Short description of the terms of maintenance.
\r\n\tBasic science studies have provided new insights into the pathophysiology of β-thalassemia. Studies of genotypic and phenotypic heterogeneity among patients and a better understanding of the control of erythropoiesis have provided new targets for designing novel agents that can be tailored to individual patient needs. JAK-2 kinase inhibitors and agents targeting the GDF-11/SMAD pathway are in clinical trials.
\r\n\r\n\tThis book will attempt to discuss the historical background of the disease and present the most up-to-date material regarding disease management in today's world for the reader to be updated on the best practice management of the disease.
",isbn:"978-1-83969-158-4",printIsbn:"978-1-83969-157-7",pdfIsbn:"978-1-83969-159-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"23abb2fecebc48a2df8a954eb8378930",bookSignature:"Dr. Akshat Jain",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10727.jpg",keywords:"History of Gene Mutation, Genetic Counselling, Anemia, Genotyping, Hemoglobin Electrophoresis, HLA typing, Hemolysis, Aplastic Anemia, Blood Transfusion, Laboratory Testing, Fetal Hemoglobin Modifiers, Gene Therapy",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 4th 2021",dateEndSecondStepPublish:"March 4th 2021",dateEndThirdStepPublish:"May 3rd 2021",dateEndFourthStepPublish:"July 22nd 2021",dateEndFifthStepPublish:"September 20th 2021",remainingDaysToSecondStep:"3 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A board-certified pediatrician with a specialization in pediatric hematology-oncology and stem cell transplantation. In collaboration with Harvard Medical School, he studied and reported the outcomes of a global hemophilia collaboration. He is a member of the American Board of Pediatrics, Hematology, and American Board of Pediatrics, also he is a Committee member for the American Society of Pediatric Hematology-Oncology Special Interest Group in Global Pediatric Hematology oncology.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"344600",title:"Dr.",name:"Akshat",middleName:null,surname:"Jain",slug:"akshat-jain",fullName:"Akshat Jain",profilePictureURL:"https://mts.intechopen.com/storage/users/344600/images/system/344600.jpg",biography:"Akshat Jain M.D. M.P.H.\n11175 Campus Street \nLoma Linda, California 92354\nPhone: (917) 331-3216\nakshatjainusa@gmail.com \n\nMEDICAL EDUCATION \n●\tS.S.R. Medical College, Belle Rive, Mauritius - MBBS, Bachelor of Medicine Bachelor of Surgery, 2007\n●\tPediatrics Residency Training ,The New York Medical College, Metropolitan Hospital , Dec2008-Dec 2011\n●\tPediatric Hematology Oncology and Stem Cell Transplant Fellowship, Cohen’s Children's Hospital of New York at LIJ-North Shore Health system. July 2012- September 2015\n●\tMaster’s in Public Health ,Hofstra University School of Public Health ,New York , August 2015\n\n\nHONORS/ AWARDS \n●\tThe New York Academy of Medicine Honorary Associate Award , December 2009\n●\tProgram Leadership Award - Committee of Interns and Residents (C.I.R./SIEU), April 2010\n●\tAmerican Academy of Pediatrics Program Delegate Award, New York Medical College, December 2010.\n●\tCitation of Honor from New York County for Excellence in Medicine and Service to Long Island, New York,Nassau county executive chambers , August 15,2015 \n●\tTimes of India N.R.I. ( Non Resident Achiever ) award , August 2015 \n●\tCertificate for academic excellence –Hofstra University School of Health Science & Human Services, New York August 26, 2015\n●\tAmerican Society of Hematology Leadership Institute Award , April 2016\n●\tGlobal Health Speaker Award , convener of Global Health Symposium, Hofstra NorthWell School of Medicine and School of Public health , May 2016\n●\tInternational Pediatric Lymphoma Meeting ,Session Chairperson of Pediatric Lymphoma , Indian Society of Hematology and Oncology , November 2016\n●\tContent Leader Award for Hematology perspective’s in the Global CoronaVirus Pandemic Preparedness Response for Medical Association of physicians of Indian Origin, April 2020.\n●\tConvener and Chairperson International Webinar for COVID 19 Coagulopathy, May 2020. \n●\tFeatured in the Top Doctors magazine 2020, ranked top pediatric Hematologist Oncologist for Southern California.\n\nNATIONAL/INTERNATIONAL POSITIONS \n●\tHofstra University Dean Advisory Board for the School of Health Professions, December 2017\n●\tEditorial Board – American Society of Pediatric Hematology Oncology Communications Committee, International Journal of Hematology Research (ISSN 2409-3548)\n●\tReviewer - JAMA Pediatrics (ISSN: 2168-6203), British Medical Journal (ISSN, 1468-5833), JAMA Oncology (ISSN: 2374-2437), International Journal of Hematology Research (ISSN 2394—806X), Journal of Pediatric Hematology and Oncology (ISSN: 1536-3678), New England Journal of Medicine (Resident 360). \n●\tMember – Core committee: American Cancer Society (A.C.S.) and American Academy of Pediatrics (A.A.P.) - Joint global pediatric Oncology taskforce.\n●\tAdvisor -World Health Organization, South East Asia for maternal and child health initiatives.( 2013-Ongoing) , Ministry of Health and Family Welfare ,Government of India ( 2014- Ongoing ) , American Academy of Pediatrics &American Cancer Society Global Taskforce on Pediatric Cancers.( 2014-Ongoing )\n●\tEditor – AAPI journal (American Association of Physicians of Indian Origin. Circulation -40,000)\n●\tVisiting Professorship in Hematology Oncology and Stem Cell Transplantation, Rajasthan University of Medical Sciences, India. ( 2009-Ongoing )\n●\tIndustry Advisor – Bayer, UniQure, Sanofi-Genzyme, Takeda, CSL Behring\n●\tDirector of International Bone Marrow Failure Consortium- India, part of the Global Hematology Initiative of Cohen Children’s Medical Center, New York, August 2015-2017. \n●\tCommittee member for the American Society of Pediatric Hematology Oncology Special Interest Group in Global Pediatric Hematology oncology. ( 2016- Ongoing)\n\n\n WORK EXPERIENCE \nNov 2017- Current Loma Linda University Children’s Hospital \n Director Division of Pediatric Hematology \n Director, Comprehensive Hemophilia Program\n Director, Comprehensive Sickle Cell Program \n Division of Pediatric Hematology Oncology and Stem Cell Transplantation\n Professor of Public Health, Loma Linda University School of Public Health \n\nMar 2017– Oct 2017 Pediatrics and Pediatric Hematology Oncology Practice \n Adventist Health Ukiah Valley, California \n\nSept 2015 –Aug 2016 Assistant Professor Pediatrics, Hofstra North Shore LIJ School of Medicine \n Section Head –Global Pediatric Hematology Oncology and Stem Cell Transplantation\n North Shore LIJ Health system.\n Associate Adjunct Faculty, Hofstra University School of Public Health.\n\nJuly 2012 – Sep 2015 The Steven and Alexandra Cohen’s Children's’ Hospital of New York at LIJ-North Shore \n Hofstra University - Pediatrics Hematology Oncology and Stem Cell Transplant Fellowship \n Chief - Jeffrey Lipton MD\n\nDec 2011- April 2012 Global Health : SMS Medical College and Group of Hospitals, Government of India \n Project Director for Project A.G.N.I. - Set up a regional Lead Poisoning prevention and \n anemia nodal center \n \n Course Director - Pediatric Subspecialty training module for Pediatricians at J.K. Lone \n Children’s Hospital for Government of India. \n\nDec 08- Dec 2011 The New York Medical College, Residency in Pediatrics \n Metropolitan Hospital, NY\n Maria Fareri Children's Hospital at Westchester.\n The Memorial Sloan Kettering Hospital. NY\n House staff on Stem Cell Transplantation service.\n \nApril – August 2008 Oklahoma State Medical Association (O.S.M.A.) Externship Program\n The Integris Baptist Teaching Hospital and Nazih Zuhdi Transplant Center\n\nRESEARCH EXPERIENCE \nNov 2017 – Ongoing: Current and ongoing – Director, Inherited Bleeding Disorder Experimental Therapeutics Program, Loma Linda University School of Medicine\nJan 2014 –July 2015 - Hofstra University School of Public Health \n Needs Assessment to barriers in cancer care for newly diagnosed patients in a resource \n Limited setting. \n Principal Investigator - Akshat Jain, Co-PI -Corrine Kyriacou \n\nJune 2012- July 2015 - Steven and Alexandra Cohen Children’s Medical Center \n Study – Non Invasive assessment of endothelial dysfunction in children with Sickle cell \n Disease. \n Co-Principal Investigator – Banu Aygun MD\n Study – Multicenter study assessing outcome of Reduced Intensity Conditioning for \n patients undergoing hematopoetic stem cell transplantation for Sickle cell disease . \n Co-Principal Investigator – Indira Sahdev MD\n \nJan 2012- Mar12 A.G.N.I. (Anterograde Growth Normalization Initiative) \n Project Director, Project of Government of India for establishment of Universal Lead \n Independent Pilot project to study effects of Elevated Blood Lead levels in children \n suffering from Developmental disorders- Adapted by W.H.O. 2014 for a National Level \n Lead Screening program, India \n \nJan 2009- Dec11 The New York Medical College, Metropolitan Hospital Center. NY\n Resident Physician – Hypothalamic volumes in patients with Growth Hormone deficiency.\n Maria Fareri Children's hospital / Dr.Richard Noto - Pediatric Endocrinology\n \nApril 2008-Dec 08 Nazih Zuhdi Transplant Institute, Integris Baptist Hospital, Oklahoma City\n Project – Single institution outcome study for Solid organ transplants\n Research Assistant Department of Hepatology\n \nOct 2007 – Dec07 Mount Sinai School of Medicine, New York, NY\n Project- Arterio-venous fistula post liver transplantation.\n Research mentor-Dr. Charissa Chang, Assistant Professor in Department of Liver Diseases. \n\nCERTIFICATION\n\n1.\tCalifornia State Medical License 8/2016- Present , New York State Licensure 8/2013-12/16\n2.\tAmerican Board of Pediatrics - Board certified, 11/14- Present\n3.\tAmerican Board of Pediatric Hematology Oncology – Board Certified , 06/2018- Present\n4.\tNeonatal Advanced Life Support 06/2009-Present \n5.\tPediatric Advanced Life Support 06/2009-Present \n6.\tECFMG Certification 12/2007-Present \n\nORAL PRESENTATIONS \n\n\n1.\tLeukemia and Lymphoma Society of America C.M.E. Symposium presentation – Leukemia and Beyond: Advances in Cancer Care and Blood Disorders in the 21st Century, October 2019\n2.\tLoma Linda University School of Medicine – Grand Rounds, Advances in the Management of Sickle Cell Disease, March 2019.\n3.\tLoma Linda University School of Medicine – Experimental Therapeutics in Sickle Cell Disease – New Horizons at Loma Linda , November 2018 .\n4.\tAdventist Health Ukiah , California - Neurological Defects of Iron Deficiency and Lead Poisoning in Humans , October 2017\n5.\tHofstra NorthWell School of Medicine - National Public Health Symposium on Global Public Health , Convener and Moderator ,April 2016 \n6.\tCleveland Clinic Children’s Medical Center, Ohio – Non BCR-ABL Myeloproliferative syndromes of childhood, January 19, 2016.\n7.\tChildren’s Hospital at SMS Medical College ,India – Pediatric Hematology Oncology Emergencies for the Tropics, November 13, 2015 \n8.\tHarvard Medical School, Boston Children’s Hospital Division of Pediatric Hematology – Advances in Global Hematology, Annual Hemophilia Twining symposium, August 2, 2015.\n9.\tNew York Medical College as Grand Rounds, Division of Pediatrics – Emergencies in Pediatric Hematology and Oncology, April 2015.\n10.\tMaurice A. Deane School of Law, Hofstra University, New York - Healthcare Access to Undocumented immigrants: Immigration reform and its impact, March 2015.\n11.\tPediatric Academic Society/Society of Pediatric Research (PAS/SPR) as platform presentation, Vancouver, BC - Global Child Health in Rich & Poor Countries Lessons Learned from Indigenous Health, May 3 2014.\n12.\tDepartment of Medicine and Medical Oncology, as Guest International faculty , SMS Medical College, India - Advances in Stem Cell Transplantation – January 2014.\n13.\tInternational health conference, Global Association of physicians of Indian Origin , New Jersey – Impact of Lead Intoxication in Low to middle income countries , August 2012.\n14.\t139st APHA Annual Meeting and Exposition 2011, Boston - Use of decision support in a Harlem pediatric emergency department to increase prescription of controller medicines to patients with poorly controlled asthma - Wilson Wang, Carolina Valez, Nicole Falanga, Vikas Bhambhani , Akshat Jain , Farhad Gazi, David Spiller, Paper no-227188 , November 2011 \n15.\tThe New York Academy of Medicine, Resident award night - False negative result in newborn screening for Congenital Adrenal hyperplasia - July 2009.",institutionString:"Loma Linda University Children's Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Loma Linda University Children's Hospital",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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The annual number of cancer cases are expected to rise from 14 million in 2012 to 22 million within the next two decades [1]. Cancer can affect everyone - the young and the old, the rich and the poor, men and women - and poses a tremendous burden on patients, families, and societies. A substantial number of cancer patients experience a significant reduction in their quality of life due to physical pain, mental anguish, and economic hardship. Scientists and doctors are continuously making efforts to find better and more effective therapies against cancer. Currently, strategically targeted cancer therapies are emerging as treatments, which use drugs or other substances, such as tyrosine kinase inhibitors and apoptosis inducing agents, to interfere with specific molecules and processes involved in cancer cell growth and survival [2].
