Article
Biochemistry & Molecular Biology
Changxu Wang, Qilai Long, Qiang Fu, Qixia Xu, Da Fu, Yan Li, Libin Gao, Jianming Guo, Xiaoling Zhang, Eric W-F Lam, Judith Campisi, Yu Sun
Summary: The soluble factor EREG, produced by senescent stromal cells, plays a crucial role in the development and malignant progression of cancer cells in the tumor microenvironment. Targeting EREG in treatment-damaged TME significantly improves cancer therapeutic efficacy and shows potential value in translational medicine.
Article
Biochemistry & Molecular Biology
Shiqi Ma, Lu Zhang, Yuan Ren, Wei Dai, Tingqing Chen, Liping Luo, Juan Zeng, Kun Mi, Jinyi Lang, Bangrong Cao
Summary: This study revealed the impact of EREG on EGFR-TKI sensitivity and its mechanisms in NSCLC, suggesting macrophage-produced EREG as a potential novel regulator and biomarker for EGFR-TKI therapy in NSCLC.
Article
Medicine, General & Internal
Rona Yaeger, Jared Weiss, Meredith S. Pelster, Alexander Spira, Minal Barve, Sai-Hong Ou, Ticiana A. Leal, Tanios S. Bekaii-Saab, Cloud P. Paweletz, Grace A. Heavey, James G. Christensen, Karen Velastegui, Thian Kheoh, Hirak Der-Torossian, Samuel J. Klempner
Summary: In this study, the researchers investigated the clinical efficacy of adagrasib in combination with cetuximab for heavily pretreated patients with metastatic colorectal cancer harboring mutant KRAS G12C. The results showed that the overall response rate was 19% in the adagrasib monotherapy group, with a median progression-free survival of 5.6 months, and 46% in the combination therapy group, with a median progression-free survival of 6.9 months. Both groups experienced reversible adverse events.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Review
Biochemistry & Molecular Biology
Wan-Li Cheng, Po-Hao Feng, Kang-Yun Lee, Kuan-Yuan Chen, Wei-Lun Sun, Nguyen Van Hiep, Ching-Shan Luo, Sheng-Ming Wu
Summary: EREG activates EGFR signaling pathways to promote cancer progression and is associated with specific types of tumors and drug resistance. Tailored therapy should be chosen based on different oncogenic mutations and cellular contexts, such as combination treatment targeting EREG/EGFR and other driver mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Salvatore J. Coniglio, Jeffrey E. Segall
Summary: High grade glioma is a deadly cancer type with high invasiveness, making understanding its invasion mechanisms crucial for treatment. Research has shown that tumor-associated microglia may promote glioma cell invasion by upregulating factors like AREG.
Article
Oncology
Daniel J. Becker, Kyung M. Lee, Steve Y. Lee, Kristine E. Lynch, Danil Makarov, Scott E. Sherman, Christy D. Morrissey, Michael J. Kelley, Julie A. Lynch
Summary: This study evaluated the clinical use of KRAS testing and EGFR mAb treatment in colorectal cancer patients in the Veterans Affairs Healthcare System. The results showed underuse of KRAS testing, especially among older patients and those treated at lower-volume CRC centers, as well as high rates of potentially guideline discordant underuse of EGFR mAb in patients with KRAS-WT tumors. Efforts to understand barriers to precision oncology are needed to maximize patient benefit.
JCO PRECISION ONCOLOGY
(2021)
Article
Oncology
Philip C. Mack, Jieling Miao, Mary W. Redman, James Moon, Sarah B. Goldberg, Roy S. Herbst, Mary Ann Melnick, Zenta Walther, Fred R. Hirsch, Katerina Politi, Karen Kelly, David R. Gandara
Summary: This study investigates the dynamic changes in circulating tumor DNA (ctDNA) as an early indicator of treatment outcome. The results show that complete clearance of mutant EGFR ctDNA at 8 weeks is highly and significantly predictive of decreased risk of progression and death in patients with EGFR mutation tissue-positive non-small cell lung cancer.
