Query: siRNA

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MicroRNA-485 Modulates the TGF- β/ Smads Signaling Pathway in Chronic Asthmatic Mice by Targeting Smurf2
Conclusion: Overexpressed miR-485 inhibits cell proliferation and promotes apoptosis of ASMCs through the Smurf2-mediated TGF- β/Smads signaling pathway in mice with chronic asthma.Cell Physiol Biochem 2018;51:692 –710
Source: Cellular Physiology and Biochemistry - November 21, 2018 Category: Cytology Source Type: research

PLCE1 Promotes the Invasion and Migration of Esophageal Cancer Cells by Up-Regulating the PKC α/NF-κB Pathway.
CONCLUSION: PLCE1 activated NF-κB signaling by up-regulating PKCα, which could promote invasion and migration of esophageal cancer cells. PMID: 30450849 [PubMed - in process]
Source: Yonsei Medical Journal - November 21, 2018 Category: Universities & Medical Training Authors: Li Y, Luan C Tags: Yonsei Med J Source Type: research

German Cockroach Extract Induces Matrix Metalloproteinase-1 Expression, Leading to Tight Junction Disruption in Human Airway Epithelial Cells.
CONCLUSION: GCE treatment increases MMP1 expression, leading to tight junction disruption, which is transcriptionally regulated and influenced by the ERK/MAPK pathway in airway epithelial cells. These findings may contribute to developing novel therapeutic strategies for airway diseases. PMID: 30450857 [PubMed - in process]
Source: Yonsei Medical Journal - November 21, 2018 Category: Universities & Medical Training Authors: Lee KE, Jee HM, Hong JY, Kim MN, Oh MS, Kim YS, Kim KW, Kim KE, Sohn MH Tags: Yonsei Med J Source Type: research

The hierarchical micro-/nanotextured topographies promote the proliferation and angiogenesis-related genes expression in human umbilical vein endothelial cells by initiation of Hedgehog-Gli1 signaling.
This study may contribute to the modification of biomaterial surfaces for better tissue integration and clinical performance. PMID: 30453796 [PubMed - as supplied by publisher]
Source: Artificial Cells, Nanomedicine and Biotechnology - November 21, 2018 Category: Biotechnology Tags: Artif Cells Nanomed Biotechnol Source Type: research

NF- κB p65 Knock-down inhibits TF, PAI-1 and promotes activated protein C production in lipopolysaccharide-stimulated alveolar epithelial cells type II.
CONCLUSIONS: The experimental findings demonstrate that NF-kB signaling pathway is involved in regulating the expressions of coagulation and fibrinolysis factors in LPS-stimulated AECII, which suggest that NF-kB signaling pathway may be a new target to correct intra-alveolar coagulation and fibrinolytic abnormalities in ARDS. PMID: 30449218 [PubMed - as supplied by publisher]
Source: Experimental Lung Research - November 21, 2018 Category: Respiratory Medicine Tags: Exp Lung Res Source Type: research

Loss of KDM6A Confers Drug Resistance in Acute Myeloid Leukemia
In conclusion, our results show that mutations in KDM6A are associated with the outgrowth of drug-resistant clones and highlight KDM6A as a novel biomarker of drug resistance in AML.DisclosuresHiddemann: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Metzeler: Novart...
Source: Blood - November 21, 2018 Category: Hematology Authors: Stief, S. M., Hanneforth, A.-L., Mattes, R., Weser, S., Vick, B., Bartoschek, M. D., Dominguez Moreno, H., Liu, W.-H., Ksienzyk, B., Rothenberg-Thurley, M., Quentmeier, H., Hiddemann, W., Metzeler, K. H., Schotta, G., Bultmann, S., Jeremias, I., Leonhardt Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster III Source Type: research

Matrix Metalloproteinase and Tissue Inhibitor of Metalloproteinases Is Associated with Multiple Myeloma Progression, Prognosis and Extramedullary Plasmacytoma
Conclusions: Our results suggest that TIMP1, 2 and MMP14, 24 were associated with EMP formation. Among those factors, TIMP1 is the one which may play a key role for MM progression and chemo-resistance based on the results revealing its upregulation by antineoplastic agents and association with poor prognosis of MM patients. Our results is consistent with a previous report describing that high serum TIMP1 concentration was associated with poor prognosis of MM. TIMP is recently shown to play another role besides negative regulator for MMP, so further study to elucidate its specific role for chemo-resistance contributes to de...
Source: Blood - November 21, 2018 Category: Hematology Authors: Ishihara, R., Murakami, Y., Homma, K., Watanabe, S., Oda, T., Sunaga, M., Yamane, E., Kobayashi, N., Osaki, Y., Ishizaki, T., Shimizu, H., Iriuchishima, H., Koiso, H., Tsukamoto, N., Yokohama, A., Nanami, G., Ino, R., Saitoh, T., Murakami, H., Handa, H. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster II Source Type: research