In multicellular organisms, the number of cells is tightly regulated to attain a balance between cell proliferation and death. Maintaining this balance is crucial for normal development and tissue size homeostasis [3]. Cell death is a fundamental process that not only plays a pivotal role in the regulation of normal physiological development and tissue balance but also acts as a defense mechanism against diseases such as cancer [4]. Over the past two decades, our knowledge of cell death and the mechanisms of its regulation have increased dramatically. Programmed cell death (PCD) is a principal mechanism of tumor suppression and is triggered in nonmalignant cells to eliminate unnecessary, aged, or damaged cells that may otherwise be harmful to the body [5]. Of note, apoptosis, autophagy, and programmed necrosis are the three main forms of PCD, easily distinguished by their morphological characteristics within the cell [6, 7]. Additionally, senescence and mitotic catastrophe (MC) are two other cell death mechanisms, often triggered in cancer cells and tissues in response to anticancer drugs [8]. Cell senescence, a state of permanent cell-cycle arrest characterized by specific changes in morphology and gene expression that differentiate it from reversible cell cycle arrest, is also considered as a type of cell death in the context of cancer therapy [9].
Accumulated data suggest that various chemotherapeutic agents can kill tumor cells through the induction of apoptosis [10]. Dysregulation of the apoptotic pathways can not only promote tumorigenesis [11, 12] but also render cancer cells resistant to chemotherapy. The ability of cancer cells to avoid apoptosis and continue to proliferate is one of the fundamental hallmarks of cancer and is a major target of cancer therapy development [12].Development of novel molecules that activate apoptosis by targeting both the intrinsic and extrinsic apoptotic pathways will advance our understanding of the mechanisms behind tumor cell proliferation, which may also lead to the development of effective cancer therapies. Autophagy is an evolutionarily conserved process that maintains cellular homeostasis by controlling protein and organelle turnover. It serves as critical adaptive response that recycles energy and nutrients during periods of starvation and stress to enable cell survival. Studies have shown that autophagy contributes to the adaptation of tumor cells to adverse microenvironments [13] and chemotherapy [13]. Autophagy may represent a major impediment to successful cancer therapy; therefore, targeting autophagy is considered a promising strategy in clinical cancer treatment. However, other studies have shown that deficiency in adequate autophagy results in various spontaneous tumors in mouse model [14], indicating a tumor suppressive role of autophagy in the process of tumorigenesis. It seems that autophagy plays dual roles as both promoter and suppressor in tumorigenesis. The dynamic role of autophagy in tumor development appears mainly dependent on tumor stage [15]. It is important to elucidate the mechanisms by which autophagy influences tumorigenesis and treatment response. Analysis of autophagic signaling may identify novel therapeutic targets. Necrosis is generally considered a passive response to massive cellular damage. However, accumulating evidence supports the existence of programmed necrosis, which involves cell swelling, organelle dysfunction, and cell lysis [16, 17]. Given the fact that many cancers have defective apoptosis machinery, it is reasonable to consider the pros and cons of activating other cell death pathways, such as necrosis, senescence and MC, and assess their therapeutic potential.
In this chapter, we discuss three major forms of PCD at molecular, cellular, and physiological levels. We also discuss the regulation mechanisms of these cell death pathways. Finally, the emerging therapies and strategies targeting these cell death pathways in the treatment of cancers are examined.
The term “apoptosis” originates from Greek words apo, which means “since, ” and ptosis, which means “dropping off, ” and it refers to leaves falling off trees or petals dropping off flowers. It was first coined by Kerr et al. in 1972 and used to describe a regulated form of cell death with specific morphological features, which is different from the necrotic cell death resulting from acute tissue injury [18]. Since then, apoptosis has become one of the most extensively studied forms of PCD that plays a critical role in normal biological processes, such as embryonic development, immune response, tissue homeostasis, and cell turnover [19], as well as in a variety of pathological conditions including cancer [20]. Studies have shown that a cell undergoing apoptosis can be described by a series of characteristic morphological changes, including cell shrinkage, membrane blebbing, chromatin condensation, and nuclear fragmentation [21]. In addition to the morphological changes, biochemical changes happening during apoptosis have also been revealed, and the three main ones are (1) the activation of caspases, (2) the breakdown of DNA and protein, and (3) the modifications of cell surface markers tagging the apoptotic cells for recognition by phagocytic cells [22].
Tissue homeostasis is maintained by an elaborate balance between cell growth by proliferation and/or survival on one side and cell death via apoptosis and other pathways on the other side. Any changes in the contribution of cell growth versus cell death can seriously affect the tissue homeostasis leading to human diseases. Accumulated evidence indicates that defect in apoptosis can contribute to cancer or onset of autoimmune responses, while excessive cell death can cause acute or chronic degenerative diseases, immunodeficiency, and infertility [23]. Under normal conditions, apoptosis represents a safeguard mechanism to prevent tumorigenesis, which indicates that evasion or resistance to apoptosis is a pivotal feature of cancer [24]. Alterations in cancer cells, which lead to impaired apoptotic signaling, not only promote tumor formation, progression, and metastasis but also contribute to treatment resistance [6-8, 24]. Thus, a better understanding of the molecular events that are involved in the regulation of apoptosis and their dysregulation in human cancers is expected to provide novel strategies for cancer therapy.
Apoptosis can be triggered by various stimuli from outside or inside of the cells, for example, by ligation of cell surface receptors, by DNA damage as a results of treatment with cytotoxic drugs or irradiation, by a lack of survival signals or by developmental death signals. These death signals of diverse origins eventually converge to activate a series of cysteine aspartyl-specific proteases (caspases) through two main pathways, namely, extrinsic (death receptor) and intrinsic (mitochondrial) pathways [25]. Caspases are central to the mechanisms of apoptosis, which cleave key cellular proteins and dismantle the cells (Figure 1). Given the death-causing effects of caspase activation, these two pathways are strictly and closely regulated at each step. Apart from the two pathways mentioned, endoplasmic reticulum (ER)-mediated apoptosis is a lesser known third pathway [26].
The extrinsic and intrinsic apoptosis signaling pathways. The extrinsic pathway primarily involves the activation of procaspase 8 by death receptors (e.g., TNFR1 and Fas/Apo 1), whereas the intrinsic pathway involves the release of factors from mitochondria, such as cytochrome c, that forms a complex with APAF1 and procaspase 9, resulting in the cleavage and activation of procaspase 9. In mammals, either active caspase 8 or caspase 9 is capable of activating effector caspases such as caspase 3 or caspase 7, which then cleave apoptotic substrates leading to apoptosis. A link between the extrinsic and intrinsic pathways is observed in certain cells. This involves the cleavage of the Bcl-2 family member Bid by caspase 8, leading to the release of cytochrome c from the mitochondria and activation of caspase 9. For detailed signaling pathways, please see Sections 2.1.1-2.1.3.
Apoptosis in response to cancer therapy proceeds through the activation of the core apoptotic machinery, including the receptor and the mitochondrial signaling pathway [10]. In many tumor cell types, the main signaling pathway leading from drug-induced damage to cell death involves the mitochondrial release of proapoptotic molecules under the control of the B-cell lymphoma 2 (Bcl-2) family of proteins. However, death receptors of the tumor necrosis factor receptor (TNFR) superfamily, mainly CD95 (APO-1/Fas), have also been shown to play a role in linking drug-induced damage to the apoptotic machinery and modulating drug response.
The extrinsic apoptotic pathway is activated by the binding of death ligands to cell surface death receptors, which transmit extracellular death signals to the intracellular apoptotic machinery to elicit cell death [27]. Although several death receptors have been identified, the best known death receptors belong to the TNFR superfamily, including TNFRs, CD95 (Fas/Apo 1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors [28]. These receptors become activated once bound by their cognate ligands such as TNF, CD95 (Fas), and TRAIL, which in turn results in death receptor aggregation, and recruitment of various adaptor proteins to the intracellular death domains (DD) of the death receptors and formation of death-inducing signaling complex (DISC). In this complex, Fas-associated death domain (FADD) recruits other DD- and/or death effector domain (DED)-containing proteins, such as procaspase 8 and procaspase 10, via homotypic death domain interactions (Figure 1) [29]. In contrast, TNF receptor-associated death domain (TRADD) recruits proteins leading to the formation of two complexes [30]. For example, TNFR1 binds to and forms complex I with TRADD, TNF receptor-associated factors 2 and 5 (TRAF2/5), receptor interacting protein 1 (RIP1), and the cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) (Figure 1). This complex is important for the TNF-induced activation of NF-κB and MAPKs and the subsequent transcription of antiapoptotic genes. In certain circumstance, RIP1 is deubiquitinated by cylindromatosis and leads to the dissociation of RIP1 and TRADD from complex I. RIP1 and TRADD then form complex II with FADD, caspase 8, and/or caspase 10, which is analogous to the DISC induced by FasL and TRAIL (Figure 1) [4, 31, 32]. The activation of caspases 8 and 10 leads to the activation of the downstream caspase cascade to mediate apoptosis. In some cells, named type I cells, the activation of effector caspases, such as caspases 3, 6, and 7, by caspase 8/10 alone can induce apoptosis [33]. However, in type II cells, activated caspase 8/10 triggers the activation of intrinsic apoptotic pathway by the cleavage of the Bcl-2-homology 3 (BH3)-only protein Bid. Cleaved Bid is myristoylated to form tBid and translocates to the mitochondria membrane, which promotes the oligomerization of Bax and Bak and causes the release of apoptotic mediators from the mitochondria (Figure 1) [34, 35].
Caspase 8 is the predominant initiator caspase in the extrinsic pathway, which plays a pivotal role in determining the cell fate following the death receptor activation. Therefore, the major signals that affect the recruitment of caspase 8 and its activation can modulate this signaling pathway. For example, cellular FADD-like interleukin-1β-converting enzyme inhibitory protein (cFLIP) shares significant structural similarities with caspases 8 and 10, which allows it to compete for binding sites and thus displace caspase 8/10 in the DISC complex. cFLIP lacks a functional caspase domain, suggesting it to be a dominant-negative inhibitor [36]. Besides caspase 8/10, cFLIP can also bind to FADD and TRAIL receptor 5 (DR5), and this interaction in turn prevents the formation of the DISC complex and the subsequent activation of caspase cascade [37]. Similarly, A20-binding inhibitor of NF-κB 1 (ABIN1) exerts its antiapoptotic effect by interfering with the interaction of RIP1 and FADD with caspase 8 [38].
cIAP1/2 contain a signature baculovirus IAP repeat (BIR), a caspase-recruitment domain (CARD), and a really interesting new gene (RING) domain at their C-terminal that exhibits E3 ubiquitin ligase activity, which help to recruit TRAF1/2 and inhibit TNFα-apoptotic signaling. Although cIAP1/2 are not efficient caspase 8 inhibitors, they can play a regulatory role in extrinsic pathway through the activation of prosurvival signals, such as NF-κB pathway. This effect was shown to result from the cIAP1/2 induction of RIP1 ubiquitination and the recruitment of TAK1, TAB2/3, and the IKK complex [39]. The NF-κB signaling pathway has been linked to death receptor signaling because RIP, which serves as an adaptor molecule for TNFR1 in the NF-κB pathway, can be cleaved by caspases. Upon TNF receptor signaling, this modulates the balance between proapoptotic and antiapoptotic signals and may even stimulate an autocrine “death loop” [10, 40]
Ubiquitination has been shown to regulate the activity of caspase 8. A clear example is that the polyubiquitination of the p10 subunit of caspase 8 by a cullin3-based E3 ligase can enhance its enzymatic activity [41]. This modification occurs after the recruitment of caspase 8 to DISC complex and allows for the binding of active caspase 8 to the polyubiquitination-binding protein, p62, which is thought to increase the stability of cleaved caspase 8 [41]. The deubiquitinating (DUB) enzyme A20 was reportedly involved in reversing this modification [41].
The intrinsic pathway, as implied by its name, is activated by internal stimuli such as DNA damaging agents, growth factor deprivation, oxidants, hypoxia, overload of calcium, and microtubule targeting drugs [42]. Upon the detection of the internal stimuli, two proapoptotic Bcl-2 family members, Bax and Bak, undergo structural changes and subsequent oligomerization at the outer membrane of the mitochondria, leading to the induction of mitochondrial outer membrane permeabilization (MOMP) and the release of mitochondrial cytochrome c (Cyt-c) into the cytosol [43-46]. The released Cyt-c assembles a multiprotein caspase-activating complex, known as the “apoptosome” [47]. The central component of the apoptosome is Apaf1 that is transiently bound by released Cyt-c in the presence of ATP or dATP, which leads to the oligomerization of Apaf1 and then the exposure of its CARD [48]. Subsequently, Apaf1 binds to procaspase 9 via interaction between their CARDs. In this complex, procaspase 9 dimerizes and autoactivates. Activated caspase 9 then cleaves and activates the downstream executioner caspases 3 and 7 to perpetrate cell death rapidly (Figure 1) [49]. Besides Cyt-c, other apoptotic factors are also released from the mitochondrial intermembrane space into the cytoplasm such as apoptosis-inducing factor (AIF), second mitochondria-derived activator of caspase/direct inhibitor of apoptosis (IAP)-binding protein with low pI (Smac/DIABLO), and Omi/high temperature requirement protein A2 (Omi/HtrA2) [50]. Smac/DIABLO and Omi/HtrA2 promote caspase activation by neutralizing the inhibitory effects on IAPs, while AIF causes DNA condensation [51-53]
The intrinsic pathway is tightly regulated by the intricate interactions between pro- and antiapoptotic members of the Bcl-2 family, which are categorized according to the organization of their Bcl-2 homology (BH) domains: (1) antiapoptotic members such as Bcl-2, Bcl-xL, Bcl-w, A1, and Mcl-1, which all possess the four BH1-BH4 domains and inhibit proapoptotic counterparts; (2) effector proapoptotic members such as Bax, Bak, and Bok, which all possess the three domains BH1-BH3; and (3) BH3-only proteins, including Bid, Bad, Bim, Bik, Bmf, Hrk, Noxa, Puma, Blk, BNIP3, and Spike, which only have the short BH3 motif and promote MOMP, either by inhibiting antiapoptotic proteins or by activating Bax and Bak [54-56]. Antiapoptotic Bcl-2 members block the oligomerization of Bax and Bak or their association with BH3-only proteins, thus preventing MOMP and Cyt-c release. However, upon a cytotoxic stimulus, the effects of antiapoptotic members are counteracted by BH3-only proteins, such as Bim and Noxa. BH3-only proteins release Bax-Bak from inhibition and allow them to promote MOMP and apoptosis.
