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The Role Of Tumor And Tumor Microenvironment On Breast Cancer Associated Adipocyte Plasticity
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Book Synopsis The Role of Tumor and Tumor Microenvironment on Breast Cancer-associated Adipocyte Plasticity by : Janina V. Pearce
Download or read book The Role of Tumor and Tumor Microenvironment on Breast Cancer-associated Adipocyte Plasticity written by Janina V. Pearce and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer-associated cachexia is a condition defined by a sustained net-negative energy imbalance. Although the different types of adipose tissue - white, beige, and brown - have been implicated in contributing to cancer-associated cachexia, the mechanisms of these maladaptive changes and their impact on whole-body energy expenditure have not been fully elucidated. Using breast cancer as our model, we demonstrate white adipose tissue browning in murine and human breast cancer; furthermore, we demonstrate that this effect is extremely localized and takes place early in tumor progression. We utilized in vitro cell culture techniques and demonstrate that cancer secreted factors and cross-talk with white adipocytes decrease expression of classic white adipose tissue-related genes. We also demonstrate in murine and human culture models that cancer secreted factors reduce white adipocyte lipid droplet size, and cross-talk between cancer cells and adipocytes results in an increase in lipolysis-related gene expression. Interestingly, our results strongly suggest that in mice, neither cancer secreted factors nor cross talk with adipocytes can induce white adipose tissue browning, indicate that this process likely occurs independently of direct cancer interactions with local white adipocytes. We demonstrate that interleukin 6, a cytokine with previous implications in white adipose tissue browning, induces interleukin 6-mediated signaling; however, that signaling alone is not enough to directly induce white adipose tissue browning. We present preliminary data suggesting that immune cell population shifts within the white adipose tissue of mice with breast cancer tumors may be source of white adipose tissue browning. We show that the Virginia Commonwealth University Health System has an identifiable population of patients with cancer with what we hypothesize as maladaptive thermogenic adipose tissue activity, and discuss ongoing experiments aimed at understanding the implications of these changes on whole body energy expenditure in human patients. Lastly, in a case of autoimmune diabetes mellitus in the setting of an extra-adrenal paraganglioma, we demonstrate that the interaction between cancer and whole-body metabolism is multifaceted. Together, these experiments demonstrate that adipose tissue plasticity occurs in breast cancer (and other cancers), and that different drivers for individual changes exist within the tumor microenvironment. We predict that further exploration of the exact mechanisms and translational implications will provide useful information to lead to new therapeutic treatments for patients with cancer-associated cachexia.
Book Synopsis Cancer Plasticity and the Microenvironment: Implications for Immunity and Therapy Response by : Petranel T. Ferrao
Download or read book Cancer Plasticity and the Microenvironment: Implications for Immunity and Therapy Response written by Petranel T. Ferrao and published by Frontiers Media SA. This book was released on 2019-11-01 with total page 186 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer cells can change and adapt, especially within the host environment; a phenomenon known as cancer plasticity. Several factors, including the immune system can influence, and be influenced by, cancer plasticity which in turn can impact upon patient responses to treatment. As such, we currently face several challenges for implementing combination therapies as effective cancer treatment strategies. We have compiled a topic with a number of articles that emphasize the various aspects of cancer plasticity, describing in particular the important role of the tumor microenvironment. As we embark on a new era of precision medicine with multi-modal therapies for improving patient outcomes, this topic highlights some relevant points for consideration that are pertinent to the incorporation and effective use of new treatments as part of cancer treatment regimens, including immune-modulating drugs.