Multiple Myeloma Cell-Derived Interleukin-32gamma Increases the Immunosuppressive Function of Macrophages By Promoting Indoleamine 2,3-Dioxygenase (IDO) Expression
Conclusion: Our study showed that MM cell-derived IL-32 induced IDO production in Ms through PR3 and the downstream STAT3 and NF-B pathways, resulting in the suppression of the proliferation and effector function of CD4+ T cells. High IL-32 expression in MM may contribute to an immunosuppressive microenvironment by upregulating IDO production in Ms and promote MM progression.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Yan, H., He, D., Huang, X., Fan, Z. E., Huang, H., Cai, Z. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster II Source Type: research

CIC-Mutation As a Potential Molecular Mechanism of Acquired Resistance to Combined BRAF/MEK Inhibition in CNS Multiple Myeloma
Central nervous system (CNS) involvement is an extremely rare extramedullary multiple myeloma (MM) manifestation, diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases.In June 2017 an 81 years old male with a light chain MM was referred to our institution for an isolated CNS MM relapse. His cerebrospinal fluid (CSF) demonstrated a high load of clonal plasma cells, however, the patient's bone marrow infiltration was very little with a percentage of...
Source: Blood - November 21, 2018 Category: Hematology Authors: Da Via', M. C., Solimando, A. G., Garitano-Trojaola, A., Barrio, S., Rodhes, N., Strifler, S., Teufel, E., Lapa, C., Einsele, H., Beilhack, A., Kortum, K. M. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster II Source Type: research

CLIC1 Cooperates with Integrins to Promote Thrombus Formation and Angiogenesis
Chloride intracellular channel 1 (CLIC1) is a member of a family of six highly homologous membrane proteins (CLIC1-6), which have been shown to be co-regulated with integrins suggesting their involvement in cell adhesion, migration and proliferation. CLIC1 is a metamorphic protein that functions as an oxidoreductase in the cytoplasm as well as an ion channel in the cell membrane. CLIC1 is upregulated in angiogenic endothelial and metastatic tumor cells. In addition, studies in CLIC1 knockout mice have shown that CLIC1 promotes platelet function. Here, we hypothesize that CLIC1 supports cell adhesive functions in platelets ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Knowles, L. M., Ampofo, E., Menger, M. D., Niewald, P., Drawz, A., Eichler, H., Pilch, J. Tags: 301. Vascular Wall Biology, Endothelial Progenitor Cells, and Platelet Adhesion, Activation, and Biochemistry: Poster II Source Type: research

Akt2 Mediates Glucocorticoid Resistance in Acute Lymphoblastic Leukemia through FoxO3a/Bim Axis and Serves As a Direct Target for Resistance Reversal
Conclusions: Akt2 might serve as a more direct and specific kinase mediating GC resistance through FoxO3a/Bim-signaling pathway in ALL, and targeting Akt2 with CCT128930 may be explored as a promising therapeutic strategy for resistance reversal.Figure.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Xie, M., Xie, Y., Yang, A., Ma, J., Wu, M., Jin, Y. Tags: 605. Molecular Pharmacology, Drug Resistance-Lymphoid and Other Diseases: Poster III Source Type: research

MiR-221/222 Promote Dexamethasone Resistance of Multiple Myeloma through Inhibition of Autophagy By Targeting ATG12
In conclusion, our data reveal that upregulation of miR-221/222 promotes Dex resistance of MM cells through inhibition of autophagy by targeting ATG12. Therefore, miR-221/222-ATG12 autophagy-regulatory axis may potentially be applied in glucocorticoid resistance prediction and treatment.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Xu, J., Su, Y., Xu, A., Fan, F., Huang, H., Hu, Y., Sun, C. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research

Silencing Long Non-Coding RNA ST3GAL6-AS1 Inhibits Adhesion and Migration of Myeloma Cells in Vitro
Conclusions: Knockdown of ST3GAL6-AS1 in MM cells significantly inhibits adhesion, migration and invasion in vitro, indicating that ST3GAL6-AS1 may play an important role in the malignant behavior of MM cells. The co-expression between ST3GAL6-AS1 and gene ST3GAL6 has been demonstrated in our previous study, which was further confirmed in present study. Researches are ongoing to address the potential mechanism among them in MM.Figure 1.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Shen, Y., Feng, Y., Chen, H., Jia, Y., Peng, Y., Zhang, R., Yang, Y., Wang, J.-L., Bai, J., Wang, F.-X., Xu, Y., Hu, J., He, A. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research

