bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon Induction By HbS, SERINC5 Upregulation and Reduction of HIV-1 Nef and AP2 Contribute to HIV-1 Restriction in Sickle Cell Disease
Authors: Kumari Namita , Jerebtsova Marina , Wang Songping , Diaz Sharmin , Nekhai Sergei 
Published: November 2020

Concerted action of numerous positively acting cellular factors is essential for Human immunodeficiency virus type 1 (HIV-1) replication but in turn is challenged by anti-viral restriction factors. Previously we showed that ex vivo one round HIV-1 replication and replication of fully competent T-tropic HIV-1(IIIB) is significantly reduced in peripheral blood mononuclear cells (PBMCs) obtained from patients with Sickle Cell Disease (SCD). Further, we identified and confirmed CDKN1A (p21) and CH25H as host restriction factors expressed in SCD PBMCs that may contribute to the HIV-1 inhibition, in addition to the previously reported SAMHD1 and IKBα. Since CH25H is an interferon stimulated gene (ISG), we analyzed IRFs and interferon expression in SCD PBMCs. Higher levels of IRF7 and IFNβ mRNA were observed in SCD PBMCs compared to controls. We probed further to ascertain if hemin or sickle Hb was responsible for interferon response. We found upregulation of IFNβ in THP-1 - derived macrophages treated with lysates of HbSS RBCs or purified HbS as compared to untreated or HbA treated controls. HbSS RBCs lysates and purified HbS inhibited HIV-1 gag mRNA expression in monocyte-derived macrophages infected with HIV-1(Ba-L). Recent clinical study showed increased levels of CD4 in HIV-1 infected SCD patients in Africa. Thus we analyzed CD4 levels in HIV-1 IIIB infected SCD PBMCs, and found them to be higher compared to controls. Levels of HIV-1 nef mRNA, that controls CD4 expression was lower in HIV-1 IIIB infected SCD PBMCs. As Nef counteracts SERINC3/5 restriction factor, we analyzed its expression as well as the expression of AP2 clathrin adaptor that is required for Nef mediated internalization of CD4. AP2 expression was lower and SERINC5 expression was higher in SCD PBMCs.
CONCLUSIONS: SCD PBMCs could resist HIV-1 infection because of the increased IFNβ production by macrophages exposed to HbSS or sickle cell RBCs. SCD PBMC have increased levels of SERNIC5 and lower levels of HIV-1 Nef and host AP2 expression that, culumlatively, can increased CD4 levels and lead to the overall improved immunological health of SCD patients.
ACKNOWLEDGMENTS: This work was supported by NIH Research Grants (1P50HL118006, 1R01HL125005, 1SC1HL150685, 5U54MD007597, 1UM1AI26617 and P30AI087714). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Disclosures
No relevant conflicts of interest to declare.
Response Adapted Therapy in ETV6/RUNX1-Positive Childhood Acute Lymphoblastic Leukemia Treated per Modified St Jude Total XV Study
Authors: Abu Shanap Mayada , Sultan Iyad , Abu-Ghosh Amal , Hashem Hasan , Tbakhi Abdelghani , Rihani Rawad 
Published: November 2020

Introduction: ETV6-RUNX1 is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a precursor-B phenotype. The presence of ETV6-RUNX1 has been associated with a relatively low rate of relapse in multiple studies. Relapses tend to occur late and have a better salvage rate than other ALL subtypes. Moreover, conflicting data in literature regarding the prognostic significance of ETV6-RUNX1 after accounting for age, initial count and treatment intensity. We sought to study the clinical features, therapy response in newly diagnosed ETV6-RUNX1-positive treated at King Hussein Cancer Center.
Methods: Patients were treated per modified St Jude Total (XV) study, risk stratification was further refined by including minimal residual disease (MRD)measurements on day 15 and day 46 of remission induction therapy. Patients with the ETV6- RUNX1 fusion or hyperdiploidy without CNS or testicular disease and a satisfactory early MRD decline (&lt;1% on day 15 and &lt;0.01% on day 46) were classified as being low-risk for relapse and were treated on lower -risk arm regardless of age and leukocyte count.
Results: Seventy patients (n=70) with ETV6-RUNX1-positive treated at our institution between May 2006 to October 2017. The median age at diagnosis, 5.8 years (range, 1.5-10.8). ETV6-RUNX1 was associated with favorable age between 1- and 6-years in 55 patients (79%), male gender in 41 patients (59%), initial leukocyte count &lt;10 in 39 patients (56%), CNS status 1 in 100% of patients. The majority, n= 58 (83%) of patients had NCI standard risk (SR) and n=12 (17%) had NCI high risk (HR). Sixty-six patients (94%) had MRD &lt;1% at day 15 and all patients achieved remission with MRD&lt;0.01% at day 46 of remission induction. All patients were treated as LR ALL per modified St Jude total XV protocol. At median follow up of (36 months; range, 26 to 154), in the subgroups of ETV6-RUNX1-positive patients classified as NCI standard risk (SR)and NCI high risk (HR) the 5-year EFS estimates were 94.1% ± 3.2 and 82%±1(P=.13), 5-year OS estimates were 100% and 92% ± 8 (p=0.31) respectively.
Conclusion: MRD treatment schema in ETV6/RUNX1 -positive patients have excellent outcomes if they achieved favorable response at day 15 and end of remission induction regardless of the age and Initial leukocyte count. Treatment reduction is feasible and declared safe for children with NCI-HR who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD post remission induction therapy.

