tbuckley/cabot-search huggingface dataset:
Translational Insights From Cell Type Variation Across Amygdala Subnuclei in Rhesus Monkeys and Humans
Authors: Shawn Kamboj, Erin L. Carlson, Bradley P. Ander, Kari L. Hanson, Karl D. Murray, Julie L. Fudge, Melissa D. Bauman, Cynthia M. Schumann, Andrew S. Fox
Journal: American Journal of Psychiatry (2024)

Theories of amygdala function are central to our understanding of psychiatric and neurodevelopmental disorders. However, limited knowledge of the molecular and cellular composition of the amygdala impedes translational research aimed at developing new treatments and interventions. The aim of this study was to characterize and compare the composition of amygdala cells to help bridge the gap between preclinical models and human psychiatric and neurodevelopmental disorders.
Discrimination Exposure, Neural Reactivity to Stress, and Psychological Distress
Authors: Devon K. Grey, Juliann B. Purcell, Kristen N. Buford, Mark A. Schuster, Marc N. Elliott, Susan Tortolero Emery, Sylvie Mrug, David C. Knight
Journal: American Journal of Psychiatry (2024)

Discrimination exposure has a detrimental impact on mental health, increasing the risk of depression, anxiety, and posttraumatic stress. The impact discrimination exposure has on mental health is likely mediated by neural processes associated with emotion expression and regulation. However, the specific neural processes that mediate the relationship between discrimination exposure and mental health remain to be determined. The present study investigated the relationship adolescent discrimination exposure has with stress-elicited brain activity and mental health symptoms in young adulthood.
Effect of pneumococcal conjugate vaccination on pneumococcal carriage in hospitalised children aged 2–59 months in Mongolia: an active pneumonia surveillance programme
Authors: Claire von Mollendorf, Tuya Mungun, Munkhchuluun Ulziibayar, Cattram D Nguyen, Purevsuren Batsaikhan, Bujinlkham Suuri, Dashtseren Luvsantseren, Dorj Narangerel, Bilegtsaikhan Tsolmon, Sodbayar Demberelsuren, Belinda D Ortika, Casey L Pell, Ashleigh Wee-Hee, Monica L Nation, Jason Hinds, Eileen M Dunne, E K Mulholland, Catherine Satzke
Journal: The Lancet Microbe (2024)
Epigenetic Biomarkers in Alzheimer's Disease: Diagnostic and Prognostic Relevance
Authors: Tapan Behl, Ashishkumar Kyada, R Roopashree, Deepak Nathiya, Renu Arya, M Ravi Kumar, Mohammad Khalid, Monica Gulati, Monika Sachdeva, Mohammad Fareed, Pratap Kumar Patra, Ankur Agrawal, Pranay Wal, Amin Gasmi
Journal: Ageing Research Reviews (2024)
Review of the WHO guideline on preventive chemotherapy for public health control of strongyloidiasis
Authors: Nathan C Lo, David G Addiss, Dora Buonfrate, Arancha Amor, Melaku Anegagrie, Zeno Bisoffi, Richard S Bradbury, Jennifer Keiser, Stella Kepha, Virak Khieu, Alejandro Krolewiecki, Jean B Mbonigaba, Jose Muñoz, Francisca Mutapi, Valdemiro Novela, Susana Vaz Nery, Luc E Coffeng, Sake J de Vlas, Jessica Bartoszko, Lorenzo Moja, Denise Mupfasoni, Antonio Montresor
Journal: The Lancet Infectious Diseases (2024)
Biofunctional Supramolecular Injectable Hydrogel with Spongy-Like Metal-Organic Coordination for Effective Repair of Critical-Sized Calvarial Defects
Authors: Yingqi Chen, Zuocheng Qiu, Xueling Hu, Tiehua Wang, Guoqing Li, Ziling Tang, Chongzhou Fang, Weibei Sheng, Jin Zhao, Fei Yu, Jian Weng, Anjaneyulu Udduttula, Geetha Manivasagam, Hui Zeng
Journal: Asian Journal of Pharmaceutical Sciences (2024)

