Artículos de revistas sobre el tema "Död metafor"

Aktivitas penambangan eksploitatif pasir di Kecamatan Selat telah memicu peningkatan pertumbuhan sektor ekonomi, namun masyarakat tampaknya tidak pernah sadar dengan dampak kerusakan lingkungan yang ditimbulkan. Fenomena penambangan eksploitatif pasir tersebut menjadi thema dan subject matter kekaryaan. Dari pengamatan mendalam pengkarya mendapat pemahaman dan insight yang menjadi pemicu proses kreatif. Problimatikanya dinyatakan ke dalam bentuk bahasa rupa menggunakan metode penyangatan/hiperbola. Untuk mewujudkan kekaryaan mengunakan metode pendekatan dan langkah-langkah kreatif melalui tahapan terstruktur, spontan dan intuitif. Metode ini telah menghasilkan elaborasi yang unik dari semua komponen imajirial sehingga melahirkan gagasan dan metafor yang kreatif. Karya-karya dibuat atau digagas di studio dan pindahkan ke, atau dirangkai di sekitar wilayah areal penambangan. Hubungan antara lokasi presentasi dan masyarakat mampu menjadi sebuah kekuatan tersendiri karena sesuai dengan konteks persoalan. Target kekaryaan tidak hanya sebagai ekspresi individual yang terbatas pada persoalan estetika namun menjadi cara atau alat untuk menyebrangkan (mengkampanyekan) isu lingkungan. Penciptaan seni adalah sebagai modus yang mampu untuk menginspirasi masyarakat agar tergugah secara kolektif maupun individual untuk berpartisipasi dalam upaya pelestarian eco-system.The exploitative sand mining in Selat District contributed to the economic growth; however, the local people were never aware that it had caused the environment to be degraded. The phenomenon of the exploitative sand mining is used as the theme and subject matter of an art creation. From what was observed by the artist, an insight into something contributed to a creative process. The problem was reflected in the form of language using the method of hyperbole. The art creation was created using the structured, spontaneous and intuitive creative steps and method which led to a unique elaboration of all the imaginary components and a creative metaphor and concept. The creation was designed in a studio before it was moved to or arranged around the mining area. The relation between the location of presentation and people could become a specific strength as it was in accordance with the context of the subject matter. The target of the art work did not only constitute an individual expression which was limited to the matter of common aesthetics but it was also used as the way of and the tool for transmitting (campaigning) an environmental issue. The art creation could be used to inspire people, as individuals and groups, to participate in the attempt made to preserve the eco-system

ABSTRACT The response of Escherichia coli central carbon metabolism to genetic and environmental manipulation has been studied by use of a recently developed methodology for metabolic flux ratio (METAFoR) analysis; this methodology can also directly reveal active metabolic pathways. Generation of fluxome data arrays by use of the METAFoR approach is based on two-dimensional13C-1H correlation nuclear magnetic resonance spectroscopy with fractionally labeled biomass and, in contrast to metabolic flux analysis, does not require measurements of extracellular substrate and metabolite concentrations. METAFoR analyses of E. coli strains that moderately overexpress phosphofructokinase, pyruvate kinase, pyruvate decarboxylase, or alcohol dehydrogenase revealed that only a few flux ratios change in concert with the overexpression of these enzymes. Disruption of both pyruvate kinase isoenzymes resulted in altered flux ratios for reactions connecting the phosphoenolpyruvate (PEP) and pyruvate pools but did not significantly alter central metabolism. These data indicate remarkable robustness and rigidity in central carbon metabolism in the presence of genetic variation. More significant physiological changes and flux ratio differences were seen in response to altered environmental conditions. For example, in ammonia-limited chemostat cultures, compared to glucose-limited chemostat cultures, a reduced fraction of PEP molecules was derived through at least one transketolase reaction, and there was a higher relative contribution of anaplerotic PEP carboxylation than of the tricarboxylic acid (TCA) cycle for oxaloacetate synthesis. These two parameters also showed significant variation between aerobic and anaerobic batch cultures. Finally, two reactions catalyzed by PEP carboxykinase and malic enzyme were identified by METAFoR analysis; these had previously been considered absent in E. colicells grown in glucose-containing media. Backward flux from the TCA cycle to glycolysis, as indicated by significant activity of PEP carboxykinase, was found only in glucose-limited chemostat culture, demonstrating that control of this futile cycle activity is relaxed under severe glucose limitation.

<p>Penulis akan meneliti kalimat bahasa Jepang dan Mandarin yang mengandung unsur metafora/hiyu「比喩」pada novel Totto-chan. Pertama penulis akan mengambil kalimat-kalimat yang mengandung unsur metafora/hiyu pada light novel tersebut. Penulis akan mengumpulkan setidaknya 4 kalimat yang mengandung unsur metafora sebagai korpus data dari penelitian ini. Adapun keempat kalimat tersebut mengandung unsur metafora yang berbeda. Sesuai dengan jenisnya, penulis akan mengumpulkan kalimat-kalimat yang mengandung unsur chokuyu「直喩」/明喻(míngyù) dan inyu「隠喩」/暗喻(ànyù) dalam beberapa kalimat. Penulis akan menganalisis arti dari perumpamaan tersebut dengan teori -teori yang penulis dapatkan dan penulis bandingkan dengan Bahasa Mandarin. Korpus data akan diteliti dan dianalisis menggunakan kajian teori mengenai metafora dan teori makna. Metode yang penulis gunakan adalah metode kepustakaan. Selanjutnya setelah data-data terkumpul, penulis akan memulai penelitian dengan cara menganalisis data menggunakan metode deskriptif analitik. Untuk simpulan sementara adalah meskipun terdapat perbedaan cara baca, tetapi terdapat persamaan fungsi dan pola gaya bahasa metafora yang mirip satu dengan yang lainnya.</p><p><em>In this research, I will analysis Japanese and Chinese metaphors texts (hiyu)/</em>「比喩」<em>using Totto-chan novel. Firstly, I will pick up some texts contain metaphors in this light novel, at least 4 sentences. Those sentences will be divided into 2 different metaphors. First is chokuyu</em>直喩」/明喻(<em>míngyù</em>)<em> and the second one is inyu</em>「隠喩」/暗喻 <em>(ànyù). Those Japanese and Chinese metaphors will be compared using Chinese and Japanese language metaphors theories. For that reasons, I will use literature collection method in this research. And after completed the sentences data, those sentences will be analyzed using descriptive analytic. As a conclusion, even though both of the words did not have similar pronunciation, intonation, and character, but both of the metaphor sentences have similar function and metaphor literary style. </em></p>