CD55 and CD59 Can Limit the Anti-Tumor Efficacy of Daratumumab in Natural Killer/T-Cell Lymphoma
In this report we show that subsequent testing in an NKTL mouse xenograft model confirms the potency of Daratumumab in vivo as evidenced by the inhibition in tumour progression and prolongation of mouse survival. When treatment was continued over a month, some tumors began to rapidly enlarge ('Resistant') while the rest remained similar or smaller ('Sensitive') than the tumour volume at the initiation of Daratumumab treatment. An mRNA analysis comparing 'Resistant' and 'Sensitive' tumors showed that while both tumours bore similar levels of CD38 expression, resistant tumours displayed an upregulation of complement inhibito...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mustafa, N., Nee, A. H. F., Chooi, J. Y., Toh, S. H. M., Hee, Y. T., Selvarajan, V., Zhou, L., Yang, J., Chng, W. J. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Poster I Source Type: research

The Role and Mechanism of Upregulation of HO-1 Expression By Activating of Adenosine-2a Receptor in the Tumor Immune Microenvironment with Diffuse Large B-Cell Lymphoma
Conclusion: It is essential for the maintenance and survival of tumor cells in the tumor immune microenvironment. Upregulation of HO-1 by A2aR receptor activation plays an important role in the immune microenvironment of DLBCL tumors.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Wang, C., Wang, J. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Poster II Source Type: research

Blockade of Ubiquitin Receptor PSMD4/Rpn10 Triggers Cytotoxicity and Overcomes Bortezomib-Resistance in Multiple Myeloma
ConclusionOur preclinical data validates targeting 19S proteasome ubiquitin receptor Rpn10 upstream of the proteasome in the ubiquitin proteasomal cascade, and provides the framework for clinical evaluation of Rpn10 inhibitors to overcome PI resistance and improve patient outcome in MM.DisclosuresAnderson: C4 Therapeutics: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder.
Source: Blood - November 21, 2018 Category: Hematology Authors: Song, Y., Ray, A., Chauhan, D., Anderson, K. Tags: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Poster II Source Type: research

Chidamide, a Novel Histone Deacetylase Inhibitor, Inhibits Multiple Myeloma Cells Proliferation through Succinate Dehydrogenase Subunit a
Most patients with multiple myeloma (MM) would finally relapse. Current chemotherapy regimens have limited effect on relapse MM patients. As a new histone deacetylase inhibitor, chidamide has been used in malignancy treatment such as peripheral T-cell lymphoma. However, it is still unknown if chidamide can be used in MM.To determine the target gene of chidamide in MM patients, we performed RNA-Seq analysis using 3 MM patients' bone marrow mononuclear cells. Their BMMCs were cultured with 6μM chidamide or not, and six of the most significantly changed coding genes were selected. Realtime RT-PCR showed that compared with ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Sun, Y., Liu, P., Li, J. Tags: 653. Myeloma: Therapy, excluding Transplantation: Poster I Source Type: research

Targeted Delivery of CpG-Mir-146a Mimic Oligonucleotides As a Therapeutic Strategy to Reduce NF-Kb-Mediated Pathogenic Inflammation and Myeloid Leukemia Progression
NF-kB signaling plays central role in the regulation of immune cell activity. The microRNA-146a-5p (miR-146a) provides negative feedback inhibition of the NF-kB pathway to prevent either excessive immunity, such as cytokine release syndrome. Low expression of miR-146a is also implicated in certain types of leukemia, especially in del(5q)-syndrome myelodysplastic and acute myeloid leukemia (MDS/AML). While miR-146a is a potential therapeutic target, the lack of efficient miRNA delivery methods limits clinical translation. We previously developed a strategy for targeted delivery of oligonucleotide therapeutics, such as siRNA...
Source: Blood - November 21, 2018 Category: Hematology Authors: SU, Y.-L., Zhang, Z., Mann, M., Wang, X., Nguyen, L. X. T., Zhang, B., Li, L., Swiderski, P., Boldin, M., Forman, S. J., Marcucci, G., Kortylewski, M. Tags: 802. Chemical Biology and Experimental Therapeutics: Poster II Source Type: research