CLINICAL CANCER RESEARCH
(2022)
Article
Pharmacology & Pharmacy
Yu-Wei Lin, Hung-Cheng Su, Emmanuel Naveen Raj, Kuang-Kai Liu, Chien-Jen Chang, Tzu-Chia Hsu, Po-Yun Cheng, Rou-Hsin Wang, Yen-Her Lai, Chien-Hung Chen, Yen-Cheng Lin, Jui- Chao
Summary: Nanoprobes provide advantages for real-time monitoring of tumor markers and tumorigenesis during cancer progression and development. In this study, a carbon-based nanoprobe, nanodiamond (ND), is used for targeting EGFR and monitoring tumorigenesis of human lung cancer cells in vitro and in vivo. The results show that ND-conjugated specific EGFR antibody cetuximab (Cet) can track the location and distribution of EGFR proteins and increase cellular uptake ability of nanocomposites in EGFR-expressed cells.
Article
Multidisciplinary Sciences
Katarzyna M. Tyc, Aslamuzzaman Kazi, Alok Ranjan, Rui Wang, Said M. Sebti
Summary: KRAS mutations are common in pancreatic and lung cancers, but not all mutant tumors are addicted to mutated KRAS. A 30-gene transcriptome signature called KDS30 has been discovered, which encodes a novel EGFR/ERBB2-driven signaling network and predicts KRAS oncogene addiction. High KDS30 tumors from KRAS-mutant patients are enriched in genes upregulated by EGFR, ERBB2, KRAS, or MEK. Combination therapy with EGFR/ERBB2 and MEK inhibitors inhibits tumor growth and prolongs survival in high KDS30 KRAS-mutant lung and pancreatic xenografts, suggesting its potential clinical application.
Article
Multidisciplinary Sciences
Koki Makabe, Takeshi Yokoyama, Shiro Uehara, Tomomi Uchikubo-Kamo, Mikako Shirouzu, Kouki Kimura, Kouhei Tsumoto, Ryutaro Asano, Yoshikazu Tanaka, Izumi Kumagai
Summary: The study focused on the interaction of an antagonistic anti-EGFR antibody clone, 528, with the extracellular region of EGFR. The findings showed that 528 recognizes the tertiary structure of EGFR and competes with EGF and cetuximab for binding, explaining its antagonistic activity.
SCIENTIFIC REPORTS
(2021)
Review
Immunology
Balakarthikeyan Janani, Mayakrishnan Vijayakumar, Kannappan Priya, Jin Hee Kim, D. S. Prabakaran, Mohammad Shahid, Sameer Al-Ghamdi, Mohammed Alsaidan, Nasraddin Othman Bahakim, Mohammad Hassan Abdelzaher, Thiyagarajan Ramesh
Summary: Colorectal carcinoma is a common and lethal form of cancer, with a high rate of metastasis. Targeted nanotherapy, particularly targeting EGFR, has the potential to improve surgical control and reduce tumor-related mortality. Antibodies conjugated with drug-loaded carriers can increase drug effectiveness and quantity delivered to the target site.
Article
Oncology
Lu Yang, Arup Bhattacharya, Yun Li, Sandra Sexton, Xiang Ling, Fengzhi Li, Yuesheng Zhang
Summary: Resistance to EGFR inhibitors in colorectal cancer is primarily due to the inability of the inhibitors to downregulate their target. The combination treatment with PEPDG278D overcomes this resistance.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Article
Multidisciplinary Sciences
Chun Hu, Carlos A. Leche, Anatoly Kiyatkin, Zhaolong Yu, Steven E. Stayrook, Kathryn M. Ferguson, Mark A. Lemmon
Summary: The epidermal growth factor receptor (EGFR) frequently mutates in human cancer, and is an important therapeutic target. However, EGFR inhibitors have limited effectiveness in glioblastoma multiforme (GBM) due to exclusive mutations in the extracellular region. This study reveals that GBM mutations impair EGFR's ability to distinguish between activating ligands, which may have implications for therapeutic targeting.
Article
Cell Biology
Hong Lu, Hao Zhang, Mei-lin Weng, Jin Zhang, Nan Jiang, Juan P. Cata, Duan Ma, Wan-Kun Chen, Chang-Hong Miao
Summary: Morphine treatment can activate MOR and promote proliferation, migration, and invasion in CRC cells, as well as increase resistance to cetuximab. It induces EGFR transactivation, leading to protumoral effects in CRC cell lines.