Abstracttitle SUMMARY /title It is a commonly held belief that the classical world not only failed to develop mechanism but that it did not even possess a lexical and conceptual equivalent to the modern metaphor of the machina mundi. On the other hand the ancient world's familiarity with a wide variety of mechanisms is well known and this can be seen in Platonic and Aristotelian lexis. This present essay proposes to reformulate the judgement regarding the absence of a general notion of the machine in the classical world and its correspondent metaphorical use in the light of the specific forms of metaphorical exchange which the philosophical and scientific thought of the ancients placed between naturalia and artificialia. In this perspective the absence of the modern metaphor appears to be compensated for in a way by the contiguous of natural demiurgy (natura opifex); a diffuse presence which utilizes the subjective aspect of projecting demiurgy as an intertechnical metaphor. In the pseudo-Aristotelian De mundo the typically modern connection between artificialist and legal metaphor comes to the surface. Besides, the world machine of the modern age was to lose its traditional semantical ties with the demiurgical machinatio only in the late eighteenth century. A more objective meaning of machina made headway in Latin culture and the term was proposed as a common name for mechanical apparatus. The new theological interest in patristics then gave the demiurgical metaphor a tendency towards the radical denaturalization of worldliness, which was particularly evident in Lattanzio.

Ngayogyakarta Negari Exhibition 2012 is part of the Festival of Arts 2012 Ngayogyakarta Hadiningrat Negari held in commemoration of the 2.5-century founding of Ngayogyakarta and 100 years of the birth of Sri Sultan Hamengkubuwono IX, followed by 124 artists Yogyakarta, both painting, photography, sculpture, audio visual, and installation as well which displayed the works of Sri Sultan Hamengkubuwono IX and Yogyakarta themed. Jogja International work sculpture by sculpture artist, Dunadi, is one of the few works of sculpture on display in this activity, similar to superhero Spider-Man but wearing blangkon and sarong. In addition to its large size and white color, which makes it interesting sculpture to be observed, studied and discussed is this artwork has conveyed symbolic, metaphoric, and typical parodik messages of Yogyakarta people. This discussion was done through art criticism and aesthetic theory in which the implementation of theories is very broad in the domain art and design. Although the artwork discussed did not pertain directly to the the domain of Visual Communication Design, sensitivity to social issues, creative approach, and beautiful execution Dunadi artist was expected to add experience and insight into the art of the artists and designers in Indonesia.

Gjennom uminnelige tider har mennesket vært fascinert av havet. I en rekke skapelsesmyter fremstår gjerne havet som en positiv størrelse, en pulserende og livgivende urtidsstrøm. Men ved siden av å være en raus kilde til liv, er havet også nært forbundet med undergang og død,forlis og drukning. Få havstykker har som den beryktede Moskenesstraumen fått denne havets dobbelthet knyttet til seg - på den ene siden verdens største barselseng, på den annen side dødens grusomme svelg. Kanskje med unntak av Bermuda-trianglet i Sargassohavet, stedet hvor skip, og etter hvert også fly, angivelig skal ha forsvunnet sporløst i årevis, er det neppe noe havområde i verden som opp gjennom århundrene er blitt beskrevet og illustrert i tilsvarende grad som Moskenesstraumen. I denne artikkelen skal jeg rette fokus mot tre av de mange som, på høyst forskjellig vis, har latt seg fascinere og inspirere av Moskenesstraumen, nemlig Petter Dass, Edgar Allan Poeog Jules Verne.

To improve students' critical thinking skills in solving High Order Thinking Skill (HOTS) questions, the ability to think metaphorically in learning is required. Thus, this study aimed to describe the metaphorical thinking process of students in solving HOTS mathematical problems by PISA approach. In this study, the research method was descriptive with a qualitative approach. The sampling technique was purposive sampling technique, which was a sampling technique suitable for this study. The results showed that based on the works of the three subjects, they had distinct characteristics in solving the problems. S1 who was classified in high category had a metaphorical form by looking at the room from the top side and based on the indicators, S1 had met the metaphorical thinking indicators. S2 who was classified in low category still did not have metaphorical form as compared to the indicators of identifying problems. However, S2 also had gone through metaphorical thinking process when compared to the indicators of connecting and deciding the main concept, as well as was able to illustrate ideas. Meanwhile, S3 who was classified in the middle category had a metaphorical form by only looking at the room side. S3 also had met several indicators of metaphorical thinking.

The metaphor of the sun, in which Plato (Republic 509b) compares the idea of the Good to the sun that dwells above the earth yet affects the phenomena occurring on it, was an inspiration for both heretical and orthodox theology in the first Christian centuries. The Gnostics, Clement of Alexandria and Origen all believed that God, like the Platonic idea of the Good, is radically transcendent in relation to the world, but at the same time is the cause of everything that exists in it. Unlike Plato, who believed that the idea of the Good is knowable and can be the subject of science, the Christian theologians of the first centuries believed that God was like a blinding light. This means that God, according to them, though intelligible, is unknowable in His essence. Therefore, God cannot be the subject of science. Another modification of the Platonic metaphor was the introduction of the element of sunlight, to which the philosopher from Athens did not refer. For the Gnostics, the rays of the sun were “eons” – spiritual beings that existed in the space between the first principle of all things and the material world. For Clement and Origen, the light that comes from the sun was the Son – the power and wisdom of God. In contrast to the Gnostics, who believed in the progressive degradation of the spiritual world through successive emanations, the Alexandrian Fathers believed that the Son possessed all the knowledge of God and therefore revealed to man the true God. Yet the revelation of God by the Son, and even the grace that assists human beings in the process of learning about God, do not give man complete knowledge of the essence of God. Thus the Gnostics, Clement and Origen, despite some doctrinal differences, all accepted the concept of the radical transcendence of God on the ontological and epistemological levels.

Methadone maintenance treatment (MMT) is aimed to reduce the harmful effects of injecting drug use. Since the first Puskesmas Poncol opened this program in 2010, there were 50 users of MMT. Currently users of MMT were 11 people, 2 people have died, no patient has recovered, and 36 others dropped out. Those did not recover, but dropped out with reasons and information that were not known by the officer. MMT is a strategic key of HIV/ AIDS prevention for injecting drug users. However, in the implementation Puskesmas Poncol was lost most of active MMT users. The research aimed to know the implementation of MMT which includes input, process, and output on heroin addict in Puskesmas Poncol. This research was qualitative research supported by quantitative data. Data collection used in-depth interviews, observation, and documentation. The result of the research showed that the service of MMT in Puskesmas Poncol was still many weaknesses, from input aspect (untrained human resources), process (methadone planning, organizing, and dose arrangement have not been well implemented), and output (services have not been evaluated).

