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Strategies for senolytic drug discovery

AGING CELL (2023)

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Review Biochemistry & Molecular Biology

Targeting cellular senescence with senotherapeutics: senolytics and senomorphics

Lei Zhang et al.

Summary: The concept of geroscience focuses on targeting the ageing process itself as a means to improve human health. Cellular senescence, a state of irreversible cell arrest, has emerged as a potential therapeutic target to extend healthspan. Senescent cells develop a secretory phenotype that promotes chronic inflammation and tissue dysfunction. Therapeutic drugs that induce selective cell death of senescent cells or suppress the expression of senescence markers are being developed.

FEBS JOURNAL (2023)

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Article Chemistry, Multidisciplinary

Engineering nanoparticle communication in living systems by stigmergy: An application to enhance antitumor therapy in triple-negative breast cancer

Alejandra Estepa-Fernandez et al.

Summary: The engineering of nanoparticle communication has gained attention, but communication between nanoparticles and living systems is still understudied. This study explores a strategy that involves nanoparticle-cell-nanoparticle communication through modifying the environment. The targeted therapy through stigmergy communication effectively inhibits tumor growth and reduces metastases in a mouse model of triple-negative breast cancer with minimal side effects.

NANO TODAY (2023)

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Article Multidisciplinary Sciences

Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types

Chandani Limbad et al.

Summary: Cellular senescence is a leading cause of age-related pathologies, and researchers have identified the gene CRYAB as a key regulator of senescence. Through single-cell RNA sequencing, they discovered that 25-hydroxycholesterol (25HC), a metabolite of cholesterol biosynthesis, has potential as a senolytic drug. They confirmed the senolytic effect of 25HC through inhibitor screening and in vivo experiments.

ISCIENCE (2022)

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Article Multidisciplinary Sciences

Identification of gingerenone A as a novel senolytic compound

Ruin Moaddel et al.

Summary: Senescent cells, which accumulate with aging, have been shown to contribute to age-associated diseases and organ dysfunction. In this study, ginger extract was found to selectively eliminate senescent cells without affecting normal cells. The major components of ginger extract, gingerenone A and 6-shogaol, showed promising senolytic properties and also suppressed the senescence-associated secretory phenotype (SASP). These findings suggest that gingerenone A may have therapeutic benefit in diseases characterized by senescent cell accumulation.

PLOS ONE (2022)

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Review Endocrinology & Metabolism

Cellular Senescence in Diabetes Mellitus: Distinct Senotherapeutic Strategies for Adipose Tissue and Pancreatic β Cells

Takaaki Murakami et al.

Summary: Increased insulin resistance and impaired insulin secretion are significant characteristics of type 2 diabetes mellitus (T2DM). Accumulation of senescent cells in adipose tissues and pancreatic beta-cells contribute to these dysfunctions. Removing senescent cells shows promise in preventing or improving diabetes-related diseases.

FRONTIERS IN ENDOCRINOLOGY (2022)

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Article Biochemistry & Molecular Biology

Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis

Pavel Deryabin et al.

Summary: In this study, a novel approach for senolysis was proposed, which involved disturbing multiple homeostasis-maintaining systems in senescent cells. The ionophore nigericin was found to be able to disrupt several key cellular processes simultaneously, leading to senolytic action towards senescent cells of different origins. The senolytic effect of nigericin was independent of the senescence-inducing stimuli. The study also suggested an interval dosing strategy to minimize negative effects on control cells and maximize the senolytic effect of nigericin.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Article Pharmacology & Pharmacy

Pharmacological senolysis reduces doxorubicin-induced cardiotoxicity and improves cardiac function in mice

Araceli Lerida-Viso et al.

Summary: Many anticancer drugs can cause premature aging in healthy tissues, resulting in accelerated aging processes and adverse effects in patients. Cardiotoxicity is a major limiting factor in the use of doxorubicin as a cancer treatment, leading to long-term morbidity and mortality. In this study, it was demonstrated that induction of senescence in the heart contributes to impaired cardiac function in mice treated with doxorubicin. Elimination of senescent cells using the senolytic Navitoclax significantly reduced senescence and cardiotoxicity markers, and restored cardiac function in mice. These results suggest the potential clinical use of senolytic therapies to alleviate cardiotoxicities induced by chemotherapy.