The inhibitor of apoptosis protein (IAP) family represents another negative regulator of the intrinsic apoptotic pathway. So far, eight members have been identified, including cIAP1, cIAP2, X-linked IAP (XIAP), neuronal apoptosis inhibitory protein (NAIP), melanoma IAP (ML-IAP), survivin, Apollon, and IAP like protein 2 (ILP2) [57]. All IAPs contain BIR domains and 70 amino acid motifs, which are essential for antiapoptotic properties of IAPs because BIR domains bind the active sites of caspases and inhibit proteolytic function. Indeed, XIAP, survivin, and cIAP1/2 have been found to directly inhibit caspases 3, 7, and 9 [58]. In case of XIAP, its BIR3 domain directly binds to the small subunit of caspase 9, while its BIR2 domain interacts with the active-site substrate-binding pocket of caspases 3 and 7 [59, 60]. Some IAPs such as cIAP1/2 and XIAP contain a highly conserved RING domain that possesses E3 ubiquitin ligase activity and may target effector caspases for ubiquitination and subsequent proteasomal degradation [61, 62].
Other apoptotic factors, for example, Smac/DIABLO, when released from the mitochondrial intermembrane space during mitochondrial apoptotic events, are able to bind to various IAPs, mainly XIAP in a manner that displaces caspases from XIAP and enables their activation. In addition, the binding of Smac/DIABLO to IAPs facilitates the latter to be degraded by proteasome [63]. However, unlike Cyt-c, the ablation of Smac/DIABLO, Omi/HtrA2, or both proteins does not lead to the inability to activate caspases or undergo apoptosis [64-66]. This suggests that there may be considerable redundancy in XIAP inhibition, and in fact other proteins have also been demonstrated to inhibit XIAP [67].
The term autophagy (from the Greek auto, meaning “oneself, ” and phagy, meaning “eating”) was first introduced by Christian de Duve based on the observation that cells were able to digest their own components [68]. Nowadays, autophagy is defined as a self-digestive cellular process by which eukaryotes degrade and recycle long-lived proteins, cellular aggregates, and damaged cellular organelles to maintain cellular homeostasis. Three types of autophagy, macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), have been identified to date, which could be distinguished from one another via different modes of delivery of the cargo to the lysosome and their function. Microautophagy is a direct engulfment of cytoplasmic components into the lysosomal lumen for degradation [69], while in CMA, a subset of soluble cytosolic proteins containing a KFERQ motif are recognized by molecular chaperons, including the HSPA8/HSC70 (heat shock 70 kDa protein 8), and directly translocated into lysosomes through a receptor (LAMP-2A) on the lysosomal membrane [70]. Macroautophagy is a process that is responsible for the delivery and degradation of macromolecules and organelles by generating specialized cytosolic vesicles (hereafter referred to as autophagy) [71].
Autophagy is activated under physiological and pathological conditions, such as nutrient starvation, hypoxia, hyperthermia, and oxidative stress, and in response to drugs and radiation. This dynamic process generates cellular energy resources that allow a cell to adapt its metabolism to energy demand. Defects in the autophagy process lead to the accumulation of damaged proteins and/or genomic damage and can cause diseases such as neurodegeneration, infectious diseases, heart diseases, and cancers [72, 73]. Although autophagy can suppress tumor growth, it clearly plays a role in promoting tumor cells to survive under stress [74]. The suppression of autophagy can sensitize cancer cells to anticancer therapy [75, 76], but under apoptosis deficiency condition, autophagy can also cause cell death through a process termed “autophagic cell death” [72, 77].
After induction by a stress signal such as starvation, the process of autophagy begins with the formation of autophagosomes, which assemble around and encapsulate the targeted proteins or organelles, and then fuse with lysosomes to form autolysosomes for degradation. This complex process can be divided into five major steps, namely, nucleation, elongation, maturation, fusion, and degradation, which are tightly controlled by a subset of molecules encoded by autophagy-related genes (ATGs) (Figure 2A). The first step of autophagy is the nucleation of the phagophore, an isolation membrane that most likely derives from the ER [78, 79]. Besides the ER, studies have also shown that the plasma membrane and membranes of mitochondria and Golgi are also involved in the formation of the phagophore [80, 81]. The phagophore then extends and sequesters the substrates destined for degradation and finally forms the characteristic double membrane vesicle, known as autophagosome. The outer membrane of the mature autophagosome then fuses with the lysosome or inner body to generate a structure named autolysosome, where the inner membrane of autophagosome and its contents are degraded by the activity of acidic hydrolases provided by the lysosome [82, 83]. The catabolic products are then either recycled into different metabolic pathways or undergo further degradation to yield energy (Figure 2A).
Schematic representations of the autophagy pathway and its regulation. (A) The five major steps of autophagy, namely, nucleation, elongation, maturation, fusion, and degradation, are illustrated. Phagophore membrane elongation and subsequent sealing of the autophagosome require two ubiquitin-like conjugation systems that mediate the formation of ATG5-ATG12 complex and LC3-II. (B) The signaling molecules and pathways involved in autophagy regulation (see Sections 3.1-3.3 for details).
Autophagy is a highly regulated process by ∼30 ATGs discovered hitherto in mammals. Several signaling pathways that initiate autophagy converge at a serine/threonine protein kinase mammalian target of rapamycin (mTOR), a key regulator of the autophagic pathway, which inhibits autophagy in the presence of nutrients and growth factors [84]. In mammals, the initiation of phagophore formation is regulated by a great deal of macromolecular complexes or groups of proteins, including the ULK1 kinase and its regulators, the autophagy-specific phosphatidylinositol 3-kinase (PI3K) complex, and the multi-spanning transmembrane protein ATG9 [85-88]. The PI3K complex, which consists of the active enzyme VPS34, a class III PI3K, together with p150 and Beclin 1, the counterparts of yeast Vps15 and Vps30/Atg6, and ATG14, catalyze the production of phosphatidylinositol-3-phosphate, thereby triggering the recruitment of effectors proteins, such as double FYVE-containing protein 1 (DFCP1) and WD-repeat domain phosphoinositide-interacting (WIPI) family proteins [89-93]. The elongation of the isolation membrane and the subsequent closure of the autophagosome require two ubiquitin-like conjugation systems. First is the ATG12-ATG5-ATG16L system: ATG12 is conjugated to ATG5 by the ATG7 (E1-like enzyme) and ATG10 (E2-like enzyme). The resulting ATG5-ATG12 complex interacts with ATG16L and then oligomerizes to form a large ATG16L complex, which localizes on the outer surface of the extending autophagosomal membrane, but it dissociates from the membrane before autophagosome formation is completed (Figure 2A) [94]. A recent study demonstrated that under certain stress conditions, autophagy can occur independently of ATG5/ATG7, suggesting the existence of an alternative pathway for autophagosome formation [95]. Second is the phosphatidylethanolamine (PE)-light chain 3 (LC3) system: LC3 (the mammalian homologue of yeast Atg8) is cleaved by the cysteine protease ATG4 and then conjugated to the lipid PE by the activity of ATG7 and ATG3 (E2-like enzyme) [94, 96]. The lipidated form of LC3 (LC3II) specifically accumulates on nascent autophagosomes and recruits cargo adaptor proteins (also known as autophagy receptors), such as p62, Nbr1, or NIX. These proteins, in turn, recruit cargo from the cytoplasm, for example, ubiquitinated protein aggregates and damaged organelles, to promote the closure of the autophagosome [97-99]. Once autophagosome formation is complete, it fuses with lysosomes through mechanisms that remain largely unknown in mammalian cells. Some regulators have been found to be involved in the autophagosome-lysosome fusion process, including LC3, the lysosomal proteins LAMP-1 and LAMP-2, the small GTP-binding protein RAB7, and the AAA-type ATPase SKD1 [100-102]. Autophagosome-lysosome fusion then leads to the activation of the hydrolases and the degradation of the sequestered cargo (Figure 2A).
The mTOR, a PI3K-related serine/threonine protein kinase, plays a key role in maintaining the balance between cell growth and proliferation. It has also been found to regulate the autophagy in response to nutrient status, growth factor signals, and cell stress [103]. In higher eukaryotes, mTOR exists in at least two distinct protein complexes, known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [104, 105]. The mTORC1 consists of mTOR, mLST8 (mammalian lethal with SEC13 protein 8), RAPTOR (regulatory-associated protein of mTOR), PRAS40 (proline-rich Akt substrate of 40 kDa), and DEPTOR (DEP domain containing mTOR-interacting protein) and is considered to be the principal regulator of autophagy [106]. mTORC1 is downstream of PI3K and is activated in response to mitogenic stimuli or nutrient availability. When nutrients and growth factors are available, mTORC1 inhibits autophagy by phosphorylating ULK1-ATG13-FIP200 complex, which is required for the phagophore formation [107, 108]. In addition, activated mTORC1 promotes mRNA translation via activating S6K and inhibiting 4EBP1. The inhibition of mTORC1 strongly induces autophagy, for example, rapamycin (an mTORC1 inhibitor), and potently induces autophagy even in the presence of rich nutrients. As indicated (see Figure 2B), mTOR activity is activated by different signaling pathways, which converge on the tuberous sclerosis complex (TSC) and the ras homolog enriched in brain (Rheb), a small GTPase that activates mTORC1 when in its GTP-bound state [109]. TSC, which is comprised of TSC1 (harmartin) and TSC2 (tuberin), acts as a GTPase-activating protein (GAP) for Rheb, promoting hydrolysis of its bound GTP and thus inhibiting Rheb and mTORC1 activity [110]. The inhibition of TSC1/2 by Akt phosphorylation allows Rheb-GTP to accumulate and activates mTOR [111]. Phosphatase and tensin homology (PTEN), a phosphoinositide-3 phosphatase, is a negative regulator of the PI3K/Akt pathway and thus an inducer of autophagy [112].
AMP-activated protein kinase (AMPK), a serine/threonine protein kinase, is another sensor of cellular energy status and regulates the metabolism of glucose and lipids in response to changes in nutrient and intracellular ATP concentration. In conditions of nutrient deprivation, reduced ATP production causes an elevated AMP/ATP ratios that activates the energy-sensing serine/threonine kinase 1(LKB1)-AMPK signaling axis [113]. Elevated AMP/ATP ratio activates the LKB1 and subsequently phosphorylates and activates AMPK. The activation of AMPK mediates the phosphorylation of TSC, which results in the inactivation of mTORC1 and induction of autophagy [114, 115]. Moreover, AMPK has also been found to directly phosphorylate RAPTOR, an activating component of mTORC1, thereby inhibits mTORC1 in a TSC-independent manner (Figure 2B) [116].
AMPK also directly regulates autophagy through the phosphorylation and activation of ULK1. Studies have shown that AMPK interacts with the N-terminal proline/serine (PS)-rich domain of ULK1, and this interaction is required for the ULK1-mediated autophagy (Figure 2B) [117]. Furthermore, AMPK has been shown to associate with and directly phosphorylate ULK1 on several amino acid sites, and this modification is required for ULK1 activation in response to nutrient deprivation [118]. It was reported that AMPK can interact with and phosphorylate ULK1 at Ser555, Ser637, and Thr659 and that AMPK-dependent phosphorylation of ULK1 is involved in the localization of ATG9 and increases autophagy efficiency [119]. Similarly, Kim et al. found that under the conditions of glucose starvation, AMPK activates ULK1 through direct phosphorylation of ULK1 on Ser317 and Ser777, thereby activating ULK1 and promoting autophagy [120]. By contrast, Shang et al. found that ULK1 undergoes dramatic dephosphorylation on Ser638 and Ser758 upon starvation, and the dephosphorylation of ULK1 leads to its dissociation from AMPK and becoming more active in autophagy induction [113, 121].
Bcl-2 family members were initially identified and characterized as regulators of apoptosis; however, more and more evidence has revealed that the members of this family also regulate the autophagy process. The antiapoptotic Bcl-2 family members, including Bcl-2, Bcl-xL, Bcl-w, and Mcl-1, have been found to interact with Beclin 1 and inhibit autophagy [122-124] (see Figure 2B). Because the overexpression of these antiapoptotic genes is commonly seen in cancer cells, the inhibition of autophagy may promote the oncogenic properties of these Bcl-2 family proteins. Indeed, the small interfering RNA (siRNA)-mediated knockdown of Bcl-2 can trigger autophagy and apoptosis in tumor cells [125, 126]. The antiapoptotic proteins were found to interact with Beclin 1 through their BH3 receptor domain and the BH3 domain of Belcin 1, thereby inhibiting Beclin-1-dependent autophagy [122]. The disruption of such interaction by ABT737, a BH3-mimetic agent, or the expression of other proteins with Bcl-2 homology 3 (BH3) domain that competitively disrupt the interaction can induce autophagy [123]. Additionally, the death-associated protein kinase, DAPK, a protein that phosphorylates Beclin 1 thereby disrupting Beclin-1-Bcl-2 interaction and inducing autophagy, is another inducer of autophagy that is commonly silenced by methylation in different types of human cancers.
In contrast to antiapoptotic proteins, the proapoptotic BH3-only proteins, such as BNIP3L, Bad, Noxa, Puma, BimEL22, and Bik, can promote autophagy [127]. For example, autophagy induced by hypoxia occurs through a hypoxia inducible factor-1 (HIF-1)-dependent transcriptional activation of BNIP3L that disrupts the interaction between Bcl-2 and Beclin 1 [128]. Furthermore, Puma, another “BH3-only” protein, induces mitochondrial autophagy in response to mitochondrial perturbations in a Bax/Bak-dependent manner [129].
