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JOURNAL ARTICLE
Stefania Bellone, Kyungjo Jeong, Mari Kyllesø Halle, Camilla Krakstad, Blair McNamara, Michelle Greenman, Levent Mutlu, Cem Demirkiran, Tobias Max Philipp Hartwich, Yang Yang-Hartwich, Margherita Zipponi, Natalia Buza, Pei Hui, Francesco Raspagliesi, Salvatore Lopez, Biagio Paolini, Massimo Milione, Emanuele Perrone, Giovanni Scambia, Gary Altwerger, Antonella Ravaggi, Eliana Bignotti, Gloria S Huang, Vaagn Andikyan, Mitchell Clark, Elena Ratner, Masoud Azodi, Peter E Schwartz, Charles M Quick, Roberto Angioli, Corrado Terranova, Samir Zaidi, Shuvro Nandi, Ludmil B Alexandrov, Eric R Siegel, Jungmin Choi, Joseph Schlessinger, Alessandro D Santin
High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D / MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36...
April 23, 2024: Proceedings of the National Academy of Sciences of the United States of America
#2
JOURNAL ARTICLE
Chloe Alexa McGhee, Hamed Honari, Monica Siqueiros-Sanchez, Yaffa Serur, Eric K van Staalduinen, David Stevenson, Jennifer L Bruno, Mira Michelle Raman, Tamar Green
BACKGROUND: RASopathies are a group of disorders characterized by pathogenic mutations in the Ras-mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD). METHODS: This study examines the effect RASopathies (NS and NF1) has on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes...
April 13, 2024: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
#3
JOURNAL ARTICLE
João Lobo, Sofia Canete-Portillo, Maria Del Carmen Rodriguez Pena, Jesse K McKenney, Manju Aron, Felipe Massicano, Brandon M Wilk, Manavalan Gajapathy, Donna M Brown, Dilek E Baydar, Andres Matoso, Nathalie Rioux-Leclerq, Chin-Chen Pan, Maria S Tretiakova, Kiril Trpkov, Sean R Williamson, Soroush Rais-Bahrami, Alexander C Mackinnon, Shuko Harada, Elizabeth A Worthey, Cristina Magi-Galluzzi
Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well-known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity and, importantly, the molecular features...
April 11, 2024: Modern Pathology
#4
JOURNAL ARTICLE
Alexandra M Haugh, Robert C Osorio, Rony A Francois, Michael E Tawil, Katy K Tsai, Michael Tetzlaff, Adil Daud, Harish N Vasudevan
BACKGROUND: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. METHODS: This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care...
March 29, 2024: Cancers
#5
Di Zhang, Ling Wang, Hua-Lei Guo, Zi-Wei Zhang, Chong Wang, Ri-Cheng Chian, Zhi-Fen Zhang
Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell invasion assay data shown in Figs. 2C and 4B were strikingly similar to data appearing in different form in a paper by different authors at a different research institute that had already been submitted for publication. Owing to the fact that the contentious data in the above article had already been submitted for publication prior to its submission to International Journal of Molecular Medicine , the Editor has decided that this paper should be retracted from the Journal...
June 2024: International Journal of Molecular Medicine
#6
JOURNAL ARTICLE
Emil Lou, Joanne Xiu, Yasmine Baca, Anwaar Saeed, Ajay Prakash, Sepideh Gholami, Subbaya Subramanian, Timothy K Starr, Elisa Fontana, Ritu Pandey, Heinz-Josef Lenz, Anthony F Shields, Chadi Nabhan, Matthew Oberley, Andreas Seeber, Wafik El-Deiry
Oncogenic drivers such as KRAS extensively modulate the tumor inflammatory microenvironment (TIME) of colorectal cancer (CRC). The influence of KRAS on modulating immune cell composition remains unclear. The objective of this study was to identify signatures of infiltrative immune cells and distinctive patterns that differ between RAS wild-type (WT) and oncogenic mutant (MT) CRC that explain immune evasion in MT tumors. A total of 7,801 CRC specimens were analyzed using next-generation DNA sequencing, whole-exome sequencing, and/or whole transcriptome sequencing...
