Apoptosis And Inhibitor of apoptosis proteins Family: A

programmed cellphoneular telephone death And Inhibitor of caspase-mediated cell death proteins Family ABackgroundApoptosis is an orchestrated biological cellular process that occurs in physiological and pathological conditions(1). It is essential for regulating development, homeostasis, and immune-system determination in organisms(2). In mammalian cells, caspase-mediated cell death is mediated by a family of cysteine proteases pass waterd caspases which ar initi exclusivelyy show in cells as in mobile procaspase trumpeters and argon twistivated by two avenues, the extrinsic ( or death receptor) and ingrained (or mitochondrial) apoptotic pathways(1).The extrinsic pathway is activated by the spine of ligands such as Fas ligand (FasL) and tumour necrosis fixings ( tumour necrosis constituent) to death receptors on the cell surface, FAS and the TNF receptor (TNFR), respectively, which leads to the formation of the death-induced sign solelying labyrinthine (DISC)(3)(4). DISC recruits caspase-8 and promotes the cascade of procaspase activation that follows(5).The indwelling pathway is triggered by extracellular and intracellular stresses, such as exalted cytosolic ca+2 , hypoxia, severe oxidative stress, deoxyribonucleic acid damage(5), which results in the permeabilization of the outer mitochondrial membrane, the w all told socket of pro-apoptotic molecules such as cytochrome C and opposite(a)s into the cytoplasm(6), the formation of the apoptosome- a large protein complex that is made up of cytochrome C, apoptotic protease activating factor 1 (APAF1) and caspase-9 and caspase activation(7).On the other hand, cell death is also modified by other mitochondrial proteins such as apoptosis-inducing factor(AIF), second mitochondria- derived activator of caspase (Smac), direct IAP Binding protein with low PI (DIABLO) and Omi/high temperature requirement protein A (Htr A2)(7). Smac/ DIABLO or Omi/HtrA2 induces cell death one by one of caspase acti vation by counteracting inhibitor of apoptosis (IAP)- mediated caspase inhibition(7)(8)( Fig. 1).The upstream caspase for the intrinsic pathway is caspase 9, musical composition that of the extrinsic pathway is caspase 8. The intrinsic and extrinsic pathways cleave the precursor forms of effector caspases, such ascaspase-3, caspase-6 and caspase-7(9). Activated effector caspases cleave umpteen springy cellular proteins such as protein kinases, cytoskeletal proteins, DNA repair proteins and inhibitory subunits of endonucleases family and dissect up the nuclear scaffold and cytoskeleton(9). They also activate DNAase, that further bring down nuclear DNA(10), which together contri furthere to the typical morphological changes in apoptosis.Dys principle of apoptosis has been implicated in numerous pathological conditions, including basecer(1). Besides, targeting the apoptotic pathways for freightercer treatment is support by several(prenominal) findings emphasizing the part of ab errant apoptosis in tumori factorsis and also vindication to anticancer treatment. Evasion from apoptosis is critical for tumor growth and a hallmark of cancer(11). One of the mechanisms by which evasion of apoptosis occurs is disrupted proportion of pro-apoptotic and anti-apoptotic proteins(1). A delicate balance in the midst of pro-apoptotic and anti-apoptotic mechanisms determines whether a cell death signal can activate the apoptotic program. It is non the unquestioning quantity but rather the ratio of these pro-and anti-apoptotic proteins that controls the regulation of cell death. In this balance, pro-apoptotic proteins activate apoptosis and anti-apoptotic proteins inhibit apoptosis(12)(13). Inhibitors of apoptosis protein (IAPs) are all-important(a) shares of the anti-apoptotic family of proteins that can inhibit caspase activation and play a key role in regulating of apoptosis in many species(1).Inhibitor of apoptosis proteins (IAPs)The inhibitor of apoptosis protein s are a group of structurally and serveally similar proteins that regulate programmed cell death, cytokinesis and signal transduction(14). The IAP ingredient is 1.6 kb in size encoding a 31 kDa protein with a zinc fingerbreadth-like motif. Many IAP family members fork over been identified in al more(prenominal) or less all species from viruses to mammals(15). They are characterized by the baculovirus IAP repeats (BIR) domain at the N- terminus, the name of which derives from the original discovery of these apoptosis suppressors in the genome of baculoviruses(16).The BIR domain contains approximately 70 amino cuttings. Although the shape of BIR domains varies among IAP members, each BIR domain is made up of cysteine and histidine residues in a well-defined pattern (CX2CX16HX6C)(15).IAP acts as endogenous inhibitor of caspases by binding of their conserved BIR domains to the active sites of caspases in vitro and vivo. IAPs inhibit caspases by