The p53 tumor suppressor protein is well known for its role as a transcription factor that regulates the expression of a series of genes, contributing to cell cycle arrest, DNA damage and repair, apoptosis, and senescence [130, 131]. Underscoring its importance in the regulation of proliferative homeostasis, it is the most commonly mutated tumor suppressor in human cancer [132]. In mammalian cells, p53 shuttles between the nucleus and the cytoplasm; activated p53 translocates to the nucleus and induces the expression of target genes. Although p53 is best known as a nuclear transcription factor, studies also demonstrate that cytoplasmic p53 mediates mitochondrial outer membrane permeabilization and transcription-independent apoptosis [133, 134].
Similarly, p53 has been shown to modulate autophagy depending on its subcellular localization. Nuclear p53 stimulates autophagy in a transcription-dependent fashion by modulating the expression of a number of regulators that inhibit the mTOR pathway. For example, p53 activates the genes encoding AMPKβ1 (a component of AMPK), TSC1/2 and PTEN, which are all known negative regulators of mTORC1, leading to the activation of autophagy [135]. In addition, sestrin 1 and sestrin 2, two p53 target genes, have been identified as a critical link between p53 activation and mTORC1 activity [136]. Sestrin is induced in response to DNA damage and oxidative stress in a p53-dependent manner and inhibits mTORC1 activity via AMPK-mediated TSC activation (Figure 2B) [136]. Furthermore, sestrin 2 was shown to be required for autophagy induction in response to various cellular stress conditions, including nutrient starvation and rapamycin exposure [137]. In addition, p53 can promote autophagy in an mTOR-independent manner via the upregulation of damage regulated autophagy modulator (DRAM), a lysosomal protein mediating autophagic cell death [138]. However, p53 can also suppress autophagy [139], an effect attributable to cytoplasmic rather than nuclear p53 (Figure 2B). A recent study indicates that cytoplasmic p53 can regulate autophagy through direct interaction with FIP200 [140]. In addition, several autophagy inducers, such as nutrient starvation, rapamycin, and ER stress, stimulate proteasome-mediated degradation of p53; hence, the inhibition of p53 degradation can suppress autophagy induced by these cellular stress signals.
For a long time, necrosis has been considered as a form of cell death that is uncontrolled and lacks underlying signaling events resulting in dramatic irreversible alterations in essential cell parameters of metabolism and cell structure [141]. This might be true for cell death in response to severe physical or chemical damage or adverse conditions; however, accumulating evidence supports the notion that necrosis is a regulated process involving multiple developmental, physiological, and pathological scenarios [142, 143]. For such a reason, it is called necroptosis or programmed necrosis. Necroptosis is characterized by cytoplasmic and organelle swelling, followed by the disruption of the cell membrane integrity, leading to the release of the cellular contents into the extracellular milieu, which may result in an inflammatory response. Unlike apoptosis, the nuclei of necrotic cells remain largely intact [144]. Necroptosis can be induced by inhibition of cellular energy production, generation of ROS, imbalance of intracellular calcium flux, or extracellular cell death signals, which are also able to induce apoptosis, suggesting that different types of cell death may share, at least in part, common mechanisms. In this sense, time and intensity of stimulus may determine the type of cell death. Indeed, one study showed that depending on glutathione depletion and oxidative stress level, apoptosis can switch to necroptosis [145].
Necroptosis can be triggered by ligands through numerous death receptors, including TNFR1 and TNFR2, TRAILR1 and TRAILR2, CD95 (Fas), and toll-like receptors (TLRs) [146-148], as well as by different kinds of physical-chemical stress stimuli, such as anticancer drugs, ionizing radiation, and calcium overload [149].
The death receptors are activated by their ligands followed by the recruitment and activation of caspase 8 that trigger the apoptosis in the absence of NF-κB survival pathway. However, under conditions that fail to trigger apoptosis, necroptosis may be an alternative cell death pathway. As shown in Figure 3, in the context of TNFR1 signaling, TNFα activates TNFR1, which in turn induces the recruitment of RIP1 kinase and other proteins, including TRADD, TRAF2, and cIAP1/2, to form a transient molecular complex referred to as complex I [144]. In complex I, RIP1 is rapidly modified by k63-linked polyubiquitination mediated by E3 ligases, cIAP1, and cIAP2. The ubiquitination of RIP1 serves as a platform to dock additional signaling molecules, IKK complex, key mediators that lead to the activation of the canonical NF-κB signaling, or inflammatory pathways [150-152]. RIP1 can be subsequently deubiquitinated by the enzyme cylindromatosis (CYLD) [153] and, together with proteins involved in cell death signaling, form complex II, which comprises as key components RIP1, TRADD, FADD, and caspase 8 [154]. The formation of complex II initiates the cell death signals, and the cell death via apoptosis or necroptosis is determined at this step. In the absence of cIAP1 or FLIP, RIP1, FADD, and caspase 8 form complex IIa to activate the caspase cascade and to induce apoptosis [31]. However, when caspase 8 activation is inhibited due to genetic or pharmacological inhibition, RIP1 together with RIP3 forms a complex that leads to the necroptotic signal transduction pathway [155]. This RIP1/RIP3-containing cytoplasmic necroptotic protein complex is called complex IIb (also known as necrosome), which constitutes a key molecular platform of necroptosis. RIP1 and RIP3 can phosphorylate reciprocally in an autocrine/paracrine manner, leading to the activation of their kinase activity [32, 156].
TNFR1 engagement- or genotoxic stress-induced formations of divergent signaling complexes, leading to the activation of NF-κB, apoptosis and necroptosis. Binding of ligands to receptors leads to the intracellular formation of complex I. Lys63-linked polyubiquitination of RIP1 (in complex I) by cIAP ligases results in cell survival through the activation of NF-κB and MAPKs. Deubiquitination of RIP1 by CYLD or inhibition of cIAP proteins leads to the conversion of complex I to complex IIa, activating the caspase cascade for apoptosis induction. Under conditions where caspase 8 activity is inhibited or RIP3 is highly expressed, RIP1 interacts with RIP3 to form complex IIb (necrosome), which mediates necroptosis. The formation of complex IIb requires the kinase activity of RIP1. RIP3 and MLKL are phosphorylated in complex IIb and translocated to the plasma membrane, where the complex mediates membrane permeabilization. In addition, the downregulation of IAPs by Smac mimetics or genotoxic stress results in the spontaneous formation of the ripoptosome, which can trigger caspase-8-mediated apoptosis or caspase-independent necroptosis.
The mixed lineage kinase domain-like protein (MLKL), also detected in complex IIb, is the most downstream effector of necroptosis so far identified [157, 158]. The N-terminal domain of MLKL is required for assembly of higher order structure and recruitment of MLKL to the plasma membrane, followed by permeabilization of the plasma membrane [159-161]. The C-terminal pseudokinase domain of MLKL interacts with RIP3 and is phosphorylated by the latter at the threonine 357 and serine 358 residues, and these phosphorylation events are critical for necroptosis [161]. In fact, blocking MLKL activity leads to necroptosis inhibition. Besides the plasma membrane, activated MLKL may translocate to intracellular membranes, possibly leading to the permeabilization of the ER, mitochondria and lysosome [160]. In addition, RIP3 phosphorylates MLKL, which in turn activates the mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5), a central downstream effector of the necrosomal complex. PGAM5 in turn initiates the dephosphorylation of GTPase dynamin-related protein 1 (DRP1), a mitochondrial fission regulator, which leads to the mitochondrial fission and mitochondrial fragmentation. This process is essential for the necroptotic pathways, as necrosis cannot occur without mitochondrial fission [162].
In addition to necrosome, another necroptosis-inducing complex referred to as ”ripoptosome” has also been identified [163, 164]. Under normal conditions, the core components of this complex, namely, RIP1, FADD, and caspase 8, are ubiquitinated by IAPs, which leads to the degradation of these core components and thereby suppresses ripoptosome formation (Figure 3). However, when exposed to Smac mimetics or genotoxic stress, IAPs are downregulated, resulting in the spontaneous formation of the ripoptosome and triggering of caspase-8-mediated apoptosis or caspase-independent necroptosis. There are three signaling pathways initiated following ripoptosome formation. (1) The formation of caspase 8 homodimers within the complex results in full catalytic activity and thus apoptosis. (2) The formation of caspase-8-cFLIPL (long splice form of FLIP) heterodimers instead results in limited catalytic activity, which is able to cleave RIP1 but is not sufficient to trigger apoptosis, leading to ripoptosome disassembly and cell survival. (3) The formation of caspase-8-cFLIPS (short splice form of FLIP) heterodimers predominates within the complex, and caspase 8 activation and RIP1 cleavage are prevented, thereby promoting ripoptosome formation. This in turn leads to the mode of cell death instead of being switched to necroptosis [163, 164].
A schematic overview of major signal transduction pathways induced by various stimuli and ultimately leading to necroptosis can be found in the review article (Figure 1) by Kaczmarek et al. [165].
cFLIP molecule has been shown to be able to modulate the activation of procaspase 8 and thereby prevents the apoptosis mediated by death receptors [166]. In the cytoplasm, RIP1 can form complex with FADD, caspase 8, and TRADD (further referred to as ripoptosome) following stimulation of T-cell receptor, TLR3, or TRL4. Remarkably, in response to genotoxic stress (DNA damage), the spontaneous formation of the ripoptosome occurs independent of death receptor activation [4, 144, 156, 163]. The ripoptosome can induce caspase-dependent or caspase-independent cell death, depending on the cellular context or differential regulation of caspase 8 by cFLIP. The cleavage of RIP1 in the ripoptosome complex by caspase 8 homodimers triggers the downstream activation of effector caspases, leading to the induction of apoptosis. Further, ripoptosome-mediated cell death or necroptosis also depends on the type of FLIP isoform. The caspase 8/FLIPL heterodimers may induce RIP cleavage, thus leading to ripoptosome disassembly and necroptosis inhibition, whereas caspase 8-/cFLIPS lacks proteolytic activity necessary for RIP1 degradation, thus leading to necroptosis induction via RIP1 and RIP3 [164]. Therefore, it is possible to divert cells to undergo apoptosis via the inhibition of necroptosis through the modulation of ratio of FLIPL to FLIPS. Indeed, previous studies have demonstrated that cFLIP protects cIAP antagonist-treated cells from Fas-induced cell death, which involves both apoptosis and necroptosis [167]. cFLIPL inhibits the formation of the cell death-inducing “ripoptosome, ” which functions in TLR3-induced apoptosis and necroptosis [164]. Furthermore, siRNA-mediated silencing of cFLIPL sensitizes cells to TNF-induced RIP1/RIP3-dependent necroptosis [168]. Therefore, FLIP plays a pivotal role not only in the regulation of apoptosis but also in necroptosis via the formation of ripoptosome and by switching between apoptotic and necroptotic mechanism.
The members of the IAP protein family exhibit E3 ubiquitin ligase activity and are characterized by BIR domains that bind the active sites of caspases and inhibit proteolytic function [169]. During the intrinsic pathway of apoptosis, Smac/DIABLO is released from mitochondria to cytosol thereby releases the caspases from the trap of IAP, leading to the activation of caspases followed by apoptotic cell death. Smac protein was shown to induce the autodegradation of cytosolic IAP1 and IAP2, allowing the formation of a caspase-8-activating complex consisting of RIP1, FADD, and caspase 8 [170]. Several mammalian IAPs may utilize ubiquitination to regulate their own stability. It has been recently found that Chal-24-induced autophagy activation can result in the degradation of c-IAP1 and c-IAP2 and the formation of ripoptosome, thus contributing to necroptosis induction [171]. Remarkably, in the absence of IAPs and under conditions where caspases are blocked, necroptosis can be stimulated via RIP1 and its downstream kinase [172]. It has been demonstrated that loss of cIAPs promotes the spontaneous formation of ripoptosome induced by genotoxic stress or TLR3 stimulation through poly (I:C), a synthetic homologue of virus-derived double stranded DNA. Such event occurs independently of death receptor stimulation and is suppressed by the cIAP1 or cIAP2 that cause RIP1 ubiquitination and degradation [164]. FLIPL knockdown is able to enhance ripoptosome aggregation, thus sensitizing cells to etoposide or TLR3-mediated cell death. The role played by ripoptosome is complex since it can stimulate caspase-8-mediated apoptosis or caspase-independent necroptosis depending on the cell types [163].
The concept of apoptosis blocking necrosis by caspase activity was firstly proved in 1998 by the finding that the pharmacological inhibition of caspase activity sensitizes TNF-mediated necrotic cell death in L929 cells [173]. Since then, this concept has been accepted as an established theory. Indeed, zVAD-fmk, a pan-caspase inhibitor, has been widely used to induce necroptosis in a variety of cell lines as well as in mice models [173, 174]. Among the caspases, caspase 8 is responsible for the switching between apoptosis and necroptosis [174]. Necroptosis but not apoptosis was observed in caspase-8-deficient Jurkat cell lines in response to Fas and TNFR stimulation. In vivo studies have also shown that caspase-8-deficient mice have significant necroptotic death, leading to embryonic lethality, which support the roles of caspase 8 in blocking necroptosis. T-cell- or intestinal epithelial cell-specific deletion of caspase 8 in mice also exhibited severe necroptotic features, inducing immunodeficiency or terminal ileitis, respectively [175, 176].
The critical roles of caspase 8 on necroptosis are known to induce the cleavage of RIP1 and RIP3 [31, 177]. Therefore, cells treated with caspase inhibitor or deficient in caspase 8 increase the RIP1-RIP3 complex formation as well as necroptosis [156, 172, 178]. In addition, CYLD was recently identified as a target of caspase 8 and a critical mediator. Caspase 8-mediated CYLD cleavage at Asp215 prevents necroptosis, whereas the expression of mutant CYLD (D215A), which is resistant to caspase 8-mediated cleavage, enhances necrosome formation and necroptosis [178].