PKM2 Mediates Chronic Myeloid Leukemia Imatinib Resistance By Regulating Glycolysis Energy Metabolism
Conclusion: Pyruvate kinase M2 (PKM2) acts as an important rate-limiting enzyme in the aerobic glycolytic pathway, and mediates abnormal metabolic pathways which promote tumor cell proliferation, invasion and drug resistance. Compared to the TKI-sensitive primary cell and cell line, PKM2 was increased in the TKI-resistant primary cell and cell line and related to glycolytic level. PKM2 inhibitor can inhibit CML cells growth, induce cell apoptosis, and combined with IM at a low dose can exhibited a synergistic anti-leukemia effect on TKI-resistant cells. Low dose PKM2 inhibitor combined with IM can enhance targeted killing ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Tong, L., Xu, N., Zhou, X., Huang, J., wan-Er, W., Chen, C., Liang, L., Liu, Q., Xiaoli, L. Tags: 631. Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research

Aurora Kinase a/MDM2-Mediated SETD2 Loss of Function in Chronic Myeloid Leukemia Patients in Blast Crisis Induces Genetic Instability and Can be Therapeutically Targeted
In conclusion, phosphorylation by Aurora Kinase A and ubiquitination by MDM2 contribute to SETD2 non-genomic loss of function in advanced-phase CML. Loss of SETD2/H3K36me3 is associated with increased DNA damage and impaired HR repair. Restoring physiological H3K36me3 levels may help improve the outcome of this critical subset of pts.Acknowledgments: study supported by AIRC (project code 16996) and AIL (Associazione Italiana contro le Leucemia, Linfomi e Mieloma).Figure 1.DisclosuresCastagnetti: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consulta...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mancini, M., De Santis, S., Monaldi, C., Bavaro, L., Martelli, M., Castagnetti, F., Gugliotta, G., Rosti, G., Fontana, M. C., Dan, E., Sinigaglia, B., Iurlo, A., Orofino, N., Abruzzese, E., Salvucci, M., Pregno, P., Gozzini, A., Crugnola, M., Albano, F., Tags: 631. Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research

Novel Insights Into Systemic Iron Regulation
Iron, an essential element in mammals, is absorbed by duodenal enterocytes, enters the circulation through the iron exporter ferroportin, (FPN), circulates bound to transferrin and is uptaken through Transferrin Receptor 1. If in excess, iron is stored in macrophages and hepatocytes and released when needed. To maintain systemic iron homeostasis and to avoid the formation of "non transferrin bound iron" (NTBI), a highly reactive form which causes organ damage, the liver synthetizes hepcidin that, binding FPN, blocks iron export to the circulation. Hepcidin integrates signals from body iron, erythropoiesis and inflammatory ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Silvestri, L., Pagani, A., Nai, A., Camaschella, C. Tags: Swinging the Iron Pendulum: Loss and Gain Through Blood Donation and Transfusion Source Type: research

Ubiquitin-Activating Enzyme E1 Inhibition Caused Acute Leukemia Cell Apoptosis By Affecting CHOP Pathway
Conclusion: The inhibition of UBE1 activity can induce AML cell apoptosis by endoplasmic reticulum stress CHOP pathway. It will provide new clues for the treatment of acute myeloid leukemia.Disclosures: No relevant conflicts of interest to declare.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Bai, J., He, A., Wang, J., Yang, Y., Shen, Y., Feng, Y., Xu, Y. Tags: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II Source Type: research

Development of Liver-Specific Thrombopoietin Targeted Sirnas: Impact on Platelet Count, Megakaryocyte Mass, and Hematopoietic Progenitors in Normal and MPN Murine Models
The Thrombopoietin (THPO)/ thrombopoietin receptor (MPL) signaling axis is not only critical for the generation of platelets and megakaryocytes, but also for the maintenance of hematopoietic stem cells (HSC) and the bone marrow niche. MPL is expressed on primitive HSC, HSC progenitors, megakaryocytes, platelets, osteoblasts and osteoclasts, clonal hematopoietic stem cells and many leukemias. THPO production is constitutive but is also increased by inflammatory cytokines. Sustained exposure to high levels of THPO not only enhances platelet production, but also has a profound effect on HSC and the bone marrow microenvironmen...
Source: Blood - November 21, 2018 Category: Hematology Authors: Desai, D., Borodovsky, A., Davis, W. P., Degaonkar, R., Yucius, K., D'Angelo, K., Gedman, P., Williams, D. M., Rogers, O., Zhao, Z. J., Spivak, J. L., Moliterno, A. R. Tags: 635. Myeloproliferative Syndromes: Basic Science: Poster III Source Type: research