JOURNAL OF CELLULAR PHYSIOLOGY
(2021)
Article
Cell Biology
Bhuminder Singh, Galina Bogatcheva, Evan Krystofiak, Eliot T. McKinley, Salisha Hill, Kristie Lindsey Rose, James N. Higginbotham, Robert J. Coffey
Summary: This study demonstrates that induction of apical mistrafficking of Y156A EREG can lead to the formation of ectopic lumens in fully formed MDCK cysts, involving metalloprotease-mediated cleavage of EREG and subsequent EGFR activity.
JOURNAL OF CELL SCIENCE
(2021)
Article
Oncology
Linda A. J. Hendricks, Nicoline Hoogerbrugge, Arjen R. Mensenkamp, Joan Brunet, Roser Lleuger-Pujol, Hildegunn Hoberg-Vetti, Marianne Tveit Haavind, Giovanni Innella, Daniela Turchetti, Stefan Aretz, Isabel Spier, Marc Tischkowitz, Arne Jahn, Thera P. Links, Maran J. W. Olderode-Berends, Ana Blatnik, Edward M. Leter, D. Gareth Evans, Emma R. Woodward, Verena Steinke-Lange, Violetta C. Anastasiadou, Chrystelle Colas, Marie-Charlotte Villy, Patrick R. Benusiglio, Anna Gerasimenko, Valeria Barili, Maud Branchaud, Claude Houdayer, Bianca Tesi, M. Omer Yazicioglu, Rachel S. van der Post, Janneke H. M. Schuurs-Hoeijmakers, Janet R. Vos, Liselotte P. van Hest, Muriel A. Adank, Floor Duijkers, Maartje Nielsen, Katja C. J. Verbeek, Yvette van Ierland, Jacques C. Giltay
Summary: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast, endometrial, and thyroid cancer. This study aimed to provide more accurate and personalized cancer risks. The results showed that PHTS patients, especially females, have a significantly higher risk of breast, endometrial, and thyroid cancer.
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
(2023)
Article
Chemistry, Applied
Jorge Leal, Gema Dura, Felix A. Jalon, Elisenda Zafon, Anna Massaguer, Jose Vicente Cuevas, Lucia Santos, Ana M. Rodriguez, Blanca R. Manzano
Summary: Luminescent platinum cyclometalated complexes have applications in optoelectronic and biological fields, especially in anticancer activity. A series of these complexes with different ligands were synthesized, and their emission wavelengths could be tuned. Density-functional theory provided descriptions of their molecular orbital characteristics, and time-dependent DFT calculations showed different excited states for different complexes. Biological studies demonstrated that some complexes exhibited cytotoxic activity against human cervical and lung carcinoma cells, and microscopy assays showed their accumulation in cytoplasmic organelles. The disruption of mitochondrial metabolism was observed, leading to a decrease in cellular ATP content. These complexes may have potential as alternative anticancer drugs.