RIP1 and RIP3 are key signaling molecules in inducing necrosis and are regulated by caspases and ubiquitination. The activity of RIP1 is specifically associated with necrosis and not with apoptosis, which is demonstrated by use of Necrostatin-1 (Nec-1) that specifically blocks the kinase activity of RIP1 [179]. Nec-1 inhibits TNF-induced necrosis in L929 cells and FasL-induced necrosis in Jurkat cells that were pretreated with caspase inhibitor zVADfmk or deficient in FADD [180]. In addition to RIP1, RIP3 kinase activity is also involved in caspase-independent cell death [177], and it has become clear that RIP3 determines cells to undergo necrosis in response to TNF treatment [32, 156, 172]. In contrast to RIP1, RIP3 is not required for TNF-induced NF-κB activation [156, 181]. RIP1 activity is essential for necrosome formation and its C-terminal RHIM domain (RIP homotypic interaction motif), allowing homotypic interaction with RIP3 to from a TNF-induced complex, which is important for stabilizing the necrosome [182]. Under necrotic cell death conditions, RIP3 also binds to other metabolic enzymes, such as the cytosolic glycogen phosphorylase (PYGL), the cytosolic glutamate-ammonia ligase (GLUL), and the glutaminolysis-initiating enzyme GLUD1, which positively modulates RIP3 enzymatic activity [32, 182]. These interactions result in glutamine production and regulate glycogenolysis. The knockdown of PYGL, GLUL, or GLUD1 partially reduced the degree of TNF- and zVAD-fmk-mediated ROS production and necrosis. It seems that both RIP1 and RIP3 are responsible for an increased cellular metabolism of carbohydrate and glutamine, leading to higher ROS formation and subsequent necrotic cell death [182, 183]. The activity of caspase 8 inhibits the necrotic cell death, likely by the cleavage of RIP1 and RIP3 [184], and downstream, through caspases 3 and 7 activation and poly-ADP-ribose polymerase (PARP)-1 [185]. Again, this demonstrates the importance of RIP1/3 and the enhanced ROS formation during the inhibition of caspases for the subsequent induction of necrosis [185-187].
The TRAIL has been considered as a promising anticancer drug since it was found that TRAIL preferentially triggers cell death in cancer cells compared to normal cells. Furthermore, unlike TNF and FasL, TRAIL and antibodies against the TRAIL receptors were confirmed to be well tolerated and safe in nonhuman primates even at relatively high concentrations [28, 188]. Recombinant human TRAIL has been shown to have the capacity to induce apoptosis in a variety of cancer cells in vitro and in tumor xenografts [11]. TRAIL receptor agonists, including recombinant TRAIL, as well as humanized antibodies against TRAIL receptors have been evaluated in clinical trials [189-191]. However, several clinical trials using such drugs as single agents to induce cancer cell death did not recapitulate the promising results obtained in animal studies, which might be due to insufficient cross-linking of TRAIL receptors by the available TRAIL agonists. This has led to the investigation of TRAIL-based combination therapies to maximize antitumor activity. It has been shown that both conventional chemotherapy with DNA damaging agents and radiotherapy induce the expression of TRAIL receptors in response to DNA damage, thus suggesting a potential synergistic effect when combining these therapies with TRAIL-targeted treatment [188, 192]. For example, histone deacetylase (HDAC) inhibitors can induce the expression of TRAIL, thereby leading to the apoptosis in acute myelogenous leukemia (AML) [193]. HDAC inhibitors enhance the synthesis of several proteins involved in TRAIL signaling, such as DR5, and are able to sensitize the TRAIL-resistant cancer cells when combined with TRAIL treatment [194, 195]. In addition, enhanced assembly of the TRAIL DISC has been proposed to confer increased sensitivity in TRAIL-based combination therapies [196]. Many cytotoxic chemotherapeutic agents have been shown to induce the stabilization of p53 tumor suppressor protein in response to DNA damage and other cellular stresses, which transcriptionally activates DR5 and other proapoptotic proteins that synergizes with TRAIL. Therefore, TRAIL combination with such agents could be a useful therapeutic strategy for cancer.
However, the efficiency of TRAIL-based therapy in human cancers is not satisfactory due to the existence of both agonistic receptors (TRAIL-R1 and TRAIL-R2) and antagonistic decoy receptors (TRAIL-R3 and TRAIL-R4) in human cells. This implies that recombinant TRAIL ligand is capable of eliciting proapoptotic or antiapoptotic signals depending on the availability of these different receptors on the cell surface. Moreover, in some cancer cells, TRAIL can induce the activation of NF-κB, thus promoting cancer cell survival rather than apoptosis [188, 197]. Thus, the context-based effect of TRAIL signaling may explain the lack of efficacy seen in recent studies of TRAIL-targeted anticancer therapy. It was reported that TRADD is a key component that activates NF-κB in TRAIL signaling, and siRNA-mediated knockdown of TRADD in cancer cells sensitizes them to TRAIL-induced apoptosis. Therefore, TRADD may serve as a target for sensitizing cancer cells to TRAIL cytotoxicity [198].
Antiapoptotic proteins of the Bcl-2 family, such as Bcl-2, Bcl-xL, and Mcl-1, are promising targets for anticancer drug development because they play a crucial role in regulating apoptosis, and the overexpression of these proteins is frequently observed in a variety of tumor types. Currently, three main strategies targeting this pathway are under investigation: (1) small molecules that affect gene or protein expression, (2) silencing of the upregulated antiapoptotic proteins with antisense oligonucleotides, and (3) BH3-only peptides or synthetic small molecule inhibitors interfering with Bcl-2 like protein function. With regard to transcription silencing, studies have shown that, depending on the tissue origin of the malignancy, the expression of Bcl-2 or Bcl-xL can be downregulated in specific types of cancer and leukemia cells by small molecule drugs that modulate the activity of retinoic acid receptors (RAR), retinoid X receptors (RXR), peroxisome proliferator-activated receptors (PPAR), vitamin D receptors (VDR), and certain other members of the steroid/retinoid superfamily of ligand-activated transcription factors (SRTFs). Consequently, RAR and RXR ligands as well as PPAR modulators have been developed and evaluated for the treatment of some types of leukemia, lymphoma, and solid tumors, such as breast and prostate cancers [23, 199]. HDAC inhibitors, which function as transcriptional repressors via interaction with retinoid receptors and other transcription factors, can also favorably modulate the expression of Bcl-2 or Bcl-xL in some tumor lines [23]. These findings provide the basis for developing novel strategies for cancer treatment by suppressing the expression of antiapoptotic Bcl-2-family genes in cancer.
Besides the chemical compounds, antisense oligonucleotides have also been studied to knockdown the Bcl-2 family of antiapoptotic proteins. One agent that is currently most advanced in clinical trials is Genasense (also known as oblimersen or G3139), which is a synthetic, 18-base, single-stranded phosphorothioate oligonucleotide targeting Bcl-2 mRNA that was developed by Genta Inc. (Berkeley Heights, NJ). More precisely, Genasense is in phase II and phase III clinical trials treating a wide variety of adult and childhood tumors [200]. In addition, treatment with Genasense markedly improved the antitumor activity of many chemotherapeutic agents, such as taxanes, anthracyclines, alkylators, doxorubicin, or dacarbazine [201-203]. In a phase III clinical trial, Genasense in combination with dacarbazine was reported to significantly improve multiple clinical outcomes and increase overall survival in patients with advanced melanoma [203]. Furthermore, a bispecific antisense oligonucleotide selectively targeting Bcl-2 and Bcl-xL has been reported to simultaneously downregulate the expression of both Bcl-2 and Bcl-xL and enhance chemosensitivity in various cancer cells [204-206].
Intracellular stress signals can activate BH-3 only proteins to antagonize antiapoptotic Bcl-2 family members. An attempt to mimic the BH3-only action was the development of BH3 mimetic compounds containing exposed BH3 domain that occupy the BH3-binding site on Bcl-2 or Bcl-xL, abrogating their antiapoptotic functions. ABT-737 and its oral derivative, ABT-263 (also called navitoclax), are among the first promising BH3 mimetics in cancer therapy [207, 208]. Both drugs avidly bind and inhibit Bcl-2, Bcl-xL, and Bcl-w, but not Mcl-1 or A1. ATB737 has been shown to be effective as a single agent against certain lymphomas and small cell lung cancer in vitro and in vivo [207] and against non-small cell cancer [209]. ATB737 has also been reported to have synergistic cytotoxicity with conventional chemotherapeutic agents, and other targeted agents, including tyrosine kinase inhibitor, EGFR inhibitor, MEK inhibitor, and BRAF inhibitor, to reverse drug resistance and kill tumor cells [210, 211]. Initial clinical trials have demonstrated a significant antitumor activity of ATB263 as a single agent in the treatment of B-cell malignancies, especially CLL [212]. Several preclinical studies have shown promising effects of combinatorial use of ATB263 with conventional cytotoxic agents or targeted therapy in both solid tumor and hematologic malignancy models [210, 213]. However, the practical use of ATB263 is limited due to its propensity to induce acute thrombocytopenia. ABT-199, a newer BH3 mimetic that specifically targets Bcl-2, has been shown to suppress the growth of Bcl-2-dependent tumors in vitro and in vivo without causing thrombocytopenia since it does not antagonize Bcl-xL, which is critical for platelet survival [214-216]. Also, ATB263 has been demonstrated to enhance the antitumor activity when administrated in combination with other chemotherapeutic agents [217, 218]. Other BH3 mimetics, such as WEHI-539, BXI-61, BXI-69, Obatoclax, S1, JY-1-106, Gossypol, and its derivatives (apogossypol, apogossypolone, and TW-37) as well as selective Mcl-1 inhibitors, have been developed, and their antitumor effects have also been investigated or are under investigation (reviewed by Vogler [211]).
IAPs play a critical role in the control of cell survival and death by regulating key signaling events such as caspase activation and NF-κB signaling that makes them become attractive molecular targets. XIAP has been reported to be the most potent inhibitor of apoptosis among all IAPs, consequently targeting XIAP using antisense oligonucleotides, or siRNA molecules have been developed in the treatment of cancer. Indeed, targeting XIAP by antisense oligonucleotides or siRNA has been demonstrated to be able to induce apoptosis and sensitize cancer cells to death receptor- and chemotherapeutic agents-induced cell death in a variety of cancer in vitro and in vivo [219-223]. Similarly, the siRNA-mediated downregulation of other IAPs, such as cFLIP and survivin, has also been shown to enhance chemotherapy activity in a range of cancers [224-226]. In addition, some chemical compounds, for example, mTOR inhibitors and HDAC inhibitors, can suppress the cFLIP expression via blocking its translation and transcription, respectively [226, 227].
Another approach for targeting IAPs is to disrupt IAP binding to caspases by small molecule IAP antagonists. IAP antagonists bind to the BIR2 or BIR3 domain of XIAP, cIAP1, and cIAP2, leading to the activation of caspase and induction of apoptosis [228]. Most of IAP antagonists are Smac mimics, and in addition to monovalent compounds that contain one Smac-mimicking unit, bivalent or dimeric IAPs have also been developed, which consists of two Smac-mimicking units that are connected via a chemical linker [229]. When used as a single agent, IAP antagonists can only effectively trigger cell death in a small subset of human malignancies, suggesting that IAP antagonist-based combination therapies might be required for the effective treatment of a majority of tumors. A variety of chemotherapeutic agents (including doxorubicin, etoposide, gemcitabine, paclitaxel, cisplatin, vinorelbine, SN38, 5-fluorouracil (5-FU), cytarabine, and HADC inhibitor vorinostat), death receptor agonists, and signal transduction modulators (including proteasome inhibitors, various kind of kinase inhibitors and monoclonal antibodies targeting growth factor receptor) have been shown to act cooperatively with IAP antagonists to enhance antitumor activity in vitro and in preclinical models of cancers [230-236]. For instance, beneficial synergistic effects were observed when IAP antagonists were used in combination with other compounds, such as bortezomib, TRAIL, or DNA damaging agents, such as melphalan, to reduce tumor burden in multiple myeloma models [237]. Along these lines, LBW242 was also highly beneficial in an FLT3-mutated AML xenograft mouse model when administered along with the protein kinase inhibitor PKC412 [238]. A recent study depicted the combinatorial effect of Pak1, a downstream Rac effector, inhibition on IAP antagonist treatment in NSCLC cell lines, rendering these cells hypersensitive to apoptotic cell death [239]. The development of combination therapy is warranted as it promotes better patient survival, as shown in a metastatic breast cancer Phase III clinical trial [240]. Combination therapy might promote synergistic effects leading to low drug dosage, as well as suppressing resistance to therapy if multiple cell survival pathways are targeted at once, although the probability of toxicity is also increased [241]. Fortunately, clinical trials with IAP antagonists have not showed any dose-limiting toxicity [242].
Therapeutic targeting of the autophagy pathway as a new anticancer strategy has been under extensive investigation. Since autophagy can play roles in tumor growth depending on the context, such as tumor type or stage, both of the autophagy-enhancing and autophagy-inhibiting agents may elicit beneficial effects in the treatment of cancer.
High levels of autophagy are commonly observed in tumor cells following anticancer therapy. For example, chemotherapeutic agents (e.g., doxorubicin, temozolomide, camptothecin, and tamoxifen), HDAC inhibitors (e.g., SAHA), tyrosine kinase inhibitor (e.g., imatinib, sorafenib), and monoclonal antibody (e.g., trastuzumab) have all been demonstrated to induce autophagy in a variety of tumor cells [243-248]. Furthermore, a number of studies have shown that genetic knockdown of ATGs or pharmacological inhibition of autophagy can effectively promote cell death induced by various anticancer agents in many cancer lines and in multiple tumor models [249-252]. These findings suggest that the activation of autophagy is a protective strategy for tumor cells to avoid being entirely killed by anticancer agents. The prosurvival ability of autophagy renders tumor cells resistant to anticancer agents, which greatly compromises curative efficacy of chemotherapy. In these contexts, the inhibition of autophagy can be a promising strategy to reestablish or increase the sensitivity of tumor cells to therapeutic agents.