promoting the degradation of active caspases, or by sequestering the caspases away from their substrates(17).When IAP family members are overexpressed, cancer cells no womb-to-tomb proceed to apoptosis and become increasingly resistant to standard chemo- and ray therapies(18)(19). Many studies direct established a circumstantial association between IAPs and cancer. Pathological over spirit of several IAP family members has been detected in several classes of human cancers(20)(21)(22).The eighter IAPs identified in humans are cIAP1, cIAP2, NAIP, Survivin, XIAP, apollon, ILP-2 and livin(23). Interestingly, many information have shown that c-IAP1, c-IAP2 and XIAP are broadly expressed in sane cells(24)(22). In normal tissues, IAPs could have some potential physiological roles, such as the regulation of the immune system(25), the answer to cell damage(25), cell pick and dissimilariation(26). On the other hand, it has been proven in many studies that survivin, dissimilar other IAPs, is prominently expressed in v ast majority of neoplasms but not in tell normal tissues(27). Survivin has been reported to be overexpressed in various cancers including front and lung cancer, prostate, gastric, colon, bladder and esophageal carcinomas, osteosarcomas and lymphomas(28)(29). Over prospect of survivin was also found to be importantly associated with poor outlook and decreased survivial rates in many cancers(30)(31).SurvivinSurvivin (also Called IAP 4) is a protein with a solid role in regulating both cell division and apoptosis. It is the weenyest member of the IAP family(29). Survivin, a 16.5 kDa intracellular protein of 142 amino acid, was discovered in 1997 by Ambrosini and colleagues(32).Structurally, survivin contains a single BIR domain. This domain is essential for its anti-apoptotic action mechanism(33). However, instead of a ring finger domain (RING) near the C-terminus shared by others members of the IAPs, survivin contains a C-terminus alpha-helical coiled-coil (CC) domain which is supposition to be important for its interaction with microtubules, hence its roles in cell cycle(34)(35)In normal tissues, survivin shows cell -cycle dependent flavour during cell division. Its expression pluss in G2/M phase and decreases rapidly in G1(29). The regulation of survivn expression and function is complex and can occur at various levels, including transcriptional regulation, post-translational modification, and protein stability regulation(27). it is modulate by a number of factors such as NF-nB(36), insulin-like growth factor I/mTOR(37), Ras oncogene family(38), E2F, Sp1, TCF, and heat shock protein (Hsp) 90(39)(40). Survivin is also adjust by p53 wild type. Additionally, post-transcriptional phosphorylation has been proven to play a regulatory role in survivin activation(41).Biologic function of survivinSurvivin as an inhibitor of apoptosisThe mechanism by which survivin inhibits apoptosis is still controversial. Initially, survivin and other IAPs were postulated to inhibit apoptosis directly by officious with the function of caspase-3, caspase- 7, and caspase-9(42). In support of this model, it was shown that survivin can interact with Smac/DIABLO physically, and so placing survivin in a interchange position in the dynamic balance of proapoptotic and antiapoptotic factors(43). However, Structural analyses of survivin indicated later that any effect on caspase should be indirect, as it overlooks the amino acid sequence that is essential in other IAPs for caspase binding. Also, the survivin gene is highly conserved in a wide range of organisms, and all of its orthologues are involved in mitotic regulation but not in cytoprotection(44). Studies of cells from survivin-knockout mice have cast further doubt on the existence of a direct link between survivin and apoptosis(45).Later experiments indicated that Survivin inhibits active caspase-9 but not active caspase-3 and caspase-7. And, survivin mediated inhibition of caspase-9 requires inter action and cooperation with other molecules such as HBXIP (hepatitis B X-interacting protein)(46) and XIAP (X- link up inhibitor of apoptosis protein) which also jockeyn as inhibitor of apoptosis protein 3 (IAP3)(47) (Fig. 3).Survivin also provides cytoprotection to cells through the inhibition of the AIF pathway, which is known to induce caspase-independent DNA fragmentation(48).Survivin as a promotor of mitosisThe cell- cycle dependent expression of survivin in normal tissues supports potently its role in cell division. During mitosis, survivin acts in a narrow quantify window at metaphase and anaphase. It is acting as an interphase between the centromere/central spindle and the chromosomal passenger complex (CPC)(49). CPC is a hetero-tetrameric complex which localizes to different sites at different times during mitosis, and is composed of four-spot components Aurora-B Kinase (enzymatic component), Borealin/Dasra, Survivin and inner centromere protein (INCENP)(50)(51). CPC i s essential for proper chromosome segregation and cytokinesis(52). Inactivation of mammalian survivin -or its orthologues in trim back organisms results in cytokinesis abnormalities, particularly spindle defects(53)(54) (Fig. 3)(55).Survivin facilitating angiogenesisIn addition to its roles in apoptosis and mitosis, survivin promotes angiogenesis. it is strongly expressed in endothelial cells (EC) during the proliferative phase of angiogenesis(56)(57) and the antisense-mediated suppression of survivin during angiogenesis stimulates vascular regression in vitro(58). Besides, exposure of cultured vascular EC to angiogenic factors such as VEGF and bFGF result in increasing survivin expression (both mRNA and protein)(59)(60).Survivin expressionIn normal physiological conditions, survivin is usually expressed in embryonic lung and fetal organs in the developmental Stages(61). The protein is also detected in mature tissues with high proliferation potential such as thymus, placenta, CD3 4+ stem cells and base colonic epithelial cells(61)(62)(63). However survivin seems to be selectively expressed in transformed cells and in most human cancers. Many studies have shown that survivin, unlike other IAPs, is prominently expressed in the vast majority of neoplasms but not in the differentiated normal tissue(27). Based on detection of protein by immunohistochemistry and mRNA by polymerase chain reaction techniques, overexpression of survivin has been reported in various human malignancies including lung cancer(64), breast cancer(65)(66) stomach(67)(68), esophagus(69), liver(70)(71), ovary cancers(72), brain(73) and hematological cancers(74).Additionally, the immunological responses which detected against survivin supports its special(prenominal) up-regulation in cancerous cells(75)(76). Survivin protein has also been shown to induce cytotoxic T-lymphocytes (CTL) response in breast cancer, melanoma and chronic lymphatic leukemia patients(76).Survivin expression can be deregulated in cancer by several mechanisms, including amplification of the survivin locus on chromosome 17q25 (77), demethylation of survivin exons(78), increased promoter activity(79), and increased upstream signaling in the phosphatidylinositol 3-kinase or mitogen activated protein kinase pathways(80).Overall, increased survivin expression in several malignancies is associated with cancer survival or disease recurrence, and resistance to chemotherapy or radiotherapy. In a depicted object of 275 patients with breast cancer exhibit that survivin was a important prognostic factor and predicted the outcome independent of patients age, tumor size and histologic grade(81). In the event of ovarian cancers, survivin expression was fit with poor prognostic factors such as high histologicgrade, mutant p53, and poor histologic type(81)(82). Also, previous(prenominal) studies demonstrate that survivin was expressed in benign brain and pituitary tumors. Although survivin was also desi gnate in normal pituitary tissue, the level of the gene expression was 6-fold higher(prenominal) in tumors than in normal pituitary tissue(83). In a flying field of 222 patients who underwent radical cystectomy, survivin was expressed in 64% of bladder tumors and 94% of malignant lymph nodes, but not in normal bladder specimens and its expression correlated with disease recurrence and disease- specialized mortality(84). Also, increased survivin expression has been associated with an unfavorable survival or disease recurrence in colorectal cancer(85), particularly in coiffure II disease in esophageal cancer(86), hepatocellular carcinoma(87), lung cancer(88), glioma(89), leukemia(90), and other cancer types. A study in oral cancer demonstrated that the extent of survivin expression was negatively correlated with the degree of differentiation(91).Additionally, survivin overexpression may be a predictive factor to determine response to chemotherapy and radiotherapy in patients with b ladder cancer(92), breast cancer(93), multiple myeloma(94), lung cancer(95) and lymphoma(96)(97). On other hand, patients with lower survivin expression were more reactive to preoperative chemotherapy with 5-flourouracil and cisplatin in esophageal cancer(98). It is also reported that patients with lower survivin expression in pretreatment biopsies were more responsive to radiotherapies in rectal cancer(99). While Overexpression of survivin was associated with resistance to a taxol-based therapy for ovarian carcinomas(100).In addition to full-length transcript (survivin (wild type)), louver splice variants, which result from splicing of survivin BIRC5 gene pre-messenger RNA (mRNA), have been expound survivin-Ex3, survivin-3B, survivin-2, survivin2 and survivin 3 with different structure and function(101)(102)(103). Previous studies showed that an imbalance in the resource transcript ratios may affect the cell to be resistant or sensitive to apoptosis(104). This