APPLIED ORGANOMETALLIC CHEMISTRY
(2023)
Article
Oncology
Jose Garcia-Pelaez, Rita Barbosa-Matos, Silvana Lobo, Alexandre Dias, Luzia Garrido, Sergio Castedo, Sonia Sousa, Hugo Pinheiro, Liliana Sousa, Rita Monteiro, Joaquin J. Maqueda, Susana Fernandes, Fatima Carneiro, Nadia Pinto, Carolina Lemos, Carla Pinto, Manuel R. Teixeira, Stefan Aretz, Svetlana Bajalica-Lagercrantz, Judith Balmana, Ana Blatnik, Patrick R. Benusiglio, Maud Blanluet, Vincent Bours, Hilde Brems, Joan Brunet, Daniele Calistri, Gabriel Capella, Sergio Carrera, Chrystelle Colas, Karin Dahan, Robin de Putter, Camille Desseignes, Elena Dominguez-Garrido, Conceicao Egas, D. Gareth Evans, Damien Feret, Eleanor Fewings, Rebecca C. Fitzgerald, Florence Coulet, Maria Garcia-Barcina, Maurizio Genuardi, Lisa Golmard, Karl Hackmann, Helen Hanson, Elke Holinski-Feder, Robert Huneburg, Mateja Krajc, Kristina Lagerstedt-Robinson, Conxi Lazaro, Marjolijn J. L. Ligtenberg, Cristina Martinez-Bouzas, Sonia Merino, Genevieve Michils, Srdjan Novakovic, Ana Patino-Garcia, Guglielmina Nadia Ranzani, Evelin Schrock, Ines Silva, Catarina Silveira, Jose L. Soto, Isabel Spier, Verena Steinke-Lange, Gianluca Tedaldi, Maria-Isabel Tejada, Emma R. Woodward, Marc Tischkowitz, Nicoline Hoogerbrugge, Carla Oliveira
Summary: This study analyzed families carrying rare CDH1 variants, comparing the cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV) or missense variants of unknown significance, and evaluated the performance of expanded criteria for CDH1 testing. The results showed that PV/LPV carriers were positively associated with lobular breast cancer, diffuse gastric cancer, and gastric cancer, while missense variants of unknown significance did not show this positive association.
Editorial Material
Biochemistry & Molecular Biology
Isabel Quintana, Mariona Terradas, Pilar Mur, Iris B. A. W. te Paske, Sophia Peters, Isabel Spier, Verena Steinke-Lange, Claudia Maestro, David Torrents, Montserrat Puiggros, Romina Royo, Raul Tonda, Genis Parra, Davide Piscia, Sergi Beltran, Matilde Navarro, Virginia Pinol, Joan Brunet, Noemi Gonzalez-Abuin, Gemma Aiza, Anna Sommer, Yasmijn van Herwaarden, Galuh Astuti, Elke Holinski-Feder, Nicoline Hoogerbrugge, Richarda M. de Voer, Stefan Aretz, Gabriel Capella, Laura Valle
Review
Medicine, General & Internal
Charlotte Carton, D. Gareth Evans, Ignacio Blanco, Reinhard E. Friedrich, Rosalie E. Ferner, Said Farschtschi, Hector Salvador, Amedeo A. Azizi, Victor Mautner, Claas Roehl, Sirkku Peltonen, Stavros Stivaros, Eric Legius, Rianne Oostenbrink
Summary: This study aims to integrate information on NF1-associated tumors to assist healthcare professionals in tumor surveillance of NF1 individuals. Personalized and targeted tumor management proposals have been defined to ensure appropriate care for those in need.
Article
Genetics & Heredity
Emadeldin Hassanin, Isabel Spier, Dheeraj R. Bobbili, Rana Aldisi, Hannah Klinkhammer, Friederike David, Nuria Duenas, Robert Hueneburg, Claudia Perne, Joan Brunet, Gabriel Capella, Markus M. Noethen, Andreas J. Forstner, Andreas Mayr, Peter Krawitz, Patrick May, Stefan Aretz, Carlo Maj
Summary: The effect of common genetic variants associated with colorectal cancer (CRC) can be assessed using polygenic risk scores (PRS), which can be used for risk stratification. The PRS, along with carrier status and family history, contribute to CRC risk prediction and can improve personalized risk stratification.
BMC MEDICAL GENOMICS
(2023)
Article
Oncology
Paula Peremiquel-Trillas, David Gomez, Jose Manuel Martinez, Sergi Fernandez-Gonzalez, Jon Frias-Gomez, Sonia Paytubi, Beatriz Pelegrina, Marta Pineda, Joan Brunet, Jordi Ponce, Xavier Matias-Guiu, Xavier Bosch, Silvia de Sanjose, Laia Bruni, Laia Alemany, Laura Costas, Mireia Diaz
Summary: New approaches using molecular biomarkers show promise in early detection of endometrial cancer. This study evaluates the effectiveness and cost-effectiveness of introducing molecular testing for postmenopausal bleeding compared to the current strategy. Results suggest that the molecular strategy is more effective and less expensive, making it a potentially cost-effective option.