Role of Arsenic Trioxide in EVI-1 Apoptosis in Patients with Acute Myeloid Leukaemia
Conclusion:Our study demonstrated that the apoptotic pathway in THP-1 cells induced by ATO is closely associated with the oncogene EVI-1, the pro-apoptotic protein JNK, p-JNK, p-P53, PUMA, Bax, caspase-9 and caspase-3 (including cleaved caspase-9 and cleaved caspase-3), and the anti-apoptotic proteins Bcl-2 and Bcl-xL. ATO can downregulate EVI-1 mRNA and oncoprotein and block the repression of EVI-1 in the JNK pathway. Furthermore, the activated JNK signalling pathway regulated the expression level of apoptosis-associated proteins, including p-P53, PUMA, Bax, Bcl-xL, Bcl-2, Bax, caspase-9 and caspase-3(Fig 6). These findin...
Source: Blood - November 21, 2018 Category: Hematology Authors: Lang, W., Chen, F., Zhou, L. Tags: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I Source Type: research

MDM2 and Aurora Kinase a Contribute to SETD2 Loss of Function in Advanced Systemic Mastocytosis: Implications for Pathogenesis and Treatment
The SETD2 gene encodes the only methyltransferase responsible for histone H3 lysine 36 trimethylation (H3K36Me3) in humans. H3K36me3 play a key role in preserving the fidelity of transcription elongation and splicing. In addition, SETD2/H3K36me3 have more recently been implicated in the maintenance of genomic integrity by regulating homologous recombination (HR) repair, Mismatch Repair (MMR) mitotic spindle assembly and chromosome segregation. SETD2 deletions and/or inactivating mutations occur in many solid tumors and have recently been found also in acute leukemias. We have reported that the HMC-1.1 and -1.2 mast cell le...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mancini, M., Monaldi, C., De Santis, S., Papayannidis, C., Rondoni, M., Bavaro, L., Martelli, M., Maria Chiara, A., Curti, A., Ficarra, E., Paciello, G., Fontana, M. C., Zanotti, R., Bonifacio, M., Scaffidi, L., Pagano, L., Criscuolo, M., Albano, F., Cice Tags: 635. Myeloproliferative Syndromes: Basic Science: Poster I Source Type: research

RAB31-Mediated Endosomal Trafficking Is Defective in RUNX1 Haplodeficiency
Conclusions: These studies provide the first evidence that RAB31 is a direct transcriptional target of RUNX1 and a mechanism for RAB31 downregulation in RUNX1 haplodeficient patients. Downregulation of RAB31 or RUNX1 results in impaired endosomal maturation/trafficking, and this may contribute to the defective handling of α-granule proteins recognized in patients with RUNX1 mutations.DisclosuresLambert: Sysmex: Consultancy; Rigel: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; Educational Concepts in Medicine: Consultancy; CSL: Consultancy; Novartis: Membership on an entity's...
Source: Blood - November 21, 2018 Category: Hematology Authors: Jalagadugula, G. S., Mao, G., Goldfinger, L. E., Wurtzel, J., Lambert, M. P., Rao, A. K. Tags: 311. Disorders of Platelet Number or Function: New Insights into the Production and Function of Platelets Source Type: research

hnRNP U and DDX47 Are Novel FANCD2 Interactors That May Help to Resolve R-Loops during Mild Replication Stress
Conclusion: We suggest that FANCD2 protects genome stability by recruiting RNA processing enzymes, including hnRNP U or DDX47, to resolve or prevent accumulation of R-loops induced by transcription-replication collisions during mild replication stress. Thus, our study may provide a novel insight to understand the mechanism of bone marrow failure and leukemogenesis in Fanconi anemia patients.DisclosuresTakaori-Kondo: Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Janssen Pharmaceuticals: Honoraria.
Source: Blood - November 21, 2018 Category: Hematology Authors: Okamoto, Y., Abe, M., Itaya, A., Tomida, J., Takaori-Kondo, A., Taoka, M., Isobe, T., Takata, M. Tags: 508. Bone Marrow Failure: Poster I Source Type: research

NCOA4 Mediates Mobilization of Hepatic Iron Stores after Blood Loss
The intracellular protein NCOA4 mediates the autophagic degradation of ferritin in vitro (Mancias et al., Nature 2014; Dowdle et al., Nat Cell Biol 2014); mice with global Ncoa4 disruption show hyperferremia, microcytic anemia, and ferritin accumulation in multiple organs, including liver (Bellelli et al., Cell Rep 2016). Here, we dissect the requirement for NCOA4 in hepatic iron mobilization after acute blood loss, using Ncoa4-targeting siRNA that was conjugated to triantennary N-acetylgalactosamine (GalNAc-Ncoa4 siRNA) to promote uptake by hepatocytes. On experimental day 0, 8-week-old female C57BL/6N mice underwent a si...
Source: Blood - November 21, 2018 Category: Hematology Authors: Li, X., Lozovatsky, L., Liu, D., Ayala-Lopez, N., Finberg, K. E. Tags: 102. Regulation of Iron Metabolism: Poster I Source Type: research

