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This project will develop new techniques for estimating population levels and population movement through social media and other types of data (e.g., WiFi hot spot data) and will also pioneer new techniques for visualizing such geospatial and temporal network data interactively using HTML5. Within the visualization work, we employ online experiments to compare various visualization alternatives. The visualization tools produced will be open-source, and we aim to produce integrations with other popular network visualization software along the lines of our previous work with sigma.js.
Population movement is a major contemporary challenge for policymakers in local government. At the macro level, demographic data created by censuses (and other survey instruments) quickly becomes out of date in the contemporary social context of high internal and external migration, meaning that local policymakers often have only a loose grasp on exactly who is living in different districts and areas. At a smaller scale, the levels of movements of local populations on a day to day basis are also notoriously difficult to measure, meaning that crafting accurate policy around issues such as commuting and public transport or tourism is highly challenging.
This strand of the project aims to drive forward research into novel solutions to this problem by creating and validating proxy measurements for both macro and micro level population flows from a range of new data sources, especially social media data and business data. These data sources stand positioned to offer major new insight into the way people move at both the micro and macro level, and thus to provide a step change in the extent to which policymakers can plan population related policy.
This part of the project will pursue research into two levels of proxy measurement. First, we will look at ways of measuring aggregate population levels from social media data (in particular geotagged data from Twitter) and data from BT (such as WiFi hotspot use data). We do not expect initial estimates to be accurate straight away: indeed we expect significant biases. The project will build upon existing work to look at a range of sociodemographic variables, such as average levels of income and education, which could be used to correct these biases or, at the very least, inform individuals already using social media data for policy about the nature of the biases.
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Network diagrams show relationship data between sets of nodes or actors. Such relationships are often complex and difficult to visualize for a non-expert. Interactive visualization allows for individuals to explore the data in a more intuitive way and ultimately gain a better understanding.
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The project is funded by InnovateUK and conducted in partnership with BT.


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text:
Q: SEPARATE THREAD VS SERVICE + SEPARATE THREAD just saw Google I/O 2010 - Android REST client applications where it was said:
 start long running operations from a Service
And as I understand (My English is poor)
 the main purpose of this is to prevent the app to be killed by the system. Right?
Is it good practice to perform all long running operation not only web ones from a Service?
As I understand if I create an object in activity and then the app process will be killed I will lose this object, but if I create this object in a service and after process will be killed - my object still will be alive. Right?
(SEPARATE THREAD)    VS      (SERVICE + SEPARATE THREAD)
What is different in the context of my question?

A: Not exactly ...
You are somewhow mixing the concepts Destroyed and Killed
Destroyed
This is something that your application should be prepared to deal with. For may different reasons (i.e. device orientation changes, and other) the OS may destroy your activity (usually calling onDestroy() beforehand, so you have opportunity to save what's important) and all objects in your activity will be lost. However you application may contain more then one activitiy and/or service, and having one activity being destroyed, doesn't mean the others will be estroyed as well.
Killed
The OS may decide for some reason kill your application. This is done by killing the process used by your application, which is the process where run all activities and services that compose your application. Your application will not have any warning, and can't do nothing to prevent this. All objects in your apllication (used by activities and services) will be lost.
Having said that, whats´s the advantage of a Service in a long running activity?
Let's use a simple example:
If your activity is in the midle of uploading a large file to a server, and the user decide to change device orientation, the activity will be destroyed and the upload interrupted. Even if restart the uploading when the activity restarts, it would start from begining again.
If you have a service doing the upload stuff under request from an activity, even if your activity is destroyd, the service remains active and the upload continues without imterruption.
Notes:
If you have a really long running service (that will be running for more then half an hour) then make it as foregroung service, otherwise it will be killed anyway.

A: 1. The Service API in Android is one of the key mechanisms for applications to do work in the background.
But it can easily implemented using a simple thread.
BUT:
*Once an application is no longer visible to the user it is generally considered expendable and a candidate to be killed by the system if it ever needs memory elsewhere. The main way applications get around this is by starting a Service component, which explicitly tells the system that they are doing some valuable work and would prefer that the system not kill their process if it doesn't truly need to.*
So as I understand that is difference between a regular thread and a Service for our case.

redpajama_set_name: RedPajamaStackExchange


text:
Blood Brothers: Mormons, Genocide, and the Nixon Administration
Russell December 19, 2008 Culture, Mormon 9 Comments
Charles Radford, a Navy yeoman, present some fascinating questions about Latter-day Saints' relationship with the government, the law, and politicians. Charles Radford was serving as a navyman aboard a ship in India. He was an active, married Latter-day Saint. In various venues, Radford was a trained stenographer who took down highly-secretive government documents about war actions in various sections of the globe. And he was a spy for the Joint Chiefs of Staff.
Charles Radford
A colorful case in point: in March 1971, East Pakistan won the majority of the seats in the National Assembly. This would center power in the ethnically distinct Bengali East Pakistan region. However, the Western military dictator, Yahya Khan would have none of it. He sent his forces to repress the Eastern Bengalis en masse, killing hundreds of thousands of East Bengalis. This would culminate in a flood of refugees to Eastern India—somewhere to the tune of 10 million. This obviously caused strains for the Indo-Pak relations. War broke out quickly—a war which the East Pakistanis won. They eventually broke off and declared themselves to be an independent Bangladesh. Around this same time, a low-level bureaucrat in Dakka, Bangladesh named Archer Blood sent a barely classified (marked with only "secret" instead of "top secret") memo declaring the U.S. government to be "morally bankrupt" for its complacency on the issue.
Radford had access to key U.S. documents regarding U.S. policy during this war. During the famed
India-Pakistan War in 1971, Nixon notably declared the United States to be neutral. However, Nixon was privately "tilting" in their direction, a reality that Radford leaked to fellow Latter-day Saint Jack Anderson, a prominent newsman for the Washington Post through stolen documents . This was no mere geopolitical move, however; Jack Anderson would win a Pulitzer Prize for his reporting on the incident. Anderson would later find himself on Nixon's enemies list and even a possible target of assassination. G. Gordon Liddy even talked to a doctor about putting LSD in his soup. Nixon's men were also considered trying to tie Anderson and Radford together through a possible homosexual relationship. I do not take that claim at all seriously—this is Nixon after all (and my M.A. thesis is on Nixon—this is a man I know something about).
Faithful Latter-day Saints—what are we to do? Anderson was as active as they come. Radford as well. Was Radford's actions justified given the horrific situation of genocide taking place? Anderson revealed secret documents about the powers-that-be to the world. Was he standing up for the right or failing to follow Christ's counsel to "render unto Caesar" and Paul's counsel to let the powers that be reign supreme until Christ comes again?
authoritygenocideGovernmentjournalismmediaMiddle Eastnewsobediencepolitics
Bookslinger
I don't know the salient details of this, and your summary of this matter is too short for me to form an opinion.
However, on another matter Anderson leaked the identities of US foreign assets, spies or informants, which resulted in them being killed. And it was obvious beforehand that the publication of their identities would lead to their deaths. It was not an accident and their deaths were not unseen.
In my opinion, Anderson has blood on his hands in that matter. I'd even say Anderson is guilty of their deaths.
If I had been in a temple at the same time as Anderson, I would have had to walk out.
I don't know about the Radford affair, but I have no qualms saying that Anderson is/was a traitor to the US.
Those are interesting and pointed words, Bookslinger.
For the sake of readers, could you explain what case you're referring to?
CarlosJC
I too read this your article and think that its too short for a unbiased opinion.
I wonder which way Anderson leans, democratic or republican o what? Plus were they actually concerned about the deaths in what was as a struggle for independence or were they out to just get Nixon? I've never heard of Radford but do know that East Bengali had sought independence for decades.
Maybe a followup post would be a good idea. And what happened with Radford who was under military law after all, so didn't he break some?
Is it a bad thing to be a traitor to the secret combinations that run our government? Much of what our government does in the world is murder in the name of getting gain or the glory of the world, the very actions which define secret combinations. Someone who speaks out against such actors is ok in my book. I admit I am not intimate with Anderson's individual case though.
Anderson did much to expose real corruption too, but in his zeal he exposed some foreign good guys working on our side in the cold war, and it resulted in scores of death-by-torture of those foreigners who were working as informants and spies for the US.
It may be hard to google, because Anderson reported on and was involved in so many different cases. I'm not sure which search words will narrow it down to the case I remember reading about.
BTW, Anderson was a democrat who hated republicans. Almost all his reporting was tainted with that bias.
Fascinating. Thanks for posting this, although I too would like more information before drawing any conclusions. Also, I'd like to know more about your thesis.
Another segment that details Jack Anderson's life and work as a Latter-day Saintis forthcoming. Given our desire to make these stories accessible, we try to keep them within a reasonable length. Anderson is the topic of a full-fledged biography by the head of George Washington University's journalism program, Mark Feldstein. So I hope for readers' understanding on that.
Re: Anderson's political affiliations, while he was decidedly Democrat, a more accurate description of his affiliation would be "muckraker." Anderson initially allied himself with Joseph McCarthy; after all, Anderson wanted the State Dep't free of Communists as much as the next guy. He (quite infamously and incorrectly) accused then-Democratic Senator of drunk driving on several occasions…a charge which he soon retracted. Granted, Anderson spilled much ink and much of it was derisive of Republicans. But to think of him as a straight-out Democratic partisan hack would be incorrect thinking.
In my view, to see Anderson as a model for the social-justice minded Latter-day Saint. He was really just doing his job very well.