Disclosures
No relevant conflicts of interest to declare.
An Essential Role for the RNA Editor-Exonuclease Axis in Terminal Erythroid Differentiation
Authors: Han Areum , Yermalovich Alena V. , Lundin Vanessa , Pearson Daniel S. , Hachimi Mariam , Sousa Patricia , Hilton Brianna , Morse Michael , Atwater John , Zhang Yosra , Hunter Pheobe , Morris Vivian , Osborne Jihan K. , Frame Jenna M. , Jing Ran , Huang Yu Chung , Kubaczka Caroline , North Trista E. , Schlaeger Thorsten , Daley George Q. 
Published: November 2020

Erythropoiesis is an intricate process by which lineage-committed erythroid progenitors become mature red blood cells. Reticulocytes are terminal-staged, immature red blood cells with residual RNA after enucleation. In the absence of pathology, reticulocytes are efficiently processed into mature red blood cells and typically represent a small percentage of cells in human peripheral blood. In contrast, when differentiated in vitro from pluripotent stem cells or CD34+ progenitor cells, red cells tend to arrest at the reticulocyte stage. Recent studies have highlighted that uridylation by Terminal Uridylyl Transferases (TUTases) occurs on a broad spectrum of RNA classes in mammalian cells. Oligo-uridylated RNA is recognized by exoribonucleases and targeted for decay. We posited that the machinery behind RNA degradation that accompanies terminal erythropoiesis might involve RNA tail editors coupled to exonuclease activity. Utilizing constitutional murine knockout models, we observed that blood from the TUTase Zcchc6 RNA editor knockout embryos exhibited reticulocytosis and a terminal maturation defect, as documented by FACS, histology, and hematological profiling. Murine strains deficient in the downstream exonuclease Dis3l2 phenocopied the RNA decay defect of the Zcchc6 KO. Conditional knockout murine models of the TUTase-Dis3l2 axis driven by the red cell specific Erythropoietin Receptor-Cre exhibited comparable phenotypes, suggesting a cell intrinsic and niche-independent role for the TUTase-Dis3l2 axis in promoting red blood cell maturation. We are modulating the expression of this axis by various methods to optimize modeling of hemoglobinopathies such as sickle cell anemia.

Disclosures
No relevant conflicts of interest to declare.
Exploring the Role of a Novel Tumor Suppressor - OSR2 in T-ALL
Authors: Sinha Arpan A. , Andrade Pilar I. , Malone-Perez Megan , Ahmed Syed T , Frazer J. Kimble 
Published: November 2020

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, representing &gt;25% of all cancers in children 0-14 years. Despite major advancements in pediatric ALL treatment, it remains the second most lethal childhood cancer, accounting for ~25% of deaths. The two types of ALL are precursor-B, or B-ALL, and precursor-T, or T-ALL, which have distinct molecular landscapes. Of these types, T-ALL comprises about 15% and 25% of pediatric and adult cases, respectively, and is historically considered more aggressive and treatment-resistant, with an inferior prognosis. In the precision medicine era, it is imperative to identify genetic alterations and aberrant gene expression patterns, to better understand tumor biology and improve treatment outcomes by identifying new therapeutic targets.
Our study investigates a novel transcription factor, odd-skipped related transcription factor 2 (OSR2), which we hypothesize is a putative T-ALL tumor suppressor. We are using a zebrafish T-ALL model expressing transgenic human MYC (hMYC) regulated by a lymphoblast-specific promoter, rag2. Prior work in zebrafish and human T-ALL found low OSR2 levels in ~95% of T-ALL. Based on this, we then used RNA-seq to analyze 10 hMYC zebrafish T-ALL, confirming low-to-absent osr2 in all 10 T-ALL relative to wild-type (WT) T cells. We further confirmed decreased osr2 expression by qRT-PCR of additional T-ALL and WT thymocytes. We hypothesized that if OSR2 suppresses T-ALL, impaired zebrafish Osr2 function might increase T-ALL incidence and shorten latency. To test this, we bred osr2-mutant fish to rag2:hMYC transgenic animals to create three genotypes: heterozygous osr2-mutant (osr2het) fish, heterozygous hMYC (hMYChet) fish, and compound-heterozygote (osr2het;hMYChet) fish. We screened these genotypes for T-ALL incidence by serial fluorescence microscopy, with T-ALL subsequently confirmed by fluorescence-based flow cytometry. By 7 months of age, we found 9/18 (50%) of double-heterozygous fish developed T-ALL, compared to 0/7 hMYChet fish (p = 0.026); osr2het fish also did not develop T-ALL. Together, our findings suggest osr2 allelic loss accelerates MYC-driven T-ALL, supporting our hypothesis that osr2 is a T-ALL tumor suppressor.