Targeting Oncoprotein Translation with Rocaglates in MYC-Driven Lymphoma
Background: c-MYC (MYC) is commonly dysregulated in aggressive B cell lymphomas. MYC associated lymphoma, especially Double Hit lymphoma (DHL) and Double-Expression Lymphoma (DEL) which are characterized by MYC and BCL2 dual overexpression usually present with the inferior outcome as rapid disease progression and poor response to standard chemotherapy regimen. Nevertheless, MYC is considered as an "undruggable" target and targeting strategies such as suppressing MYC transcription by bromodomain (BRD)-4 inhibitors have been widely investigated in both preclinical models and clinical trials. However, increasing evidence has ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Zhang, X., Bi, C., Lu, T., Yue, T., Zhang, W., Zhang, X., Cheng, W., Tian, T., Lunning, M. A., Vose, J. M., Pelletier, J., Porco, J. A., Tao, J., Fu, K. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Specific Pathway Inhibitors Source Type: research

Exosomes Derived from Cancer Associated Fibroblasts Elicit Survival and Drug Resistance of Primary Lymphoma Cells
ConclusionOur results suggest that CAFs and exosomes secreted from them are involved in the survival and drug resistance of patient lymphoma cells and play a pivotal role in the microenvironment of non-Hodgkin lymphoma. Exosomes would be a novel attractive therapeutic target.DisclosuresKiyoi: Sanofi K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Celgene Corporation: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Chuga...
Source: Blood - November 21, 2018 Category: Hematology Authors: Kunou, S., Shimada, K., Hikita, T., Aoki, T., Sakamoto, A., Hayakawa, F., Oneyama, C., Kiyoi, H. Tags: 622. Lymphoma Biology-Non-Genetic Studies: Poster III Source Type: research

The Abnormal Expression and Mutation of Recombination Signal Binding Protein-Jk Gene Mightbe Contribute to the Proliferation of CD59- Clone in Paroxysmal Nocturnal Hemoglobinuria Patients
Conclusion: High expressed RBPJ was associated with hemolysis index in PNH, and inhibiting it can induced the apoptosis of PNH primary cells in vitro, indicating RBPJ may be involved in the proliferation of PNH clones.Figure.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Fu, R., LI, L., Liu, Z., Liu, H., Wang, H., Chen, Y., Shao, Z. Tags: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Poster III Source Type: research

The Novel Tumor Suppressor SAMHD1 Is Differentially Expressed and Partly Regulated By MYC in Peripheral T-Cell Lymphomas (PTCL)
Conclusions: SAMHD1 is shown for the first time to be differentially expressed among PTCL types and its regulation may involve MYC. Preliminary survival analysis shows no significant associations of SAMHD1 expression with EFS and OS in this cohort of PTCL, however, analysis of a larger PTCL study group is underway to draw definite conclusions.DisclosuresÖsterborg: Gilead: Consultancy, Research Funding; Beigene: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Abbvie: Research Funding.
Source: Blood - November 21, 2018 Category: Hematology Authors: Farrajota Neves Da Silva, P., Tsesmetzis, N., Xagoraris, I., Wasik, A. M., Kokaraki, G., Tzoras, E., Osterborg, A., Sander, B., Herold, N., Rassidakis, G. Tags: 622. Lymphoma Biology-Non-Genetic Studies: Poster III Source Type: research

PIG-a Gene Expression Deficiency Association with Reduced DNA Damage Checkpoint Response and Activation
Conclusion:The above-mentioned results showed that there were decreased expressions of both DNA damage response checkpoint genes and repair genes in both the PIG-A CRISPR knockout leukemia cell lines as well as in the PNH patients. PIG-A mutation is globally associated with reduced DNA damage response capability and increased cellular stability. Our finding explains, at least partially, why PIG-A gene mutation status could be seen as a biomarker of mutagenesis and how PNH cells dominantly expend via clonal escape.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Pu, J. J., Lu, S., Nemesure, M., Teye, E. K., Schleicher, E., Moldovan, G.-L., Brodsky, R. A., Chen, F. Tags: 508. Bone Marrow Failure: Poster III Source Type: research