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search filter All ContentAll JournalsBlood Advances
About Blood Advances
The role of RUNX1 and RUNX1T1 in normal cells
Structure and function of RUNX1-RUNX1T1 fusion protein
Molecular pathogenesis of RUNX1-RUNX1T1 fusion protein and role in leukemogenesis
Studies of RUNX1-RUNX1T1 rearranged mouse models
Cooperating mutations in AML with RUNX1-RUNX1T1
RUNX1-RUNX1T1 and miR
Therapeutic targeting of AML with t(8;21); RUNX1-RUNX1T1
Conclusions and future directions
REVIEW ARTICLE| January 14, 2020
An update on the molecular pathogenesis and potential therapeutic targeting of AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1
Sayer Al-Harbi
Department of Molecular Oncology, Research Center, and
Mahmoud Aljurf
Adult Hematology/Bone Marrow Transplantation, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; and
Mohamad Mohty
Hopital San Antoine, Assistance Publique des Hôpitaux de Paris, Sorbonne Universite, INSERM Unité Mixte de Recherche 938, Paris, France
Fahad Almohareb
Syed Osman Ali Ahmed
Blood Adv (2020) 4 (1): 229–238.
https://doi.org/10.1182/bloodadvances.2019000168
Sayer Al-Harbi, Mahmoud Aljurf, Mohamad Mohty, Fahad Almohareb, Syed Osman Ali Ahmed; An update on the molecular pathogenesis and potential therapeutic targeting of AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1. Blood Adv 2020; 4 (1): 229–238. doi: https://doi.org/10.1182/bloodadvances.2019000168
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Myeloid Neoplasia, Review Article
runx1 translocation partner 1 protein, leukemogenesis
Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1);RUNX1-RUNX1T1, one of the core-binding factor leukemias, is one of the most common subtypes of AML with recurrent genetic abnormalities and is associated with a favorable outcome. The translocation leads to the formation of a pathological RUNX1-RUNX1T1 fusion that leads to the disruption of the normal function of the core-binding factor, namely, its role in hematopoietic differentiation and maturation. The consequences of this alteration include the recruitment of repressors of transcription, thus blocking the expression of genes involved in hematopoiesis, and impaired apoptosis. A number of concurrent and cooperating mutations clearly play a role in modulating the proliferative potential of cells, including mutations in KIT, FLT3, and possibly JAK2. RUNX1-RUNX1T1 also appears to interact with microRNAs during leukemogenesis. Epigenetic factors also play a role, especially with the recruitment of histone deacetylases. A better understanding of the concurrent mutations, activated pathways, and epigenetic modulation of the cellular processes paves the way for exploring a number of approaches to achieve cure. Potential approaches include the development of small molecules targeting the RUNX1-RUNX1T1 protein, the use of tyrosine kinase inhibitors such as dasatinib and FLT3 inhibitors to target mutations that lead to a proliferative advantage of the leukemic cells, and experimentation with epigenetic therapies. In this review, we unravel some of the recently described molecular pathways and explore potential therapeutic strategies.
Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1) constitutes ∼4% to 8% of AML. This subtype is associated with the M2 subtype of the FAB classification, younger age at presentation, a characteristic immunophenotype, frequent coexpression of CD19, and additional cytogenetic abnormalities, including loss of sex chromosome, del(9q), and trisomy 8, and a favorable outcome.1
Much has been learned in recent decades of the role of this translocation in leukemogenesis, of the concurrent mutations, and the downstream pathways that may be involved. In this review, we present an up-to-date overview of the molecular features of this subtype of AML, focusing on the disruption caused by RUNX1-RUNX1T1 fusion, the cooperating mutations that have been uncovered, the activation of oncogenes and signaling pathways, and the role of microRNAs (miRs). A greater understanding of the mechanisms of disease paves the way for exploring novel targets for therapy.
The RUNX1T1 gene is a transcriptional corepressor belonging to the human RUNX1T1 homolog family, that includes MTG16 (Myeloid Translocation Gene on chromosome 16) and MTGR1 (Myeloid translocation Gene-Related protein 1). The gene comprises 4 Nervy homology domains (Nervy homology regions [NHR] 1 to 4) (Figure 1). RUNX1T1 is expressed in many normal tissues, especially brain and heart, and is implicated in angiogenesis.2 Hematopoietic expression of RUNX1 is limited to erythropoiesis, albeit transiently, where its expression has been shown to be regulated by GATA-1.3 RUNX1T1 does not interact directly with DNA, but is recruited by transcription factors, including GFI1 and BCL6, forming multiprotein complexes. RUNX1T1 in turn recruits a number of corepressors to facilitate transcriptional repression.
Schematic model of RUNX1, RUNX1T1, and RUNX1-RUNX1T1 domains. The translocation t(8;21)(q22;q22) generates a fusion gene consisting of the RUNX1 gene from chromosome 21 and the RUNX1T1 gene from chromosome 8. AD, activation domain; ID, inhibitory domain; RHD, runt homology domain; TAD, transactivation domain.
The RUNX1 gene comprises 12 exons, including RHD and the transactivation domain, and encodes the α subunit of the core-binding factor that binds DNA (Figure 1). RUNX1 is a key transcriptional factor crucial for hematopoietic differentiation and myeloid development.4 Its role is evidenced by the absence of fetal liver hematopoiesis and lethality in knockout animal models, by the germline mutations predisposing to familial platelet disorder, and by the recently defined World Health Organization entity of myeloid neoplasms with RUNX1 mutations.5,6
The t(8;21)(q22;q22.1) translocation is a leukemogenic alteration that leads to a novel chimeric gene RUNX1-RUNX1T1, generated on the derivative chromosome 8. This translocation generates a fusion gene, which consists of the RUNX1 gene from chromosome 21 and the RUNX1T1 gene from chromosome 8. The breakpoint in RUNX1 occurs between exons 5 and 6; the translocation juxtaposes the 5′ end of the RUNX1 gene, including the RHD domain, with the 3′ end of the RUNX1T1 gene, with its 4 NHR domains (Figure 1). The generated fusion protein consists of 752 amino acids; the first 177 amino acids are derived from RUNX1, whereas the 575 amino acids are from RUNX1T1.7 Structurally, RUNX1-RUNX1T1 therefore has 5 domains: the RHD from RUNX1 and NHR domains 1 to 4 from RUNX1T1.4
The RUNX1T1 segment mediates the recruitment of corepressors complex histone deacetylase (HDAC), SMRT, N-CoR, and mSin3 to the binding domain of RUNX1, which results in the blocking of RUNX1 target genes.8,9 This prevents cell differentiation, increases cell survival, and ultimately, promotes leukemogenesis (Figure 2A-B).8,10 Although the expression of RUNX1T1 is low in normal hematopoietic cells, t(8;21) leads to high levels of RUNX1T1 expression.11 The RUNX1-RUNX1T1 fusion transcript may be detected in the blood and bone marrow of t(8;21) patients with AML and is a marker for minimal residual disease detection.12
A schematic representation of the role of normal core binding factor and RUNX1-RUNX1T1 fusion protein in hematopoiesis and leukemogenesis, respectively. (A) Core binding factor (CBF) and its role in transcription: The CBF comprises 2 subunits (α and β) that are involved in transcription of genes involved in hematopoiesis. (B) The RUNX1-RUNX1T1 rearrangement leads to recruitment of ETO (encoded by RUNX1T1) that recruits transcriptional repressors, including N-Cor/SMRT and HDAC, that inhibit transcription of hematopoietic genes. GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-3, interleukin-3; TCRb, T-cell receptor beta.
RUNX1-RUNX1T1 directly regulates transcription and blocks differentiation to promote leukemia progression. It has been proposed that the interaction between the Runt domain of the RUNX1-RUNX1T1 protein and the non-DNA binding partner of the RUNX protein CBFβ is essential for leukemogenesis.13 In fact, RUNX1-RUNX1T1 acts as a dominant repressor for all RUNX1-mediated hematopoietic genes to disrupt normal hematopoietic differentiation and promote a preleukemic state (Figure 2).14 In addition, RUNX1-RUNX1T1 blocks critical hematopoietic transcription factors by interfering with their transcriptional activity. These transcription factors include PU.1, GATA1, and CEBPA, which are key regulators for myeloid differentiation.15-17 RUNX1-RUNX1T1 with the N-CoR corepressor also blocks differentiation by colocalizing primarily at promoter regions enriched with motifs for hematopoietic regulator and myeloid differentiation factors.18 The repressor function of RUNX1-RUNX1T1 is not limited to differentiation genes but also extends to inhibit some tumor suppressor genes, including RUNX3 and neurofibromatosis-1 (NF1)19,20 (Figure 3).