Aim. To assess the parameters reflecting sarcopenia (body composition, muscle strength, muscle function) in order to determine the effectiveness of metformin in patients with sarcopenia.Material and methods. Systematic searches of clinical trials were carried out in MEDLINE databases through PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ResearchGate from January 1990 to March 2019. For statistical processing, the R language with the RStudio software was used. The following packages were used: googlesheets4, tidyverse, meta, dmetar, metafor. The metaanalysis included 391 patients with both established for the first time and existing long-term type 2 diabetes (T2D), with prediabetes, impaired glucose tolerance (IGT), as well as patients without impaired glucose metabolism. In comparison groups (194 patients who received metformin and 197 patients who received placebo), the effect of metformin on lean body mass (LBM), fat mass, muscle strength and muscle function was assessed, which made it possible to indirectly evaluate the potential effect of metformin on sarcopenia.Results. The use of metformin in patients with different glucose metabolism (type 2 diabetes, IGT, prediabetes) did not lead to significant changes in body composition (on average, LBM increased by 0,9 kg (MD, 0,8815; CI (-0,11; 1,87), p=0,0818), fat mass decreased by 0,7% (MD, -0,6856; CI (-1,54; 0,17), p=0,1170), but muscle strength significantly increased by 0,5 kg (SMD, 0,5241, CI (0,2265; 0,8217), p=0,0006).Conclusion. Meta-analysis has confirmed that the use of metformin has an effect on muscle strength, which makes it possible to consider it for sarcopenia treatment. Unfortunately, a small number of studies have not allowed to analyze the effect of metformin on a number of characteristics: muscle strength, muscle function (walking speed, functional tests). At the moment, a much larger prospective study is needed to form a final opinion on the rationale of metformin therapy in patients with sarcopenia.

Exposure to aristolochic acid (AA) is linked to kidney disease and urothelial cancer in humans. The major carcinogenic component of the AA plant extract is aristolochic acid I (AAI). The tumour suppressor p53 is frequently mutated in AA-induced tumours. We previously showed that p53 protects from AAI-induced renal proximal tubular injury, but the underlying mechanism(s) involved remain to be further explored. In the present study, we investigated the impact of p53 on AAI-induced gene expression by treating Trp53(+/+), Trp53(+/-), and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for six days. The Clariom™ S Assay microarray was used to elucidate gene expression profiles in mouse kidneys after AAI treatment. Analyses in Qlucore Omics Explorer showed that gene expression in AAI-exposed kidneys is treatment-dependent. However, gene expression profiles did not segregate in a clear-cut manner according to Trp53 genotype, hence further investigations were performed by pathway analysis with MetaCore™. Several pathways were significantly altered to varying degrees for AAI-exposed kidneys. Apoptotic pathways were modulated in Trp53(+/+) kidneys; whereas oncogenic and pro-survival pathways were significantly altered for Trp53(+/-) and Trp53(-/-) kidneys, respectively. Alterations of biological processes by AAI in mouse kidneys could explain the mechanisms by which p53 protects from or p53 loss drives AAI-induced renal injury in vivo.

Background: Glucose transporter 1 (GLUT1) is a ubiquitously expressed protein highly expressed on the surface of erythrocytes. As a member of insulin signaling pathway, GLUT1 is responsible for basal and growth factor-stimulated glucose uptake. The insulin signaling pathway is involved in several different biologic functions including cellular metabolism, energy regulation, cell cycle control, and stress response. We have previously identified several components of the insulin signaling pathway, including FOXO3, AMPK, and IGFBP3, to be associated with fetal hemoglobin (HbF) levels in erythroid progenitor cells from sickle cell disease (SCD) patients. We have shown that metformin, a FOXO3 and AMPK activator, induces HbF in vitro. Furthermore, our preliminary data of metformin clinical trial in patients with SCD suggests that metformin can induce HbF in vivo. Studies in non-erythroid cells have reported that metformin increases production and surface expression of GLUT1; increase in the activated form of both AMPK and FOXO3 is also associated with elevated GLUT1 surface expression and its activation. Given these interesting associations, we hypothesized that GLUT1 levels may be associated with HbF levels in patients with SCD. To test this, we measured the expression levels of GLUT1 on the surface of red blood cells (RBC) from patients with SCD and investigated its correlation with hematologic indices. Methods: Applying a receptor binding domain labeling technique using anti GLUT1 antibody (Metafora Biosystems), we quantified GLUT1 expression measuring its geometric mean fluorescence intensity index on the surface of the RBCs by flow cytometry (Attune NxT). GLUT1 and CD71+ expression was measured on peripheral blood samples collected from 13 pediatric patients with HbSS (all on hydroxyurea, none on transfusion therapy) under an IRB approved protocol from Baylor College of Medicine. Patients ranged from 4 to 21 years of age; 52% were male. 4 HbAA normal donors were also analyzed, ages 28 to 43 years old, 50% male. HbF levels were obtained on the same date of collection by HPLC (Agilent, 1260 infinity-2). Complete blood count with differential and absolute reticulocyte count (ARC) was measured by ADVIA-120 hematology analyzer (Siemens). Flow cytometry data was analyzed by FlowJo software. P-values were calculated using Student's t-test. Results and conclusions: We identified a strong positive correlation between GLUT1 expression and HbF on the surface of hydroxyurea treated HbSS RBCs, R2=0.41. Possible variables contributing to this correlation are HU treatment differences, patient age, and RBC stage of maturation. However, 1) there was no correlation between GLUT1 levels and absolute neutrophil count (ANC), suggesting that variations in HU usage did not contribute to the association; 2) there was no association between patient age and GLUT1 levels; 3) there was also no correlation between GLUT1 levels and ARC or %CD71 positivity, suggesting that the GLUT1:HbF correlation was not due to more early stage erythroid cells with higher HbF levels due to a maturation arrest (Figure 1). GLUT1 expression was significantly higher on the surface of HbSS RBCs and CD71+ cells compared to HbAA (Figure 2); this is possibly due to the increased metabolic demand for glucose in the sickle RBC, but may also impact the basal HbF level of the sickle RBC. We hypothesize that cells with higher HbF levels have higher levels of activated AMPK, which activates FOXO3, a positive regulator of HbF (Zhang et al., Blood 2018), consistent with a metabolic stress state. Metabolic stress leads to an increase in GLUT1, to facilitate glucose transport. Future work will explore potential causative relationships between GLUT1 levels and HbF, and determine whether pharmacologic manipulation of GLUT1 may increase HbF in patients with SCD. Disclosures Petit: Metafora-biosystems: Equity Ownership, Other: CEO and co-founder.