BRITISH JOURNAL OF CANCER
(2023)
Article
Genetics & Heredity
Adria Lopez-Fernandez, Guillermo Villacampa, Monica Salinas, Elia Grau, Esther Darder, Estela Carrasco, Ares Solanes, Angela Velasco, Maite Torres, Elisabet Munte, Silvia Iglesias, Sara Torres-Esquius, Noemi Tuset, Orland Diez, Conxi Lazaro, Joan Brunet, Sergi Corbella, Judith Balmana
Summary: This study aims to analyze the psychological impact of genetic testing and to identify the profile of individuals at higher risk. Factors such as high neuroticism score, high baseline cancer worry, and a positive genetic test result were found to be independently associated with higher psychological impact. The highest risk profile consisted of women with high levels of neuroticism and a positive result. Uncertainty was mainly associated with high neuroticism levels, regardless of the genetic test result. A holistic approach to personalized genetic counseling should include the assessment of personality dimensions.
JOURNAL OF GENETIC COUNSELING
(2023)
Article
Genetics & Heredity
Nuria Duenas, Hannah Klinkhammer, Nuria Bonifaci, Isabel Spier, Andreas Mayr, Emadeldin Hassanin, Anna Diez-Villanueva, Victor Moreno, Marta Pineda, Carlo Maj, Gabriel Capella, Stefan Aretz, Joan Brunet
Summary: Polygenic risk scores (PRSs) have been used to stratify colorectal cancer (CRC) risk in the general population, but its role in Lynch syndrome (LS) is still conflicting. This study aimed to assess the ability of PRS to refine CRC risk prediction in European-descendant individuals with LS. The results showed that PRS was not significantly associated with CRC risk in the entire cohort, but it was slightly associated with an increased risk of CRC or advanced adenoma (AA) in individuals with early-onset disease.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Oncology
Lenka Stolarova, Petra Kleiblova, Petra Zemankova, Barbora Stastna, Marketa Janatova, Jana Soukupova, Maria Isabel Achatz, Christine Ambrosone, Paraskevi Apostolou, Banu K. Arun, Paul Auer, Mollie Barnard, Birgitte Bertelsen, Biobank Japan, Marinus J. Blok, Nicholas Boddicker, Joan Brunet, Elizabeth S. Burnside, Mariarosaria Calvello, Ian Campbell, Sock Hoai Chan, Fei Chen, Jian Bang Chiang, Anna Coppa, Laura Cortesi, Ana Crujeiras-Gonzalez, Consortium Czecanca, Kim De Leeneer, Robin De Putter, Allison DePersia, Lisa Devereux, Susan Domchek, Anna Efremidis, Christoph Engel, Corinna Ernst, D. Gareth R. Evans, Lidia Feliubadalo, Florentia Fostira, Olivia Fuentes-Rios, Encarna B. Gomez-Garcia, Sara Gonzalez, Christopher Haiman, Thomas van Overeem Hansen, Jan Hauke, James Hodge, Chunling Hu, Hongyan Huang, Nur Diana Binte Ishak, Yusuke Iwasaki, Irene Konstantopoulou, Peter Kraft, James Lacey, Conxi Lazaro, Na Li, Weng Khong Lim, Sara Lindstrom, Adriana Lori, Elana Martinez, Alexandra Martins, Koichi Matsuda, Giuseppe Matullo, Simone McInerny, Kyriaki Michailidou, Marco Montagna, Alvaro N. A. Monteiro, Luigi Mori, Katherine Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Janet E. Olson, Julie Palmer, Barbara Pasini, Alpa Patel, Maria Piane, Bruce Poppe, Paolo Radice, Alessandra Renieri, Nicoletta Resta, Marcy E. Richardson, Toon Rosseel, Kathryn J. Ruddy, Marta Santamarina, Elizabeth Santana Dos Santos, Lauren Teras, Amanda E. Toland, Amy Trentham-Dietz, Celine M. Vachon, Alexander E. Volk, Nana Weber-Lassalle, Jeffrey N. Weitzel, Lisa Wiesmuller, Stacey Winham, Siddhartha Yadav, Drakoulis Yannoukakos, Song Yao, Valentina Zampiga, Magnus Zethoven, Ze Wen Zhang, Tomas Zima, Amanda B. Spurdle, Vega Ana, Maria Rossing, Jesus Del Valle, Arcangela De Nicolo, Eric Hahnen, Kathleen B. M. Claes, Joanne Ngeow, Yukihide Momozawa, Paul A. James, Fergus J. Couch, Libor Macurek, Zdenek Kleibl
