of all metastatic cancers arise as recurrences from initially nonmetastatic disease. Capturing all incident metastatic cancer cases across all tumor types in population-based cancer registries, not only based on initial stage at diagnosis, would be critical to better understand the disparities in metastatic disease burden and the effectiveness of primary prevention, screening, and therapies for primary and metastatic disease.See related article by Devasia et al., p. 659
Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency
Authors: Das Anirban , Tabori Uri , Sambira Nahum Lauren C. , Collins Natalie B. , Deyell Rebecca , Dvir Rina , Faure-Conter Cecile , Hassall Timothy E. , Minturn Jane E. , Edwards Melissa , Brookes Elissa , Bianchi Vanessa , Levine Adrian , Stone Simone C. , Sudhaman Sumedha , Sanchez Ramirez Santiago , Ercan Ayse B. , Stengs Lucie , Chung Jill , Negm Logine , Getz Gad , Maruvka Yosef E. , Ertl-Wagner Birgit , Ohashi Pamela S. , Pugh Trevor , Hawkins Cynthia , Bouffet Eric , Morgenstern Daniel A. 
Published: May 2023

AbstractPurpose:Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD).Patients and Methods:Twenty patients were screened, and 10 were ultimately included in the response cohort of whom nine had TMB &gt;10 mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5 and 10 mut/Mb.Results:Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% [95% confidence interval (CI), 27–93]. Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37 months (range, 32.4–60), culminating in 2-year OS of 43% (95% CI, 18.2–100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with an MMR-proficient tumor and TMB 7.4 mut/Mb.Conclusions:Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint inhibitors, including upfront management of cancer.See related commentary by Mardis, p. 4701
Abstract A002: Early changes in circulating cell free KRAS G12C as a possible blood-based response biomarker for adagrasib in non-small cell lung cancer (NSCLC). &lt;/title&gt;
Authors: Paweletz Cloud , Heavey Grace A. , Kuang Yanan , Kheoh Thian , Anderes Kenna , Christensen James , Jänne Pasi A. 
Published: May 2023

Abstract
Introduction: While tumor imaging has a fundamental role in drug development as a determinant of clinical response it may not always be a rapid measure of treatment effect. Changes in plasma ctDNA levels, on the other hand, has the potential to be a more readily available measure of response. Here we report on early plasma response measurements of KRAS G12C ctDNA by digital droplet PCR (ddPCR) in a Phase 2 trial of Adagrasib, a potent, orally available, small molecule covalent inhibitor of KRAS G12C, in patients with advanced non-small cell lung cancer with KRAS G12C mutation. Methods/Results: To study the timing of plasma response, we performed serial ddPCR on 60 KRAS G12C-mutant NSCLC patients that participated in cohort A of the KRYSTAL-1 phase 2 clinical trial. Cohort A evaluated adagrasib at 600 mg orally BID in patients with NSCLC previously treated with platinum-based chemotherapy. We analyzed the change in ctDNA levels at 2 specific intervals: between cycles 1 and 2 (i.e. initial change) and at start of cycles 4. Of 60 pts, 7 pts were excluded because of missing C1D1 draws, 13 pts were excluded for non-detectable KRAS G12C level at C1D1 and 1 patient was excluded because of a missing C2D1 draw leaving us with 39 evaluable patients for plasma response assessment. We found that most of the response in ctDNA could be seen during the initial 3-4 week treatment period, well before the first scan at 6-8 weeks. 38 pts (97.4%) showed any decrease in plasma levels from baseline levels. 35 patients (89.7%) show a decrease &gt;90% and 33 pts (84.6%) achieved complete clearance at C2D1. Patients with complete ctDNA clearance at C2D1 showed improved ORR (60.6% vs 33.3%), while ctDNA clearance at C4 was associated with an improved survival (12.6 months vs 5.4 months) and PFS (HR 0.3). Conclusion: Our results support using early plasma response of KRAS G12C assessed at 2-3 weeks to inform the interpretation of initial imaging performed at 6-8 weeks
Citation Format: Cloud Paweletz, Grace A. Heavey, Yanan Kuang, Thian Kheoh, Kenna Anderes, James Christensen, Pasi A. Jänne. Early changes in circulating cell free KRAS G12C as a possible blood-based response biomarker for adagrasib in non-small cell lung cancer (NSCLC). &lt;/title&gt; [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A002.
Abstract A014: Inhibition of KrasG12D with a novel small molecule inhibitor alters the pancreatic cancer microenvironment
Authors: Kemp Samantha B. , Cheng Noah , Markosyan Nune , Sor Rina , Kim Il-Kyu , Hallin Jill , Shoush Jason , Quinones Liz , Brown Natalie , Bassett Jared B. , Joshi Nikhil , Yuan Salina , Smith Molly , Vostrejs William P. , Perez-Vale Kia Z. , Kahn Benjamin , Mo Feiyan , Donahue Timothy R. , Radu Caius G. , Clendenin Cynthia , Christensen James G. , Vonderheide Robert H. , Stanger Ben Z. 
Published: May 2023