Abstract Abstract 2480 Acute myeloid leukemia (AML) represents one of the most genetically heterogeneous malignancies; however, some processes are commonly dysregulated. One of the most frequently dysregulated processes in AML is Wnt signaling. In solid cancers, aberrant Wnt signaling has been shown to promote cancer by increasing nuclear accumulation of β-catenin and with consequent activation of target genes. In AML, overexpression of β-catenin is also common; in addition however, patient studies and genetic models indicate that other components of the Wnt pathway are also commonly dysregulated and may mediate transcriptional changes independently of β-catenin. The aim of this study was to identify aberrantly regulated Wnt components and target genes in AML by interactome analysis of the AML Affymetrix GeneChip® 3` expression microarray datasets; a network building algorithm used to understand relationships between genes. Analysis and interpretation of microarray data is still both biologically and computationally challenging. To address this, we performed batch adjustment to the large scale AML dataset by merging gene expression profile (GEP) data derived from different database sources (including different array platforms). GEPs data were generated from our AML patients enrolled in two different AML NCRI-MRC UK clinical trials using two different Affymetrix platforms, HG-U133A (n=216) and HG-U133Plus2.0 (n=139). GEPs from normal CD34+ bone marrow samples were downloaded from ArrayExpress (n=26). In order to compare AML vs. normal haematopoietic GEP, all data were merged into a single dataset. Individual. CEL files were imported into Partek® Genomics Suite™ and GC-RMA normalization was applied. Linear contrasts, mixed model analysis of variance with false discovery rate correction (P<0.05) and threshold analysis (>1.5 or <1.5 fold-change) were applied to the adjusted data followed by gene enrichment analysis using MetaCore™ (GeneGo Inc). Batch adjustment was performed using Distance Weight Discrimination (DWD) method to the merged GEPs. Prior to further inferential and gene ontology testing, the DWD merged datasets showed significant reduction in the source of data bias with GEP clustered according to their biological variation rather than technical variation. As a result, we present a final list of 58 significant changes in the expression of Wnt related genes in AML. Enrichment by protein function analysis highlighted 8 Wnt transcription factors to be dysregulated (TCF7L2/TCF4, MYC, NANOG, WT1, RUNX2, p300, TCF7, SMAD2), along with 5 receptors (CD44, FZD3, FZD4, FZD5, LDLR), 3 types of phosphatases (B56G, PR61-β, PPP2R5A) and other categories of Wnt related objects (n=33). Consistent findings were seen with previously established Wnt-associated genes specific to AML (CD44, WT1, MYC) showing that data sources from DWD adjustment was effective. We sought to evaluate the significant biological and functional relationships within the genes in the final dataset by transcription factor target modeling using MetaCore™ Interactome tools. Direct network interaction uncovered TCF7L2/TCF4 as the most significantly upregulated Wnt transcription factor with concurrent high expression of its downstream Wnt responsive genes CD44, AXIN1, ID2 that were also present in the final list. Importantly, β-catenin is unlikely to contribute to this transcriptional activation due to the fact that our data showed increased transcription of β-catenin degradation complexes (or negative regulation of Wnt signalling). Specifically, RUVBL1, that directly increases β-catenin activity was significantly downregulated, whereas the other significantly overexpressed upstream genes (APC, CSNK1E, AXIN1, WT1) are known to have inhibitory effect on β-catenin-mediated transcription. In summary, by using multiple GEP data from a large AML cohort in conjunction with robust statistical adjustments, we have identified TCF7L2/TCF4 mediated transcription as the most significant Wnt-regulated process to be altered in AML compared with normal blasts. We also predict that transcription of TCF7L2/TCF4 regulated genes is likely to be independent of β-catenin, supporting observations in genetic models which indicate that β-catenin (and γ-catenin) are redundant for normal haematopoiesis and are not required for TCF-mediated transcription. Disclosures: No relevant conflicts of interest to declare.

Background: Salvage autologous stem cell transplant (SAT)is an alternative treatment option for relapsed multiple myeloma patients that offers additional progression-free survival (PFS2) and overall survival (OS2) advantage over salvage chemotherapy. We conducted a meta-analysis to evaluate the outcomes of salvage transplant in patients with relapsed multiple myeloma after initial transplant. Methods: This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search on PubMed, Embase, Cochrane and Web of Science was conducted up to December 31st, 2018. Two independent reviewers screened the literature and extracted data. All studies including randomized, retrospective or prospective studies in multiple myeloma patients who underwent salvage autologous transplant were included. Abstracts, posters, review articles, case reports and studies with syngeneic and tandem transplant were excluded. Articles were excluded if they did not provide transplant related outcomes data. The search terms included "Salvage autologous stem cell transplantation", "Second autologous stem cell transplantation", "multiple myeloma". 'Meta' and "Metafor' libraries in R software (CRAN Project) were used for the analysis. Pooled estimates and 95% confidence intervals were calculated using DerSimonian-Laird (DL) random effects model. Heterogeneity between studies was evaluated using Q test and sensitivity analysis. Results: The search strategy identified over 3260 articles; 16 studies (n = 1113 patients; 1 randomized trial; 15 retrospective studies) were selected for this meta-analysis. The sample size of the studies varied between 25 and 200 patients. All studies used melphalan conditioning for salvage transplant. A significant number of patients in about 10 studies received maintenance after initial transplant. Only one study included patients who received maintenance therapy after salvage transplant. Pooled rate of patients achieving partial response or more(≥PR) after salvage transplant was 76% (95%CI: 68-83; I2=84%). Pooled rate of transplant related mortality (TRM2) was 5.5% (95%CI: 2.6-9.3; I2=78%). The pooled estimates showed a median progression free survival (PFS2) 13.5 months (95%CI: 11.3 - 15.6; I2=100%), overall survival (OS2) 34.3 months (95%CI: 27.9 - 40.7; I2=100%). The results are shown in figures 1&2. Conclusion: SAT approach had favorable outcomes of achieving durable PFS and OS in relapsed myeloma patients. A Higher TRM was observed with salvage transplant than in upfront transplant. Prospective randomized trials are needed to define benefits of SAT in comparison with "best non-ASCT" therapy in patients with MM who relapse after primary therapy. Figure 1 Disclosures Mansour: Abbvie: Other: Stock; Astra Zeneca: Other: Stock; Bluebird Bio: Other: Stock; CRISPR: Other: Stock; Editas: Other: Stock; Johnson and Johnson: Other: Stock; Novartis: Other: Stock.

