bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geochronology, geochemistry, and tectonic setting of Ordovician metavolcanic rocks in the Liberty–Orrington belt, Maine: implications for the evolution of peri-Gondwanan arcs in the northern Appalachians
Authors: Johnson Sophia A. , West David P. , Peterman Emily M. 
Published: December 2023

The Yarmouth Island Formation of the East Harpswell Group (EHG) is an assemblage of metamorphosed volcanic and sedimentary rocks exposed in Casco Bay, Maine. Although previously interpreted to have been deposited ca. 445 Ma, two new U–Pb zircon ages from metavolcanic rocks in the unit indicate prolonged magmatism between ca. 469–474 Ma and correlation with adjacent rocks of the more regionally extensive Casco Bay Group (CBG) in the Liberty–Orrington belt. New detrital zircon results from metasedimentary rocks in the EHG support this correlation; the age spectra indicate a peri-Gondwanan sedimentary source, consistent with earlier published results from the CBG. Detailed geochemical studies of the metavolcanic rocks in the Yarmouth Island Formation indicate a wide range of sub-alkaline compositions (SiO2 = 47.9–77.5 wt.%), flat chondrite-normalized rare earth element distributions, and a prominent negative Nb anomaly in normalized spider plots. Tectonic discrimination plots suggest eruption in a volcanic arc setting with continental crustal influence. This tectonic setting, when combined with the co-existence of marine sedimentary rocks, suggests a transitional setting between that of subduction and subsidence in a marine setting, perhaps due to the onset of back-arc rifting. Similarities in age, lithologic character, sediment provenance, and volcanic rock geochemistry indicate a strong correlation between these rocks in the Liberty–Orrington belt and those along strike in the southern portion of the Miramichi belt of eastern Maine and southern New Brunswick. These findings confirm the preservation of >500 km long, ca. 470 Ma, arc/back-arc terrane within the Ganderia superterrane in the northern Appalachians.
Expressive, Scalable, Mid-air Haptics with Synthetic Jets
Authors: Shen Vivian , Harrison Chris , Shultz Craig 
Published: December 2023

Non-contact, mid-air haptic devices have been utilized for a wide variety of experiences, including those in extended reality, public displays, medical, and automotive domains. In this work, we explore the use of synthetic jets as a promising and under-explored mid-air haptic feedback method. We show how synthetic jets can scale from compact, low-powered devices, all the way to large, long-range, and steerable devices (Figure
1
). We built seven functional prototypes targeting different application domains to illustrate the broad applicability of our approach. These example devices are capable of rendering complex haptic effects, varying in both time and space. We quantify the physical performance of our designs using spatial pressure and wind flow measurements and validate their compelling effect on users with stimuli recognition and qualitative studies.
Epigenetic Cooperativity as a Therapeutic Vulnerability in Cancer
Authors: Kazansky Yaniv , Kentsis Alex 
Published: December 2023

AbstractNUT carcinoma (NC) is one of the most common types of undifferentiated carcinomas affecting young adults with a dismal prognosis. NUT carcinomas often involve chromosomal translocations, leading to the production of BRD4-NUT fusion protein that generates large domains of hyperactive chromatin and activates oncogenic gene expression. Bromodomain and extraterminal domain (BET) bromodomain inhibitors offer a direct means to block BRD4-mediated gene activation but have shown limited clinical efficacy in patients. In this issue of Cancer Research, Huang and colleagues report an unexpected discovery of a synthetic lethal NC dependency on Polycomb repressive complex 2 (PRC2)–mediated gene repression, including EZH2, the catalytic subunit of PRC2. EZH2 is highly expressed in NC patient tumors and a specific inhibitor of its methyltransferase activity, tazemetostat, exhibits potent antitumor cell activity. While the repressed and activated chromatin domains in NC cells are distinct, the resultant gene expression changes exhibit convergent features, including dysregulation of CDKN2A and the E2F-RB1 axis. As a result, combined treatment of NC tumors with tazemetostat and the BET inhibitor mivebresib produces marked antitumor therapeutic synergy in vitro and in vivo, associated with enhanced suppression of RB1 function through convergent remodeling of NC gene expression. This study advances epigenetic cooperativity as a distinct mode of gene expression dysregulation in NC and nominates a compelling combination epigenetic strategy for investigation in clinical trials for patients.See related article by Huang et al., p. 3956
Data from Differential Benefit of Metronomic Chemotherapy Among Triple-Negative Breast Cancer Subtypes Treated in the IBCSG Trial 22–00
Authors: Joaquin Garcia Andrea , Rediti Mattia , Venet David , Majjaj Samira , Kammler Roswitha , Munzone Elisabetta , Gianni Lorenzo , Thürlimann Beat , Laáng István , Colleoni Marco , Loi Sherene , Viale Giuseppe , Regan Meredith M. , Buisseret Laurence , Rothé Françoise , Sotiriou Christos 
Published: December 2023