PHARMACOLOGICAL RESEARCH (2022)

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Article Cell Biology

A focused natural compound screen reveals senolytic and senostatic effects of Isatis tinctoria

Eun-Jung Kim et al.

Summary: This study identifies woad extracts as potential anti-senescence agents for skin aging, suggesting their attractiveness as cosmetic ingredients.

ANIMAL CELLS AND SYSTEMS (2022)

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Review Clinical Neurology

Aging, Senescence, and Dementia

Q. Behfar et al.

Summary: This study investigates the connection between cellular senescence and Alzheimer's disease. The findings suggest that senescent cells are present in the brains of Alzheimer's disease patients, and specific proteins associated with senescence are increased in their cerebrospinal fluid and plasma samples. Genetic studies also support the involvement of senescence-related genes in Alzheimer's disease. These findings highlight the potential role of cellular senescence as a therapeutic target for Alzheimer's disease.

JPAD-JOURNAL OF PREVENTION OF ALZHEIMERS DISEASE (2022)

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Article Biochemistry & Molecular Biology

A guide to assessing cellular senescencein vitroandin vivo

Estela Gonzalez-Gualda et al.

Summary: Cellular senescence is a physiological mechanism with beneficial roles in physiology, but can also have antagonistic effects in diseases and cancer. Despite the establishment of a general set of hallmarks describing senescence, complexities such as phenotype heterogeneity have made recognition and evaluation challenging.

FEBS JOURNAL (2021)

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Review Chemistry, Medicinal

Inhibitors of bromodomain and extra-terminal proteins for treating multiple human diseases

Ewelina Kulikowski et al.

Summary: The clinical development of BET protein inhibitors is unique, as they are being widely evaluated for treating various human diseases due to their novel mechanism of action. Among the BET protein family, BRD4 is extensively studied, and its activity at latent enhancers is a representative example of BET protein function. The role of BET proteins in embryonic development, cancer, cardiovascular, autoimmune, and metabolic diseases makes them attractive targets for therapeutic intervention.

MEDICINAL RESEARCH REVIEWS (2021)

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Review Medicine, Research & Experimental

Implication of cellular senescence in the progression of chronic kidney disease and the treatment potencies

Yao Wang et al.

Summary: Chronic kidney disease (CKD) shares similarities with cellular senescence, and understanding the regulation of cellular senescence in CKD has potential implications for treatment. Senotherapeutics could be a novel strategy for managing CKD by targeting cellular senescence.

BIOMEDICINE & PHARMACOTHERAPY (2021)

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Article Cell Biology

Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis

Christopher D. Wiley et al.

Summary: Cellular senescence is a stress or damage response that leads to permanent proliferative arrest and secretion of factors with potent biological activities. Senescent cells activate the biosynthesis of oxylipins, including prostaglandins, which promote the senescence arrest and SASP by activating RAS signaling. The release of specific prostaglandins, such as 15deoxy-delta-12,14-prostaglandin J2, serves as a biomarker for senolysis in culture and in vivo.

CELL METABOLISM (2021)

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Article Medicine, Research & Experimental

Identification of GL-V9 as a novel senolytic agent against senescent breast cancer cells

Dawei Yang et al.

Summary: The study demonstrated that GL-V9 can eliminate senescent cancer cells and induce apoptosis, potentially improving the outcome of cancer chemotherapy.

LIFE SCIENCES (2021)

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Article Cell Biology

Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair

Katie J. Mylonas et al.

Summary: This study demonstrated the impact of senescent cells on functional loss in human aging, chronic kidney disease, and radiation nephropathy, as well as the causative role of senescence in enhanced fibrosis in aged and irradiated murine kidneys after injury. Treatments targeting senescent cells, such as the B cell lymphoma 2/w/xL inhibitor ABT-263, were shown to reduce senescent cell numbers and restore regenerative capacity in kidneys, leading to improved function and reduced fibrosis after injury, suggesting a potential therapeutic option for protecting aging and vulnerable kidneys.