alternative splic ing of Survivin has been shown to have correlation with disease activity in various patient studies. For example, studies showed that Survivin-Ex3 and survivin-3B were found to be highest in tumors with progress histological grade and were associated with poor prognosis(105)(106). On other hand, the expression of survivin-2 was significantly higher in small tumor size and was inversely associated with aliform node positive carcinomas(106).Besides different splicing forms, immunohistochemical studies have demonstrated that survivin also localize in distinct nuclear and cytoplasmic subcellular pools. Cytosolic Survivin is believed to act as apoptotic suppressor while nuclear Survivin is postulated to regulate cell division(29). in that respect are conflicting data of pathological significance of nuclear Survivin. some(prenominal) Splicing studies showed that nuclear staining of survivin is associated with favorable prognosis(107), while others showed Its expression in the nuclei of tumor cells appears to be associated with unfavorable clinical outcomes(108)(109). Also, the cellular localization of Survivin isoforms differs. while survivin-2 and Survivin 2a are localized in both nuclear and cytoplasmic compartments, survivin-Ex3 is localized in both mitochondria and nucleus(110).Additionally, Methylation and Phosphorylation are critical requirements for survivin function. Several observations show that survivin is unmethylated in cancer but may be selectively methylated in normal tissues with individual variations(111)(112). Methylation may play an important role in the p53 mediated suppression of survivin(113). Another critical requirement for survivin function is the phosphorylation on Thr34(114)Treatment approachesDue to important role of Survivin in tumor cell division, apoptosis, chemo resistance and survival, survivin represents a unique target for biologic therapy in many human malignancies. Several novel experimental therapeutic strategies have been actual to block the expression or function of Survivin in tumour cells. These take on immunotherapeutic approaches to induce immune response against Survivin, small molecule inhibitors/antagonists of survivin function, and nucleic acid based approaches which interfere with Survivin gene expression(115) such as antisense oligonucleotides (ASOs), ribozymes and small interfering RNAs (siRNAs)(116). Also, Vaccine approaches such as dendritic cell based (DC) vaccines, DNA vaccines(117), peptide vaccines for Survivin have also been evaluated in preclinical or clinical studies.Survivin ASOs were get-go used against malignant melanoma cell lines. Transfection with the ASOs triggered spontaneous apoptosis linked to decreased endogenous survivin expression(118) . Treatment with LY2181308, a specific inhibitor of Survivin mRNA which has already entered the phase 1 trial(119). YM-155 is a novel small-molecule survivin suppressant which inhibits survivin mRNA transcription and protein express ion in p53-deficient cancer cells in vitro(120). YM155 has also shown to be rough-and-ready in vivo models of prostate, pancreatic, and lung cancer(120)(121). Ribozyme mediated approaches have also been evaluated for inhibition of Survivin expression. Down-regulation of human Survivin gene expression and increased apoptosis was maked by using two loggerhead ribozymes (RZ-1, RZ-2) targeting human Survivin mRNA (122)PIQL Success-Tolerant motion process in the CloudPIQL Success-Tolerant Query Processing in the CloudAdvanced Topics in Foundations of DatabasesPIQL Success-Tolerant Query Processing in the Cloud Stavros Anastasios IakovouIntroductionIn our days it is widely know that modern web applications are directly linked with databases. In addition, the number of the users is highly increas- ing through the time and as result the related databases protrude overloading. Furthermore, despite the fact that data indepence would be ideal for im- plemeting lithe applications developers knuckle undern this idea in sound out to avoid expensive queries. Hence, Michael Armbrust et al.1 implemented a new declarative language called PIQL, a scale independent language.A large number of frameworks have already appeared in found to facilitate developers to create modern web applications. However, this plethora of websites with millions of users led to database failures due to lack of request managing. As a result, there was a demand on implementation of a new system that allow for control all these requests and provide efficient results to users.A few methods have introduced and one of the most popular is no(prenominal)QL. Despite the fact that NoSQL provided a high level interface, data indepen- dence created scalability problems since a large number of queries took a lot of time. This led to to several issues like performance failing and user disatisfaction as well. In order to avoid this bad situation scientists hand coded key/value implementations. On