Abstract
Approximately 90% of pancreatic ductal adenocarcinoma (PDAC) patients harbor an oncogenic KRAS mutation, with Gly-to-Asp mutations (KrasG12D) being most common. PDAC is characterized by a robust, immunosuppressive tumor microenvironment that is rich in myeloid-derived suppressor cells (MDSCs) and has a paucity of T cells. The majority of therapeutic interventions in PDAC are ineffective, in part, due to this immunosuppressive TME. We aimed to examine the efficacy of a small molecule KrasG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14d. MRTX1133 treatment additionally reduced metastatic burden after 7d of treatment. An increase in tumor cell death was identified after only 36h of treatment, with concomitant loss of tumor cell proliferation. Inhibition of KrasG12D led to marked shifts in the TME composition. MRTX1133-treated tumors had an increase in fibroblasts, collagen deposition, and blood vessel density. There was a robust increase in M1-like macrophages after MRTX1133 treatment. Further, there was a loss of MDSCs, along with an increase in cytotoxic T cells. Proteome profiling on tumor cells treated with MRTX1133 identified a loss of tumor cell-derived GM-CSF (a MDSC recruiter), as well as an increase in CCL2 (a macrophage recruiter), providing evidence that MRTX1133 alters the TME through tumor secreted factors. T cells were necessary for MRTX1133’s full anti-tumor effect, and T cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KrasG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.
Citation Format: Samantha B. Kemp, Noah Cheng, Nune Markosyan, Rina Sor, Il-Kyu Kim, Jill Hallin, Jason Shoush, Liz Quinones, Natalie Brown, Jared B. Bassett, Nikhil Joshi, Salina Yuan, Molly Smith, William P. Vostrejs, Kia Z. Perez-Vale, Benjamin Kahn, Feiyan Mo, Timothy R. Donahue, Caius G. Radu, Cynthia Clendenin, James G. Christensen, Robert H. Vonderheide, Ben Z. Stanger. Inhibition of KrasG12D with a novel small molecule inhibitor alters the pancreatic cancer microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A014.
Abstract A031: KRAS (G12C) mediated mRNA translation program
Authors: Singh Kamini 
Published: May 2023