e15080 Background: A number of studies have addressed the association between Immune related Adverse Events (IrAE) and outcome in patients treated with Immune Checkpoint Inhibitors (ICI). Only a minority of them considered the effect of immortal time bias (ITB), and results of these papers are conflicting. The aim of our meta-analysis was to assess the relationship between IrAE and outcomes for patients treated with ICIs, with a focus on ITB in weighing the role of this association. Methods: PubMed, Embase (Ovid), and Scopus were searched through January 2, 2020. Studies reporting the prognostic impact of IrAE development on outcome in advanced cancer patients treated with anti PD-1 or PD-L1.Two investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Author name, cancer type, PD-1 and PD-L1 inhibitor used, number of patients, number and type of all adverse events, presence of a landmark analysis, median OS and PFS and difference between patient with or without IrAE in terms of OS and PFS (Hazard Ratio) and ORR (Odds Ratio) were extracted. Data were pooled using a random-effects model. Main outcome were Overall Survival (OS), Progression Free Survival (PFS) and Overall Response Rate (ORR). Analysis was performed with dedicated software (R studio version 1.2.1335, metafor package). Results: A total of 29 articles comprising 7430 patients were included. 7 papers published the results of survival analysis according to landmark analysis, 2 papers published only the naïve analysis while stating that a landmark analysis resulted non significant, and the others did not perform a landmark analysis. IrAEs were associated with improved outcomes with high heterogeneity ( I2 70.8%, p < 0.001 for OS; 65.7%, p 0.002 for PFS; 62.1%, p 0.001 for ORR). When subgroup analysis was performed according to the adoption of a landmark approach, the association between IrAE and outcome remains significant for OS, PFS and ORR but the effect size was smaller ( HR 0.61 vs 0.41 for OS, ANOVA Q-test for difference between subgroup p = 0.015; HR 0.66 vs 0.47 for PFS, ANOVA Q-test p 0.029; OR 2.59 vs 6.77 for ORR, ANOVA Q-test p < 0.001) while heterogeneity was substantially reduced (I2 for papers using LM 43% for OS, p 0.115; 9.7% for PFS, p 0.355; 0.0% for ORR, p 0.556). Conclusions: Our analysis suggests a significant confounding effect of ITB as well as a real effect of IrAE development on outcome.

Abstract Abstract 4714 Background Morphologic examination of CSF cytospin is the standard method in the detection of CNS involvement of childhood acute lymphoblastic leukemia (ALL). However, the result widely varies depending on the status of cell degeneration caused by cytospin procedure. We performed interphase fluoroscence in situ hybridization (FISH) on CSF cytospin cells to examine its potential usefulness in detecting malignant cell population in the CSF. Materials and Methods The study used 19 CSF cytospin specimens of the childhood ALL patients under treatment. All of them had cytogenetic abnormalities in the bone marrow nuclear cells at the initial diagnosis. None of the patients showed malignant cells in morphologic examination of the cytospin. Interphase FISH was performed to detect recurrent genetic abnormalities including rearrangement of BCR/ABL, TEL/AML1, MLL and IgH rearrangement, and p16 deletion using LSI BCR/ABL dual color, dual fusion translocation probe, LSI TEL/AML1 ES dual color translocation probe, LSI MLL dual color, break apart rearrangement probe, LSI IGH dual color, break apart rearrangement probe, and LSI p16/CEP 9 dual-color probe (Abbot Molecular Diagnostics). FISH signals were interpreted using automated slide scanning system (Metafer 4 system) and manually read for confirmation. Result Two patients had the same cytogenetic abnormalities in CSF cytospin as observed in the bone marrow mononuclear cells: one patient had 4 copies of AML1 gene, suggesting tetrasomy 21 or multiple fusion partner gene other than chromosome 12, both in bone marrow and in CSF; the other had 3 copies of p16 gene including one with low signal intensity both in bone marrow and in CSF. Ten patients did not have any cytogenetic abnormalities. We could not interpret the result in the other 7 patients due to low cell count and/or low signal intensity. Conclusion Out of 19 who were diagnosed not to have malignant cell in CSF in morphologic examination, 2 patients had cells with the same clonal abnormalities in the CSF as bone marrow. Our result indicates that FISH study would be helpful in evaluating CSF involvement of hematologic malignancies including ALL. In order to improve the performance, it is required to prevent degeneration of the cells by prompt specimen delivery and slide preparation. Disclosures: No relevant conflicts of interest to declare.

e20592 Background: Concurrent chemoradiation (cCRT) has been the standard first line treatment for patients with limited-stage small cell lung cancer (LS-SCLC) for decades. Despite continued progress in refining chemotherapy and radiation modalities, the prognosis for LS-SCLC remains unsatisfactory with cCRT alone. Recent clinical trials have sought to further improve survival by combining cCRT and other newly developed therapeutic agents in treating LS-SCLC. Severe (grade 3 or higher) pneumonitis is one of the major toxicities related to cCRT. The objective of this study was to establish a benchmark rate of pneumonitis in LS-SCLC patients receiving first line cCRT. Methods: A systematic literature review and meta-analysis was performed in accordance with Cochrane, PRISMA, and Food and Drug Administration guidelines to summarize and quantify the incidence of grade 3−5 and fatal pneumonitis (including radiation pneumonitis) in patients with LS-SCLC exposed to cCRT alone. MEDLINE, Embase, and the Cochrane Central Register were searched from 2014 to July 16, 2020 to identify relevant randomized controlled trials (RCTs) and non-RCT studies (observational studies or non-randomized trials). The study quality of included RCTs and non-RCT studies was evaluated using the Revised Cochrane Risk of Bias Tool for Randomized Trials (RoB2) and the Newcastle-Ottawa scale, respectively. The incidence of pneumonitis across studies was pooled using a frequentist method with correction for zero events, using the metafor package in R 3.6.1. Results: Thirteen studies (4 RCTs, 9 non-RCTs) were included in the review. Patient populations were comparable across studies and the median follow-up ranged from 20−59 months. All patients received etoposide with either cisplatin or carboplatin, and radiation doses, given once or twice daily, ranging from 40−72 Gy. While all RCTs were open-label studies that could have some deviations from the intended interventions, this did not impact the reported incidence of pneumonitis. All non-RCTs were of high quality. Ten studies were included in the meta-analysis (3 RCTs, 7 non-RCTs; 1,539 patients). The pooled incidence of grade 3−5 pneumonitis was 3.28% [95% confidence interval (CI): 1.52−5.04%] in RCTs from random-effects model, and 6.34% [95% CI: 3.64−9.04%] in non-RCTs from fixed-effects model. The pooled incidence risk of grade 5 (fatal) pneumonitis was 0.29% [95% CI: 0.00−0.62%] in RCTs and 0.88% [95% CI: 0.02−1.74%] in non-RCTs, both from fixed-effects model. Conclusions: In LS-SCLC patients exposed to cCRT, the incidence of grade 3−5 pneumonitis and fatal pneumonitis ranges from 3.28−6.34% and 0.29−0.88%, respectively. These results can be used to understand the safety of other therapeutic agents with regard to pneumonitis when used in combination with cCRT to treat patients with LS-SCLC.