The common inhibitors of autophagy can be categorized into three types according to their action mechanisms: (1) inhibit the formation of autophagosome via restraining the recruitment of Class III PI3K to the membrane, such as 3-methyladenine (3-MA) and Wortmannin; (2) prevent the degradation of proteins within autophagosome by disrupting lysosomal function, such as chloroquine (CQ) and its analog hydroxychloroquine (HCQ); and (3) intervene in the fusion of autophagosome with lysosome, such as bafilomycin A1 (BafA), a direct inhibitor of vacuolar ATPase [253].
CQ and its derivative HCQ are the most common autophagy inhibitors used in clinical trials. Preclinical studies have shown that CQ and HCQ are equipotent at autophagy inhibition and potentiate the anticancer effects of different drugs both in vitro and in vivo. For example, Amaravadi et al. reported that in a Myc-induced lymphoma mouse model, QC and HCQ significantly enhance the cytotoxic effects of p53 expression and alkylating agents and substantially impair the recurrence of tumor after chemotherapy [254, 255]. In chronic myelocytic leukemia (CML) cell lines, the inhibition of autophagy by CQ markedly augments the cell death induced by imatinib, a tyrosine kinase inhibitor that is a first-line therapeutic agent for BCR/ABL-positive CML [256]. CQ has also been shown to promote the cytotoxic effects of SAHA, an HDAC inhibitor, to overcome imatinib-resistant CML cells [246]. In a colon cancer xenograft model, CQ in combination with vorinostat was shown to significantly reduce tumor burden and increase apoptosis [257]. Similarly, CQ enhances the anticancer effect of the saracatinib, an src inhibitor, in a xenograft mouse model of prostate cancer [258]. Currently, phase I/II clinical trials are ongoing to evaluate the potential benefits of CQ and HCQ in combination with standard cancer therapies for a variety of cancers [259], and these clinical trials are listed at http://www.clinicaltrial.gov/.
In addition to CQ and its derivatives, other potential autophagy inhibitors have also been studied for their anticancer efficacy in vivo and in vitro, including 3-MA, BafA, monensin, and pepstatin A [260-262]. For example, the inhibition of autophagy by 3-MA increases cell death induced by 5-fluorouracil (5-FU) in colon cancer xenograft model [263] as well as enhances cytotoxicity induced by imatinib in glioma cell lines [264]. BafA in combination with tyrosine kinase inhibitors, such as imatinib, nilotinib, or dasatinib, significantly increase cell death in CML cells [256]. However, it must be remembered that the cytotoxic effects of these different agents might not be solely due to the inhibition of autophagy; targeting key autophagy proteins would be a more potent and specific approach. These include ULK1, Beclin 1, or ATG proteins.
Although the concept of “autophagic cell death” in mammalian cells remains largely controversial, studies do show that autophagy is required for the efficient killing of tumor cells in certain circumstances [252]. Certain tumor cells become highly resistant to apoptosis and chemotherapy by overexpression of Bcl-2 or Bcl-xL, lack of Bax and Bak, loss of Beclin 1, or exposure to pan-caspase inhibitors [76]. Most anticancer drugs exhibit limited effect on this subset of tumor cells. Fortunately, studies have demonstrated that the induction of autophagy may be an alternative way for cancer treatment when apoptosis is blocked [265, 266]; however, the conditions under which autophagy can function as a primary cell-death mechanism remain to be defined.
Among the potential targets in autophagy, Akt-mTOR pathway is the most investigated one. mTOR inhibitors, including rapamycin and its analogs everolimus (RAD-001), temsirolimus (CCI-779), and deforolimus (AP-23573), have been developed and studied for their ability to induce autophagy and cell death. Everolimus and temsirolimus have been approved for the treatment of renal cell carcinoma and mantle cell lymphoma [267]. Rapamycin has been shown to inhibit cell growth and initiate cell death in mantle cell lymphoma cell lines and various primary tumor cells, such as malignant gliomas, breast cancers, renal cell carcinomas, non-small cell lung cancers, and cervical and uterine cancers [13, 253]. Everolimus induces massive autophagy in leukemia [268], in advanced pancreatic cancer [269], and in many other cancers [270], accompanied by reduced tumor burden. In addition, everolimus in combination with etoposide, cisplatin, or doxorubicin display synergistic effects without significant increase in toxicity [271]. However, rapamycin and its analogs would inevitably activate Akt kinases, which associate with the induction of insulin receptor substrate-1, jeopardizing the antitumor effects of these mTOR inhibitors [272]. Other inhibitors, including ATP-competitive inhibitors of both mTORC1 and mTORC2 as well as the dual PI3K-mTOR inhibitor NVP-BEZ235 [273, 274], have exhibited more potent capacity to induce autophagy in cancer cells [275, 276].
Antiapoptotic Bcl-2 family members are frequently overexpressed in many human tumor types, rendering tumor cells resistant to apoptosis. Bcl-2 family members are important regulators involved in both apoptosis and autophagy. As a result, the modulation of Bcl-2 family proteins leads to not only apoptotic but also autophagic cell death. The underlying mechanism of this effect reflects the fact that Bcl-2/ Bcl-xL proteins can bind and disrupt the autophagic function of Beclin 1, which contains a BH3 domain [277]. This is notably the case for BH3 mimetics (ABT737, ABT236, gossypol, obatoclax) that targets Bcl-2/Bcl-xL, thus allowing Beclin 1 to be released to trigger autophagy [277, 278]. Obatoclax has been shown not only to induce cell death on its own but also to potentiate the effects of other anticancer agents such as the dual EGFR/HER2 inhibitor lapatinib, or HDAC inhibitors [279]. Although the inhibitory effect affects both apoptosis and autophagy, the tumor cells preferentially undergo autophagic cell death in apoptosis-defective cells. For example, doxorubicin primarily induces autophagy at low doses while apoptosis at high doses, and the combination of Bcl-2 siRNA treatment with a low dose of doxorubicin enhances the autophagic response, tumor growth inhibition, and cell death [126].
In pursuit of new drugs to selectively kill renal cell carcinoma (RCC), Giaccia and colleagues identified a compound, STF-62247, that strongly induced autophagy and massive vacuolization in VHL (a tumor suppressor gene lost in 75% of RCCs)-deficient RCC cells with no apparent apoptosis induction. Blocking autophagy using ATG5 or ATG7 siRNA or 3-MA prevents STF-62247-induced cell death, indicating that this compound induces cell death by autophagy in VHL-deficient RCC cells [280]. In addition, other autophagic cell death-inducing anticancer agents have been developed and studied [279].
The accumulating data have indicated that necrotic cell death can be activated to induce the damage of tumor tissue. DNA-damaging agents are the most widely used and effective chemotherapeutic approach for cancer treatment, which has been shown to be able to stimulate a regulated form of necrosis [281]. The PARP is activated in response to DNA damage, which facilitates the access of DNA repair enzymes to damaged DNA. The hyperactivation of PARP depletes cytosolic nicotinamide adenine dinucleotide (NAD) and induce necrosis [282], which may lead to selectively killing tumor cells because highly proliferating tumor cells depend on cellular NAD to generate energy through aerobic glycolysis. PARP-mediated necrosis may explain the phenomenon that neither Bax/Bak nor p53 deficiency impedes cell death in response to DNA-damaging agents. Jouan-Lanhouet et al. found that the death receptor ligand TRAIL induces necroptosis in human HT29 colon and HepG2 liver cancer cells via RIP1/RIP3-dependent PARP1 activation and depletion of cellular ATP levels, suggesting PARP1 activation as an effector mechanism downstream of RIP1/RIP3 [283].
There are more and more compounds and anticancer drugs that have been demonstrated to induce cancer cell death through necrosis, such as shikonin, FTY720, staurosporine, derivatives of amiloride (5-benzylglycinyl-amiloride and glycinyl-amiloride), and BI2536 (a small molecule inhibitor of the mitotic kinase Plk1). Most of them were not necessarily designed in a mechanism-based fashion but were only later found to induce necrotic features in the dying cells [284-289]. Shikonin, a naturally occurring naphthoquinone, was reported to induce necroptotic cell death in cancer cells that can be prevented by RIP1 inhibitor necrostatin-1, a specific inhibitor of necroptosis. Moreover, shikonin-induced necroptosis can overcome drug- and apoptosis-resistant cancer cell lines overexpressing P-glycoprotein, MRP1, BCRP, Bcl-2, or Bcl-xL [284, 285]. FTY720, a sphingolipid analogue drug that mimics ceramide, was shown to target the I2PP2A/SET oncoprotein, which results in the activation of tumor suppressor PP2A and subsequently induces RIP1-mediated necroptotic cell death and tumor growth inhibition [286]. Staurosporine, an inhibitor of a broad spectrum of protein kinases, has been shown to induce necroptosis in leukemia cells when caspase activation is inhibited. The induction of necroptosis was blocked by several pharmacological inhibitors, including necrostatin-1, HSP90 inhibitor geldanamycin, MLKL inhibitor necrosulfonamide, and a cathepsin inhibitor CA-074-OMe, which has been demonstrated to rescue the caspase-independent necrotic cell death of leukemia cells treated by staurosporine [289]. Other anticancer agents have also been shown to induce necroptosis via different mechanisms.
Bonapace et al. reported that obatoclax (GX15-070), a putative antagonist of Bcl-2 family members, could overcome glucocorticoid resistance in childhood acute lymphoblastic leukemia (ALL) through the induction of autophagy-dependent necroptosis, which bypassed the block in mitochondrial apoptosis [290]. Obatoclax was also shown to promote the assembly of the necrosome on autophagosomal membranes, thereby connecting obatoclax-induced autophagy to necroptosis signaling pathways [291]. Coimmunoprecipitation assays demonstrated that obatoclax promoted the physical interaction of ATG5, a constituent of autophagosomal membranes, with FADD, RIP1, and RIP3 as key components of the necrosome [291].
Small molecule inhibitors targeting IAPs such as Smac mimetics, which have been developed to induce apoptotic cancer cell death, have been found to also engage necroptotic cell death. He et al. first reported that, upon the inhibition of caspase activity, Smac mimetics in combination with TNFα provoke a strong necroptotic response in Smac mimetic-resistant cancer cells [172]. Similarly, Smac mimetic BV6 promotes TNFα-induced necroptosis not only in leukemia cell lines deficient in caspase 8 or FADD but also in primary, patient-derived ALL cells [292]. This Smac mimetic/TNFα-triggered necroptosis occurred in an RIP1-dependent but caspase-independent manner in these leukemia cells lacking caspase 8 or FADD; however, in FADD- or caspase-8-proficient leukemia cells, the same cotreatment of Smac mimetic and TNFα induced apoptotic cell death [292]. This illustrates that Smac mimetic can prime leukemia cells to TNFα-mediated cell death via either necroptosis or apoptosis depending on the cellular context. Mechanistically, by promoting the degradation of cIAP proteins, Smac mimetics stimulate the necrosome formation and promote necroptosis [293]. Furthermore, a recent study demonstrated that Smac mimetic cooperates with demethylating agents to synergistically induce cell death and can circumvent apoptosis resistance of AML cells by switching to necroptosis [294].
Targeted toxins are fusion proteins that combine a targeting protein, such as a ligand for a specific receptor, and a toxic peptide derived from a bacterial pathogen [295]. Diphtheria toxin GM-CSF (DT-GMCSF) was shown to kill AML cells by simultaneously activating both caspase-dependent apoptosis and caspase-independent necroptosis [296]. Interestingly, DT-GMCSF-induced necroptotic cell death even occurred in apoptosis-resistant AML cells, indicating that necroptosis may open new perspectives for cancer drug development in AML [296].
The dysregulation of the cell death process is closely related to cancer progression and resistance to chemotherapy. The concept to therapeutically target apoptotic signal transduction pathways has significant implications for cancer therapy since intact apoptosis programs are critically required for the antitumor activity of most current cancer therapies that are used in clinical oncology. The reactivation of apoptosis not only directly induces cell death in tumor cells but also sensitizes tumor cells to other chemotherapeutic or targeted therapy agents. However, given the wide variety of genetic and epigenetic defects that lead to apoptosis resistance in most cancers, understanding the mechanism and regulation of other cell death pathways in response to antitumor agents is important. Autophagy and necrosis are two nonapoptotic cell death models that can be triggered as a consequence of cancer therapy and may have overlapping but separable regulatory networks. Unlike apoptosis or necrosis, autophagy has been shown to exert dual functions in cancers. On one hand, autophagy can function as a survival pathway in response to anticancer agents; hence, autophagy inhibitors may be used as adjuvants to standard cancer therapies. On the other hand, autophagy can lead to cell death in certain circumstances; thus, autophagy inducers may help to eradicate cancer cells. As the effect of autophagy on cancer therapy varies depending on cell context such as cell type, phases, and microenvironment, personalized pharmacotherapeutic strategies should be adopted alone or most likely in combination with standard chemotherapeutic agents.
The success of compounds like the BH3 mimetics, Smac mimetics, TRAIL, and mTOR inhibitors in preclinical studies is proof that the reactivation of defective cell death pathways in cancer cells is possible and can effectively eradicate tumor cells. Therefore, efforts should be put to further delineate and identify regulatory components of the different cell death pathways that can be targeted and manipulated to execute death. Understanding the crosstalk between the different cell death pathways as well as between cell death and non-cell death pathways in cancer is crucial to spot prospective convergence points between pathways. Targeting the convergence points will allow the switching between pathways and improvisation of alternate means of inducing cancer cell death. For example, TNF signaling to the NF-κB prosurvival and inflammatory pathway can be rerouted to the necroptotic pathway to promote cell death just by modulating cIAP levels [163].
Within the large and modern hospitals, an increasingly common problem is the efficient management of the maintenance of the medical equipment, the quality of the assistance and the profitability. If effective management of medical equipment maintenance is to be applied, the management structure should apply appropriate planning, management and implementation processes. This is essential for providing quality health services while saving resources. Medical equipment management includes inspection and preventive and corrective maintenance operations [1].