Summary of the various molecular mechanisms that may interact in the pathogenesis of AML t(8;21); RUNX1-RUNX1T1, and potential therapies. Fusion RUNX1-RUNX1T1 leads to aberrations in a number of intracellular pathways including downregulation of tumor suppressors, activation of oncogenes, abnormal activation of specific signaling pathways, and block of transcription factors, and often occurs with concurrent mutations. These may be amenable to therapeutic targeting. PARP, poly(ADP-ribose) polymerase.
RUNX1-RUNX1T1 contributes to increased proliferation through its interaction with a number of factors. Hypoxia-inducible factor 1α (HIF1α) is a transcription factor that is overexpressed in RUNX1-RUNX1T1–positive patients with AML. HIF1α/RUNX1-RUNX1T1 interactions are essential to drive a high proliferation rate both in in vitro and in mice models. HIF1α is overexpressed in RUNX1-RUNX1T1–positive patients with AML and drives proliferation through increasing DNMT3a activity, causing DNA hypermethylation.21 RUNX1-RUNX1T1 fusion also mediates upregulation of Pontin, a highly conserved AAA+ ATPase involved in multiple cellular functions, to drive cell cycle progression and proliferation necessary for the oncogenic growth of t(8;21) cells.22 WNT and RAS signaling are also constitutively active to drive proliferation in patients with AML with t(8;21).23,24 In addition, Myeloid Ecotropic Viral Integration Site (MEIS2) expression levels are high in patients with AML t(8;21) and found to drive growth of RUNX1-RUNX1T1 cells by binding strongly to the DNA binding domain of RUNX1.25
RUNX1-RUNX1T1 expression in hematopoietic progenitors leads to enhanced self-renewal and a block in differentiation, and the forkhead box protein 01 (FOXO1) transcription factor has been implicated in this role. FOXO1 is aberrantly activated to drive self-renewal pathways of preleukemic stem cells (LSCs) in t(8;21) AML.26 Informative binding studies have shown that the DNA binding motif of FOXO1 binds and activates a stem cell molecular signature in RUNX1-RUNX1T1 cells. High FOXO1 expression thus plays an oncogenic role in mediating self-renewal and impaired differentiation of human CD34+RUNX1-RUNX1T1 hematopoietic stem cells (HSCs).
Recently, a new role for RUNX1-RUNX1T1 in promoting leukemogenesis has been proposed. In general, normal hematopoietic cells express physiological levels of aminoterminal enhancer of split and small nucleolar RNAs, but in contrast, RUNX1-RUNX1T1 cells induce high aminoterminal enhancer of split expression and small nucleolar RNAs formation, in what may facilitate LSC proliferation.27
Epigenetically, RUNX1-RUNX1T1 cells have been found to express unique epigenetic signatures to promote leukemogenesis. RUNX1-RUNX1T1 affects histone deacetylation and DNA methylation through mediating HDACs and DNMT1 recruitments, which lead to transcriptional silencing. Moreover, JMJD1C, a histone demethylase, is reported to function as a transcriptional coactivator for RUNX1-RUNX1T1 to increase proliferation in leukemia cells.28
A role for RUNX1-RUNX1T1 in inhibiting apoptosis has also been proposed. Antiapoptotic proteins BCL-2 and BCL-XL are frequently overexpressed in RUNX1-RUNX1T1 rearranged cells.29,30 Depletion of RUNX1-RUNX1T1 has been shown to increase apoptosis and cell cycle arrest. Mitogen-activated protein kinase 1 mediates resistance to RUNX1-RUNX1T1 suppression.31 In addition, RUNX1-RUNX1T1 has been reported to impair the activity of genes involved in the DNA repair machinery. Furthermore, POLE and OGG1 genes have been found to be downregulated in RUNX1-RUNX1T1 cells, causing an increase in DNA damage.32,33 Finally, the E3 ubiquitin ligase STUB1 has been identified as a negative regulator of the RUNX1-RUNX1T1 fusion protein. STUB1 binds to the RUNX1-RUNX1T1 complex to promote its ubiquitination and degradation. STUB1 overexpression causes dramatic growth inhibition in RUNX1-RUNX1T1 cells but not in other leukemia cells or normal blood cells (Figure 3).34
Is the RUNX1-RUNX1T1 fusion an early or late aberration in AML with t(8;21)? A number of lines of evidence, both preclinical and clinical, point to t(8;21) being an early event in leukemogenesis. RUNX1-RUNX1T1 transcripts can be detected in Guthrie cards from newborns who develop AML later on in life.35 Analysis of clonal composition of a series of AML cases by polymerase chain reaction and targeted sequencing has revealed that RUNX1-RUNX1T1 aberrations carry the features of a preleukemic lesion, namely, that they are present early in the preleukemic clone, are also found in clones when patients relapse, and lead to nonleukemic hematopoiesis in the marrows of mice in xenotransplantation models.36
Mouse models have been crucial to our understanding, in vivo, of the mechanisms of leukemogenesis of AML t(8;21). Mouse studies have demonstrated that RUNX1 knockout during embryonic development leads to complete failure of HSC production, whereas targeting RUNX1 in hematopoietic cells promotes a preleukemic state.37 To prevent embryonic lethality, a conditional RUNX1-RUNX1T1 knock-in led to expansion of myeloid progenitor cells but did not block their differentiation nor initiate leukemia.38 RUNX1-RUNX1T1 alone is not thought to be sufficient to induce leukemogenesis, and additional mutations are needed to develop leukemia in mice.38-40 However, 2 RUNX1-RUNX1T1 truncation variants within the carboxyterminal have been reported to directly induce leukemia in vivo.39,41 RUNX1-ETO9a is a RUNX1-RUNX1T1 splice variant that lacks the NHR3/NHR4 domains and was able to induce AML after a few months when transplanted into mice.9,42 This splice variant was also detected in t(8;21)-positive patients with AML and found to correlate with short survival. A further study suggested that expressing RUNX1-RUNX1T1 fusion protein in mice lead to increased cell migration and impaired cell adhesion. This provides an explanation for an additional feature for RUNX1-RUNX1T1–containing cells that mediate migration across the bone marrow barrier to accelerate tumor progression and may help explain why this subtype is associated with extramedullary disease more often.43
As highlighted above, the occurrence of the RUNX1-RUNX1T1 rearrangement is not thought to be sufficient to initiate leukemia, and secondary genetic events are needed. High expression of RUNX1-RUNX1T1 in progenitor HSCs promotes differentiation and cell self-renewal but does not appear to be sufficient to induce AML.27,44,45 A number of cooperative mutations may contribute to leukemogenesis.38,39 By carrying out high-throughput screening on 106 patient samples, Duployez and colleagues reported that 96% of t(8;21) AML cases carried additional cytogenetic or mutational anomalies. In addition to confirming mutations in KIT, FLT3-ITD, and RAS (40%, 26%, and 10%, respectively), 42% had mutations in epigenetic regulators (ASXL1/2 and EZH2) and 18% of samples had cohesin complex mutations, notably of RAD21, STAG2, SMC1a, and SMC3. Concurrent tyrosine kinase, chromatin modifier, and cohesin mutations were associated with the highest risk of relapse, indicating the multiple pathways, including chromatin interactions with RUNX1, that may effect leukemogenesis.46 These findings were further confirmed by Christen and colleagues, who, in addition to reporting frequent class I mutations that rendered a proliferative advantage affecting the RAS/RTK pathway, including KIT, JAK2, FLT3, NRAS/KRAS, CBL, and PTPN11, also reported on hitherto unreported mutations in GIGYF2, DHX15, and G2E3, and were able to present a chronology of leukemogenesis whereby epigenetic mutations occurred before tyrosine kinase mutations.47
The aforementioned studies also confirmed the poor prognostic impact of high burden KIT mutations.46 KIT mutations are reported in up to 46% of patients with AML t(8;21), and these are associated with worse outcomes.48 Several reports indicate that the RUNX1-RUNX1T1 fusion protein and c-KIT play a fundamental role in tumorigenesis of AML. KIT mutations were found necessary in transforming HSCs into LSCs in RUNX1-RUNX1T1 cells.49,50 Mechanistically, RUNX1-RUNX1T1 transactivates KIT expression by direct binding to KIT promoter through the RUNX1 motif.51 This finding is supported by significantly high c-KIT expression levels in t(8;21) patients with AML. In fact, high c-KIT expression predicts poor prognosis in these patients.52 A possible mechanism for the worse outcome may be the finding that active c-KIT along with REtr, a C-terminal truncated variant of RUNX1T1, has been reported to expand proliferation of CD34+ progenitor cells and augment DNA repair machinery to drive chemoresistance.50 RUNX1-RUNX1T1 along with KIT mutations has been shown to transform murine bone marrow cells to AML.53 Moreover, it has been reported that amyloid precursor protein (APP) in cooperating with KIT mutations promotes apoptosis but not proliferation through the PI3K/AKT signaling pathway.54 Knockdown of APP arrests both colony formation and migration but not differentiation, cell cycle, or apoptosis in Kasumi-1 cells. In RUNX1-RUNX1T1–rearranged patients with AML, APP was significantly correlated with extramedullary leukemia, bone marrow cellularity, white blood cell count, and KIT mutations. This study also suggested that RUNX1-RUNX1T1 might adversely affect the prognosis of patients with AML with t(8;21) by upregulating APP expression.55