Abstract
KRAS-dependent activation of mRNA translation signaling is a common feature in cancer however, the KRAS-specific translation landscape and functional proteome are not fully characterized in a genome-wide manner. We show that mutant KRAS drives specific mechanisms of translational control to support cancer growth. We have utilized the technology of ribosome footprinting combined with advanced sequencing methodology to define the translation landscape affected by a specific inhibitor of KRAS, sotorasib that targets G12C mutant KRAS activity. We show that acute treatment of sotorasib inhibits the translation of key oncogenic proteins including MYC and MYC targets. KRAS (G12C) inhibition profoundly affects the translation of ribosomal proteins and translation elongation factors. G12C mutant KRAS remarkably affects the translation of proteins involved in the ROS and DNA repair pathways in cancer. Moreover, these translational changes are mediated through specific RNA motifs and RNA binding proteins. In summary, our study defines the KRAS (G12C) specific regulation of translation and provides the mechanism of KRAS (G12C) mediated regulation of cancer proteome.
Citation Format: Kamini Singh. KRAS (G12C) mediated mRNA translation program [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A031.
Abstract A032: Targeting RAS beyond KRAS, a review
Authors: Singh Neetu , Tyson Darren R. , Sarma Partha Pratim , Katike Sathish , Bhavar Prashant K. , Surampudi Uday Kumar 
Published: May 2023

Abstract
RAS proteins belong to the family of GTPases and plays instrumental role in cellular growth and proliferation and dysregulation of RAS signalling is one of the key drivers of tumorigenesis. The RAS protein has four isoforms namely KRAS4A, KRAS4B, NRAS and HRAS with amino acid codons 12, 13 and 61 as common hotspots for RAS mutations. Each of these hotspot mutations appears across several cancer types, however each of them have been noted to have specific distribution across different tissues. For example, mutations in codon 12 of KRAS are most common in pancreatic, lung and colorectal cancer, NRAS mutations affecting Q61 and G12 are most prevalent in melanoma and haematological malignancies, respectively, and HRAS mutations are more frequently altered in thyroid, bladder and head and neck cancers. Substantial efforts have been made to develop small molecule inhibitors targeting KRASG12C, with demonstrated success in clinic. Early success with KRASG12C has prompted researchers targeting other RAS isoforms, such as H-RAS and N-RAS to address RAS mutated cancer burden. Discovery of pan-RAS monobody that binds to all RAS isoforms have opened new opportunities. Development of small molecule inhibitors of RAS membrane association is gaining potential as a therapeutic strategy to curb RAS signalling; Lonafarnib and Tipifarnib, inhibitors of farnesyltransferase that lipidate Ras to facilitate membrane localization, have shown effectiveness in HRAS mutated cancers and are in active clinical evaluation. Although the lack of a hydrophobic binding pocket in NRAS poses challenges to drug targeting, specific strategies such as amphiphile-mediated depalmitoylation to target the post-translational modification of NRAS and reduce its activity are being investigated. The wide variety of approaches to target the RAS signalling pathway, beyond KRAS, have resulted in a broadening patent landscape. While finding ways to specifically target RAS mutants remains a daunting challenge, herculean efforts to make clinically useful RAS-targeted drugs are beginning to provide a bounty of weapons to fight against RAS-driven tumors.
Citation Format: Neetu Singh, Darren R. Tyson, Partha Pratim Sarma, Sathish Katike, Prashant K. Bhavar, Uday Kumar Surampudi. Targeting RAS beyond KRAS, a review [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A032.
Abstract B006: Novel direct RAS inhibitors for pancreatic cancer
Authors: Clarke Geoff , Arshad Tariq , Donninger Howard , von Baby Becca , Ferrill Rachel , Sabo Mike , Burlison Joe , Trent John 
Published: May 2023