\nThe efficient management of maintenance and repair work must be planned and implemented using appropriate maintenance strategies to keep the devices safe and functional in accordance with the basic functional specifications. In addition to the high initial investments, medical equipment requires continuous and costly maintenance during its useful life. The issue of maintenance is the main point of discussion of the management of medical devices. Studies have shown that the most frequent cause of stopping of medical equipment is poor maintenance, planning and management. To solve this problem, it is necessary to establish and regulate an adequate system for the proper maintenance and use of medical equipment. Perfect maintenance is the equation of performance, risk, resources and costs to achieve this goal [2, 3].
\nThe first maintenance policies developed consist of interventions on equipment, which run until it stops accidentally (breakdown) in place due to wear or because of defects. The intervention is considered satisfactory as long as the equipment/system is operating at a minimum acceptable level (reactive maintenance). The development and increase of the complexity of medical equipment and devices have led to modernizing and updating maintenance techniques and policies. Depending on the costs related to the spare parts and materials, respectively to the losses due to the time spent in repair, several types of maintenance policies have been developed [4].
\nDue to the way the health services are organized, the technical staff in the health units should not only perform maintenance and repair work but also be actively involved in the acquisition and management of the equipment. For example, they can plan equipment services and manage stocks; they can provide technical consultancy for procurement and can develop technical cost estimates. I can also make budget forecasts regarding the maintenance costs of medical equipment.
\nIn providing high-quality health services, medical equipment plays an essential role, because when the equipment is not used or properly maintained human damage can occur. In many situations, noncalibration, modification or repair of medical equipment by unqualified personnel can result in injury to the patient or loss of medical record. Preuse testing, preventative maintenance, malfunction reports (and incident reports) and repair procedures are just a few of the necessary actions prior to performing the medical act, to avoid injury caused by the use of medical equipment.
\nEven if the medical equipment used in the hospital is purchased, rented or borrowed, the commitment to safety is an essential element of any process related to the use of medical equipment. Proper maintenance and proper use of medical equipment ensures maximum efficiency and increased availability of equipment, at optimal costs and under satisfactory conditions of quality, safety and environmental protection [5].
\nIn order to make the process of maintenance of the medical equipment more efficient, it is necessary to consider the use of a maintenance program of the equipment that takes into account its characteristics and the defects that appear to the medical equipment. The application of such a program of maintenance of medical equipment could be effective in applying correct maintenance strategies for the management of the older technological devices and the new high-tech devices, due to their different characteristics.
\nMaintenance was long considered as a subordinate function, entailing an inevitable waste of money. There was a tendency to lump it together with troubleshooting and repairing machinery that was subject to wear and obsolescence. However, hospitals today are realizing that maintenance is not merely a ‘partner’ in medical services: it is an indispensable requirement for quality medical services [6]. Its relation with equipment performance is a question of integrated strategy at senior management level. As such, the maintenance function becomes a management responsibility.
\nThe structure that determines the goals and objectives of maintaining medical equipment is very important. If the goals and objectives are progressive, then the maintenance structure is recognized as a contributor to the hospital’s foundation line, and thus, variations can be used on some of the more conventional organizational structures.
\nObjectives of maintenance management: the more specific objectives of maintenance management are as follows [7]:
To optimize the reliability of equipment and infrastructure
To ensure that equipment and infrastructure are always in good condition
To carry out prompt emergency repair of equipment and infrastructure so as to secure the best possible availability for medical use
To improve operational safety
To train medical personnel in specific maintenance skills
To advise on the acquisition, installation and operation of medical devices
To ensure medical environmental protection
Within the clinical engineering department of any hospital, a crucial aspect of the activities is the activity of maintenance and preventive maintenance of the medical equipment, because it involves significant human and financial resources. Therefore, the optimization of the use of the resources available in the clinical engineering departments is done by evaluating the efficiency of the preventive maintenance programs of the medical equipment [8].
\nForms of maintenance:
\nMaintenance has three major forms:
Design-out maintenance
Preventive maintenance, which includes systematic (periodic) maintenance and condition-based maintenance
Corrective maintenance
These are illustrated in Figure 1.
\nThe forms of maintenance.
Maintenance can also be divided into planned and unplanned maintenance (or scheduled and unscheduled) (Figure 2). The following chart highlights the relation to the previous chart.
\nPlanned and unplanned forms of maintenance.
\nTable 1 briefly explains the terms used in the two charts.
\nMaintenance | \nMaintenance is the function whose objective is to ensure the fullest availability of production equipment, utilities and related facilities at optimal cost and under satisfactory conditions of quality, safety and protection of the environment. | \n
Design-out maintenance | \nThis is also known as plant improvement maintenance, and its object is to improve the operation, reliability or capacity of the equipment in place. This sort of work usually involves studies, construction, installation, start-up and tuning. | \n
Preventive maintenance | \nThe principle of preventive maintenance is anticipation. It is put into practice in two forms: systematic (periodic) maintenance and condition-based maintenance. | \n
Corrective maintenance | \nThis is also called breakdown maintenance, palliative or curative maintenance. This form of maintenance consists of the following: \n
| \n
Systematic maintenance | \nThis consists of servicing equipment at regular intervals, either according to a time schedule or on the basis of predetermined units of use (hours of operation or distance traveled). The aim is to detect failure or premature wear and to correct this before a breakdown occurs. The servicing schedule is usually based on manufacturers’ forecasts, revised and adjusted according to experience of previous servicing; this information is recorded in the machine’s file. This type of maintenance is also called periodic maintenance. | \n
Condition-based maintenance | \nThis type of maintenance of the medical equipment is easy to apply because it does not require the disassembly of the equipment, the same technique based on the inspection by listening to the equipment involved. Predictive maintenance requires continuous observation of equipment to detect possible faults or to monitor its condition. | \n
Planned maintenance | \nThis is maintenance that is known to be necessary sufficiently in advance for normal planning and preparation procedures to be followed. | \n
Unplanned maintenance | \nThis is maintenance that is not carried out regularly as the need for it is not predictable; it is sometimes called unscheduled maintenance. | \n
Short description of the terms of maintenance.
The seven forms of maintenance distinguished above are the main types currently used in practice. Although preventive and predictive maintenance strategies differ in many ways, a maintenance program comprising both strategies yielded positive results. The maintenance strategy evaluation demonstrated that strategies based on performance verification and safety testing results and the manufacturers’ recommendations led to a significant reduction in equipment failures and a significant increase in corrective maintenance.
\nAn efficient strategy in the correct application of the maintenance of medical devices consists of the use of a maintenance strategy for older devices and another strategy for high-tech devices. We must keep in mind that older medical devices to which only corrective maintenance has been applied cannot be included in preventive maintenance strategies, such as new high-tech devices. Maintenance costs would increase greatly if we also reported old devices in the maintenance process [9, 10].
\nThe access today is put on performance verification and safety testing in the use of medical equipment, which leads to a change in the maintenance strategies of the devices without necessarily taking into account the manufacturer’s recommendations. Also, the decision-making in the management of medical equipment should be based on all the results of medical equipment malfunctions and the existence of a detailed history for each medical device.
\nPerformance measurement is a key management tool. In terms of maintenance management, an essential issue is to ensure that the planned and executed maintenance activities have given the expected results. Efficient use of indicators can facilitate this fact. Such an indicator, represented by key performance indicators (Kpi) is able to evaluate important aspects of the maintenance function. To this end, it has been shown that the measurement of maintenance performance is dominated by delay indicators (equipment, maintenance costs and safety performance).
\nThe reduced use of the peak indicators in the maintenance process can also be observed. The obtained results did not show direct correlations between the maintenance objectives pursued and the Kpi used. Subsequent analyzes revealed that only a small part of the companies involved have a high percentage of decisions and changes caused by the use of Kpi and only a few are satisfied with their performance measurement systems. By analyzing the correlation, a strong positive linear relationship was identified between the degree of satisfaction and the changes/decisions of the process that are triggered by the use of Kpi, the people least satisfied with the least decisions and changes triggered by the use of Kpi. These observations indicate some inefficiency of performance measurement systems in improving driving performance [11].
\nThe components of a system, such as pumps, electric or hydraulic motors, transmission systems, etc. as integral parts of it, must operate at optimal parameters to ensure that the overall performance of the device is achieved. Addressing the maintenance problems and establishing the procedures and the maintenance strategy for equipment must therefore take into account both monitoring and diagnosing at the level of each component, but also the influence of the system variables. Most of the time, the cause of a defect is found in the variations of the process parameters, and a nonintegrative approach to monitoring and diagnosing the system can lead to inefficient actions. Thus, in addition to the most popular techniques of monitoring and diagnosis (vibration monitoring, thermography and tribology), other parameters of a system such as flow rates, voltages, currents, temperatures, etc. must be considered.
\nIn systems equipped with computer control or semiautomatic control, most of these parameters are purchased and used in the command and control process. Their type and number vary from system to system, but the algorithm for applying the monitoring and diagnostic procedure is similar. The collection of these parameters, together with the application of the traditional technologies of predictive maintenance, will provide all the necessary data for the analysis of the state and the performances of the system [12].
\nSince a large part of the equipment used in the medical field belongs to the category of electromechanical systems, the analysis of the maintenance technologies will focus on these, from the simplest (examples: electric motor-pump type drive systems) to complex devices.
\nIt should be kept in mind that, in any system, the maintenance program will focus on its critical components. A critical component is defined as the element directly involved in the proper functioning of the device, on which the entire system depends, its efficiency and, last but not least, the quality of the product.
\nSome of the technologies for monitoring and diagnosing the state of a system are set out in the following. Vibration analysis is one of the most widely used detection methods to diagnose defects in electromechanical systems. This method measures the vibrations of the system, usually with an accelerometer, and then examines the frequency spectrum generated to identify significant frequencies from the point of view of the state of the equipment. Certain frequencies are typical of the system in normal operation. Changing the amplitude of certain harmonics, for example, can mean the presence of a defect. The data can be collected periodically, using a portable system, or continuously, by installing a continuous monitoring system. A major advantage is that the measurements are fast and noninvasive, and the functioning of the tested system is not disturbed [13].
\nAnother key parameter that can provide information about one’s status of equipment/system is temperature. This is an important indicator of the mechanical, electrical or load conditions applied to a component. Thermography is a predictive maintenance technique that uses instruments that can monitor infrared energy emission to determine operating conditions.
\nInfrared scanning is recommended as a regular maintenance procedure in many situations, extracting solid results as quickly as possible and without interrupting process flow, a key benefit to the industry, regardless of the age of the equipment. As an advantage of scanning a large area in a very short time, the ease with which data can be stored and processed for further analysis of images, the high mobility of the thermography camera that can be positioned at any time and place, the thermographic evaluation that is done uninterrupted and equipment inspection staff who are out of danger are emphasized.
\nLubrication fluid analysis can be used to determine mechanical wear, lubrication or fluid condition. The presence of metallic particles in the lubricating fluid suggests the existence of a wear, their analysis providing information on the part subjected to wear. For fluid analysis, it uses complex equipment, which is why this method is not so often used in practice.
\nThis strategy prioritizes the training of technicians to maintain an optimal number of actions, very important for essential medical equipment frequently used in medical institutions.
\nPrioritization of medical equipment maintenance should be performed for each new type of device during the inspection received when the device is added to the inventory. The device will then be assigned a test frequency. Subsequently, the maintenance history of the device will be monitored to evaluate the effectiveness of the maintenance program.
\nThe end point of providing an organizational tool to the biomedical or clinical engineer would ensure the safe and efficient performance of medical equipment. The system must be evaluated on criteria such as:
Data management for medical devices, manufacturers and suppliers
Acquisition conditions
Implementation and management of quality and safety protocols and procedures, including necessary documentation and data
Carrying out corrective maintenance activities
Routine procedure planning, such as acceptance testing, preventive maintenance, quality and safety inspections
Management and monitoring of training provided by manufacturers or technical staff including biomedical engineer or clinical engineer [14]
The risk assessment was divided into four main areas: clinical function, failure avoidance probability, history of incidents and regulatory or manufacturer requirements. Devices would be evaluated on the aforementioned criteria and be assigned a score. The values would be added and a cumulative score is given for each device type. The total score would act as a quantifiable indicator for the maintenance policy. A total score of 12 or more would indicate a semiannual testing, a score between 9 and 11 would require annual testing, whereas a score of 8 or less would suggest a lesser necessity for annual testing, either biannual or no schedule, depending on clinical use. The end result would be an increase in the cost-effectiveness of the test program, less equipment downtime leading to improved patient care and a higher financial return to direct patient care activities.
\nTo illustrate the applicability of risk assessment criteria, we evaluated two types of devices extensively used in healthcare: the defibrillator and the enteral feeding pump. Defibrillators are devices that correct or prevent arrhythmias (e.g., ventricular fibrillation and ventricular tachycardia) by sending an electrical impulse to the heart. External defibrillators, in particular, send high electrical impulses through the thoracic wall, stopping the independent action of the individual myofibers, so that the intrinsic pacemaker can take over. A set charge, between 0 and 360 J, is generated and delivered through paddles or disposable electrodes through the chest wall to the heart, determining a global contraction. Most defibrillators include an electrocardiograph to monitor the patient’s rhythm, while others even include the pacer function. The clinical use is typically for emergency heart pacing such as severe bradycardia, asystole, pacemaker failure or ventricular fibrillation.
\nFor this particular type of device, the assessment should include electrical safety evaluation—ground wire resistance, chassis and lead leakage—and inspection of parameters’ performance, which includes measuring the energy output of the defibrillator throughout its range. This would include determining the value output at the lowest, midlevel and highest settings. The range of error should be with 15% of the set energy level (for 360 J, the output should be ranging from 206 to 414 J). Other performance tests would be determining the output levels at maximum setting for 10 charge cycles. The final output should still be within 15% of the recommended setting and charge time should not exceed 15 seconds. The appraisal for functional assessment frequency would be twice a year (Table 2) [15].