FLT3 mutations have been reported in up to 16% of t(8;21) patients, although evidence for their impact on prognosis has been conflicting. FLT3-ITD mutations with a high allelic burden appear to portend inferior survival. In contrast, FLT3-TKD mutations, especially with a high mutant level, have been associated with a better outcome.47 RAS mutations are reported in 20% to 30% of cases, with NRAS being more frequent than KRAS mutations. These mutations do not, however, appear to have an impact on relapse or survival. CBL mutations are frequently mutated in t(8;21) AML and have been found to play a critical factor in expanding CD34+ cells. CBL mutations in coordination with RUNX1-RUNX1T1 can cause both myeloid proliferation and expansion of human CD34+ cells through STAT5/AKT/ERK/Src signaling.56,57 JAK2 mutations have also been shown to impact survival. The PTPN11 gene, coding for a phosphatase acting downstream of tyrosine kinases, is infrequently mutated, and mutations in this gene lead to constitutive autophosphorylation of KIT kinase activity, although this does not appear to impact outcome.58,59 GIGYF2, an RTK signaling regulator, was also recently reported to be mutated in 2% of cases.47
Mutations of epigenetic regulators have been reported in AML with t(8;21). Mutations in DNA methylation regulator TET2 with the presence of RUNX1-RUNX1T1 have been shown to induce leukemia in mice models.60 The additional sex combslike (ASXL2) gene is frequently mutated in patients with AML with t(8;21) but not in patients with other cytogenetic abnormalities or RUNX1-mutated AML.61,62 In at least 1 series, patients carrying ASXL2 mutations were found to have a higher incidence of relapse.61 Unlike age-related clonal hematopoiesis, ASXL1 and ASXL2 mutations appear to be late events in AML t(8;21).47
Recently, mutations in the transcription regulator ZBTB7A that mediates hematopoietic development have been associated with t(8;21) in patients with AML, as have mutations in DHX15 and those involving the cohesin complex; the role of these mutations in leukemogenesis and clinical outcome remains to be determined.63,64
miRs are small noncoding RNA molecules involved in the regulation of gene expression.65,66 It has been proposed that RUNX1-RUNX1T1 mediates the expression of some miRs that are known to function as tumor suppressor genes or oncogenes.67 The miR miR-130a acts as an oncogene in t(8;21) AML cells by mediating leukemogenesis and a more aggressive disease course. RUNX1-RUNX1T1 was found to directly upregulate miR-130a expression and drive resistance to etoposide.68 MiR-126 is another miR that is mediated by RUNX1-RUNX1T1. Overexpression of miR-126 is correlated with unfavorable survival in patients with AML with t(8;21). MiR-126 also mediates leukemogenesis by activating genes that are highly expressed in LSCs and progenitor cells.69 MiR-383 expression has been reported to suppress expression of one of the thanatos-associated proteins (THAPs), namely, THAP10, that regulate chromatin modification, apoptosis, cell proliferation, and transcriptional regulation.70 THAP10 acts as a tumor suppressor, and RUNX1-RUNX1T1 transcriptionally induces the expression of miR-383 that in turn suppresses THAP10 function.71
RUNX1-RUNX1T1 also mediates downregulation of some miRs involved in cell differentiation and tumor suppression, further implicating miRs in leukemogenesis. MiR-223 and miR-222/221 are known to regulate differentiation and have been found to be downregulated in t(8;21) patients with AML as compared with normal bone marrow cells.72 The expression of miR-9 has been negatively correlated with expression levels of silent mating type information regulation homolog-1 that is a class III HDAC that mediates differentiation, cell proliferation, and gene expression. In addition, overexpression of miR-9 decreases silent mating type information regulation homolog-1 expression and blocks proliferation in RUNX1-RUNX1T1–positive AML cell lines.73 On the other hand, epigenetic silencing of tumor suppressor gene miR-193a was found to accelerate the oncogenic activity of RUNX1-RUNX1T1 cells by activating the PTEN/PI3K signal pathway.74
Therapy of AML with t(8;21), especially in the upfront setting, relies on standard anthracycline and cytarabine, followed by 2 to 4 courses of cytarabine consolidation. The increased chemosensitivity compared with other AML subtypes may to some extent be explained by the demonstration of an activated p53 pathway, leading to increased apoptosis and DNA damage.33 Addition of gemtuzumab ozogamicin (GO), an anti-CD33 antibody, further improves outcomes, and the beneficial effect is seen despite the expression of CD33 often being weak in AML t(8;21) and regardless of the level of expression, possibly due to its action on CD33+ hematopoietic progenitors. It is thought that the efficacy of GO is attenuated by the expression of p-glycoprotien that contributes to multidrug resistance; p-glycoprotein is reduced in AML t(8;21) compared with other subtypes, and this may further offer an explanation of why these patients have better outcomes with GO.75-77 Despite this relative chemosensitivity, treatment failure, especially in relapse, remains a challenge. Strategies to search for a cure can therefore target one or more of a number of steps in leukemogenesis.
Can RUNX1/RUNX1T1 be targeted at the level of the gene? RUNX1 deletion in RUNX1-RUNX1T1–transformed human CD34+ cells induced apoptosis and inhibited tumor growth. In these studies, targeting the Runt domain of RUNX1 proteins blocked the RUNX1/CBFβ interaction and decreased survival and proliferation of leukemic cells.78,79 These experiments provide proof of principle of such an approach in a preclinical setting.
The most attractive prospect would be the development of a small molecule that can block the activity of the abnormal RUNX1-RUNX1T1 protein. A novel compound that binds specifically to the Runt domain of RUNX proteins has been shown to disrupt the interaction of RUNX1-RUNX1T1 with CBFβ and has shown high antitumor activity in RUNX1-RUNX1T1 leukemia cell lines.80 Comprehensive screening of more than two thousand US Food and Drug Administration–approved drugs identified 2 common agents, namely, methylprednisolone and methotrexate, as highly effective in Kasumi-1 cells.81 Virtual screening of an array of molecules identified a compound, named Compound 7.44, that was able to disrupt RUNX1/RUNX1T1 tetramerization and thus block its oncogenic potential, while allowing differentiation and promoting prolonged survival in mouse models.82
Some natural agents have been also reported to be effective in targeting the RUNX1-RUNX1T1 fusion protein. Celastrol is a natural compound extracted from the Chinese herb Tripterygium wilfordii Hook. Celastrol has been shown to block cell proliferation and induce apoptosis by targeting the RUNX1-RUNX1T1 protein.83 Oroxylin A also shows antitumor activity in RUNX1-RUNX1T1 cells. Oroxylin A reduces the expression of RUNX1-RUNX1T1 protein, promotes the expression of differentiation-related proteins C/EBPα and P21, and prolongs the survival of AML-bearing mice.84 A further compound, Oridonin, was shown by investigators in China to cleave RUNX1-RUNX1T1 oncoprotein and selectively promote apoptosis in t(8;21) leukemia cells.85 Esculetin is another natural agent that was shown to therapeutically target RUNX1-RUNX1T1 cells and was shown to dramatically decrease the half-life of RUNX1-RUNX1T1 messenger RNA.86
Because RUNX1-RUX1T1 leads to recruitment of HDAC to RUNX1 binding domains, epigenetic approaches have been studied in RUNX1-RUNX1T1 models, and there are a number of hypomethylating agents and HDAC inhibitors used in therapy that would make them attractive agents. RUNX1T1 has been reported to interact with HDACs to induce histone acetylation levels in RUNX1-RUNX1T1 cells. The pan-HDAC inhibitor panobinostat depletes APP levels and inhibits proliferation.87 In addition, treatment of mice bearing t(8;21) AML with panobinostat leads to dramatic responses that were independent of functional p53 or activation of apoptotic markers.88 Moreover, a panobinostat and arsenic trioxide combination degraded the RUNX1-RUNX1T1 protein and caused cell cycle arrest, increased differentiation of AML blasts, and lead to complete responses in a mouse model.89 HDAC inhibitors also block leukemogenesis in RUNX1-RUNX1T1 cells.90 An HDAC inhibitor phenylbutyrate has been found to promote differentiation and apoptosis by targeting the RUNX1-RUNX1T1 protein.91 Cell lines with RUNX1-RUNX1T1 have been shown to be some of the most sensitive AML cell lines to Lysine-specific demethylase 1 inhibition; targeting Lysine-specific demethylase 1 completely eradicated tumor growth in a RUNX1-RUNX1T1 xenograft model.92