Disclosures
No relevant conflicts of interest to declare.
Incidence of Invasive Fungal Infection (IFI) in ACUTE Myeloid Leukemia (AML) on Primary Prophylaxis with Voriconazole in Tertiriary Care Center in Pakistan
Authors: Riaz Shazia , Saeed Maria , Imran Ahmed 
Published: November 2020

OBJECTIVE:
The aim of this study was to establish the incidence of IFI in AML patients receiving voriconazole prophylaxis in developing country.
METHOD:
This prospective study was conducted at The Children's Hospital, Lahore from July 2019 to December 2019 under Prospective AML registry approved by Institutional Review Board. All, consecutive patients of AML, either newly diagnosed or previously diagnosed cases with persistent fever and prolonged neutropenia, were included. Moreover, all patients of AML receiving chemotherapy also received voriconazole prophylaxis. Data of 64 patients was computed in accordance with age, gender, FAB classification, chemotherapy regimen and anti-fungal therapy. EORTC/MSG criteria was used to determine and classify IFI as proven, probable, or possible after performing CT chest and PNS, x-ray PNS, and abdominal ultrasound. CT scan was independently reviewed by a trained radiologist. Data was analyzed by SPSS version 22.
RESULTS:
Total 64 patients of AML were included in the study. The mean age of presentation was 6 years, range 1.5years to 16 years with 45 % males. Out of 64 patients, fungal infection was suspected in 50 patients (78%) due to persistent fever and prolonged neutropenia. In suspected 50 patients, probable and possible fungal infections were found in 22(34.37%) Patients. Eighteen 18/22 (81.81 %) were probable and 4/22 (18.18 %) were possible fungal infection. Majority of the cases 13/22 (59%) patients developed fungal infection during or after course of first induction therapy.
CONCLUSION:
Patients with high-risk hematologic malignancies especially AML are more at risk to develop IFI. In our study despite primary prophylaxis with voriconazole, incidence was higher than that reported in the literature from developed countries. Our data suggests that there is need to further improve supportive care measures and implement IFI preventive measures to decrease the incidence of IFI and improve survival.

Disclosures
No relevant conflicts of interest to declare.
Aberrant Cell Cycle Programming Confers Rapid Lethality in the EuSOX11+ CCND1 MCL Mouse Model
Authors: Edwards Donna R , Kuo Pei-yu , Lagana Alessandro , Park Seongjee , Nedumaran Pavithra , Leshchenko Violetta , Christie Stephanie , Jatiani Shashidhar , Teruya-Feldstein Julie , Parekh Samir 
Published: November 2020