March 21, 2024: Mol Ther Oncol
#7
JOURNAL ARTICLE
Jingjing Jiang, Lingyan Jiang, Benjamin J Maldonato, Yingyun Wang, Matthew Holderfield, Ida Aronchik, Ian P Winters, Zeena Salman, Cristina Blaj, Marie Menard, Jens Brodbeck, Zhe Chen, Xing Wei, Michael J Rosen, Yevgeniy Gindin, Bianca J Lee, James W Evans, Stephanie Chang, Zhican Wang, Kyle J Seamon, Dylan Parsons, James Cregg, Abby Marquez, Aidan C A Tomlinson, Jason K Yano, John E Knox, Elsa Quintana, Andrew J Aguirre, Kathryn C Arbour, Abby Reed, W Clay Gustafson, Adrian L Gill, Elena S Koltun, David Wildes, Jacqueline A M Smith, Zhengping Wang, Mallika Singh
UNLABELLED: RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models...
April 9, 2024: Cancer Discovery
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JOURNAL ARTICLE
Urszula N Wasko, Jingjing Jiang, Tanner C Dalton, Alvaro Curiel-Garcia, A Cole Edwards, Yingyun Wang, Bianca Lee, Margo Orlen, Sha Tian, Clint A Stalnecker, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Stephen A Sastra, Carmine F Palermo, Marie C Hasselluhn, Amanda R Decker-Farrell, Stephanie Chang, Lingyan Jiang, Xing Wei, Yu C Yang, Ciara Helland, Haley Courtney, Yevgeniy Gindin, Karl Muonio, Ruiping Zhao, Samantha B Kemp, Cynthia Clendenin, Rina Sor, William P Vostrejs, Priya S Hibshman, Amber M Amparo, Connor Hennessey, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Jens Brodbeck, Lorenzo Tomassoni, Basil Bakir, Nicholas D Socci, Laura E Herring, Natalie K Barker, Junning Wang, James M Cleary, Brian M Wolpin, John A Chabot, Michael D Kluger, Gulam A Manji, Kenneth Y Tsai, Miroslav Sekulic, Stephen M Lagana, Andrea Califano, Elsa Quintana, Zhengping Wang, Jacqueline A M Smith, Matthew Holderfield, David Wildes, Scott W Lowe, Michael A Badgley, Andrew J Aguirre, Robert H Vonderheide, Ben Z Stanger, Timour Baslan, Channing J Der, Mallika Singh, Kenneth P Olive
Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations1,2 . RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RAS(ON) multi-selective)3 . As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS4 , we assessed the therapeutic potential of the RAS(ON) multi-selective inhibitor RMC-7977 in a comprehensive range of PDAC models...
April 8, 2024: Nature
#9
JOURNAL ARTICLE
Emily R Hildebrandt, Shaneela A Hussain, Michelle A Sieburg, Rajani Ravishankar, Nadeem Asad, Sangram Gore, Takahiro Ito, James L Hougland, Timothy M Dore, Walter K Schmidt
Ras GTPases and other CaaX proteins undergo multiple post-translational modifications at their carboxyl-terminus. These events initiate with prenylation of a cysteine and are followed by endoproteolytic removal of the 'aaX' tripeptide and carboxylmethylation. Some CaaX proteins are only subject to prenylation, however, due to the presence of an uncleavable sequence. In this study, uncleavable sequences were used to stage Ras isoforms in a farnesylated and uncleaved state to address the impact of CaaX proteolysis on protein localization and function...