Abstract
RAS oncogenes are frequently activated by mutations in pancreatic and lung cancer, where they appear to act as driving mutations. This study examines the activity of a series of novel direct RAS inhibitors with a predicted unique interaction region. We have used in silico library screening followed by Medicinal Chemistry optimization to develop the compounds. We have validated the agents using Microscale Thermophoresis to quantify binding to recombinant RAS protein as well as NMR analysis of the drug/RAS complex. We used 3D growth inhibition assays in mutant RAS cell lines and protein-based RAS signaling assays to quantify and characterize the action of the family of inhibitors. We have identified compounds that bind wild type K-RAS and H-RAS but exhibit preferential binding to the K-RAS-G12D and KRAS-G12C mutants. We can suppress the association of mutant RAS protein with its effector RAF-1 in treated cells. We also observe suppression of mutant RAS signaling and inhibition of 3D cell growth of mutant RAS cell lines with the agents. As the compound family are predicted to bind to a different site than either AMG-510 (K-RAS G12C specific) or MRTX-1133 (K-RAS G12D specific), agents we have also tested co-operative activity with these drugs. Our compounds enhanced the effects of MRTX-1133 against K-RAS G12D cells and had a similar effect on AMG-510 in K-RAS G12C cell lines. These agents may serve as novel anti-RAS therapeutics and may have potential to enhance the activity or suppress resistance to AMG-510 and MRTX-1133.
Citation Format: Geoff Clarke, Tariq Arshad, Howard Donninger, Becca von Baby, Rachel Ferrill, Mike Sabo, Joe Burlison, John Trent. Novel direct RAS inhibitors for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B006.
Abstract B012: Effects of adagrasib on oncogenic signaling, immune cell regulation and biomarkers of response in preliminary clinical analyses
Authors: Hallin Jill , Hover Laura , Fernandez-Benet Julio , Pavlicek Adam , Anderes Kenna , Jänne Pasi A. , Riely Gregory J. , Spira Alexander I. , Zhang Jun , Olson Peter , Christensen James G. 
Published: May 2023

Abstract
The recent approval of KRAS G12C inhibitors has provided novel treatment options for lung, colorectal and other cancer patients harboring this mutation and has changed the landscape of research for these cancers. Current priorities in the field include characterizing the mechanism of action of KRAS G12C inhibitors and the mechanisms underlying resistance to KRAS inhibition. Utilizing access to pre and post-treatment patient samples from KRYSTAL-1, preliminary gene expression analyses from baseline and post-adagrasib (Cycle 1, Day 8) treated patient samples demonstrated multiple oncogenic pathway gene signatures, including MYC, mTOR, cell cycle, EMT and inflammation-related signatures, were significantly regulated by adagrasib. KRAS/MAPK pathway and cell cycle-related genes including ETV4, CCND1, DUSP6, TOP1, and CENPA, as well as the Singh KRAS dependency signature were significantly downregulated in Cycle1, Day 8 compared to baseline tumor biopsies. Genes implicated in inflammation and the immune response were significantly upregulated in Cycle 1, Day 8 compared to baseline tumor biopsies. In agreement with the gene expression data as well as findings from syngeneic mouse models, preliminary immunohistochemical analysis on matched baseline, post-adagrasib treated (Cycle 1, Day 8), and end of treatment FFPE patient samples revealed marked changes in tumor cell mechanistic biomarkers and immune cell types following adagrasib treatment. These observations included decreased tumor Ki67 and increased tumor PD-L1, as well as marked alterations in tumor immune cell composition, including increased CD8+ T cells and decreased MDSCs following adagrasib treatment in several patients. Finally, flow cytometry and TCRb sequencing data from adagrasib and pembrolizumab-treated patient blood samples demonstrated an increase in several activated CD8+ T cell populations and the emergence of new T cell clones in a subset of patients after combination treatment. Together, these data suggest robust evaluation of patient biopsies pre and post adagrasib treatment may better predict outcomes that can be achieved in patients harboring KRASG12C mutant cancers and can guide early clinical development strategies, including support for combining adagrasib with immune checkpoint inhibitors.
Citation Format: Jill Hallin, Laura Hover, Julio Fernandez-Benet, Adam Pavlicek, Kenna Anderes, Pasi A. Jänne, Gregory J. Riely, Alexander I. Spira, Jun Zhang, Peter Olson, James G. Christensen. Effects of adagrasib on oncogenic signaling, immune cell regulation and biomarkers of response in preliminary clinical analyses [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B012.