Approaches that target antiapoptotic pathways have been investigated with positive results in preclinical models. The proteosome inhibitor bortezomib and the BCL-2 inhibitor ABT-737 induce apoptosis and block proliferation of RUNX1-RUNX1T1 cells both in vitro and in vivo.93,94 A novel oxazine derivative, ZGDHu, was found to block the growth of Kasumi 1 cells via decreasing nuclear factor κB activity, depleting RUNX1-RUNX1T1 fusion protein and causing cell cycle arrest. A further drug that has been found to be highly effective in inducing apoptosis of RUNX1-RUNX1T1 cells is fingolimod. Fingolimod is a sphingosine analog and a US Food and Drug Administration–approved drug for treating patients with multiple sclerosis.95 Fingolimod has shown high antitumor activity in mice models and primary leukemic cells isolated from patients with AML t(8;21).96 A further mechanism that may be targeted to enhance leukemic cell death is poly(ADP-ribose) polymerase inhibition, and RUNX1-RUNX1T1 AML cells were shown to be highly sensitive to poly(ADP-ribose) polymerase inhibitors.97
Finally, given the occurrence of secondary mutations, including KIT, FLT3, and JAK2, as uncovered by high-throughput screening studies in AML t(8;21) and their impact on survival, these may be the most amenable targets with currently available tyrosine kinase inhibitors.23,24 Dasatinib, a tyrosine kinase inhibitor with activity against KIT mutations, has been trialed both in patients with minimal residual disease and in the upfront setting, and although initial reports suggest a modest impact, results of randomized trials are awaited.98 Modest antileukemic responses have been reported with the JAK2 inhibitor ruxolitinib in refractory AML.99 The recently approved FLT3 inhibitor midostaurin was demonstrated to result in improved survival in all FLT3 mutated patients and patients with t(8;21), and an FLT3 mutation would be eligible for this agent, although the proportion of patients with favorable risk in the trial was relatively small.100 A further surface protein that may be targeted is protease activated receptor-1, one of a family of integral membrane G protein–coupled receptors that are upregulated on some AML cells, and targeting protease activated receptor-1 has been shown to inhibit leukemogenesis in RUNX1-RUNX1T1 cells.101
Great strides have been made in understanding the pathobiology of AML with t(8;21), especially with the aid of molecular technologies that have revealed the mutational landscape, downstream pathways, and cooperating mutation and their role in leukemogenesis. However, a number of questions remain: why do patients with this subtype of AML have better survival than others with chemotherapy, and how can this relative chemosensitivity be further exploited? As the translocation is considered an early lesion in leukemogenesis, can the fusion protein be better targeted with small molecules, to recapitulate the CML success story? Also, while deep sequencing technologies have further revealed a pattern of concurrent mutations, their role in leukemogenesis remains to be elucidated.
Despite progress in the understanding of the biology of AML t(8;21), there is a relative paucity, partly due to this subtype of AML comprising a minor subset of patients with AML, of an adequate number of dedicated clinical trials of agents targeting the pathways involved in leukemogenesis. This will require prospective phase 1 to 2 multinational trials involving a large number of centers, which may not always be feasible or supported. Although a disease-specific targeted therapy is a modality that will continue to be pursued, in the absence of such a drug, combinations of standard chemotherapeutic agents with or without anti-CD33 immunoconjugates are likely to be trialed with pathway-specific agents and tyrosine kinase inhibitors. Greater implementation in clinical practice of myeloid next-generation sequencing panels will mean more of the recently discovered cooperating mutations may be identified and potentially targeted. Given the recent reports of the occurrence of JAK2 mutations, albeit in a small proportion, further trials of JAK2 inhibitors would be warranted. Potential pathways that warrant further studies as potential targets include the hedgehog signaling pathway, for which a drug (Glasdegib) has recently been approved in AML, newer BCL-2 inhibitors, and targeting GLI1. Targeting FOXO1 by genetic and pharmacological approaches inhibits proliferation of t(8;21) AML cell lines and provides a further potential approach for targeting cancer stem cells.
Although for relapsing patients an allogenic transplant will salvage a significant proportion, rapid advancements in the field of immunotherapy, bispecific T-cell engagers, and chimeric antigen receptor T-cell and NK cells hold promise in adding to the armamentarium of available therapies for those who fail current lines of therapy.
Contribution: S.A.-H. and S.O.A.A. wrote the manuscript; S.O.A.A., M.A., M.M., and F.A. conceptualized the review, edited the manuscript, and provided input; and all authors reviewed and approved the draft individually.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Syed Osman Ali Ahmed, Adult Hematology/Bone Marrow Transplantation, Oncology Center, MBC-64, King Faisal Specialist Hospital and Research Center, POB 3354, Riyadh 11211, Saudi Arabia; e-mail: syedahmed@kfshrc.edu.sa.
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Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein
AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation
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Pontin is a critical regulator for AML1-ETO-induced leukemia
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Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO
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Implications of NRAS mutations in AML: a study of 2502 patients
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MEIS2 is an oncogenic partner in AML1-ETO-positive AML
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Ptasinska
A FOXO1-induced oncogenic network defines the AML1-ETO preleukemic program
AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia
Nat Cell Biol
JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors
Genes Dev
Klampfer
Zelenetz
Nimer
The AML1/ETO fusion protein activates transcription of BCL-2
Griesinger
The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO
Maiques-Diaz
Sánchez-López
MAPK8-mediated stabilization of SP1 is essential for RUNX1-RUNX1T1-driven leukaemia
Alcalay
Meani
Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair
J Clin Invest
p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death
Shikata
The ubiquitin ligase STUB1 regulates stability and activity of RUNX1 and RUNX1-RUNX1T1
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Buffler
In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia
Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia
de Bruijn
Haploinsufficiency of AML1 affects the temporal and spatial generation of hematopoietic stem cells in the mouse embryo
Higuchi
Kumaravelu
Yeoh
Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia
AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations
Bäsecke
Schwieger
AML1/ETO promotes the maintenance of early hematopoietic progenitors in NOD/SCID mice but does not abrogate their lineage specific differentiation
Leuk Lymphoma
Hetherington
Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model
AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) acute myeloid leukemia-M2
Termanini
AML1/ETO accelerates cell migration and impairs cell-to-cell adhesion and homing of hematopoietic stem/progenitor cells
Fenske
Pengue
Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice
Pearn
Musson
Transcriptional dysregulation mediated by RUNX1-RUNX1T1 in normal human progenitor cells and in acute myeloid leukaemia
Duployez
Marceau-Renaut
Boissel
Comprehensive mutational profiling of core binding factor acute myeloid leukemia
Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients
Beghini
Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study
Kikushige
The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell
Exp Hematol
Wichmann
Quagliano-Lo Coco
Activating c-KIT mutations confer oncogenic cooperativity and rescue RUNX1/ETO-induced DNA damage and apoptosis in human primary CD34+ hematopoietic progenitors
AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer
J Cell Biochem
High expression of c-kit mRNA predicts unfavorable outcome in adult patients with t(8;21) acute myeloid leukemia
C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice
Amyloid precursor protein cooperates with c-KIT mutation/overexpression to regulate cell apoptosis in AML1-ETO-positive leukemia via the PI3K/AKT signaling pathway
Oncol Rep
Amyloid precursor protein has clinical and prognostic significance in AML1-ETO-positive acute myeloid leukemia
Oncol Lett
Schibler
Gasilina
UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO
Aranaz