Berpikir metaforis adalah aktivitas mental dengan menggunakan metafora-metafora yang sesuai dengan situasi yang dihadapi. Metafora adalah suatu ide untuk mengaitkan masalah yang dihadapi dengan pengalaman sehari-hari dan materi matematika yang dikenalnya. Penelitian yang dilakukan merupakan penelitian deskriptif dengan pendekatan kualitatif yang bertujuan untuk mendeskripsikan profil berpikir metaforis siswa SMP dalam memecahkan masalah pengukuran ditinjau dari gaya kognitif. Subjek penelitian ini adalah dua siswa yang terdiri atas siswa bergaya kogntif reflektif (SR) dan siswa bergaya konitif impulsif (SI). Pengumpulan data dilakukan dengan pemberian tugas pemecahan masalah dan wawancara semi terstruktur. Triangulasi waktu digunakan untuk menguji kredibilitas data. Hasil penelitian ini adalah deskripsi berpikir metaforis yang terdiri atas connect, relate, explore, analyze, transform dan experience. Secara umum, deskripsi berpikir metaforis kedua sebjek ialah sebagai berikut. Pada tahap connect, SR menghubungkan dua ide yang berbeda. Ide pertama adalah menentukan selisih keliling kedua persegipanjang dengan cara memisalkan pergeseran titik pada salah satu sisi persegipanjang sesuai keinginannya, perubahan keliling persegipanjang dengan memisalkan penambahan ukuran panjang dan lebar persegipanjang tersebut, dan jumlah panjang semua rusuk balok setelah panjang, lebar, dan tinggi balok diperpanjang sepertipada umumnya. Sedangkan ide yang kedua, ketiga hal tersebut dinyatakan dalam bentuk persamaan. Pada tahap relate, SR menghubungkan ide yang berbeda dengan pengetahuan yang dia miliki. SR menghubungkan dengan beberapa materi di matematika. Pada tahap explore, SR membuat model yang sesuai dengan permasalahan yang ia hadapi dan mendeskripsikan kesamaan kedua ide yang ia temukan. Pada tahap analyze, SR menjelaskan kembali langkah-langkah yang ia lakukan dalam menemukan selisih keliling kedua persegipanjang, perubahan keliling persegipanjang, dan jumlah panjang semua rusuk balok yang dinyatakan dalam bentuk persamaan serta mendeskripsikan kembali kesamaan kedua ide yang ia temukan. Pada tahap transform, SR menyimpulkan besarnya selisih keliling kedua persegipanjang setelah titik pada salah satu sisi persegipanjang digeser ke kiri atau kanan, perubahan keliling persegipanjang, dan jumlah panjang semua rusuk balok dengan tepat. Pada tahap experience, SR dapat menerapkan hasil yang didapat untuk menyelesaikan permasalahan yang dihadapi. Pada tahap connect, SI menghubungkan dua ide yang berbeda. SI memiliki dua ide yang berbeda. Ide pertama adalah menghitung selisih keliling kedua persegipanjang sebelum titik pada salah satu sisi persegipanjang digeser, perubahan keliling persegipanjang dengan memisalkan penambahan ukuran panjang dan lebar persegipanjang tersebut, dan jumlah panjang semua rusuk balok sebelum ukuran panjang, lebar, dan tinggi balok berubah. Sedangkan ide yang kedua, ketiga hal itu dinyatakan dalam bentuk persamaan. Pada tahap relate, SI mengaitkan ide yang berbeda dengan pengetahuan yang dia miliki. SI menghubungkan dengan beberapa materi yang ia pelajari di matematika. Pada tahap explore, SI membuat model yang sesuai dengan permasalahan yang ia hadapi namun, ia tidak dapat mendeskripsikan kesamaan kedua ide yang ia temukan. Pada tahap analyze, SI menjelaskan kembali langkah-langkah yang ia lakukan sebelumnya dan tidak dapat mendeskripsikan kesamaan kedua ide yang ia temukan. Pada tahap transform, SI menyimpulkan besarnya selisih keliling kedua persegipanjang setelah titik pada salah satu sisi persegipanjang digeser digeser ke kiri atau kanan, perubahan keliling persegipanjang, dan jumlah panjang semua rusuk balok dengan tepat. Pada tahap experience, SI dapat menerapkan hasil yang didapat untuk menyelesaikan permasalahan yang dihadapi.Metaphorical thinking is the mental activity by using metaphors that fit the situation. Metaphor is an idea to link the problems faced by everyday experience and the familiar mathematical material. This research is descriptive research with qualitative approach that aimed to describe the metaphorical think profile of junior high school students for solving measurement problem based on cognitive style. The subjects of this research are two students consist of a student with cognitive style (SR) and a student with cognitive impulsive style (SI). The data collecting technique that used in this research is by giving the assignment of problem solving and semi-structured interviews. Triangulation of time used to test the credibility of the data out of this research. The result of this study is description of metaphorical thinking consists of connect, relate, explore, analyze, transform and experience. In general, description of metaphorical thinking of the two subjects is as follows. At connect stage, SR connected two different ideas. The first idea is to determine the difference between the two rectangular perimeter by supposing the friction of point in one of the rectangulars side as SR wanted, the change of rectangle perimeter by supposing the extension of the length and width of the rectangle, and the total length of all the sides of the square after length, width, and height of the square that is extended just like in general. While the second idea is three of it is assumed using equation. At relate stage, SR connected the ideas that contrast with the knowledge SR had that related to some material in mathematics. At explore stage, SR created a model that appropriate to the problems SR faced and describes the similarities of two ideas that SR found. At analyze stage, SR reexplained the steps SR did in finding the difference between two rectangular perimeter, the changing of rectangle perimeter, and the total length of all sides of the square that is assumed using some equation and redescribe the similarities of two ideas that he found. At transform stage, SR concluded the difference magnitude between two rectangles after point in one of the rectangulars side is shifted to the left or right, the perimeter changing of rectangle, and the total length of all the sides of the square appropriately. At this stage of experience, SR could apply the results obtained to resolve the problems faced. At connect stage, SI connected two different ideas. SI had two different ideas. The first idea is to calculate the difference between the two rectangular perimeter before point in one of the rectangulars side is shifted, the changes of rectangle perimeter by letting addition of the length and width of the rectangle, and the total length of all sides of square before the length, width, and height of the square was changed. While the second idea is to assume them as x equation. At relate stage, SI associated different ideas with the knowledge that SI had. SI connected with some materials that SI had learned in mathematics. At explore stage, SI made the model appropriate to the problems SI faced, but SI could not describe the similarity of the two ideas that SI found. At analyze stage, SI reexplained the steps which SI had done before and can not describe the similarities of the two ideas that SI found. At transform stage, SI summed up the magnitude both of rectangles perimeter after point in one of the rectangulars side is shifted to the left or right, the perimeter changing of rectangle, and the total length of all the sides square appropriately. At experience stage, SI could apply the results obtained to resolve the problems faced.