<div>AbstractPurpose:<p>To explore whether specific triple-negative breast cancer (TNBC) molecular subtypes are predictive for a benefit from maintenance low-dose cyclophosphamide and methotrexate (CM) in the adjuvant IBCSG 22–00 phase III clinical trial.</p>Experimental Design:<p>RNA sequencing was performed on a selection of 347 TNBC formalin-fixed paraffin-embedded (FFPE) tumor samples following a case–cohort-like sampling. TNBC subtypes were computed on gene expression data. The association between TNBC subtypes and treatment outcome was assessed using a Cox proportional-hazards interaction test.</p>Results:<p>Immunomodulatory (IM) and basal-like/immune activated (BLIA) molecular subtypes showed a significant survival benefit when treated with low-dose CM [disease-free survival (DFS): HR, 0.5; 95% confidence interval (CI), 0.28–0.89; <i>P</i><sub>interaction</sub> = 0.018 and HR, 0.49; 95% CI, 0.27–0.9; <i>P</i><sub>interaction</sub> = 0.021]. Moreover, a high expression of regulatory T-cell immune signature was associated with a better prognosis in the CM arm, in line with a potential immunomodulating role of cyclophosphamide. In contrast, a worse outcome was observed in tumors with a mesenchymal (M) subtype treated with low-dose CM (DFS: HR, 1.9; 95% CI, 1.2–3; <i>P</i><sub>interaction</sub> = 0.0044).</p>Conclusions:<p>Our results show a differential benefit of low-dose CM therapy across different TNBC subtypes. Low-dose CM therapy could be considered as a potential strategy for TNBC tumors with IM subtype in the early-disease setting.</p></div>
Pancreatic Cancer's PD1-Roadblock: When T-Cell Reinvigoration Is Not Enough
Authors: Lander Varintra E. , DeNardo David G. 
Published: December 2023

SummaryPD1-blockade combinations in pancreatic ductal adenocarcinoma have been poorly effective, and the underlying reasons for this are unknown. A recent study revealed that chemoradiation plus PD1-blockade reinvigorates tumor-specific T cells; however, this T-cell activation is accompanied with exaggerated NFκB signaling, which may limit productive tumor-controlling immunity.See related article by Ali et al., p. 542
Abstract A010: Gloriosine induces cell cycle arrest by autophagic cell death through negative regulation of YAP transcriptional activity in non-small cell lung cancer. Gloriosine is a potent alkaloid derivative having potent anti cancer activity
Authors: Dey Biswajit , Goel Bharat , Chatterjee Essha , Singh Hoshiyar , Jain Shreyans , Guru Santosh Kumar 
Published: December 2023