Book Synopsis Tumor Microenvironment by : Jacinta Serpa
Download or read book Tumor Microenvironment written by Jacinta Serpa and published by Springer Nature. This book was released on 2020-03-04 with total page 430 pages. Available in PDF, EPUB and Kindle. Book excerpt: The way a cell undergoes malignant transformation should meet their capacity of surviving in the microenvironment of the organ where the cancer will develop. Metabolic adaptation is for sure one of the criteria that must be accomplished, driven by metabolic plasticity that allows the adaptation of cancer cells to the availability of energy and biomass sources that will sustain cell survival and proliferation. Each human organ has a particular microenvironment which depends on several cell types and in some cases also on symbiotic microorganisms. These biological partners are constantly sharing organic compounds and signaling molecules that will control mitogenesis, cell death and differentiation, accounting for the organ's function. Nevertheless, cancer cells are capable of taking advantage of this metabolic and signaling microenvironmental dynamics. In this book, we intend to present the different components of the microenvironment driving the metabolic fitness of cancer cells. The metabolic changes required for establishing a tumor in a given microenvironment and how these metabolic changes limit the response to drugs will generally be the major items addressed. It is important to mention not only aspects of the microenvironment that stimulate metabolic changes and that select better adapted tumor cells, but also how this regulation of cell plasticity is made. Thus, the signaling pathways that orchestrate and are orchestrated throughout this panoply of metabolic rearrangements will also be addressed in this book. The subjects will be presented from the conceptual point of view of the cross-cancer mechanisms and also particularizing some models that can be examples and enlightening within the different areas.
Book Synopsis Epithelial-Mesenchymal Plasticity in Cancer Metastasis by : Mohit Kumar Jolly
Download or read book Epithelial-Mesenchymal Plasticity in Cancer Metastasis written by Mohit Kumar Jolly and published by MDPI. This book was released on 2020-12-29 with total page 512 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recent studies have highlighted that epithelial-mesenchymal transition (EMT) is not only about cell migration and invasion, but it can also govern many other important elements such as immunosuppression, metabolic reprogramming, senescence-associated secretory phenotype (SASP), stem cell properties, therapy resistance, and tumor microenvironment interactions. With the on-going debate about the requirement of EMT for cancer metastasis, an emerging focus on intermediate states of EMT and its reverse process mesenchymal-epithelial transition (MET) offer new ideas for metastatic requirements and the dynamics of EMT/MET during the entire metastatic cascade. Therefore, we would like to initiate discussions on viewing EMT and its downstream signaling networks as a fulcrum of cellular plasticity, and a facilitator of the adaptive responses of cancer cells to distant organ microenvironments and various therapeutic assaults. We hereby invite scientists who have prominently contributed to this field, and whose valuable insights have led to the appreciation of epithelial-mesenchymal plasticity as a more comprehensive mediator of the adaptive response of cancer cells, with huge implications in metastasis, drug resistance, tumor relapse, and patient survival.
Book Synopsis The Tumor Microenvironment by : Rebecca G. Bagley
Download or read book The Tumor Microenvironment written by Rebecca G. Bagley and published by Springer Science & Business Media. This book was released on 2010-09-02 with total page 765 pages. Available in PDF, EPUB and Kindle. Book excerpt: The fact that tumors are composed of both tumor cells and host cells has long been known. These tumor-associated cells include vascular endothelial cells and pe- cytes, as well as inflammatory cells such as neutrophils, monocytes, macrophages, mast cells and eosinophils, and lymphocytes. The tumor cells also interact with stromal cells and with elements of the tissue extracellular matrix. What has been less appreciated is the role that these cells could have in modulating the growth, invasion, and metastasis of the tumor. Early on, the elements of what we now call the tumor microenvironment were considered to be more or less innocent bysta- ers to the role of the tumor cells as they grew and invaded local sites. Today, there is an increased understanding of the critical role of the tumor microenvironment as dramatically influencing the course of tumor development and dissemination. This volume represents a superb compilation of the latest thoughts and data regarding the role of each essential component of the tumor microenvironment in cancer development and progression. Perhaps, the earliest recognition of the role of nonmalignant cells as cancer re- lators was the recognition that lymphocytes can participate in what was termed “immune surveillance” in the 1960s. Our understanding of tumor immunity has improved markedly since then, and there are now successful clinical studies sh- ing the potential use of immune-based therapies in cancer treatment.