Background Cellular immunotherapies represent an enormously promising strategy for relapsed/refractory multiple myeloma (RRMM). Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in early-phase clinical studies. Here, we summarize the current body of evidence on the role of anti-BCMA CAR T cell therapy for RRMM. Methods We performed a systematic literature review to identify all publicly available prospective studies. We searched Medline, Cochrane trials registry, and www.clinicaltrials.gov. To include the most recent evidence, meeting abstracts from international hematology congresses were added. A conventional meta-analysis was conducted using meta and metafor packages in R statistical software. Pooled event rates and 95% confidence intervals (CIs) were calculated using the inverse variance method within a random-effects framework. Main efficacy outcomes were overall response, complete response (CR), and minimal residual disease (MRD). Furthermore, relapse rates, progression-free survival, and overall survival were evaluated. In terms of safety, outcomes were cytokine release syndrome (CRS), neurotoxicity, and hematologic toxic effects. Results Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included in quantitative analyses. Patients received a median of seven prior treatment lines (such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, stem cell transplantation) which included autologous stem cell transplantation in 90% of patients. The median age of patients was 59 years and median follow-up duration ranged from 1.1 to 11.3 months. Most studies used 4-1BB (or CD137), a member of the TNF receptor superfamily, as an activation-induced T-cell costimulatory molecule. Most studies used fludarabine and cyclophosphamide for lymphodepletion while one study used busulfan and cyclophosphamide and one study used cyclophosphamide only. Most studies used the former Lee criteria for CRS grading. Anti-BCMA CAR T cells resulted in a pooled overall response of 82% (95% CI, 74-88%). The pooled proportion of CR in all evaluable patients was 36% (95% CI, 24-50%). Within responders, the pooled proportion of MRD negativity was 77% (95% CI, 67-85%). Higher dose levels of infused CAR+ cells were associated with higher overall response rates resulting in a pooled proportion of 88% (95% CI, 78-94%). In addition, peak CAR T cell expansion appeared to be associated with responses.The presence of high-risk cytogenetics appeared to be associated with lower overall response rates resulting in a pooled proportion of 68% (95% CI, 47-83%). The presence of extramedullary disease at time of infusion did not influence outcome and was associated with similar response rates compared with RRMM patients who did not have extramedullary disease, resulting in a pooled proportion of 78% (95% CI, 47-93%). The pooled relapse rate of all responders was 45% (95% CI, 27-64%) and the median progression-free survival was 10 months. In terms of overall survival, pooled survival rates were 84% (95% CI, 60-95%) at last follow-up (median, 11 months). In terms of safety, the pooled proportion of CRS of any grade was 69% (95% CI, 51-83%). Notably, the pooled proportions of CRS grades 3-4 and neurotoxicity were 15% (95% CI, 10-23%) and 18% (95% CI, 10-31%). Peak CAR T cell expansion appeared to be more likely in the setting of more severe CRS in three studies. Most hematologic toxic effects of grade 3 or higher were neutropenia (85%), thrombocytopenia (70%), and leukopenia (60%). Conclusion Anti-BCMA CAR T cells showed high response rates, even in high-risk features such as high-risk cytogenetics and extramedullary disease at time of CAR T cell infusion. Toxicity was manageable across all early-phase studies. However, almost half of the patients who achieved a response eventually relapsed. Larger studies with longer follow-up evaluating the association of response and survival are needed. Disclosures Ayuk: Novartis: Honoraria, Other: Advisory Board, Research Funding. Kroeger:Medac: Honoraria; Sanofi-Aventis: Honoraria; Neovii: Honoraria, Research Funding; Riemser: Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding.

Lifelong maintenance of the blood system requires the preservation of a healthy hematopoietic stem cell (HSC) pool. Integrity of the HSC compartment is disrupted by severe homeostatic perturbations following acute infection or irradiation, which result in HSC loss and lead to dramatic hematological dysfunctions. HSC fitness is also affected by organismal patho-physiological conditions, which are associated with chronic low-grade stress. These chronic conditions present, over time, a unique challenge to the maintenance of the long-lived HSCs. However, the mechanisms by which the HSC pool adapts to chronic, low-grade stress conditions remain largely unknown. We focus on obesity as a model of chronic stress that potentially affects the health of the HSC compartment. Obesity is a chronic pathological state, which is established and persists over long period of time and therefore, is a prime candidate to alter long-lived HSCs. Obesity becomes progressively associated with an array of systemic and local alterations that include metabolic dysregulations, unresolved low-grade inflammation andalteration of BM microenvironment, all conditions that have been linked to HSC defects (Nagareddy et al, Cell Metabol., 2013; Naveiras et al, Nature, 2009; Luo et al, Cell Metabol., 2015; Ambrosi et al, Cell Stem Cell, 2017).Consistent with these studies, we recently showed that obesity alters the composition of the HSC-SLAM (Lin- ckit+ Sca1+ CD48+ CD150-) compartment and leads to a progressive loss of HSC fitness upon serial competitive transplantation assays (Lee et al, J. Exp. Med.,2018). Mechanistically, we established that the oxidative stress induced by obesity dysregulates the expression of the transcription factor Gfi1 and contributes to the long-term alteration of the HSC functions. Following this work, we confirmed that obesity mainly affects the short and long-term stress response of the most primitive HSC compartment (defined as HSC-SLAM CD34- CD49b-) but not of the downstream short-term HSC subsets, therefore indicating that obesitydisrupts intrinsic mechanisms regulating self-renewal activity. Genome-wide gene expression analyses indicated that HSCs isolated from obese mice dysregulate multiples genes involved in the phosphatidylinositol signaling pathway (e.g. Pik3c2a, Pik3c2b, Pi3kap1, Pi3kip1), upstream of the Akt signaling molecule. Phospho-flow cytometry analyses showed that HSCs freshly isolated from obese mice display constitutive Akt activation. In vivopharmacological Akt inhibition did not significantly change the size or phenotype of the HSC-SLAM compartment in obesity but led to the normalization of their functions in condition of transplantation-induced regenerative stress. These results indicate that the aberrant Akt activation in obesity-primed HSCs directly contributes to their hyperactivity upon transplantation, which ultimately results in the erosion of their self-renewal potential. We next explored the mechanisms that allow HSCs to remain quiescent in obesity despite the constitutive activation of Akt and the continued presence of oxidative stress condition. We focused on FoxO3, which is a key transcriptional regulator of HSC quiescence and direct Akt target. We found that FoxO3 in obesity-primed HSCs become insensitive to its normal upstream regulators such as Akt and p38, leading to the maintenance of its nuclear location in oxidative stress condition. As consequence, we observed that obesity-primed HSCs were more resistant to oxidative stress than their normal counterparts, suggesting an increase protection against ROS-mediated senescence and apoptosis. Altogether, these results suggest that chronic metabolic stresses associated with obesity progressively affect the wiring of the HSCs and modify their oxidative stress response. The uncoupling of FoxO3 to its environmental regulators in obesity could be viewed as a key adaptive strategy to ensure the survival and function of the HSC compartment in condition of chronic metabolic stress. More broadly, these results highlight how patho-physiological conditions associated with chronic low-grade stress (such as obesity) could shape the characteristic of the HSC compartment at steady state. Progressive alteration of the normal HSC stress response in such conditions could be an unrecognized contributing factor for the development of hematological diseases. Disclosures Cancelas: Cerus Co.: Research Funding; TerumoBCT: Consultancy, Research Funding; Macopharma Inc: Research Funding; Cytosorbents: Research Funding; Cellphire: Research Funding; Velico: Consultancy, Research Funding; Fresenius-Kabi: Research Funding; Hemanext: Consultancy, Research Funding.