SCIENCE TRANSLATIONAL MEDICINE (2021)

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Review Cell Biology

Dissecting primary and secondary senescence to enable new senotherapeutic strategies

Tesfahun Dessale Admasu et al.

Summary: Cellular senescence is a stable cell cycle arrest state in response to stress or damage, which can limit the replication of old, damaged, and precancerous cells in the short term. Secondary senescence refers to the induction of non-senescent cells to undergo senescence by primary senescent cells, through paracrine and juxtacrine mechanisms.

AGEING RESEARCH REVIEWS (2021)

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Review Cell Biology

Cellular senescence in knee osteoarthritis: molecular mechanisms and therapeutic implications

Jinwei Xie et al.

Summary: Cellular senescence plays a significant role in the onset and progression of osteoarthritis, but the link between cellular senescence and the disease remains unclear. Current evidence supports the involvement of senescent cells of different cell types in osteoarthritis, with a focus on the underlying mechanisms of senescence in chondrocytes.

AGEING RESEARCH REVIEWS (2021)

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Review Cell Biology

The Paradoxical Role of Cellular Senescence in Cancer

Jing Yang et al.

Summary: Cellular senescence in cancer presents a dual role, acting as both a preventative measure and a promoter of tumor development. Senescent cells contribute to oncogenesis through their secretory phenotype, both inhibiting tumor growth and creating an environment conducive to tumor progression.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Review Endocrinology & Metabolism

Bone Aging, Cellular Senescence, and Osteoporosis

Robert J. Pignolo et al.

Summary: This study focuses on the physiological changes in aging bones and the role of cellular senescence in age-related osteoporosis. It reviews different aspects of bone aging, including remodeling deficits, uncoupling phenomena, and the accumulation of senescent cells in the bone microenvironment, as major mechanisms for age-related osteoporosis. The study also discusses the potential therapeutic interventions based on clearing senescent cells or suppressing the senescence-associated secretory phenotype.

JBMR PLUS (2021)

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Article Cell Biology

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

Yonghan He et al.

AGING CELL (2020)

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Article Cell Biology

Galactose-modified duocarmycin prodrugs as senolytics

Ana Guerrero et al.

AGING CELL (2020)

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Article Cell Biology

Identification of SYK inhibitor, R406 as a novel senolytic agent

Hyun-Ji Cho et al.

AGING-US (2020)

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Article Cell Biology

The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice

Anuj K. Sharma et al.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2020)

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Review Oncology

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

Lynda Wyld et al.

CANCERS (2020)

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Article Chemistry, Multidisciplinary

Preclinical antitumor efficacy of senescence -inducing chemotherapy combined with a nanoSenolytic

Irene Galiana et al.

JOURNAL OF CONTROLLED RELEASE (2020)

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Review Medicine, General & Internal

Senolytic drugs: from discovery to translation

J. L. Kirkland et al.

JOURNAL OF INTERNAL MEDICINE (2020)

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Article Cell Biology

Clearance of senescent cells during cardiac ischemia-reperfusion injury improves recovery

Emily Dookun et al.

AGING CELL (2020)

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Review Rheumatology

A roadmap to target interleukin-6 in osteoarthritis

Renske Wiegertjes et al.

RHEUMATOLOGY (2020)

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Article Cell Biology

A new model to investigate UVB-induced cellular senescence and pigmentation in melanocytes

Ines Martic et al.

MECHANISMS OF AGEING AND DEVELOPMENT (2020)

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Article Biology

Senotherapeutic drugs for human intervertebral disc degeneration and low back pain

Hosni Cherif et al.

ELIFE (2020)

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Review Cell Biology

Senescence and the SASP: many therapeutic avenues

Jodie Birch et al.

GENES & DEVELOPMENT (2020)

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Article Medicine, General & Internal

Curcumin and o-Vanillin Exhibit Evidence of Senolytic Activity in Human IVD Cells In Vitro

Hosni Cherif et al.