Book Synopsis Characterizing the Multi-faceted Dynamics of Tumor Cell Plasticity by : Satyendra Chandra Tripathi
Download or read book Characterizing the Multi-faceted Dynamics of Tumor Cell Plasticity written by Satyendra Chandra Tripathi and published by Frontiers Media SA. This book was released on 2021-03-01 with total page 336 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Breast Cancer Metastasis and Drug Resistance by : Aamir Ahmad
Download or read book Breast Cancer Metastasis and Drug Resistance written by Aamir Ahmad and published by Springer Nature. This book was released on 2019-08-27 with total page 427 pages. Available in PDF, EPUB and Kindle. Book excerpt: Resistance to therapies, both targeted and systemic, and metastases to distant organs are the underlying causes of breast cancer-associated mortality. The second edition of Breast Cancer Metastasis and Drug Resistance brings together some of the leading experts to comprehensively understand breast cancer: the factors that make it lethal, and current research and clinical progress. This volume covers the following core topics: basic understanding of breast cancer (statistics, epidemiology, racial disparity and heterogeneity), metastasis and drug resistance (bone metastasis, trastuzumab resistance, tamoxifen resistance and novel therapeutic targets, including non-coding RNAs, inflammatory cytokines, cancer stem cells, ubiquitin ligases, tumor microenvironment and signaling pathways such as TRAIL, JAK-STAT and mTOR) and recent developments in the field (epigenetic regulation, microRNAs-mediated regulation, novel therapies and the clinically relevant 3D models). Experts also discuss the advances in laboratory research along with their translational and clinical implications with an overarching goal to improve the diagnosis and prognosis, particularly that of breast cancer patients with advanced disease.
Book Synopsis Metabolic Plasticity of Cancer by : Tuuli Käämbre
Download or read book Metabolic Plasticity of Cancer written by Tuuli Käämbre and published by Frontiers Media SA. This book was released on 2020-12-24 with total page 176 pages. Available in PDF, EPUB and Kindle. Book excerpt: This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.
Book Synopsis Role of Tumor Microenvironment in Breast Cancer and Targeted Therapies by : Manzoor Ahmad Mir
Download or read book Role of Tumor Microenvironment in Breast Cancer and Targeted Therapies written by Manzoor Ahmad Mir and published by Elsevier. This book was released on 2022-08-10 with total page 298 pages. Available in PDF, EPUB and Kindle. Book excerpt: Role of Tumor Microenvironment in Breast Cancer and Targeted Therapies discusses the current understanding of breast cancer tumor microenvironment components, their role in tumorigenicity and the development of therapeutic resistance, along with updates on recent advances. Presents up-to-date knowledge on the interplays of stromal components surrounding breast tumor cells Explores recent advances and trends in the molecular mechanisms of breast tumorigenesis and how to explore further molecular targets
Book Synopsis Biomarkers of the Tumor Microenvironment by : Lars A. Akslen
Download or read book Biomarkers of the Tumor Microenvironment written by Lars A. Akslen and published by Springer. This book was released on 2017-08-02 with total page 537 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book reviews different aspects of the cancer microenvironment, and its regulation and importance for tumor progression. Practical applications, in terms of how biomarkers are increasingly included in therapy protocols, will also be discussed. Biomarkers of the Tumor Microenvironment: Basic Studies and Practical Applications is aimed at research pathologists in the cancer field, and also cancer researchers from other backgrounds, especially those using morphology techniques and models focusing on cross-talk between different cell types in tumors.