Abstract
Autophagy plays a dual role in the development and advancement of various tumor. YAP, a component of the Hippo pathway, is known to be associated with autophagy. This study aims to explore the relationship between YAP and autophagy with respect to cell death pathway in lung cancer. Non-small cell lung cancer (NSCLC) accounts for most of the cancer death among all types of lung cancer. Here, we explored antiproliferative and antimigratory effect of compound gloriosine on A549 cells through Autophagy/Hippo signalling pathway. In the present study, we demonstrated that gloriosine inhibits cell viability of A549 cell lines (at 100nM concentration of 24 hours of treatment) in vitro by inducing autophagy with very low toxicity to normal breast cells MCF10A (&gt;1000nM). At 100nM concentration gloriosine led to G2/M cell cycle arrest after an hour of treatment in A549 cell lines. Furthermore, it affects (at 25nM) Hippo signalling through retention of YAP protein into cytoplasm and inhibiting YAP localization into nucleus, suppressing the expression of downstream target gene. Inhibition of YAP localization supresses AKT/mTOR pathway which ultimately leads to activation of autophagy dependent cell death. Spheroid formation assay reveals gloriosine treatment can inhibits tumor relapse and reduce the size of the spheroid of A549 cells in a dose dependent manner. This molecule also inhibits lung cancer tumor growth in nude mice at 27% and 64% with dose of 1mg/kg and 5mg/kg body weight respectively. These current results suggest that gloriosine has the potential to serve as a new anticancer drug candidate.
Citation Format: Biswajit Dey, Bharat Goel, Essha Chatterjee, Hoshiyar Singh, Shreyans Jain, Santosh Kumar Guru. Gloriosine induces cell cycle arrest by autophagic cell death through negative regulation of YAP transcriptional activity in non-small cell lung cancer. Gloriosine is a potent alkaloid derivative having potent anti cancer activity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A010.
Abstract A021: Screening of novel therapeutic markers for ovarian cancer stem cells
Authors: Choi Dong Kyu , Min Sang Hyun 
Published: December 2023

Abstract
Drug resistance in epithelial ovarian cancer is reportedly attributed to the existence of cancer stem cells, because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells. We screened an FDA-approved compound and clinical libraries, and found several small molecule drugs that target ovarian CSCs. These drugs decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. Since these drugs harbor target proteins, we investigated the expression of the target proteins in ovarian CSC and found the increased level of the protein expression and new therapeutic markers of ovarian CSCs. Downregulation of these genes reduced the stem-cell-like properties of ovarianCSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with chemo agents, synergistic ect was shown in inhibiting the viability and proliferation of ovarian CSCs. Our results suggested that these may be potential therapeutic drugs for preventing ovarian cancer recurrence.
Citation Format: Dong Kyu Choi, Sang Hyun Min. Screening of novel therapeutic markers for ovarian cancer stem cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A021.
Abstract A058: Investigating the molecular role of BRD9 in synovial sarcoma
Authors: Topal Salih , Dominici Claudia , Collins Michael , Lahr David L , Zhou Qianhe , Uzan Flore , Mayhew David , Adam Ammar , Garbitt-Amaral Victoria , Antonakos Brandon , Mikse Oliver , Ahmad Hafiz , Parikh Salonee , Lin Mei Yun , Wu Hsin-Jung , Sandoval Gabriel , Soares Luis M. M. , Muwanguzi Jordana , Chen Huawei , Yang Zhaoxia , Lowe Jason T. , Netherton Matt , Zawadzke Laura , Voigt Johannes , Huang Liyue , Ruppel Sabine , Chan Ho Man , Kruger Ryan , Millan David S. , Innis Scott , Bellon Steven F. 
Published: December 2023