\nCriteria | \nRisk | \nScore | \n
---|---|---|
Clinical function | \n\n | \n |
No patient contact | \n1 | \n\n |
Device may make contact with the patient who is noncritical | \n2 | \n\n |
Device is used for patient diagnosis or direct monitoring | \n3 | \n\n |
Device is used to deliver direct treatment to the patient | \n4 | \n\n |
Device is used for a life support | \n5 | \n5 | \n
Problem avoidance probability | \n\n | \n |
Maintenance would not impact reliability of the device | \n1 | \n\n |
Common device failure modes are unpredictable | \n2 | \n\n |
Common device failure is predictable and can be avoided by preventive maintenance | \n3 | \n\n |
Specific regulatory requirements dictate preventive maintenance or testing | \n4 | \n4 | \n
Incident history | \n\n | \n |
No history | \n1 | \n\n |
A significant history of incidents exists | \n2 | \n2 | \n
Manufacturers/regulatory requirements for specific schedules | \n\n | \n |
No requirements | \n1 | \n\n |
There are requirements for testing | \n2 | \n2 | \n
Total | \n\n | 13 | \n
Times per year tested | \n2(hight level) | \n
Sample risk assessment for defibrillator.
Enteral feeding pumps are used in patients who have gastrointestinal complications and who cannot consume adequate nutrients for certain reasons. The feeding solutions are transmitted to the patient through temporary feeding tubes or surgically implanted. These pumps can precisely control the flow of liquid supply solutions that are administered entirely through the digestive tract. These pumps are based on a pump mechanism such as a rotary peristaltic pump, a linear peristaltic pump or a volumetric pump. Most pumps record the dose frequency, dose settings and volume infused into memory. Audible and visual alarms alert the user to flow changes or malfunctions.
\nThe quantity of volume delivered must be within 10% of the established volume. Thus, for a set volume of 10 ml, the measured volume must be between 9 and 11 ml. The measured occlusion pressure must be within 1 psi of the pump occlusion pressure. For an occlusion pressure of 20 psi, the measured pressure must be between 19 and 21 psi. The recommended frequency of the functional test is annually (Table 3).
\nCriteria | \nRisk | \nScore | \n
---|---|---|
Clinical function | \n\n | \n |
No patient contact | \n1 | \n\n |
Device is in contact with the patient who is not critical | \n2 | \n\n |
Device is used for patient diagnosis or direct monitoring | \n3 | \n\n |
Device is used to deliver direct treatment to the patient | \n4 | \n4 | \n
Device is used for a life support | \n5 | \n\n |
Problem avoidance probability | \n\n | \n |
Maintenance would not impact reliability of the device | \n1 | \n\n |
Common device failure modes are unpredictable | \n2 | \n2 | \n
Common device failure is predictable and can be avoided by preventive maintenance | \n3 | \n\n |
Specific regulatory requirements dictate preventive maintenance or testing | \n4 | \n\n |
Incident history | \n\n | \n |
No history | \n1 | \n1 | \n
A significant history of incidents exists | \n2 | \n\n |
Manufacturers/regulatory requirements for specific schedules | \n\n | \n |
No requirements | \n1 | \n1 | \n
There are requirements for testing | \n2 | \n\n |
Total | \n\n | 8 | \n
Times per year tested | \n1(normal) | \n
Sample risk assessment for enteral feeding pump.
Before returning the equipment to medical personnel, it must be ensured that it has been adjusted to the original specific settings. Make sure that the volume of the audible alarms is loud enough to be heard under normal operating conditions [15].
\nMaintenance costs represent a large part of total cost functioning of health systems. Depending on the specifics of each device, the costs of maintenance can represent from 15 to 60% of the value of the expenses. For the situation in which the equipment works in safe conditions until a certain level of wear or a defect in the initial state has been established, we discuss about preventive and predictive maintenance. In such cases, the equipment will be stopped at an early date, and the repair will only be done where needed. This type of maintenance allows the early detection, localization and identification of the defect or the worn part, as well as the calculation of the operating life in safe conditions of the device. The activity of preventive and predictive type makes possible the planning of the stop, the preparation of the intervention team, the provision of the necessary spare parts and respectively the minimization of the parking time for repair [16].
\nPredictive maintenance represents a superior qualitative leap in a modern maintenance system, regardless of the domain or the specific production, because it offers all the information needed for the following:
Early detection of the defects
Location
Diagnosis of defects
Calculation of the operating life in safe conditions of the medical equipment
The common premise from which the predictive maintenance starts is that the periodic or continuous monitoring of the mechanical, electrical or other indicators of the functioning of the systems or processes can provide the data necessary to ensure the maximum interval between the repair and maintenance works, respectively, to minimize the cost of interruptions of maintenance. Unplanned maintenance can be the cause of possible failures, sometimes major. However, predictive maintenance is more than that. It is in fact the means of improving and increasing the productivity, product quality and overall efficiency of the systems in question. Predictive maintenance is actually a philosophy or attitude that, based on operating conditions, allows the optimization of the entire medical system. A comprehensive management of predictive maintenance uses the best methods to obtain the operating parameters of the component subsystems of a medical system, on the basis of which it will schedule maintenance and repair activities. Including predictive maintenance in the general maintenance program optimizes the availability of devices and equipment and greatly reduces maintenance costs. By using the records of the entire care of historical repair components and maintained maintenance, we can make a mathematical prediction model for the entire world.
\nClassifications of different types of failures and the establishment of policies for analysis involve three different levels: system level, failure peak and component level. Results analyzed can be set for a model for optimizing maintenance/inspection.
\nIt is considered a continuous process so that it can be put into operation or rejected (scrap). The way of monitoring the functionality is as follows: first, check each product; continue checking until the consecutive k linear products are reached (full inspection). From this point, the inspection of the equipment is no longer deterministic, “piece by piece”; they will be chosen randomly, independently of the other, with probability α. Continue random monitoring (partially verified) until a defect is discovered, and then revert to previous monitoring and so on. Suppose the probability of a product being defective is q. It is understood that if a problem is found, the item is removed temporarily or permanently.
\nAverage of all relevant product cycle is equal to:
\nIt can be shown that the proportion of undetected defective items is given by:
\nAnother model that offers good results when used in this field is known as “replacing a durable good.” This is based on the assumption, for example, that the service life of the equipment is represented by a continuous random variable with the distribution function H and the density h and that a policy to replace the good says that it will happen if it has a major failure or if it is still in operation, it is acceptable to reach a certain “age,” say the T years. We assume that the price of similar new equipment is C1, and when the equipment fails, we seriously consider a C2 amount, corresponding to the provision of the equipment.
\nThe average length of a life cycle of equipment can be expressed as:
\nDepending on the distribution of H, which is usually uniform (0, T0), where T0 is a standard period, depending on the case, for example 10 years and costs C1 and C2, one can estimate the value of T, which will reduce to a minimum the cost of having an older, optimizing device. As in the field of health care, failure prevention is more effective than focusing on remedying them. Repairs are almost always expensive, requiring overspecialized personnel and often expensive parts. However, corrective maintenance is a permanent component of medical technology management.
\nCorrective maintenance allows a device to maintain its full performance of functions, through effective interventions at the time of a problem. However, this action must be well planned, because it acts not only on the level of symptoms, but also on the level of finding and solving the cause of the defect itself.
\nUsers and technical staff have the obligation to maintain medical equipment at a level of safety as high as possible, compared to other types of usual equipment. Most complex medical equipment works, for example, in the intensive care unit. They have an electrical connection that in certain situations of first defect can create injuries or even death of the patient by electric shock. Patients connected to such medical equipment are not able to respond to dangerous conditions or pain. Other types of medical equipment work to support life, and a problem, sometimes even minor in some respects, can lead to the death of the patient when the equipment is used incorrectly or is poorly maintained. The life cycle of medical equipment, from the point of view of media technology management, comprises 4 stages and 9 themes according to current standards (Figure 3) [17, 18, 19, 20].
\nLife cycle of the medical equipment.
An important stage in the life of medical equipment is that of maintenance and repairs that involve certain assumptions and challenges.
\nSome assumptions are as follows:
Maintenance culture exists and is respected by the technicians, users and other staff.
Technical staff are present, trained and know how to maintain and repair the equipment.
Preventive maintenance schedules exist and they are performed regularly.
Technicians have access to spare parts, on stock in the hospital or ordered in and spare parts are delivered within 24 hours if necessary.
Technicians have access to and know how to use test equipment to calibrate and test medical equipment.
A maintenance system of medical equipment should be considered as a simple system with inputs/outputs. Inputs to the system are data of defective equipment, materials and spare parts, consumables, data and information on its use, local and global policies and procedures. The result is reliable and well-configured medical equipment that can be achieved only by efficient planning of maintenance and service. The system to be functional has a set of rules that must be implemented. These activities include planning, scheduling, executing and controlling.
\nThe control is performed having as objective the organization and functioning of the maintenance system. The objectives coincide with the organization’s objectives and include equipment availability, costs and quality. An important role is played by the feedback that is used to improve the performance of the medical system/equipment [21].
\nThe existence of an effective maintenance control system improves the reliability of the equipment and increases its service life without having unscheduled shutdowns. Maintenance control contains a set of activities, tools and procedures used to coordinate and allocate maintenance resources, including those for specialized personnel, to achieve the objectives of the system, including the following:
Work control
Quality control and processes
Cost control
An essential element of maintenance control is the work order system used for planning, executing and controlling maintenance work. The work order system consists of the necessary documents and the well-defined workflow process. The documents provide means for planning and collecting the information needed to monitor and report maintenance work.
\nCurrently, the process of controlling the maintenance of medical equipment involves four stages:
Concrete and coherent setting of objectives and standards: the control process begins with planning; the objectives and performance standards to be pursued are established. Performance objectives must be clear results that must be achieved.
Methods of measuring effective performance: the purpose is to accurately determine the results of performance (output standards) and/or performance efforts (input standards). Quantification must be accurate to identify significant differences between what was actually achieved and what was originally planned at the beginning of the process [22, 23].
An important role is played by the comparison of the results obtained following the measurements with imposed objectives and standards. This stage is expressed by the control equation: Need for action = Desired performance − Actual performance. Sometimes, a comparison with data from the history of equipment use, data collected from the medical device file, can be taken into account for an evaluation of current performance. Or you can use a relative comparison that tracks the performance of other equipment in the same model, meeting the same standard, used by people with similar training. In comparison, maintenance standards are scientifically established by methods such as time and motion studies. Preventive maintenance routines, for example, are measured in terms of expected time in each routine performed, depending on operating hours or time intervals.
Carrying out corrective actions: the last step in the control process is to take all necessary measures to correct problems, nonconformities or improvements. Effective management is one that pays attention to situations that show the greatest need for correction. It saves time, energy and other valuable resources, focusing on critical and priority areas. Maintenance managers must pay special attention to two types of situations: a problematic situation in which the real performance is below the imposed standard and a second situation, of opportunity, in which the real performance is above the standard.
The oldest and most common maintenance and repair strategy is “fix it when it breaks.” The appeal of this approach is that no analysis or planning is required. The problems with this approach include the occurrence of unscheduled downtime at times that may be inconvenient, perhaps preventing accomplishment of committed production schedules. These problems provide motivation to perform maintenance and repair before the problem arises. The simplest approach is to perform maintenance and repair at preestablished intervals, defined in terms of elapsed or operating hours. This strategy can provide relatively high equipment reliability, but it tends to do so at excessive cost (higher scheduled downtimes) [24]. A further problem with time-based approaches is that failures are assumed to occur at specific intervals. The only way to minimize both maintenance and repair costs and probability of failure is to perform ongoing assessment of machine health and ongoing prediction of future failures based on current health and operating and maintenance history [25, 26, 27].
\nThis is the motivation for prognostics: minimize repair and maintenance costs and associated operational disruptions, while also minimizing risk of unscheduled downtime. Preventive maintenance is the strategy organized to perform maintenance at predetermined intervals to reduce the probability of failure or performance degradation. It can be classified into constant interval, age-based or imperfect maintenance:
Constant interval maintenance: as the name suggests, it is done at fixed intervals (in addition to any maintenance prompted by failure that is performed when it manifests). Intervals are selected to balance high risk of failure with long intervals and high preventive maintenance costs with short intervals.
Age-based maintenance: in this strategy, preventive maintenance at fixed intervals is carried out only after the system has reached a specific age.
Imperfect maintenance: in the above to be restored to its original condition after a preventive maintenance. However, it may be the case that the condition of the system is in between good (original) and bad (failure). This is the premise of imperfect maintenance strategies, which take into consideration the uncertainty of the current state of the equipment while scheduling future activities [28, 29].
Providing quality medical services involves correct and efficient resource management and planning. An important element in achieving this is a balance between costs involved in the investment of new equipment and its maintenance. Proper use and proper maintenance of medical equipment must be supported by a clear policy in the field, technical guidance and practical tools for maintaining the functional parameters of media equipment. By using functional medical equipment, it will be possible to significantly improve the quality of the medical act and the efficiency of such a service. Consistent management practices in this area will help increase efficiency in the field of health.
\nAn analysis of the maintenance of medical equipment is made to assess the lifespan of that equipment, which can be extended or shortened depending on the actions taken. Equipment maintenance is crucial for its lifespan. If maintenance periods are not met, on time and on a regular basis, medical equipment will be damaged to the point where it will cost more to repair than to replace. If no decisions are made at all in the maintenance of medical equipment, it will degrade irreparably. The importance of maintenance activities consists in the efficient management of the equipment; this task requires extensive information about the medical device. Thus, it is necessary to know the history of the equipment, how it has been exploited in the past, to say if the situation is improving and to learn from previous situations.
\nFinally, records provide staff with valuable technical information and evidence that they can use when they need arguments or need help or additional resources. The maintenance of the database system helps to keep track of repair services and other actions for optimal operation of medical equipment.
\nThe authors declare no conflict of interest.
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