Book Synopsis Adipose Tissue and Its Role in Modulating the Mammary Tumor Microenvironment by : Bo Ri Seo
Download or read book Adipose Tissue and Its Role in Modulating the Mammary Tumor Microenvironment written by Bo Ri Seo and published by . This book was released on 2014 with total page 209 pages. Available in PDF, EPUB and Kindle. Book excerpt: Targeting cancer cells has been the primary focus of most cancer therapies, and only recently has the interaction of cancer cells with host stroma been recognized as a driving force for cancer evolution. In the presence of tumor-derived physicochemical cues, the host stroma fails to fulfill its primary role - the maintenance of tissue or organ homeostasis - and in fact aids in shaping a pro-tumorigenic microenvironment, ultimately promoting tumor progression. This interaction of cancer cells with the host stroma often complicates conventional cancer therapy and ultimately leads to unfavorable outcomes. The mammary stroma is largely composed of adipose tissue, and upon the onset of mammary tumors, the residing stromal vascular cells and adipocytes possibly partake in extracellular matrix (ECM) remodeling and blood vessel recruitment. Both tumor-associated ECM remodeling and neovascularization are typically mediated by myofibroblasts, which are known to be recruited or differentiated from other stromal cells. However, whether tumor-derived biochemical and mechanical cues can induce the conversion of adipose-derived stem cells (ASCs) or adipocytes into myofibroblastic cells is yet unknown. Furthermore, obesity has been highlighted as a risk factor for breast cancer possibly due to its role in modulating the mammary microenvironment. Nevertheless, whether obesity influences the phenotype of host cells in the mammary stroma in a manner similar to tumors, thereby advancing tumorigenesis, has yet to be determined. The goal of this dissertation is to find answers to these aforementioned unanswered questions by leveraging in vivo and in vitro engineering techniques. The results presented here demonstrate that implanted or host ASCs and adipocytes indeed possess pro-tumorigenic potential to stimulate breast tumor malignancy in part due to their ability to convert into myofibroblastic lineages upon tumor or obesity-associated microenvironmental cues. The findings of this work emphasize the importance of contextual cues and their roles in inducing the participation of the host stroma in regulating mammary tumor progression. Finally, the conclusions of this work potentially provide new insight for the development of therapeutic approaches for cancer and tissue regeneration.
Book Synopsis Tumor Microenvironment by : Jacinta Serpa
Download or read book Tumor Microenvironment written by Jacinta Serpa and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This book will allow readers to discover the crucial role of tumor microenvironment (TME) in the selection of cancer cells that are more prone to carry on cancer initiation and progression. The metabolic remodeling, as the basis of life overall, allows the adaptive establishment of a tumor in a certain TME, which in turn presents a variety of selective pressures. Coupled with the late diagnosis, the poor therapy response are the main hurdles limiting oncological disease control and eventual cure. Thus the metabolic plasticity of cancer cells often underlies chemoresistance. This edited work presents an exhaustive description and comprehensive view of cancer metabolism as a weapon used by cancer cells to adapt to TME. TME and the organ microenvironment is analyzed as a whole, considering cancer cells, stromal cells and microbiota. This complex circuit is observed as the support for disease development and therapy evasion but also as a valuable kernel, presenting new players to be targeted in a more precise cancer therapy. The various threads of cancer biology related to TME and metabolic adaptation will be addressed including: 1) key players in the metabolic network; 2) the way adaptive metabolic features are sustained by TME; 3) TME and metabolic signaling, accounting for cancer cells survival; 4) metabolic fitness driven limitations in therapy response, and 5) the way TME and cancer metabolism can be helpful in the design of new drugs. In addition, the usefulness, technical strengths and weaknesses of analytical techniques useful in cancer metabolomics will be presented in an integrative way. Moreover, the use of innovative and traditional in vitro and in vivo cancer models, as powerful tools to address the influence of TME in cancer progression and metabolic reprogramming will be also presented. This work was written by experts and dedicated to researchers with interests in cancer biology, TME, cancer metabolism and therapy. It will interest the Advances in Experimental Medicine and Biology readership, including basic researchers, analytic researchers, bio-engineers and clinicians.
Download or read book Tumor Organoids written by Shay Soker and published by Humana Press. This book was released on 2017-10-20 with total page 225 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer cell biology research in general, and anti-cancer drug development specifically, still relies on standard cell culture techniques that place the cells in an unnatural environment. As a consequence, growing tumor cells in plastic dishes places a selective pressure that substantially alters their original molecular and phenotypic properties.The emerging field of regenerative medicine has developed bioengineered tissue platforms that can better mimic the structure and cellular heterogeneity of in vivo tissue, and are suitable for tumor bioengineering research. Microengineering technologies have resulted in advanced methods for creating and culturing 3-D human tissue. By encapsulating the respective cell type or combining several cell types to form tissues, these model organs can be viable for longer periods of time and are cultured to develop functional properties similar to native tissues. This approach recapitulates the dynamic role of cell–cell, cell–ECM, and mechanical interactions inside the tumor. Further incorporation of cells representative of the tumor stroma, such as endothelial cells (EC) and tumor fibroblasts, can mimic the in vivo tumor microenvironment. Collectively, bioengineered tumors create an important resource for the in vitro study of tumor growth in 3D including tumor biomechanics and the effects of anti-cancer drugs on 3D tumor tissue. These technologies have the potential to overcome current limitations to genetic and histological tumor classification and development of personalized therapies.