SAMHD1 Is Variably Expressed in Mantle Cell Lymphoma and Correlated to SOX11 but Not to Survival
ConclusionsIn MCL the expression of SAMHD1 varies over a broad range and correlates to expression of SOX11. However, no significant difference in PFS or OS among patients receiving Ara-C containing induction chemotherapy is found in this study.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Wasik, A. M., Marin, E., Merrien, M., de Matos Rodrigues, J., Lord, M., Xagoraris, I., Christensson, B., Rassidakis, G., Jerkeman, M., Ek, S., Sander, B. Tags: 622. Lymphoma Biology-Non-Genetic Studies: Poster III Source Type: research

HMGB1 Interacts with the MLL-AF4 Fusion Complex to Regulate Pro-Leukemic Gene Transcription in Infant Acute Lymphoblastic Leukemia
In this study, we generated an HMGB1 siRNA knockdown in primary MLL-ALL cells from 3 infants to test our hypothesis that HMGB1-MLL interactions regulate pro-leukemic gene expression and represent a rational therapeutic target.CD19-selected leukemic blasts were isolated from the cryopreserved bone marrow or peripheral blood specimens of 3 infants with cytogenetically confirmed MLL-AF4 rearrangements. HMGB1 knockdown was confirmed by comparing HMGB1 mRNA and protein expression, by qPCR and Western Blot, in cells transfected with HMGB1 vs. control sequence siRNA. First, determined whether HMGB1 knockdown affected expression o...
Source: Blood - November 21, 2018 Category: Hematology Authors: Toia, L. M., Braverman, E. L., Magno, J. A., Shand, J. C. Tags: 602. Disordered Gene Expression in Hematologic Malignancy, including Disordered Epigenetic Regulation: Poster II Source Type: research

Overexpressed Melk Promotes the Stability of EZH2 through Phosphorylation in Natural Killer/T Cell Lymphoma (NKTL)
In this study, we examined EZH2 protein turnover mechanisms in the NKTL context.The serine/threonine kinase Melk is one of the overexpressed genes in NKTL patient samples and cell lines, and the interaction between Melk and EZH2 was established by co-immunoprecipitation. Inhibition of Melk using inhibitor or siRNA both resulted in a decrease of EZH2 protein levels in NKTL cells, whereas there was no change in the mRNA level of EZH2, suggesting that Melk regulated EZH2 at the protein level. Next, we observed a change of EZH2 ubiquitination upon manipulation of Melk expression.Next, in order to confirm that Melk truly affect...
Source: Blood - November 21, 2018 Category: Hematology Authors: Li, B., Kappei, D., Yan, J., Eichhorn, P., Ng, S. B., Chng, W. J. Tags: 622. Lymphoma Biology-Non-Genetic Studies: Poster II Source Type: research

SHP1 Deficiency Is Responsible for the Constitutive Activation of the BCR Pathway in GCB DLBCL
In this study, we investigated whether activation of the BCR pathway in GCB DLBCL is potentially caused by deficiency of the phosphatase SHP1, which is an important negative regulator of the BCR pathway and has been reported to be downregulated in approximately 40% of primary DLBCL tumors. For this purpose, we first correlated SHP1 expression with the presence of phosphorylated SYK and BLNK in the GCB DLBCL cell lines OCI-Ly1, OCI-Ly7, OCI-Ly18, SU-DHL-4, SU-DHL-6, WSU-NHL, SU-DHL-8, Toledo, BJAB, OCI-Ly19, OCI-Ly4, and Farage. Immunoblotting analysis revealed that SHP1 is expressed in SU-DHL-8, Toledo, BJAB, OCI-Ly19, OCI...
Source: Blood - November 21, 2018 Category: Hematology Authors: Sasi, B. K., Turkalj, S., Kalkan, H., Porro, F., Bojnik, E., Pyrzynska, B., Zerrouqi, A., Bobrowicz, M., Winiarska, M., Priebe, V., Bertoni, F., Mansouri, L., Rosenquist, R., Efremov, D. G. Tags: 622. Lymphoma Biology-Non-Genetic Studies: Poster II Source Type: research

Musashi 2 Is Overexpressed in Poor Outcome CLL Patients and Their Proliferative Fraction and Silencing This Gene Induces Apoptosis and Increases Cell Adhesion and Movement
The growth of CLL cells stems from a small fraction of dividing CD5+B cells. The size and rate of growth of this proliferative fraction (PF) correlates directly with poor outcome prognostic markers and inversely with time-to-first-treatment. Furthermore, since dividing cells upregulate DNA mutators (AID and APOBEC), the PF can acquire new DNA abnormalities that can lead to more lethal disease. Hence, cells of the PF are important targets for therapy.By gene expression profile analysis, we found that Musashi 2 (MSI2) is highly expressed in the PF (CXCR4DimCD5Bright) compared with the resting fraction (RF) that expresses the...
Source: Blood - November 21, 2018 Category: Hematology Authors: Palacios, F., Yan, X.-J., Ferrer, G., Barrientos, J. C., Kolitz, J. E., Allen, S. L., Kanti R., R., Chiorazzi, N. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research