Abstract
Bromodomain-containing protein 9 (BRD9) represents a potential selective vulnerability for tumors with specific alterations in the Brahma-associated factor (BAF) chromatin remodeling complex.  One example of such a modification is the incorporation of the SS18-SSX fusion into BAF complexes.  This alteration is a hallmark of synovial sarcoma, and thought to drive tumorigenesis. As BRD9 is a subunit unique to ncBAF, tumors that depend on ncBAF for survival may be susceptible to BRD9 degradation. Accordingly, selective BRD9 degradation is a potential therapeutic approach to treat such diseases. Previous work has shown that loss of BRD9 causes cell and tumor proliferation defects (Brien et al. 2018, Michel et al. 2018).  To explore the mechanism by which degradation of BRD9 causes cell and tumor proliferation defects in synovial sarcoma, we utilized a multi-omic approach using RNA-seq, ATAC-seq, and ChIP-seq data to understand the molecular impact of loss of BRD9 on relevant cell lines and animal model tumors. ChIP-seq revealed genome-wide colocalization of BRD9 and Myc on chromatin, and BRD9 degradation can lead to MYC loss at the majority of these co-bound regions.  Genes commonly regulated in synovial cell lines treated with a BRD9 degrader in vitro and/or in vivo are enriched in MYC target genes, ribosome biogenesis genes and cell cycle genes. Furthermore, the genes commonly downregulated in synovial cell lines treated with a BRD9 degrader have notable MYC binding at their promoter regions. Therefore, we propose that these downregulated genes might be potential MYC targets, specifically in synovial sarcoma, and that downregulation leads to observed proliferation defects.
Citation Format: Salih Topal, Claudia Dominici, Michael Collins, David L Lahr, Qianhe Zhou, Flore Uzan, David Mayhew, Ammar Adam, Victoria Garbitt-Amaral, Brandon Antonakos, Oliver Mikse, Hafiz Ahmad, Salonee Parikh, Mei Yun Lin, Hsin-Jung Wu, Gabriel Sandoval, Luis M. M. Soares, Jordana Muwanguzi, Huawei Chen, Zhaoxia Yang, Jason T. Lowe, Matt Netherton, Laura Zawadzke, Johannes Voigt, Liyue Huang, Sabine Ruppel, Ho Man Chan, Ryan Kruger, David S. Millan, Scott Innis, Steven F. Bellon. Investigating the molecular role of BRD9 in synovial sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A058.
Abstract A063: Epigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia
Authors: Lee Changhu , Kim Min , Park Chanho , Jo Woobeen , Park Jiyoung 
Published: December 2023

Abstract
Hyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia induces Neuregulin 1 (Nrg1) overexpression in breast cancer, which subsequently promotes tumor progression. However, molecular mechanisms underlying hyperglycemia-induced Nrg1 overexpression remain poorly understood. Here, we show that hyperglycemia causes active histone modifications at the Nrg1 enhancer, forming enhanceosome complexes where recombination signal binding protein for immunoglobulin kappa J region (RBPJ), E1A binding protein p300 (P300), and SET domain containing 1A (SETD1A) are recruited to upregulate Nrg1 expression. Deletions in RBPJ-binding sites causes hyperglycemia-controlled Nrg1 levels to be downregulated, resulting in decreased tumor growth in vitro and in vivo. Mice with modest-temporary hyperglycemia, induced by low-dose short-exposure streptozotocin, display accelerated tumor growth and lapatinib resistance, whereas combining lapatinib with N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-S42 phenylglycine t-butyl ester (DAPT) ameliorates tumor growth under these modest hyperglycemic conditions by inhibiting NOTCH and EGFR superfamilies. NOTCH activity is correlated with NRG1 levels, and high NRG1 levels predicts poor outcomes, particularly in HER2-positive breast cancer patients. Our findings highlight the hyperglycemia-linked epigenetic modulation of NRG1 as a potential therapeutic strategy for treating breast cancer patients with diabetes.
Citation Format: Changhu Lee, Min Kim, Chanho Park, Woobeen Jo, Jiyoung Park. Epigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A063.
Abstract A101: Novel KRAS inhibitors suppress MAPK pathway signalling and display potent anti-proliferative activity across a broad range of KRAS mutant cell lines
Authors: Bhamra Inder , Mason Helen , Woodcock Simon , Anderson Katie , Kelly James , Haydon Grace , La Montagna Manuela , Brierley Megan , Bishop Emma , Keeler Ross , Ryan James , Jackson Paula , Aylott Helen , Ho Kelvin , Leng Daniel , Jones Clifford , Phillips Caroline 
Published: December 2023

