المؤلفون: Albert Grinshpun, Douglas Russo, Wen Ma, Ana Verma, Francisco Hermida-Prado, Shira Sherman, Giorgio Gaglia, Sheheryar Kabraji, Gregory Kirkner, Melissa E. Hughes, Nancy U. Lin, Zachary Sandusky, Agostina Nardone, Cristina Guarducci, Quang-De Nguyen, Sandro Santagata, Zsuzsanna Nagy, Rinath Jeselsohn

المصدر: npj Breast Cancer, Vol 10, Iss 1, Pp 1-12 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2374-4677Test

الوصول الحر: https://doaj.org/article/7c7a103652a4404eac1f649798184d56Test

المؤلفون: Peter Tsvetkov, Shannon Coy, Boryana Petrova, Margaret Dreishpoon, Ana Verma, Mai Abdusamad, Jordan Rossen, Lena Joesch-Cohen, Ranad Humeidi, Ryan D. Spangler, John K. Eaton, Evgeni Frenkel, Mustafa Kocak, Steven M. Corsello, Svetlana Lutsenko, Naama Kanarek, Sandro Santagata, Todd R. Golub

المصدر: Science

مصطلحات موضوعية: Iron-Sulfur Proteins, Multidisciplinary, Ionophores, Cell Death, Lipoylation, Cell Respiration, Citric Acid Cycle, Dihydrolipoyllysine-Residue Acetyltransferase, Article, Mitochondria, Mice, Hydrazines, Hepatolenticular Degeneration, Animals, Homeostasis, Humans, Regulated Cell Death, Metabolic Networks and Pathways, Copper

الوصف: Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::823d9210499ec728084765ef9240f1cbTest
https://europepmc.org/articles/PMC9273333Test/

المؤلفون: Giorgio Gaglia, Sheheryar Kabraji, Danae Rammos, Yang Dai, Ana Verma, Shu Wang, Caitlin E. Mills, Mirra Chung, Johann S. Bergholz, Shannon Coy, Jia-Ren Lin, Rinath Jeselsohn, Otto Metzger, Eric P. Winer, Deborah A. Dillon, Jean J. Zhao, Peter K. Sorger, Sandro Santagata

المصدر: Nature cell biology. 24(3)

مصطلحات موضوعية: Neoplasms, Cell Cycle, Humans, Cell Biology, Cell Proliferation

الوصف: Proliferation is a fundamental trait of cancer cells, but its properties and spatial organization in tumours are poorly characterized. Here we use highly multiplexed tissue imaging to perform single-cell quantification of cell cycle regulators and then develop robust, multivariate, proliferation metrics. Across diverse cancers, proliferative architecture is organized at two spatial scales: large domains, and smaller niches enriched for specific immune lineages. Some tumour cells express cell cycle regulators in the (canonical) patterns expected of freely growing cells, a phenomenon we refer to as 'cell cycle coherence'. By contrast, the cell cycles of other tumour cell populations are skewed towards specific phases or exhibit non-canonical (incoherent) marker combinations. Coherence varies across space, with changes in oncogene activity and therapeutic intervention, and is associated with aggressive tumour behaviour. Thus, multivariate measures from high-plex tissue images capture clinically significant features of cancer proliferation, a fundamental step in enabling more precise use of anti-cancer therapies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f9304cc071f63f3ed34620ca42a832eeTest
https://pubmed.ncbi.nlm.nih.gov/35292782Test

المؤلفون: Sandro Santagata, Nathanael S. Gray, Theresa D. Manz, Nami Kim, Nobufumi Sekino, Xiao Zhen Zhou, Futoshi Suizu, Giorgio Gaglia, Dipikaa Akshinthala, Shizhong Ke, Benika J. Pinch, Manuel Hidalgo, Babara Wegiel, Kun Ping Lu, Senthil K. Muthuswamy, Yutaka Nezu, Kenoki Ohuchida, Shin Kibe, Gerburg M. Wulf, Chenxi Qiu, Nir London, Tae Ho Lee, Yoshinao Oda, Ana Verma, Kazuhiro Koikawa, John G. Clohessy, Masafumi Nakamura

المصدر: Cell. 184:4753-4771.e27

مصطلحات موضوعية: Tumor microenvironment, Combination therapy, medicine.medical_treatment, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Gemcitabine, Targeted therapy, Cancer immunotherapy, Pancreatic cancer, Cancer cell, medicine, Cancer research, Cancer-Associated Fibroblasts, medicine.drug

الوصف: Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::8f244531e6abf1f689b70ad78c1eb411Test
https://doi.org/10.1016/j.cell.2021.07.020Test

المؤلفون: Pablo Solís-Muñoz, Christopher Willars, Juan Carlos López, Michael A. Heneghan, William Bernal, Julia Wendon, Georg Auzinger, Ana Verma

المصدر: Journal of Infection. 66:80-86

مصطلحات موضوعية: Adult, Male, Microbiology (medical), medicine.medical_specialty, Antifungal Agents, medicine.medical_treatment, Observation, Liver transplantation, Loading dose, Gastroenterology, Cohort Studies, Liver Function Tests, Cholestasis, Amphotericin B, Internal medicine, medicine, Aspergillosis, Humans, Aged, Voriconazole, Analysis of Variance, medicine.diagnostic_test, business.industry, Middle Aged, Triazoles, medicine.disease, Surgery, Pyrimidines, Infectious Diseases, Liver, Elevated transaminases, Female, Chemical and Drug Induced Liver Injury, business, Liver function tests, Fluconazole, medicine.drug

الوصف: There are no studies regarding to these effects in patients with severe liver dysfunction.The aims of this study were to characterize voriconazole hepatotoxicity in patients with severe liver dysfunction and to compare it with a matched cohort treated with liposomal amphotericin B.This is an observational study, in which adults patients treated with at least 4 doses of voriconazole were included. Patients treated with liposomal amphotericin B were used as control group.Sixty nine percent of patients treated with voriconazole showed changes in liver function tests (LFTs) during therapy. They showed elevated transaminases in 35%, cholestasis in 15% or a combination of both in 45%. According to the CTC classification, all patients with hepatotoxicity had a severe reaction. The Roussel Uclaf Causality Assessment Method score in all patients with hepatotoxicity was greater than 8. There was a correlation between initial loading dose greater than 300 mg (4.5 mg/kg) and the risk of hepatotoxicity (p0.001). The control group developed alterations in the LFTs in only 10.3% of patients.Voriconazole should be used with caution in patients with severe liver dysfunction and following liver transplantation, with frequent monitoring of LFTs or using liposomal amphotericin B instead.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2b385318775439c2ff0b2cf199dea5e5Test
https://doi.org/10.1016/j.jinf.2012.09.011Test