JOURNAL OF CLINICAL MEDICINE (2019)

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Article Multidisciplinary Sciences

SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs

Heike Fuhrmann-Stroissnigg et al.

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS (2019)

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Article Medicine, General & Internal

Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

Uxia Nogueira-Recalde et al.

EBIOMEDICINE (2019)

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Review Medical Laboratory Technology

Hallmarks of senescence and aging

Slavica Dodig et al.

BIOCHEMIA MEDICA (2019)

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Review Cell Biology

Chemotherapy-induced senescence, an adaptive mechanism driving resistance and tumor heterogeneity

Jordan Guillon et al.

CELL CYCLE (2019)

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Article Medicine, General & Internal

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

LaTonya J. Hickson et al.

EBIOMEDICINE (2019)

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Article Cell Biology

Trends in age-related disease burden and healthcare utilization

Vincenzo Atella et al.

AGING CELL (2019)

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Article Medicine, General & Internal

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

Jamie N. Justice et al.

EBIOMEDICINE (2019)

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Article Cell Biology

The curcumin analog EF24 is a novel senolytic agent

Wen Li et al.

AGING-US (2019)

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Article Engineering, Biomedical

Polymeric microsphere-facilitated site-specific delivery of quercetin prevents senescence of pancreatic islets in vivo and improves transplantation outcomes in mouse model of diabetes

Shiva Pathak et al.

ACTA BIOMATERIALIA (2018)

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Article Geriatrics & Gerontology

Projections of multi-morbidity in the older population in England to 2035: estimates from the Population Ageing and Care Simulation (PACSim) model

Andrew Kingston et al.

AGE AND AGEING (2018)

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Article Cell Biology

Oxidation resistance 1 is a novel senolytic target

Xin Zhang et al.

AGING CELL (2018)

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Review Cell Biology

Stress, cell senescence and organismal ageing

Joao Pedro de Magalhaes et al.

MECHANISMS OF AGEING AND DEVELOPMENT (2018)

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Review Biochemistry & Molecular Biology

Metabolic Kinases Moonlighting as Protein Kinases

Zhimin Lu et al.

TRENDS IN BIOCHEMICAL SCIENCES (2018)

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Review Cell Biology

Hallmarks of Cellular Senescence

Alejandra Hernandez-Segura et al.

TRENDS IN CELL BIOLOGY (2018)

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Review Geriatrics & Gerontology

Oxidative stress, aging, and diseases

Ilaria Liguori et al.

CLINICAL INTERVENTIONS IN AGING (2018)

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Article Medicine, General & Internal

Fisetin is a senotherapeutic that extends health and lifespan

Matthew J. Yousefzadeh et al.

EBIOMEDICINE (2018)

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Article Cell Biology

Azithromycin and Roxithromycin define a new family of senolytic drugs that target senescent human fibroblasts

Bela Ozsvari et al.

AGING-US (2018)

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Article Oncology

Senolytic Cocktail Dasatinib+Quercetin (D+Q) Does Not Enhance the Efficacy of Senescence-Inducing Chemotherapy in Liver Cancer

Kristina Kovacovicova et al.

FRONTIERS IN ONCOLOGY (2018)

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Article Biochemistry & Molecular Biology

Chemical screening identifies ATM as a target for alleviating senescence

Hyun Tae Kang et al.

NATURE CHEMICAL BIOLOGY (2017)

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Article Biochemistry & Molecular Biology

Targeting cellular senescence prevents age-related bone loss in mice

Joshua N. Farr et al.

NATURE MEDICINE (2017)

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Article Multidisciplinary Sciences

Cellular senescence drives age-dependent hepatic steatosis

Mikolaj Ogrodnik et al.

NATURE COMMUNICATIONS (2017)

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Article Multidisciplinary Sciences

Techniques to Induce and Quantify Cellular Senescence

Nicole Noren Hooten et al.

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS (2017)

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Article Biochemistry & Molecular Biology

Unmasking Transcriptional Heterogeneity in Senescent Cells

Alejandra Hernandez-Segura et al.

CURRENT BIOLOGY (2017)

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Article Cell Biology

New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463

Yi Zhu et al.