Abstract To date, whole genome and exome sequencing studies of follicular lymphoma (FL) have primarily focused on identification of small site mutations that are recurrent in FL tumorigenesis or involved in tumor clonal evolution. A comprehensive genomic and transcriptomic survey of various mutation types including large structural variants (SVs) in FL cases with detailed clinical annotations and long-term follow-up has not been accomplished. To gain insight into genetic biomarkers that may predict clinical features, we performed exome and whole genome mate-pair sequencing of fresh frozen tumor and paired peripheral blood DNAs, and transcriptome sequencing of tumor RNAs, from 8 FL patients. The patients we selected were either below the median age of FL onset (n=7, median 54.5 yrs) or had a family history of lymphoma (n=1). These patients were clinically diverse, and included patients who had Grade 1 or 2 disease (n=4), classified as “indolent”; and patients with Grade 3a disease (n=2) or who subsequently had pathologic transformation (n=2), classified as “aggressive”. The coding regions of the genome (exome) were captured using Agilent SureSelect Target Capture Kit V2.0, and sequenced at 100-bp paired-end. The single nucleotide variants (SNVs) and small insertions and deletions (INDELs) were called using The Genome Analysis Toolkit (GATK), and the exon level copy number variants (CNVs) we identified using patternCNV. The whole-genome mate-pair libraries of both normal and tumor DNAs with 3kb insert sizes were sequenced paired end at 50-bp. The large SVs of CNVs, large INDELs, translocations, and inversions were identified using the SnowShoes-SV algorithm. The RNA sequencing libraries of 8 FL tumors were constructed using Illumina TruSeq protocol, and sequenced at 50-bp paired end. The RNA-Seq data were analyzed using TopHat and the fusion transcripts were identified using SnowShoes-FTD. Our analysis of SNVs and INDELs revealed mutations in previously reported genes including MLL2, CREBBP, TNFRSF14, and histone cluster genes (HIST1H2AM, HIST1H2BD). In addition, we identified novel recurrent mutations in cysteine-rich PAK1 inhibitor (CRIPAK) in 25% of the tumors. In a secondary analysis performed by Sanger sequencing or re-analysis of publically available RNA sequencing data, we identified CRIPAK mutations in 44% of FL (n=32) and 28% of DLBCL tumors (n=102). Bioinformatics analysis shows that the coding region of CRIPAK is highly enriched with the protein functional domain, post-SET, which is usually found in histone lysine methyltransferases (HMTase) genes including MLL2 and EZH2 that are known to be important in lymphomagenesis. Interestingly, CRIPAK is part of the same regulatory network consisted of previously identified lymphoma genes including MLL2, EZH2, CREBBP, and EP300, according to the shortest path algorithm by MetaCore (Philadelphia, Pennsylvania). Recurrent SVs identified in the FL tumors included the well-known IGH-BCL2 translocation, or t(14;18), in 6 out of 8 cases (75%) and the chr1q amplifications in 4 out of 8 (50%) tumors. Other non-recurrent large CNVs involving entire chromosomes or chromosome arms, as well as other inter- and intra-chromosomal structural variants were detected in individual tumors. In addition, we identified and validated 6 fusion transcripts from the transcriptome sequencing data in 3 out of 8 cases (38%). While our sample size is small, we found that SNVs and INDELs in MLL2, CREBBP, TNFRSF14, CRIPAK, and histone cluster genes, as well as t(14;18), did not distinguish indolent or aggressive tumors. However, all aggressive (4/4, 100%) and none of the indolent tumors had gains in chr1q; and the presence of RNA fusion transcripts were observed in aggressive tumors only (3/4, 75%). Additionally, we found that aggressive tumors had higher numbers of genes with point mutations (SNVs and short INDELs) (40 ± 7.6 vs. 26 ± 2.6; aggressive vs. indolent), higher numbers of genes impacted by copy number aberrations (1060 ± 263.7 vs. 233 ± 133.9), and higher numbers of large SVs (24 ± 10 vs. 6 ± 1.6). Taken together, our comprehensive analysis of 8 FL tumors reveals genetic diversity among newly diagnosed FL patients, identifies novel and recurrent mutations in CRIPAK, and finds that high tumor complexity and DNA instability may be indicators of aggressive disease. Disclosures No relevant conflicts of interest to declare.

Die idee van die tempelmotief is my fokuspunt in hierdie artikel en daarom gaan ek teoretiseer oor die retoriese vraag waarmee die apostel Paulus die gemeente in Korinte konfronteer: Ouk oidate hoti naos theou este kai to pneuma tou theou en humin oikei? [Weet julle nie dat julle ’n tempel van God is en die Gees van God in julle woon nie?] (1 Kor. 3:16). Het hierdie vraag enige etiese implikasies vir die gemeente in Korinte ingehou en het dit nog enige hermeneutiese waarde vir die geloofsgemeenskap in die postmoderne leefwêreld waarin hulle hulself bevind?The metaphor ‘you are the temple of God’ as an ethical core moment in a postmodern world. The idea of the temple motif is my focal point in this article, and therefore, I am going to theorise on the rhetorical question asked by Paul in his first letter to the Corinthians: Ouk oidate hoti naos theou este kai to pneuma tou theou en humin oikei? [Do you not know that you are God’s temple and that God’s Spirit dwells in you?] (1 Cor 3:16). Did this question hold any ethical implications for that congregation, and does it still have any hermeneutical value for the faithful community in the postmodern milieu in which they find themselves today?