Book Synopsis Tumor Microenvironment by : Alexander Birbrair
Download or read book Tumor Microenvironment written by Alexander Birbrair and published by Springer Nature. This book was released on 2020-02-10 with total page 136 pages. Available in PDF, EPUB and Kindle. Book excerpt: Revealing essential roles of the tumor microenvironment in cancer progression, this volume focuses on non-hematopoietic cells within the tumor microenvironment.Further, it teaches readers about the roles of distinct constituents of the tumor microenvironment and how they affect cancer development. Topics include fibroblasts, adipocytes, mesenchymal stem cells, stellate cells, and more. Taken alongside its companion volumes, Tumor Microenvironment: Non-Hematopoietic Cells updates us on what we know about the different aspects of the tumor microenvironment as well as future directions. Useful for introducing the newer generation of researchers to the history of how scientists focused in the tumor microenvironment and how this knowledge is currently applied for cancer treatments, it will be essential reading for advanced cell biology and cancer biology students as well as researchers seeking an update on research in the tumor microenvironment. All of the chapter authors are renowned international experts in the cancer biology field in specific subfields that will be the focus of their chapters.
Book Synopsis In Vitro Models and Imaging Tools to Assess Roles of Obesity Associated Stromal Microenvironment on Breast Cancer Progression by : Lu Ling
Download or read book In Vitro Models and Imaging Tools to Assess Roles of Obesity Associated Stromal Microenvironment on Breast Cancer Progression written by Lu Ling and published by . This book was released on 2020 with total page 193 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer is a complex disease that is often tissue and context dependent. Tumor microenvironment has been shown to have pivotal roles in regulating tumor initiation, growth and metastasis. Enrichment of cancer associated fibroblasts (CAFs) have been shown to promote cancer cell invasion by modulating physiochemical components of ECM, promoting angiogenic behaviors of endothelial cells (ECs) and shuffling metabolites to satisfy tumor metabolic demands. Obesity worsens the prognosis for breast cancer patients, and adipose stromal cells (ASC)-mediated fibrotic ECM remodeling of breast tissue plays a role in this process. Obese ASCs have been shown to share many similarities to CAFs. Whether or not obese vs. lean ASCs differentially affect the other factors important to progression of premalignant breast cancer, remains unclear. In this dissertation, I proposed the hypothesis that obese vs. lean ASCs can prime the breast tissue microenvironment to be permissive to breast cancer progression by remodeling the surrounding extracellular matrix (ECM), altering angiogenesis and reprogramming metabolism. Leveraging different tissue engineering strategies, I designed numerous physiologically relevant 3D in vitro models and developed advanced imaging tools to investigate 1) how does obese ASC and ECM remodeling mediate breast cancer cell invasion? 2) how does ASC and ECM remodeling contribute to angiogenesis? 3) what is the metabolic interplay between ASC and tumor cells during cancer invasion? Results from these studies suggest that 1) direct cell-cell contact with ASCs enables collective tumor cell migration and obese ASCs are more effective than their lean counterparts. Both matrix metalloproteinase-dependent proteolytic activity and ASC contractility are important during obese ASC mediated collective cancer migration. 2) Obese ECMs promote the proangiogenic behavior of ECs by altering their proliferative, secretory, and invasive capacities as compared to lean ECMs. 3) A label free multiphoton anisotropy imaging platform can be used to measure NAD(P)H dynamics as an indirect readout for cell metabolism. Combining with gold standard seahorse analysis, it is a powerful tool to allow us to monitor the metabolic states of ASCs and tumor cells in various culture platforms. In summary, tools and models developed in this dissertation provide novel insights into how different aspects of obesity associated microenvironmental changes are functionally related to breast cancer cell invasion, which increase the understanding of how obesity promotes breast cancer.