In clinical settings, regenerating critical-sized calvarial bone defects presents substantial problems owing to the intricacy of surgical methods, restricted bone growth medications, and a scarcity of commercial bone grafts. To treat this life-threatening issue, improved biofunctional grafts capable of properly healing critical-sized bone defects are required. In this study, we effectively created anti-fracture hydrogel systems using spongy-like metal-organic (magnesium-phosphate) coordinated chitosan-modified injectable hydrogels (CPMg) loaded with a bioinspired neobavaisoflavone (NBF) component. The CPMg-NBF hydrogels showed outstanding anti-fracture capabilities during compression testing and retained exceptional mechanical stability even after 28 d of immersion in phosphate-buffered saline. They also demonstrated prolonged and stable release profiles of Mg2+ and NBF. Importantly, CPMg-NBF hydrogels revealed robust biphasic mineralization and were non-toxic to MC3T3-E1 cells. To better understand the underlying mechanism of Mg2+ and NBF component, as well as their synergistic effect on osteogenesis, we investigated the expression of key osteogenic proteins in the p38 MAPK and NOTCH pathways. Our results showed that CPMg-NBF hydrogels greatly increased the expression of osteogenic proteins (Runx2, OCN, OPN, BMPS and ALP). In vivo experiments showed that the implantation of CPMg-NBF hydrogels resulted in a significant increase in new bone growth within critical-sized calvarial defects. Based on these findings, we expect that the CPMg-NBF supramolecular hydrogel has tremendous promise for use as a therapeutic biomaterial for treating critical-sized calvarial defects.
Akkermansia muciniphila-derived acetate activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis in metabolic-associated fatty liver disease
Authors: Aoxiang Zhuge, Shengjie Li, Shengyi Han, Yin Yuan, Jian Shen, Wenrui Wu, Kaicen Wang, Jiafeng Xia, Qiangqiang Wang, Yifeng Gu, Enguo Chen, Lanjuan Li
Journal: Acta Pharmaceutica Sinica B (2024)