Mantle Cell Lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation. This hallmark oncogenic event transposes CCND1 (11q13) under the control of the immunoglobin heavy chain (IGH) locus (14q32) resulting in constitutive cyclin D1 expression. Although Cyclin D1 (CCND1) overexpression is a key hallmark of MCL, CCND1 overexpressing murine models do not effectively recapitulate the MCL phenotype. Our published data demonstrated that SOX11 binds and regulates components in multiple oncogenic pathways in MCL (Kuo et. al., Oncogene 2015). Furthermore, we recently demonstrated that SOX11 promotes BCR signaling to drive MCL-like pathogenesis utilizing a SOX11 overexpressing (Eu-SOX11) murine model (Kuo et. al., Blood 2018). Given that the majority of classic human MCL co-express CCND1 and SOX11, we hypothesize that these oncogenes may cooperate to drive the pathogenesis of classical MCL.
To study in vivo cooperation between CCND1 and SOX11, we crossed Eu-SOX11 mice with Eu-CCND1 mice to generate Eu-SOX11:CCND1 double transgenic (DT) mice. We have previously reported an significant increase in the fraction of CD5+CD19+CD23- MCL cells in the peripheral blood, spleens, lymph nodes and bone marrow of Eu-SOX11 mice and this fraction was further enhanced in DT mice (Fig.1A). We have now conducted a 2-year survival analysis on all 4 genotypes and found significantly reduced survival in DT as compared to Eu-SOX11 mice (Fig.1B). Median survival in DT mice is 16.5 months as compared to 19.7 months in Eu-SOX11 mice.
Taken together, our results demonstrate a B-cell specific in vivo cooperation between SOX11 and CCND1 towards promoting a lethal MCL phenotype. RNA sequencing of splenocytes from DT versus SOX11-Tg mice showed significant enrichment of E2F1 target genes (p&lt;.02) as a top oncogenic pathway (Fig.1C). Our previous results with CDK4/6 inhibition demonstrate a profound reduction in S phase in MCL cells (Divakar et. al., Leukemia 2016).
We have developed small molecule SOX11 inhibitors using a SOX11-DNA homology model we built using the crystal structure of the SOX4-DNA binding domain as a template. SOX11 small molecular inhibitors in combination with CDK4 inhibitors will be used to further dissect the mechanism of cooperation between SOX11 and CCND1 and develop a therapeutic strategy for MCL that is mechanistically distinct from BTK or Bcl-2 inhibition.

Disclosures
Teruya-Feldstein: Edge Anthem: Consultancy. Parekh:Karyopharm: Research Funding; Celgene: Research Funding; Foundation Medicine: Consultancy.
RNF5 Defines Acute Myeloid Leukemia Growth and Susceptibility to Histone Deacetylase Inhibitors
Authors: Khateb Ali , Deshpande Anagha , Feng Yongmei , Lazar Ikrame , Lee Joo Sang , Fabre Bertrand , Li Yan , Finlay Darren , Fujita Yu , Zhang Tongwu , Pass Ian , Livneh Ido , Burian Carol , Mason James R. , Almog Ronit , Horesh Nurit , Ofran Yishai , Brown Kevin , Vuori Kristiina , Jackson Michael , Ruppin Eytan , Deshpande Aniruddha J. , Ronai Ze'ev A. 
Published: November 2020

Acute myeloid leukemia (AML) remains an incurable blood cancer largely due to rapid emergence of resistance to conventional treatments. Thus, new therapeutic modalities are greatly needed to halt AML development. Here, using genetic and xenograft mouse models, we reveal that inhibition of the ubiquitin ligase RNF5 in human AML cell lines and in MLL-AF9-driven AML severely decreased the leukemogenic potential of those cells and prolonged survival of model leukemic mice. These findings suggest the possibility that targeting a single gene, namely RNF5, could effectively inhibit different AML subtypes. We initially focused on RNF5 as its expression is upregulated in AML patient cohorts as well as in AML-derived cell lines compared with normal hematopoietic cells. Furthermore, high RNF5 expression in AML patient specimens correlated with poor prognosis, relapse and short overall patient survival. By contrast, specimens from AML patients who responded to therapy exhibited low RNF5 levels. In vitro, RNF5 loss impaired the clonogenic potential of MLL-AF9-transduced bone marrow cells and markedly attenuated growth and survival of AML but not CML or T-ALL cell lines, in which RNF5 is also highly expressed. High-throughput screen and bioinformatics analysis identified RNF5 and ER-associated degradation (ERAD) components, as augmenting AML cell sensitivity to histone deacetylase (HDAC) inhibition. Indeed, inhibition of RNF5 sensitized AML cells to HDAC inhibitors. Correspondingly, a favorable prognosis was observed in AML patients exhibiting low expression of RNF5 and HDAC. Collectivity, our studies identify a potential new therapeutic modality based on targeting RNF5 to inhibit AML and suggest that RNF5 expression could serve as a prognostic marker and means to stratify patients for treatment with HDAC inhibitors.

Disclosures
Ofran: AbbVie: Membership on an entity's Board of Directors or advisory committees. Vuori:Bionano Genomics: Membership on an entity's Board of Directors or advisory committees.
Biological interpretation of deep neural network for phenotype prediction based on gene expression
Authors: Hanczar Blaise , Zehraoui Farida , Issa Tina , Arles Mathieu 
Published: November 2020

Abstract

Background
The use of predictive gene signatures to assist clinical decision is becoming more and more important. Deep learning has a huge potential in the prediction of phenotype from gene expression profiles. However, neural networks are viewed as black boxes, where accurate predictions are provided without any explanation. The requirements for these models to become interpretable are increasing, especially in the medical field.