Miguéliz
CBL RING finger deletions are common in core-binding factor acute myeloid leukemias
Hatlen
Vacic
Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles
J Exp Med
Goemans
Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia
Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis
Micol
Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations
Inoue
ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia
Dutta
Opatz
ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation
Gedman
The genomic landscape of core-binding factor acute myeloid leukemias
Nat Genet
Burge
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets
MicroRNA expression profiles classify human cancers
Calin
MicroRNA signatures in human cancers
Nat Rev Cancer
MiR-130a is aberrantly overexpressed in adult acute myeloid leukemia with t(8;21) and its suppression induces AML cell death
Ups J Med Sci
Overexpression and knockout of miR-126 both promote leukemogenesis
Clouaire
Roussigne
Ecochard
Amalric
The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity
A novel epigenetic AML1-ETO/THAP10/miR-383 mini-circuitry contributes to t(8;21) leukaemogenesis
EMBO Mol Med
Racanicchi
Zardo
Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein
AML1-ETO promotes SIRT1 expression to enhance leukemogenesis of t(8;21) acute myeloid leukemia
Epigenetic silencing of microRNA-193a contributes to leukemogenesis in t(8;21) acute myeloid leukemia by activating the PTEN/PI3K signal pathway
Linenberger
Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin
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P-glycoprotein expression in de novo acute myeloid leukemia
Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial
J Clin Oncol
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Leshkowitz
Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1
Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
Illendula
Grembecka
A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFβ in leukemic cells
Corsello
Identification of AML1-ETO modulators by chemical genomics
Schanda
Wohlan
Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization
Haematologica
Celastrol induces cell apoptosis and inhibits the expression of the AML1-ETO/C-KIT oncoprotein in t(8;21) Leukemia
Oroxylin A, a natural anticancer flavonoid compound, induces differentiation of t(8;21)-positive Kasumi-1 and primary acute myeloid leukemia cells
J Cancer Res Clin Oncol
Targeting of AML1-ETO in t(8;21) leukemia by oridonin generates a tumor suppressor-like protein
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127ra38
Sawney
Saluja
Esculetin downregulates the expression of AML1-ETO and C-Kit in Kasumi-1 cell line by decreasing half-life of mRNA
J Oncol
Increased expression of amyloid precursor protein promotes proliferation and migration of AML1/ETO-positive leukemia cells and be inhibited by panobinostat
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Verbrugge
Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors
Vidacs
Combining the differentiating effect of panobinostat with the apoptotic effect of arsenic trioxide leads to significant survival benefit in a model of t(8;21) acute myeloid leukemia
Clin Epigenetics
Klisovic
Maghraby
Parthun
Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells
Saunthararajah
Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells
Balasubramanian
Pharmacological inhibition of the histone lysine demethylase KDM1A suppresses the growth of multiple acute myeloid leukemia subtypes
Bortezomib interferes with C-KIT processing and transforms the t(8;21)-generated fusion proteins into tumor-suppressing fragments in leukemia cells
N-Ras(G12D) induces features of stepwise transformation in preleukemic human umbilical cord blood cultures expressing the AML1-ETO fusion gene
Billich
Baumruker
Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis
Nat Rev Drug Discov
FTY720 induces apoptosis of M2 subtype acute myeloid leukemia cells by targeting sphingolipid metabolism and increasing endogenous ceramide levels
Fung
Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors
Paschka
Schlenk
Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial
Eghtedar
Verstovsek
Estrov
Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia
Mandrekar
Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation
N Engl J Med
Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia
Continuous Publishing Alert
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After using IFL or IFD to restore an image of a Linux OS on an Intel firmware RAID drive to an Intel firmware RAID drive on a different system, or to an Intel firmware RAID drive that has been deleted and recreated since the image was taken, the restored system fails to boot properly. In some cases, the boot results in a kernel panic, with an error message about not being able to find or mount the root file system. In other cases, the boot stops at a command prompt, with the RAID not running.
Because the RAID is on a different system, or has been deleted/recreated since the image was taken, the UUIDs of the firmware RAID drive are now different. There are typically 2 UUIDs associated with a firmware RAID drive; one for the "container", and one for the RAID drive itself. These UUIDs are stored in the firmware of the RAID controller card (not on the drive), and are usually used in the Grub boot loader's configuration file so that the RAID array can be identified and started at boot time. If the UUIDs have changed, but the Grub configuration file has not been updated with the new UUIDs, then the RAID array will not be started.
Note that the UUIDs referenced above are only the ones for the actual firmware RAID container and drive. Other UUIDs, such as for the Linux root partition, swap partition, and other Linux partitions, will not be changed from the original system that was imaged.
The Grub configuration file needs to be updated with the new UUIDs to get the RAID to run, and the system to boot properly.
1. From the IFL boot disk, restore the image to the firmware RAID drive in the normal manner.
2. After the restore, reboot the system back into the IFL boot disk to ensure that the RAID drive and its partitions are recognized, and that the RAID is running. You can verify that the RAID is running by confirming that the RAID drive is detected by IFL (shows up in the list of drives).
3. Determine where the /boot directory resides. This can be either a dedicated /boot partition, or it could be included in the root partition. If the Linux OS is using LVM on top of the firmware RAID (a typical install choice for Redhat, CentOS, Fedora, etc.), there will be a separate /boot partition. Otherwise it could be either way.
In the example above, the 2nd "ARRAY" line contains the 2 new UUIDs that you will need to copy/paste into the Grub configuration file to replace the old ones. The 1st one on the line is the container UUID, while the 2nd one is for the drive itself.
7. For Grub legacy (menu.lst or grub.conf), the UUIDs to change will be on the "kernel" lines. There will usually be 2 or more "kernel" lines in the file, and each instance of the line will contain the same UUIDs.
8. For Grub2 (grub.cfg), the UUIDs to change will be on the "linux" lines. There will usually be 2 or more "linux" lines in the file, and each instance of the line will contain the same UUIDs.
9. Important: The UUIDs that are specified as root=<UUID> or root=UUID=<UUID> should not be changed. These are for the root partition, for which the UUID did not change.
11. Important: Copy/paste the 1st UUID on the 2nd line of output from the 'mdadm -Es' command executed in step 5 into the Grub configuration file to replace the 1st UUID specified with rd.md.uuid=<UUID> on each "kernel" or "linux" line. This step will have to repeated once for each "linux" or "kernel" line in the Grub configuration file.
12. Important: Copy/paste the 2nd UUID on the 2nd line of output from the 'mdadm -Es' command executed in step 5 into the Grub configuration file to replace the 2nd UUID specified with rd.md.uuid=<UUID> on each "kernel" or "linux" line. This step will have to repeated once for each "linux" or "kernel" line in the Grub configuration file.
13. If the above changes were made correctly, the restored system should now boot normally from the RAID drive.
1. An alternative method for managing this issue would be to prepare the updated Grub configuration file ahead of time, and store the file on the source system so that it is included in the source image. For example, it could reside in the boot/grub directory on the source system, and be named grub.conf-target, or something similar. Then, after the restore, the file containing the updated UUIDs can be copied to overwrite the source system's Grub configuration file. The target system's UUIDs can be determined ahead of time because the RAID drive must exist before the restore takes place. They can be displayed by booting the target system with IFL, and running the command 'mdadm -Es', as explained in step 5 above.