Book Synopsis Examining How Obesity-Associated Inflammation Promotes Mammary Gland and Mammary Tumor Fibrosis by : Genevra Kuziel
Download or read book Examining How Obesity-Associated Inflammation Promotes Mammary Gland and Mammary Tumor Fibrosis written by Genevra Kuziel and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Obesity is a global health concern. In postmenopausal women, obesity is a significant risk factor for development of hormone receptor positive breast cancer. Regardless of menopausal status of the patient or hormone receptor status of the tumor, obesity ultimately results in decreased patient survival. Within adipose tissue, obesity induces a state of low-grade chronic inflammation. This is driven by macrophage recruitment to the adipose tissue to clear out dying and dead adipocytes. Obesity-induced chronic inflammation is associated with adipose tissue fibrosis. The research presented in this thesis focused on examining changes within the mammary gland and mammary tumor microenvironments with weight gain and weight loss, and the link between inflammation and fibrosis. The importance of inflammatory CCL2-CCR2 signaling was also examined. CCL2 is a chemokine first expressed by adipocytes in obese adipose tissue and is critical for recruitment of inflammatory macrophages to the pathologically expanding adipose tissue. CCR2 is the receptor for CCL2. Finally, the research focused on describing the role of fibrocytes in the mammary gland and mammary tumor microenvironments. Fibrocytes are cells that originate in the myeloid progenitor cell population and can be recruited to areas of inflammation and fibrosis, as well as wound healing, and contribute to the myofibroblast population and extracellular matrix (ECM) production. These cells have not yet been examined in obesity or obesity-associated breast cancer.In the first research chapter, the influence of obesity and the importance of CCR2 signaling to the development of the mammary gland microenvironment were examined using a diet-induced obesity mouse model and a CCR2 knockout mouse model. In the second research chapter, the influence of obesity as well as weight loss on the mammary gland and mammary tumor microenvironments was examined using a diet-induced obesity mouse model. In the third research chapter, the importance of CCL2 signaling and CD11b+ myeloid lineage cells to mammary tumor growth and development of the mammary tumor microenvironment was examined. This research utilized the Human-In-Mouse (HIM) model to create a mammary gland microenvironment with increased stromal CCL2 signaling, as well as the CD11b-DTR mouse model. Overall, the research presented in this thesis demonstrates the importance of obesity associated inflammation for the development of collagen fibrosis in both mammary gland and mammary tumor, along with suggested participation from elevated myeloid lineage fibrocytes. Elucidating the contributions of obesity to mammary tumor formation, tumor growth, and the composition of the tumor microenvironment may ultimately lead to better treatment options for obese breast cancer patients.
Book Synopsis Adipose-Derived Stem Cells by : Jeffrey M. Gimble
Download or read book Adipose-Derived Stem Cells written by Jeffrey M. Gimble and published by Humana Press. This book was released on 2011-08-24 with total page 474 pages. Available in PDF, EPUB and Kindle. Book excerpt: During the past decade, a wide range of scientific disciplines have adopted the use of adipose-derived stem/stromal cells (ASCs) as an important tool for research and discovery. In Adipose-Derived Stem Cells: Methods and Protocols, experts from the field, including members of the esteemed International Federation of Adipose Therapeutics and Science (IFATS), provide defined and established protocols in order to further codify the utilization of these powerful and accessible cells. With chapters organized around approaches spanning the discovery, pre-clinical, and clinical processes, much of the emphasis is placed on human ASC, while additional techniques involving small and large animal species are included. As a volume in the highly successful Methods in Molecular BiologyTM series, the detailed contributions include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and notes on troubleshooting and avoiding known pitfalls. Comprehensive and cutting-edge, Adipose-Derived Stem Cells: Methods and Protocols serves as a vital reference text for experienced researchers as well as new students on the path to further exploring the incredible potential of ASCs.