Emerging evidences have indicated the role of ferroptosis in the progression of metabolic-associated fatty liver disease (MAFLD); thus, inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics. Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila (A. muc); however, whether it can alleviate ferroptosis remains unclear. The current study indicates A. muc intervention efficiently reversed high-fat high-fructose diet (HFHFD)-induced lipid peroxidation and ferroptosis in the liver. These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1α axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon A. muc treatment, and acetate was identified as a key activator of hepatic AMPK signalling. Mechanistically, microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate (AMP), which triggered AMPK activation. Furthermore, a colonization assay in germ-free mice confirmed that A. muc mediated antiferroptotic effects in the absence of other microbes. These data indicated that A. muc exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid (PUFA) synthesis.
Pembrolizumab With or Without Maintenance Olaparib for Metastatic Squamous Non–Small-Cell Lung Cancer That Responded to First-Line Pembrolizumab Plus Chemotherapy
Authors: Maximilian Hochmair, Michael Schenker, Manuel Cobo Dols, Tae Min Kim, Ozgur Ozyilkan, Maria Smagina, Leonova Viktoriya, Terufumi Kato, Alexander Fedenko, Flavia De Angelis, Achim Rittmeyer, Jhanelle E Gray, Alastair Greystoke, Himani Aggarwal, Qinlei Huang, Bin Zhao, Humberto Lara-Guerra, Ernest Nadal
Journal: Journal of Thoracic Oncology (2024)
Host RNA N6-methyladenosine and incoming DNA N6-methyldeoxyadenosine modifications cooperatively elevate the condensation potential of DNA to activate immune surveillance
Authors: Na Wang, Qiaoling Liu, Bo Wang, Zhuo Yang, Siru Li, Ran Li, Xinyuan Liang, Jiayu Fan, Hui Wang, Zhen Sun, Ling Dong, Yueru Hou, Shengnan Wang, Chengli Song, Yang Wang, Chunshan Quan, Qingkai Yang, Lina Wang
Journal: Molecular Therapy (2024)
Promoting Translational Readthrough of Nonsense Mutations in Cystic Fibrosis Mouse Model: Assessing the Biodistribution and Efficacy of the NV848 1,2,4-Oxadiazole Compound for the Rescue of the CFTR protein Expression
Authors: Ignazio Fiduccia, Federica Corrao, Maria Grazia Zizzo, Riccardo Perriera, Francesco Genovese, Emanuele Vitale, Davide Ricci, Raffaella Melfi, Marco Tutone, Andrea Pace, Laura Lentini, Ivana Pibiri
Journal: Molecular Therapy (2024)
Multimodal pancreatic cancer detection using methylated DNA biomarkers in pancreatic juice and plasma CA 19-9: A prospective multicenter study
Authors: Megan M L Engels, Calise K Berger, Douglas W Mahoney, Sanne A Hoogenboom, Dhruv Sarwal, Derk C F Klatte, Jaime De La Fuente, Sonal Gandhi, William R Taylor, Patrick H Foote, Karen A Doering, Adriana M Delgado, Kelli N Burger, Barham K Abu Dayyeh, Aliana Bofill-Garcia, Bhaumik Brahmbhatt, Vinay Chandrasekhara, Ferga C Gleeson, Victoria Gomez, Vivek Kumbhari, Ryan J Law, Frank J Lukens, Massimo Raimondo, Elizabeth Rajan, Andrew C Storm, Eric J Vargas Valls, Jeanin E van Hooft, Michael B Wallace, John B Kisiel, Shounak Majumder
Journal: Clinical Gastroenterology and Hepatology (2024)
Enhanced mucosal antibody- and T-cell responses against SARS-CoV-2 after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.
Authors: Gabriel Laghlali, Matthew J Wiest, Dilara Karadag, Prajakta Warang, Jessica J O'Konek, Lauren A Chang, Seokchan Park, Vivian Yan, Mohammad Farazuddin, Katarzyna W Janczak, Adolfo García-Sastre, James R Baker, Pamela T Wong, Michael Schotsaert
Journal: Molecular Therapy (2024)
Combined intraocular and intravenous gene delivery for therapy of gyrate atrophy of the choroid and retina
Authors: Fabio Dell'Aquila, Roberto Di Cunto, Elena Marrocco, Eugenio Del Prete, Alfonso D'Alessio, Lucia De Stefano, Simone Notaro, Edoardo Nusco, Alberto Auricchio
Journal: Molecular Therapy (2024)
Pathologic complete response (pCR) rates for patients with HR+/HER2- high-risk, early-stage breast cancer (EBC) by clinical and molecular features in the phase II I-SPY2 clinical trial
Authors: L A Huppert, D Wolf, C Yau, L Brown-Swigart, G L Hirst, C Isaacs, L Pusztai, P R Pohlmann, A DeMichele, R Shatsky, D Yee, A Thomas, R Nanda, J Perlmutter, D Heditsian, N Hylton, F Symmans, L J Van't Veer, L Esserman, H S Rugo
Journal: Annals of Oncology (2024)
A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses
Authors: Wenqiang Shi, Wei Xu, Luyao Song, Qiongya Zeng, Gen Qi, Ying Qin, Zhikun Li, Xianglei Liu, Zheng Jiao, Yonggang Zhao, Nan Liu, Huili Lu
Journal: Molecular Therapy (2024)
Introducing a G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.
Authors: Chang Li, Aphrodite Georgakopoulou, Kiriaki Paschoudi, Anna K Anderson, Lishan Huang, Sucheol Gil, Maria Giannaki, Efthymia Vlachaki, Gregory A Newby, David R Liu, Evangelia Yannaki, Hans-Peter Kiem, André Lieber
Journal: Molecular Therapy (2024)
Navigating the Orphan Medicinal Product Designation: Evidence Requirements for Gene Therapies in Europe
Authors: G M Palomo, T Pose-Boirazian, F Naumann-Winter, E Costa, D M Duarte, M E Kalland, E Malikova, D Matusevicius, D Vitezic, K Larsson, A Magrelli, V Stoyanova-Beninska, S Mariz
Journal: Molecular Therapy (2024)
Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors for recurrent nephrolithiasis among patients with pre-existing nephrolithiasis or gout: target trial emulation studies
Authors: Natalie McCormick, Chio Yokose, Na Lu, Deborah J Wexler, J Antonio Aviña-Zubieta, Mary A De Vera, Saiajay Chigurupati, Kiara Tan, Chixiang Chen, Rozalina McCoy, Gary C Curhan, Hyon K Choi
Journal: BMJ (2024)