Originally printed July 15, 2010.
The Iowa City Book Festival officially kicks off Friday night with a chance to dine with many of the authors participating in the weekend's events -- the dinner already is sold out. The festival then begins in earnest Saturday with a host of opportunities to meet with authors, filmmakers and publishers. And Sunday -- titled "A Day in the City of Literature" -- the readings move out from university settings and bookstores and in to jewelry stores, clothing shops, churches and museums.
But every great Iowa City-linked writer, poet and publisher had to start somewhere. And where the book festival offers an opportunity to celebrate the Iowa City's literary past and present, local residents have an opportunity tonight to observe a literary experiment in progress and perhaps to catch a glimpse of Iowa City's literary future.
Mark Rahe, a local graduate of the Iowa Writers' Workshop, will read from his first book of poems, "The Smaller Half," at 7 p.m. in Prairie Lights Books.
Rahe is the type of poet who always notices "the entrances to homes / where a wheelchair couldn't go" ("Summer"). Who proudly announces, "I've signed the petition against me" ("Petition"). Who bemoans to a friend that he "would have responded sooner, / but they didn't allow smoking on the train" ("Dear Paul"). Who contemplates, "How the stretch is not yet a yawn / but yawn becoming" ("Outstretched").
And with titles such as "Hangover at the Family Diner," "There Are Cabs That Will Come Too Late" and "Felix's Helixes," Rahe's poems bear all the marks of a workshop graduate. Christina Mengert, in her review of "The Smaller Half" for www.constantcritic.com, lists those tell-tale workshop signs as: "(The poems are) slightly narrative, with the occasionally surreal image twisting our sense of time and place; (they employ) explosive, Donne-like openings followed by short, well-crafted lines, and an ending that lifts off the page as the poem gently but firmly settles into heavy silence."
It's not surprising, then, that "The Smaller Half" isn't merely the work of one workshop graduate; it represents the collaboration between three graduates. Not only is "The Smaller Half" Rahe's first book of poetry; it's also the debut publication of Rescue+Press, a Milwaukee-based operation run by workshop graduates Caryl Pagel and Daniel Khalastchi.
"We really felt that the book chose us and that it would give us a wide audience," Khalastchi said in a phone interview last month. "We approached Marc and asked him he wanted to help us get all this off the ground. And he entrusted his work to two people who had never done this before."
Khalastchi said Rescue Press came about because the more he and Pagel spoke with their writing colleagues and students, the more they realized there are far more good writers out there than there are publishers to print them.
"It's so difficult to get good work into print," Khalastchi said. "There's really a state of emergency in print media. ... We're just trying to rescue the world from the absence of pieces of literature."
Although Khalastchi and Pagel so far have saved only one book from a non-print existence, Khalastchi said they are working to ensure that Rescue+Press isn't limited by their contacts and aesthetic preferences.
That's why the call for submissions on the press's website (www.rescue-press.org) reads: "We are interested in small collections of artwork, comics, compositions, essays, experiments, how-tos, interrogations, lectures, lists, manifestos, notes, outlines, poetry, procedures, questions, reviews, sketches, stories, technical prose, textbooks, travel writing and anything else that transforms us."
It's unclear what the future holds for either Rescue+Press or for Rahe's poetry. But the collaboration among Rahe, Khalastchi and Pagel is just one small, recent example of the many such presses and literary partnerships that have dotted Iowa City's history. Observing this present day example is an opportunity to watch a little bit of that history unfold.
Or, in Rahe's words, it's an opportunity to lift our faces and to open our eyes to "something carried in the cold / some trivia brought down from above / that gains weight as it approaches" ("Stray").