AGING-US (2017)

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Article Biochemistry & Molecular Biology

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice

Jianhui Chang et al.

NATURE MEDICINE (2016)

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Article Cell Biology

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents

Yingying Wang et al.

AGING-US (2016)

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Article Cell Biology

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Christopher D. Wiley et al.

CELL METABOLISM (2016)

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Article Multidisciplinary Sciences

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL

Reut Yosef et al.

NATURE COMMUNICATIONS (2016)

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Article Oncology

Is senescence-associated β-galactosidase a marker of neuronal senescence?

Malgorzata Piechota et al.

ONCOTARGET (2016)

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Article Cell Biology

Replicatively senescent cells are arrested in G1 and G2 phases

Zhiyong Mao et al.

Aging-US (2016)

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Article Cell Biology

The Achilles' heel of senescent cells: from transcriptome to senolytic drugs

Yi Zhu et al.

AGING CELL (2015)

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Editorial Material Cell Biology

Radiation-induced accelerated senescence A fate worse than death?

Regina M. Day et al.

CELL CYCLE (2014)

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Article Biochemistry & Molecular Biology

Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation

M. Ogrunc et al.

CELL DEATH AND DIFFERENTIATION (2014)

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Article Cell Biology

Characterization of novel markers of senescence and their prognostic potential in cancer

M. Althubiti et al.

CELL DEATH & DISEASE (2014)

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Article Public, Environmental & Occupational Health

Multimorbidity in Older Adults

Marcel E. Salive

EPIDEMIOLOGIC REVIEWS (2013)

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Article Oncology

Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease

Andrew W. Roberts et al.

JOURNAL OF CLINICAL ONCOLOGY (2012)

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Review Dermatology

UV, stress and aging

Florence Debacq-Chainiaux et al.

DERMATO-ENDOCRINOLOGY (2012)

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Article Multidisciplinary Sciences

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

Darren J. Baker et al.

NATURE (2011)

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Article Cell Biology

Curcumin-mediated lifespan extension in Caenorhabditis elegans

Vivian Hsiu-Chuan Liao et al.

MECHANISMS OF AGEING AND DEVELOPMENT (2011)

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Article Cell Biology

Weak p53 permits senescence during cell cycle arrest

Olga V. Leontieva et al.

CELL CYCLE (2010)

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Article Biochemical Research Methods

Protocols to detect senescence-associated beta-galactosidase (SA-beta gal) activity, a biomarker of senescent cells in culture and in vivo

Florence Debacq-Chainiaux et al.

NATURE PROTOCOLS (2009)

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Review Biotechnology & Applied Microbiology

Targeting innate immunity protein kinase signalling in inflammation

Matthias Gaestel et al.

NATURE REVIEWS DRUG DISCOVERY (2009)

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Article Biochemical Research Methods

A quantitative chemiluminescent method for studying replicative and stress-induced premature senescence in cell cultures

Vinicius Bassaneze et al.

ANALYTICAL BIOCHEMISTRY (2008)

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Review Biochemistry & Molecular Biology

Many roads lead to oncogene-induced senescence

S. Courtois-Cox et al.

ONCOGENE (2008)

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Article Multidisciplinary Sciences

The Btk tyrosine kinase is a major target of the Bcr-Abi inhibitor dasatinib

Oliver Hantschel et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2007)

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Article Chemistry, Medicinal

2-aminothiazole as a novel kinase inhibitor template.: Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor

Jagabandhu Das et al.

JOURNAL OF MEDICINAL CHEMISTRY (2006)

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Article Geriatrics & Gerontology

The limitations and validities of senescence associated-β-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells

NC Yang et al.

EXPERIMENTAL GERONTOLOGY (2005)

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Meeting Abstract Hematology

The crystal structure of Abl kinase with BMS-354825, a dual SRC/ABL kinase inhibitor.

JS Tokarski et al.

BLOOD (2004)

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Review Biochemistry & Molecular Biology

Control of apoptosis by p53

JS Fridman et al.

ONCOGENE (2003)

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