Results
We focus on explaining the predictions of a deep neural network model built from gene expression data. The most important neurons and genes influencing the predictions are identified and linked to biological knowledge. Our experiments on cancer prediction show that: (1) deep learning approach outperforms classical machine learning methods on large training sets; (2) our approach produces interpretations more coherent with biology than the state-of-the-art based approaches; (3) we can provide a comprehensive explanation of the predictions for biologists and physicians.

Conclusion
We propose an original approach for biological interpretation of deep learning models for phenotype prediction from gene expression data. Since the model can find relationships between the phenotype and gene expression, we may assume that there is a link between the identified genes and the phenotype. The interpretation can, therefore, lead to new biological hypotheses to be investigated by biologists.
Hidden paths to endless forms most wonderful: Complexity of bacterial motility shapes diversification of latent phenotypes
Authors: Rendueles Olaya , Velicer Gregory J. 
Published: November 2020

AbstractBackgroundEvolution in one selective environment often latently generates phenotypic change that is manifested only later in different environments, but the complexity of behavior important to fitness in the original environment might influence the character of such latent-phenotype evolution. UsingMyxococcus xanthus,a bacterium possessing two motility systems differing in effectiveness on hard vs. soft surfaces, we test (i) whether and how evolution while swarming on one surface—the selective surface—latently alters motility on the alternative surface type and (ii) whether patterns of such latent-phenotype evolution depend on the complexity of ancestral motility, specific ancestral motility genotypes and/or the selective surface of evolution. We analysze an experiment in which populations established from three ancestral genotypes—one with both motility systems intact and two others with one system debilitated—evolved while swarming across either hard or soft agar in six evolutionary treatments. We then compare motility-phenotype patterns across selective vs. alternative surface types.ResultsLatent motility evolution was pervasive but varied in character as a function of the presence of one or two functional motility systems and, for some individual-treatment comparisons, the specific ancestral genotype and/or selective surface. Swarming rates on alternative vs. selective surfaces were positively correlated generally among populations with one functional motility system but not among those with two. This suggests that opportunities for pleiotropy and epistasis generated by increased genetic complexity underlying behavior can alter the character of latent-phenotype evolution. No tradeoff between motility performance across surface types was detected in the dual-system treatments, even after adaptation on a surface on which one motility system dominates strongly over the other in driving movement, but latent-phenotype evolution was instead idiosyncratic in these treatments. We further find that the magnitude of stochastic diversification at alternative-surface swarming among replicate populations greatly exceeded diversification of selective-surface swarming within some treatments and varied across treatments.ConclusionCollectively, our results suggest that increases in the genetic and mechanistic complexity of behavior can increase the complexity of latent-phenotype evolution outcomes and illustrate that diversification manifested during evolution in one environment can be augmented greatly by diversification of latent phenotypes manifested later.
BrrICE1.1 is associated with putrescine synthesis through regulation of the arginine decarboxylase gene in freezing tolerance of turnip (Brassica rapa var. rapa)
Authors: Yin Xin , Yang Yunqiang , Lv Yanqiu , Li Yan , Yang Danni , Yue Yanling , Yang Yongping 
Published: November 2020

Abstract

Background
In the agricultural areas of Qinghai-Tibet Plateau, temperature varies widely from day to night during the growing season, which makes the extreme temperature become one of the limiting factors of crop yield. Turnip (Brassica rapa var. rapa) is a traditional crop of Tibet grown in the Tibet Plateau, but its molecular and metabolic mechanisms of freezing tolerance are unclear.

Results
Here, based on the changes in transcriptional and metabolic levels of Tibetan turnip under freezing treatment, the expression of the arginine decarboxylase gene BrrADC2.2 exhibited an accumulative pattern in accordance with putrescine content. Moreover, we demonstrated that BrrICE1.1 (Inducer of CBF Expression 1) could directly bind to the BrrADC2.2 promoter, activating BrrADC2.2 to promote the accumulation of putrescine, which was verified by RNAi and overexpression analyses for both BrrADC2.2 and BrrICE1.1 using transgenic hair root. The function of putrescine in turnip was further analyzed by exogenous application putrescine and its inhibitor DL-α-(Difluoromethyl) arginine (DFMA) under freezing tolerance. In addition, the BrrICE1.1 was found to be involved in the ICE1-CBF pathway to increase the freezing stress of turnip.

Conclusions
BrrICE1.1 could bind the promoter of BrrADC2.2 or CBFs to participate in freezing tolerance of turnip by transcriptomics and targeted metabolomics analyses. This study revealed the regulatory network of the freezing tolerance process in turnip and increased our understanding of the plateau crops response to extreme environments in Tibet.