text:
Q: Flexbox on IOS scrolls differently I noticed the scrolling functionality is different when using a flexbox based layout vs a position: fixed footer. The fixed footer is much smoother and shows a scrollbar. Flexbox isn't smooth at all, and does not show the scrollbar. I'd much prefer to use flexbox for my layout, but want the nicer scroll. Is there any way to achieve it with flexbox?
I'm testing on IOS 10 Iphone 7. Happens on both chrome and safari
Flexbox example
Fixed footer example
HTML:

        <meta name=viewport content="width=device-width,initial-scale=1">

            ...lots of content so it would scroll

        footer

Flexbox method:
html, body {
    height: 100%;
    margin: 0;
    padding: 0;
}

body {
    -webkit-flex-direction: column;
    flex-direction: column;
    display: flex;
}

#main {
    -webkit-flex: 1 1 auto;
    overflow-y: auto;
    min-height: 0px;
}

.footer {
    height: 72px;
    min-height: 72px;
    background-color: blue;
}

Fixed footer method:
html, body {
    height: 100%;
    margin: 0;
    padding: 0;
}

#main {
    padding-bottom: 72px;
}

.footer {
    position: fixed;
    bottom: 0;
    height: 72px;
    min-height: 72px;
    width: 100%;
    background-color: blue;
}

A: there's nothing to do with Flexbox.it's only the problem about overflow.so add this : -webkit-overflow-scrolling: touch; will work.


Welcome to Social Media Breakfast Madison! We're a non-profit, volunteer-run organization with a focus on social media education. At our FREE monthly events, we focus on networking , caffeine, and educational topics around social media. We welcome an ever-growing audience of diverse local professionals from a variety of industries. Join us at our next monthly event! You can find us the third Wednesday of every month, from 7:30 - 9:00 a.m. Check out our upcoming events for more details.
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This 52" genuine leather belt boasts three brilliant, gold finished plates between 8 rows of heavy duty snaps. The center plate is a commanding 9-3/4" X 7" and features 42 synthetic gemstones and a glitter epoxy border. Ships unassembled with a sheet of 6 stock, full color polydomed Main Event inserts in a beautiful satin lined presentation box.