the one ha nd, this provided the de- sirable scalability but, on the other hand is was not easy replete for the developers to write that kind of code to parallelize their queries so as to fi achieve high scalability. Another significant issue is time consuming functions rewrites.Now, at one time we talked about several problems occured by queries in the next section we forget discuss about PIQL. More specifically, we go out present this method and give a brief summary of the implementation. In the rest of the document we will discuss about the performance of the previous imple- mentation.What is PIQL?In this section we will discuss and analyze the PIQL (PerformanceInsightful Query Language) model. One important advantage of PIQL is that intro- duced the caprice of scale independency. More specifically, the model pre- serves the logical data independence. The most significant about data this technique is that performace fend fors not only on small datasets but also in large as well. For t his reason this is called supremacy-tolerant since the success is for every large dataset. unless why PIQL is successful? The answer is on the limitation on key/value store operations.As we antecedently mentioned, one goal of PIQL is to avoid issues when the database gets larger. PIQL uses static analysis in order to fi the correct number of operation in every graduation of the execution. in the beginning we move to the next step of the analysis of the methodology we should mention the four queries classes. The fi one is called constant since the processing time is constant. The second one is the move class. More specifically this class refers to bounded data when the site becomes more popular. For instance, in case of Facebook every user has a limit of 5000 friends. The trinity class is called sub-linear or linear and is referring to queries that become more successfull when the data increase linearly. The last one is Super-linear where intermediate calculations are necessary for the queries.Now, once we mentioned all the necessary theoritical parts of PIQL we will discuss on its structure. Every master of ceremonies is directly connected with a Distributed Key/Value Store. Hence, this methodology maintains the scalability and the response time is now predictable. A significant drawback of this technique is that a specific key/value store is required so as to maintain data locality. On the other hand, this method is non-blocking and according to Chen et al.2 can reduce memory latency.Another important benefit of PIQL is that extends the cardinality con- straint of regular focalisation to diff ent directions as well. More specifi , these cardinalities provide several information on its relationships. For in- stance, a Facebook user should have no more than 5000 friends. This is a very significant information since selecting the wrong number for limita- tions can lead back to the previous problems. Thinking again the Facebook limitations for the maximum number of friends on Facebook, according to Brandtzg et al.3 a significant issue that occurs is the lack of seclusion. Hence, the limitations are not only important for the performance but also for the user protection as well. In addition, the same person can create a new meshing for free and add his new friends there. As a result, 5000 friends is not very a limitation for a user and is provided in terms of privacy and performance. According to Michael Armbrust et al.1 their algorithm for scale inde- pendent optimization contains two phases. The fi one is reffering to come off operator insertion. In order to maintain scalability, the algorithm starts by fi a linear join ordering on the query parser. Depsite the fact that go against operator is already contained due to LIMIT which in contained in the reg- ular query, scientists have introduced data-stop operators which are pushed in lower levels in order to preserve the sign rules without the demand ofrestart the whole system.N ext, subsequently fiphase 1 the second step which is called remote op- erator matching. As we previously mentioned we should ensure scalabiliy. Hence, the intermediate results are bounded. But how all these logical op- erators are mapped on remote operators? For Index Scan, that nub that maximum one attribute can be affected by predicates. As for Index Foreign Key join the number of tuples after the join is less than or than the tuples of the initial plan.References1 Armbrust, Michael, et al. PIQL Success-tolerant query processing in the cloud. Proceedings of the VLDB Endowment 5.3 (2011) 181-192.2 Chen, Tien-Fu, and Jean-Loup Baer. Reducing memory latency via non- blocking and prefetching caches. Vol. 27. No. 9. ACM, 1992.3 Brandtzg, Petter Bae, Marika Lders, and Jan Hvard Skjetne. Too many Facebook friends? Content sharing and sociability versus the imply for pri- vacy in social network sites. Intl. Journal of HumanComputer Interaction 26.11-12 (2010) 1006-1030.