Summary: This study determined the functional consequences of CHEK2 missense variants in patients with breast cancer. The study found that carriers of functionally impaired variants were associated with a moderate risk, while carriers of functionally wild-type/intermediate variants had no clinically relevant breast cancer risk.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Laura Costas, Irene Onieva, Beatriz Pelegrina, Fatima Marin, Alvaro Carmona, Marta Lopez-Querol, Jon Frias-Gomez, Paula Peremiquel-Trillas, Jose Manuel Martinez, Eduard Dorca, Joan Brunet, Marta Pineda, Jordi Ponce, Xavier Matias-Guiu, Silvia de Sanjose, Francesc Xavier Bosch, Laia Alemany, Sonia Paytubi
Summary: This study evaluated the use of urine samples for the detection and molecular classification of endometrial cancer. Mutations in DNA from urine supernatant samples were identified in 100% of endometrial cancer cases, while only one control showed variants at a low frequency. The results suggest that urine samples may offer a user-friendly and reliable tool for endometrial cancer detection and classification.
CLINICAL CANCER RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Mariona Terradas, Noemi Gonzalez-Abuin, Sandra Garcia-Mulero, Julen Viana-Errasti, Gemma Aiza, Josep M. Piulats, Joan Brunet, Gabriel Capella, Laura Valle
Summary: Germline mutations in MBD4 cause an autosomal recessive syndrome characterized by increased risk of acute myeloid leukemia, gastrointestinal polyposis, colorectal cancer, uveal melanoma, and schwannomas. However, a study of 728 patients with colorectal cancer, polyposis, and other suggestive phenotypes found that the identified heterozygous MBD4 variants were not associated with the disease.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Genetics & Heredity
Sara Fernandez-Castillejo, Barbara Roig, Mireia Mele, Sara Serrano, Monica Salvat, Montserrat Querol, Joan Brunet, Marta Pineda, Adela Cisneros, David Parada, Joan Badia, Joan Borras, Marta Rodriguez-Balada, Josep Guma
Summary: Multigene panel testing by next-generation sequencing can detect germline pathogenic or likely pathogenic variants in genes beyond those associated with a certain cancer phenotype. Opportunistic genetic screening based on this method can increase the diagnostic yield, facilitate the diagnosis of asymptomatic individuals, and provide an opportunity for early management of cancer.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Medicine, General & Internal
Beatriz Pelegrina, Sonia Paytubi, Fatima Marin, Jose Manuel Martinez, Alvaro Carmona, Jon Frias-Gomez, Paula Peremiquel-Trillas, Eduard Dorca, Alba Zanca, Marta Lopez-Querol, Irene Onieva, Yolanda Benavente, Marc Barahona, Sergi Fernandez-Gonzalez, Javier De Francisco, Victor Cano, August Vidal, Lara Pijuan, Julia Canet-Hermida, Nuria Duenas, Joan Brunet, Marta Pineda, Xavier Matias-Guiu, Jordi Ponce, Francesc Xavier Bosch, Silvia De Sanjose, Laia Alemany, Laura Costasa
Summary: This study aimed to evaluate genetic alterations to detect and molecularly classify cases of endometrial cancer using non-invasive samples. The research found that molecular classification of endometrial cancer using clinician-collected and self-collected cervicovaginal samples showed significant differences in disease-free survival. Non-invasive molecular classification has the potential to improve patient care and survival.
Article
Cell Biology
Elisabet Cuyas, Sara Verdura, Begona Martin-Castillo, Javier A. Menendez
Summary: MOTS-c is an exercise-mimetic peptide expressed in multiple tissues and can be detected as a circulating hormone in the blood. Its mechanisms of action involve insulin sensitization, enhanced glucose utilization, suppression of mitochondrial respiration, and targeting of the folate-AICAR-AMPK pathway. The regulatory actions of the anti-diabetic drug metformin on MOTS-c have not been evaluated in detail.