To emulate target trials comparing recurrence of nephrolithiasis among patients with pre-existing nephrolithiasis (overall and stratified by concomitant gout) initiating sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus an active comparator.
Reply to Wang et al.
Authors: Nitin Jagtap, Rupjyoti Talukdar, D. Nageshwar Reddy
Journal: Endoscopy (2024)

Letter to: Comments on "Predictors of persistent pain after extracorporeal shockwave lithotripsy for painful chronic calcific pancreatitis"Endoscopy 2024; 56(11): 888-888DOI: 10.1055/a-2336-4274
A single molecule carrier for ocular posterior segment diseases
Authors: Xiao-Ling Zhang, Yu-Xin Yue, Yang Yang, An-Kang Ying, Rong Ma, Jie Chen, Fang-Yuan Chen, Xiao-Yun Hou, Yu-Chen Pan, Da-Zhuang Ren, Tao Yang, Zhi-Qing Li, Dong-Sheng Guo
Journal: Journal of Controlled Release (2024)
The current evidence of solution-focused brief therapy: A meta-analysis of psychosocial outcomes and moderating factors
Authors: E Vermeulen-Oskam, C Franklin, L P M Van't Hof, G J J M Stams, E S van Vugt, M Assink, E J Veltman, A S Froerer, J P C Staaks, A Zhang
Journal: Clinical Psychology Review (2024)
Exploring the diagnostic performance of optimal diagnosis techniques in detecting recurrence
Authors: Xiaohan Jiang, Min Fu, Min Wang, Zhining Fan
Journal: Endoscopy (2024)

Letter to: Linked-color imaging versus high definition white-light endoscopy for evaluation of post-polypectomy scars of nonpedunculated lesions: LCI-Scar studyEndoscopy 2024; 56(04): 283-290DOI: 10.1055/a-2204-3236
Who benefits from long-term plastic stents after walled-off necrosis treatment: prix fixe for all or à la carte?
Authors: Tomotaka Saito, Takuji Iwashita, Sho Takahashi, Mamoru Takenaka, Yousuke Nakai
Journal: Endoscopy (2024)

See also: Impact of long-term transmural plastic stents on recurrence after endoscopic treatment of walled-off pancreatic necrosisEndoscopy 2024; 56(09): 676-683DOI: 10.1055/a-2307-7123
ESGE – shining a light on diversity, equity and inclusion
Authors: Alanna Ebigbo, Maria Pellisé
Journal: Endoscopy (2024)

The European Society of Gastrointestinal Endoscopy (ESGE) was officially established in 1964, and for the past 60 years, ESGE has stood for quality, education, scientific rigor, and promoting research in gastrointestinal endoscopy. The ESGE Days annual congress, numerous workshops, webinars, and of course the guidelines, quality, curriculum, education, and research committees have solidified ESGE's position at the forefront of the global endoscopy community.
No Difference in Prognosis between Atypical Intradermal Smooth Muscle Neoplasms and Dermal Leiomyosarcoma: Local Recurrence, Metastasis, and Overall Survival in a Nationwide Cohort of 423 Patients
Authors: Kiya Abebe, Mathias Ørholt, Erik E F Bak, Andreas Larsen, Anne Lene Wagenblast, Grethe Schmidt, David Hebbelstrup Jensen, Michael M Petersen, Anand C Loya, Søren Daugaard, Mikkel Herly, Jason L Hornick, Thomas Mentzel, Peter Vester-Glowinski
Journal: Journal of the American Academy of Dermatology (2024)
A cross-attention-based deep learning approach for predicting functional stroke outcomes using 4D CTP imaging and clinical metadata
Authors: Kimberly Amador, Noah Pinel, Anthony J Winder, Jens Fiehler, Matthias Wilms, Nils D Forkert
Journal: Medical Image Analysis (2024)