March 27, 2024: Bioorganic Chemistry
#10
JOURNAL ARTICLE
Megha Bhat Agni, Pramukh Subrahmanya Hegde, Praveen Rai, Monika Sadananda, Damodara Gowda K M
Maternal nutrition was recognized as a significant part of brain growth and maturation in most mammalian species. Timely intervention with suitable nutraceuticals would provide long-term health benefits. We aim to unravel the molecular mechanisms of perinatal undernutrition-induced impairments in cognition and synaptic plasticity, employing animal model based on dietary nutraceutical supplementation. We treated undernourished dams at their gestational, lactational, and at both the time point with Astaxanthin (AsX) and Docosahexaenoic acid (DHA), and their pups were used as experimental animals...
April 5, 2024: Molecular Neurobiology
#11
JOURNAL ARTICLE
Dayan A Carrión-Estrada, Arturo Aguilar-Rojas, Sara Huerta-Yepez, Mayra Montecillo-Aguado, Martiniano Bello, Arturo Rojo-Domínguez, Elena Arechaga-Ocampo, Paola Briseño-Díaz, Marco Antonio Meraz-Ríos, María Del Rocío Thompson-Bonilla, Rosaura Hernández-Rivas, Miguel Vargas
INTRODUCTION: Breast cancer (BC) is the leading cause of cancer-related deaths among women, with triple-negative breast cancer (TNBC) representing one of the most aggressive and treatment-resistant subtypes. In this study, we aimed to evaluate the antitumor potential of C14 and P8 molecules in both TNBC and radioresistant TNBC cells. These compounds were chosen for their ability to stabilize the complex formed by the overactivated form of K-Ras4BG13D and its membrane transporter (PDE6δ)...
2024: Frontiers in Oncology
#12
JOURNAL ARTICLE
Joshua K Stone, Natalia von Muhlinen, Chenran Zhang, Ana I Robles, Amy L Flis, Eleazar Vega-Valle, Akihiko Miyanaga, Masaru Matsumoto, K Leigh Greathouse, Tomer Cooks, Giorgio Trinchieri, Curtis C Harris
Change within the intratumoral microbiome is a common feature in lung and other cancers and may influence inflammation and immunity in the tumor microenvironment, affecting growth and metastases. We previously characterized the lung cancer microbiome in patients and identified Acidovorax temperans as enriched in tumors. Here, we instilled A. temperans in an animal model driven by mutant K-ras and Tp53. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells...
April 3, 2024: Oncogenesis
#13
JOURNAL ARTICLE
Erik K Larsen, Maria Abreu-Blanco, Dana Rabara, Andrew G Stephen
Homogenous time-resolved FRET (HTRF) assays have become one of the most popular tools for pharmaceutical drug screening efforts over the last two decades. Large Stokes shifts and long fluorescent lifetimes of lanthanide chelates lead to robust signal to noise, as well as decreased false positive rates compared to traditional assay techniques. In this chapter, we describe an HTRF protein-protein interaction (PPI) assay for the KRAS4b G-domain in the GppNHp-bound state and the RAF-1-RBD currently used for drug screens...
2024: Methods in Molecular Biology
#14
JOURNAL ARTICLE
Albert H Chan, Dhirendra K Simanshu
RAS proteins play a vital role in regulating downstream signaling and essential cellular processes, positioning them as key players in normal cellular physiology and disease development. Among the various isoforms of RAS, KRAS stands out as one of the most frequently mutated genes in human cancer. The prevalence of RAS mutations in cancer often involves single amino acid substitutions at codons 12, 13, or 61. These mutations disrupt the RAS protein's inherent ability to transition between its active and inactive states, resulting in a constant activation signal and driving uncontrolled cell growth...
2024: Methods in Molecular Biology
#15
REVIEW
Mona Elgazzaz, Catalin Filipeanu, Eric Lazartigues
ACE2 (angiotensin-converting enzyme 2), a multifunctional transmembrane protein, is well recognized as an important member of the (RAS) renin-angiotensin system with important roles in the regulation of cardiovascular function by opposing the harmful effects of Ang-II (angiotensin II) and AT1R (Ang-II type 1 receptor) activation. More recently, ACE2 was found to be the entry point for the SARS-CoV-2 virus into cells, causing COVID-19. This finding has led to an exponential rise in the number of publications focused on ACE2, albeit these studies often have opposite objectives to the preservation of ACE2 in cardiovascular regulation...