Abstract
KRAS is the most frequently mutated oncogene across different cancer types. Redx Pharma are developing novel, orally bioavailable, small molecule inhibitors of KRAS. These compounds display activity against a broad spectrum of the most frequently occurring KRAS mutations whilst maintaining selectivity over NRAS and HRAS protein isoforms. Isoform selective multi-KRAS inhibitors were identified using biochemical SOS1-independent nucleotide exchange assays (NEA) and validated by surface plasmon resonance (SPR) spectroscopy. Compounds of interest were the further triaged using relevant cancer cell lines for inhibition of phospho-ERK (pERK) and anti-proliferative effects both in 2 and 3-dimensional assay formats. KRAS selective inhibitors retaining activity across a spectrum of mutations were identified, these compounds exhibit picomolar affinity for KRAS, translating into low nanomolar antiproliferative activity. As further confirmation of MAPK pathway inhibition, treatment of relevant cancer cell lines with Redx compounds resulted in suppression of DUSP6 and SPTY4 gene expression. Cellular washout experiments indicated sustained inhibition of pERK post washout of compounds consistent with high affinity compounds with extended residency time at KRAS. Optimisation towards KRAS inhibitors suitable for clinical evaluation is ongoing.
Citation Format: Inder Bhamra, Helen Mason, Simon Woodcock, Katie Anderson, James Kelly, Grace Haydon, Manuela La Montagna, Megan Brierley, Emma Bishop, Ross Keeler, James Ryan, Paula Jackson, Helen Aylott, Kelvin Ho, Daniel Leng, Clifford Jones, Caroline Phillips. Novel KRAS inhibitors suppress MAPK pathway signalling and display potent anti-proliferative activity across a broad range of KRAS mutant cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A101.
Abstract A159: Mechanisms of uveal melanoma sensitivity to velcrin treatment and SLFN12-mediated cancer cell death
Authors: Kotynkova Kristyna , Andersen Sawyer , Garvie Colin , Wu Xiaoyun , Lee Sooncheol , McGaunn Joseph , Kaplan Bethany , Tseng Moony , Cherniack Andrew D , Meyerson Matthew , Greulich Heidi 
Published: December 2023

Abstract
Velcrins are a novel class of compounds that kill cancer cells expressing elevated levels of PDE3A and SLFN12. These compounds induce PDE3A-SLFN12 heterotetramer complex formation, resulting in upregulation of the RNase activity of SLFN12. SLFN12 cleaves tRNA-Leu-TAA, which leads to the inhibition of global translation and, consequently, apoptosis of cells expressing sufficient levels of both proteins. Uveal melanoma, a type of melanoma that occurs in the eye, is genomically distinct from cutaneous melanoma. Whereas mutations of BRAF, NRAS, KRAS, and HRAS are common in cutaneous melanoma, uveal melanomas instead harbor mutually exclusive mutations of the G protein alpha subunits, GNAQ and GNA11. Around 50% of patients will develop metastatic disease with a very poor prognosis. Immunotherapy is not effective for these patients, nor are any targeted therapies available beyond tebentafusp, with an ORR of 9%. We found that a subset of uveal melanoma cell lines expresses elevated levels of PDE3A and SLFN12 and is sensitive to velcrin treatment. We are currently assessing whether velcrin treatment of these cell lines results in cleavage of tRNA-Leu-TAA, inhibition of protein synthesis, and tumor cell death, with the goal of developing a new treatment for uveal melanoma patients. To further understand the mechanism of velcrin-induced cancer cell death, we hypothesized that the primary function of PDE3A in the PDE3A-SLFN12 heterotetramer is the dimerization of SLFN12. Based on our cryo-EM structure of the PDE3A-SLFN12 complex, we identified SLFN12 I131 as a critical residue in the SLFN12 homodimer interface. We showed that a SLFN12 I131Q mutation disrupts SLFN12 dimerization and prevents tRNA-Leu-TAA cleavage in vitro. We have also shown that wild-type SLFN12 can dimerize independently of PDE3A or PDE3A-velcrin interactions. In PDE3A-depleted cells, the overexpression of wild-type SLFN12 results in cell death. We are currently testing SLFN12 I131Q for its ability to initiate SLFN12-dependent cytotoxicity in cells. Additionally, we are preparing different SLFN12 constructs that would allow us to induce chemical dimerization of SLFN12 and we plan to test if the forced dimerization of SLFN12 rescues its RNase activity and results in cell death.
Citation Format: Kristyna Kotynkova, Sawyer Andersen, Colin Garvie, Xiaoyun Wu, Sooncheol Lee, Joseph McGaunn, Bethany Kaplan, Moony Tseng, Andrew D Cherniack, Matthew Meyerson, Heidi Greulich. Mechanisms of uveal melanoma sensitivity to velcrin treatment and SLFN12-mediated cancer cell death [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A159.