Acute ischemic stroke (AIS) remains a global health challenge, leading to long-term functional disabilities without timely intervention. Spatio-temporal (4D) Computed Tomography Perfusion (CTP) imaging is crucial for diagnosing and treating AIS due to its ability to rapidly assess the ischemic core and penumbra. Although traditionally used to assess acute tissue status in clinical settings, 4D CTP has also been explored in research for predicting stroke tissue outcomes. However, its potential for predicting functional outcomes, especially in combination with clinical metadata, remains unexplored. Thus, this work aims to develop and evaluate a novel multimodal deep learning model for predicting functional outcomes (specifically, 90-day modified Rankin Scale) in AIS patients by combining 4D CTP and clinical metadata. To achieve this, an intermediate fusion strategy with a cross-attention mechanism is introduced to enable a selective focus on the most relevant features and patterns from both modalities. Evaluated on a dataset comprising 70 AIS patients who underwent endovascular mechanical thrombectomy, the proposed model achieves an accuracy (ACC) of 0.77, outperforming conventional late fusion strategies (ACC = 0.73) and unimodal models based on either 4D CTP (ACC = 0.61) or clinical metadata (ACC = 0.71). The results demonstrate the superior capability of the proposed model to leverage complex inter-modal relationships, emphasizing the value of advanced multimodal fusion techniques for predicting functional stroke outcomes.
Insights from the BKEVER Trial comparing everolimus versus mycophenolate mofetil for BK Polyomavirus infection in kidney transplant recipients
Authors: Sophie Caillard, Nicolas Meyer, Morgane Solis, Dominique Bertrand, Maite Jaureguy, Dany Anglicheau, Laure Ecotiere, Matthias Buchler, Nicolas Bouvier, Betoul Schvartz, Jean Philippe Rerolle, Anne Elisabeth Heng, Lionel Couzi, Agnes Duveau, Emmanuel Morelon, Yann LeMeur, Léonard Golbin, Eric Thervet, Ilies Benotmane, Samira Fafi-Kremer
Journal: Kidney International (2024)
Eosinophil extracellular traps drive T follicular helper cell differentiation via VIRMA-dependent MAF stabilization in bullous pemphigoid
Authors: Shengxian Shen, Hui Fang, Xia Li, Yifan Zhou, Xin Tang, Haijun Miao, Liang Li, Jiaoling Chen, Ke Xue, Chen Zhang, Mengyang Chu, Bingyu Pang, Yaxing Bai, Hongjiang Qiao, Erle Dang, Shuai Shao, Gang Wang
Journal: Journal of Allergy and Clinical Immunology (2024)
Blood markers for type-1,-2, and -3 inflammation are associated with severity of acutely decompensated cirrhosis
Authors: Zhujun Cao, Yujing Yao, Minghao Cai, Chenxi Zhang, Yuhan Liu, Haiguang Xin, Baoyan An, Hui Wang, Yide Lu, Ziqiang Li, Yaoxing Chen, Yan Huang, Min Xin, Ruokun Li, Zhuping Qian, Yi Zhou, Xiaogang Xiang, Richard Moreau, Qing Xie
Journal: Journal of Hepatology (2024)
Bimetallic Peroxide-Based Nanotherapeutics for Immunometabolic Intervention and Induction of Immunogenic Cell Death to Augment Cancer Immunotherapy
Authors: Min Han, Shiying Zhou, Zunde Liao, Chen Zishan, Xiangting Yi, Chuanbin Wu, Dongmei Zhang, Yao He, Kam W Leong, Yiling Zhong
Journal: Biomaterials (2024)
Ru Single-Atom Nanozymes Targeting ROS-Ferroptosis Pathways for Enhanced Endometrial Regeneration in Intrauterine Adhesion Therapy
Authors: Yuxiang Liang, Jian Meng, Zhaowei Yu, Yuqian Guo, Xiao Zhang, Yujia Yan, Shaobo Du, Shanshan Jin, Jing Li, Hailan Yang, Xiaozheng Zhang, Zhizhen Liu, Liping Li, Jun Xie
Journal: Biomaterials (2024)
Liver Cancer in 2021: Global Burden of Disease Study
Authors: En Ying Tan, Pojsakorn Danpanichkul, Jie Ning Yong, Zhenning Yu, Darren Jun Hao Tan, Wen Hui Lim, Benjamin Koh, Ryan Yan Zhe Lim, Ethan Kai Jun Tham, Kartik Mitra, Asahiro Morishita, Yao-Chun Hsu, Ju Dong Yang, Hirokazu Takahashi, Ming-Hua Zheng, Atsushi Nakajima, Cheng Han Ng, Karn Wijarnpreecha, Mark D Muthiah, Amit G Singal, Daniel Q Huang
Journal: Journal of Hepatology (2024)
Exercise-changed gut mycobiome as a potential contributor to metabolic benefits in diabetes prevention: an integrative multi-omics study
Authors: Yao Wang, Jiarui Chen, Yueqiong Ni, Yan Liu, Xiang Gao, Michael Andrew Tse, Gianni Panagiotou, Aimin Xu
Journal: Gut Microbes (2024)