April 3, 2024: Hypertension
#16
JOURNAL ARTICLE
Chun-Liang Chen, Ramizah Syahirah, Sandeep K Ravala, Yu-Chen Yen, Thomas Klose, Qing Deng, John J G Tesmer
The conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate by phosphoinositide 3-kinase γ (PI3Kγ) is critical for neutrophil chemotaxis and cancer metastasis. PI3Kγ is activated by Gβγ heterodimers released from G protein-coupled receptors responding to extracellular signals. Here we determined cryo-electron microscopy structures of Sus scrofa PI3Kγ-human Gβγ complexes in the presence of substrates/analogs, revealing two Gβγ binding sites: one on the p110γ helical domain and another on the p101 C-terminal domain...
April 2, 2024: Nature Structural & Molecular Biology
#17
Jaebin Kim, Edwin Bustamante, Peter Sotonyi, Nicholas D Maxwell, Pooja Parameswaran, Julie K Kent, William C Wetsel, Erik J Soderblom, Bence Rácz, Scott H Soderling
One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associated with hippocampal-dependent working memory and longer-term forms of learning and memory and that Rac1 can modulate forms of both pre- and postsynaptic plasticity. How these different cognitive functions and forms of plasticity mediated by Rac1 are linked, however, is unclear...
March 18, 2024: bioRxiv
#18
JOURNAL ARTICLE
Identification of a gene expression signature associated with brain metastasis in colorectal cancer.
Marlies Michl, Francesco Taverna, Christine Woischke, Pan Li, Frederick Klauschen, Thomas Kirchner, Volker Heinemann, Michael von Bergwelt-Baildon, Arndt Stahler, Tobias Marcus Herold, Vindi Jurinovic, Jutta Engel, Jörg Kumbrink, Jens Neumann
PURPOSE: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event with poor prognosis. Apart from (K)RAS status and lung and bone metastasis no biomarkers exist to identify patients at risk. This study aimed to identify a gene expression signature associated with colorectal BM. METHODS: Three patient groups were formed: 1. CRC with brain metastasis (BRA), 2. exclusive liver metastasis (HEP) and, 3. non-metastatic disease (M0). RNA was extracted from primary tumors and mRNA expression was measured using a NanoString Panel (770 genes)...
March 17, 2024: Clinical & Translational Oncology
#19
REVIEW
Sophie Laroche, Olivier Scatton, Frederic Charlotte, Jean-Baptiste Bachet, Chetana Lim, David Fuks, Claire Goumard
BACKGROUND: Optimal management of colorectal liver metastasis (CRLM) is based on a combination of chemotherapy and surgical resection. The tumor regression grade (TRG) score is a histological scoring system to evaluate response to chemotherapy. The prognosis of a heterogeneous response in cases of multiple metastases has not been evaluated according to the TRG score. PATIENTS AND METHODS: All patients who underwent liver resection for multiple CRLM after neoadjuvant chemotherapy in two tertiary centers from January 2015 to April 2019 were retrospectively included...
March 28, 2024: Annals of Surgical Oncology
#20
JOURNAL ARTICLE
Sanaa Mansoor, Minkyung Baek, Hahnbeom Park, Gyu Rie Lee, David Baker
Mapping the ensemble of protein conformations that contribute to function and can be targeted by small molecule drugs remains an outstanding challenge. Here, we explore the use of variational autoencoders for reducing the challenge of dimensionality in the protein structure ensemble generation problem. We convert high-dimensional protein structural data into a continuous, low-dimensional representation, carry out a search in this space guided by a structure quality metric, and then use RoseTTAFold guided by the sampled structural information to generate 3D structures...
March 28, 2024: Journal of Chemical Theory and Computation
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