Background The importance of gut microbes in mediating the benefits of lifestyle intervention is increasingly recognized. However, compared to the bacterial microbiome, the role of intestinal fungi in exercise remains elusive. With our established randomized controlled trial of exercise intervention in Chinese males with prediabetes (n = 39, ClinicalTrials.gov:NCT03240978), we investigated the dynamics of human gut mycobiome and further interrogated their associations with exercise-elicited outcomes using multi-omics approaches.
From Roe to Dobbs: 50 Years of Cause and Effect of US State Abortion Regulations
Authors: Caitlin Myers
Journal: Annual Review of Public Health (2024)

The Roe era was hardly a monolith. For more than 50 years—beginning with abortion reforms in the 1960s and continuing through the Dobbs decision in 2022—state regulations of abortion were neither uniform nor consistent. States reformed and repealed abortion bans leading up to the Roe decision in 1973. Following Roe, they enacted both demand-side regulations of people seeking abortions and supply-side regulations of people providing abortions. The resulting laboratory of state policies affords natural experiments that have yielded evidence on the effects of abortion regulations on demographic, health, economic, and other social outcomes. I present a brief history of state policy variation from 1967 through 2016 and review the empirical scholarship studying its effects. This literature demonstrates that the liberalization of abortion access in the 1960s and 1970s allowed women greater control over their fertility, resulting in increased educational attainment and earnings. Subsequent state restrictions in the 1980s through 2010s had the opposite effect, particularly when they increased the financial and logistical costs of obtaining an abortion. I conclude with a discussion of implications for the post-Dobbs era, considering to what extent evidence from the past foretells the future.
RNA Damage Responses in Cellular Homeostasis, Genome Stability, and Disease
Authors: Hani S. Zaher, Nima Mosammaparast
Journal: Annual Review of Pathology Mechanisms of Disease (2024)

All cells are exposed to chemicals that can damage their nucleic acids. Cells must protect these polymers because they code for key factors or complexes essential for life. Much of the work on nucleic acid damage has naturally focused on DNA, partly due to the connection between mutagenesis and human disease, especially cancer. Recent work has shed light on the importance of RNA damage, which triggers a host of conserved RNA quality control mechanisms. Because many RNA species are transient, and because of their ability to be retranscribed, RNA damage has largely been ignored. Yet, because of the connection between damaged RNA and DNA during transcription, and the association between essential complexes that process or decode RNAs, notably spliceosomes and ribosomes, the appropriate handling of damaged RNAs is critical for maintaining cellular homeostasis. This notion is bolstered by disease states, including neurodevelopmental and neurodegenerative diseases, that may arise upon loss or misregulation of RNA quality control mechanisms.
Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma
Authors: Megan E. Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A. Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A. Behrmann, Katherine E. Vest, James Brugarolas, Pier Paolo Scaglioni, David R. Plas, Krushna C. Patra, Shuchi Gulati, Julio A. Landero Figueroa, Jarek Meller, John T. Cunningham, Maria F. Czyzyk-Krzeska
Journal: Cancer Discovery (2024)

Abstract Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu’s role in ccRCC. Elevated Cu levels stimulate CuCOX biogenesis, providing bioenergetic and biosynthetic benefits that promote tumor growth. This effect is complemented by glucose-dependent glutathione production, which facilitates detoxification and mitigates Cu-H2O2 toxicity. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics reveal increased oxidative metabolism, altered glutathione and Cu metabolism, and diminished HIF activity during ccRCC progression. Thus, Cu drives an integrated oncogenic remodeling of bioenergetics, biosynthesis, and redox homeostasis, fueling ccRCC growth, which can be targeted for new therapeutic approaches.