SF3B1 Mutations Associate with Low CD20 Expression in CLL: Another NOTCH1-Dependent Mechanism?
ConclusionsIn addition to NOTCH1-mut cases, also CLL cases bearing SF3B1 mutations are characterized by a lower CD20 expression, allegedly through a more active NOTCH1 pathway, potentially resulting in clinical resistance to anti-CD20 monoclonal antibodies.DisclosuresZaja: Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria; Sandoz: Honoraria; Abbvie: Honoraria.
Source: Blood - November 21, 2018 Category: Hematology Authors: Pozzo, F., Bittolo, T., Tissino, E., Vit, F., Vendramini, E., Bomben, R., Zucchetto, A., Dal Bo, M., Laurenti, L., D'Arena, G. F., Di Raimondo, F., Chiarenza, A., Pozzato, G., Zaja, F., Del Poeta, G., Gattei, V. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research

Endogenous STAT3-Activated Wnt5a Provides CLL Cells with Survival Advantage
In conclusion: STAT3 induces the expression of both ROR1 and its ligand Wnt5a. In that way STAT3 activates a micoenvironment-independent pro-survival pathway in CLL cells.DisclosuresBose: Incyte Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corporation: Research Funding. Thompson: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membe...
Source: Blood - November 21, 2018 Category: Hematology Authors: Rozovski, U., Li, P., Harris, D. M., Liu, Z., Jain, P., Ferrajoli, A., Burger, J. A., Bose, P., Thompson, P. A., Jain, N., Wierda, W. G., Keating, M. J., Estrov, Z. E. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research

Wnt5a Induces ROR1 Dependent Tyrosine Phosphorylation of DOCK2, and Enhanced Activation of ERK to Promote Proliferation of CLL Cells
We examined whether the proline-rich-domain (PRD) of ROR1, and SH3-binding motifs with the PRD that were necessary for these effects. We found that PRD and more specifically proline at 808 position of ROR1 was required to enhance phosphorylation of DOCK2 and activation of ERK1/2 over that seen in MEC1 cells lacking ROR1. We also found that inhibition of Rac using a small molecule inhibitor of Rac1/2 could suppress the capacity of Wnt5a to induce activation of ERK, suggesting that Wnt5a induced activation of Rac was required for activation of ERK. Finally, Wnt5a could not enhance the proliferation of CLL cells when treated ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Kipps, T., Rassenti, L. Z., Widhopf II, G. F., Kipps, T. J. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research

Wnt5a Induces Association of ROR1 with Ca2+/Calmodulin-Dependent Protein Kinase II and ROR1-Dependent Calcium Influx in Chronic Lymphocytic Leukemia
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen that is expressed on CLL cells, but not on normal postpartum tissues. We found that ROR1 was a receptor for Wnt5a, which could enhance CLL-cell proliferation (Yu J, et al, JCI 126:585, 2016; Yu J, et al, Leukemia 31:2608, 2017; Hasan MK, et al, Blood 132:170, 2018). We performed mass spectrometry-based proteomics to interrogate immune-precipitates of Wnt5a-activated ROR1 and identified Ca2+/calmodulin-dependent protein kinase II (CaMKII), a serine/threonine-specific protein kinase. Recent studies demonstrated that high levels of different is...
Source: Blood - November 21, 2018 Category: Hematology Authors: Chen, L., Chen, Y., Yu, J., Zhang, L., Rassenti, L. Z., Kipps, T. J. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research

Hemoglobin S Induces Exposure of Red Blood Cell Membrane Skeleton Microdomains Bearing Mannose That Stimulate Phagocytosis By Macrophages: A Molecular Basis for Hemolysis in Sickle Cell Disease but Protection Against Plasmodium Falciparum malaria
Heterozygosity for Hemoglobin (Hb) S, sickle cell trait (SCT), affects over 40 million people and confers resistance to severe infection by Plasmodium falciparum. Homozygosity for HbS, or compound heterozygosity with certain other alleles of Hb, affects over 4 million individuals and causes sickle cell disease (SCD). Hemolytic anaemia is a prominent feature of SCD and is mainly extravascular, mediated by hepatic and splenic macrophages. No ligands for this process have been identified. As many macrophage phagocytic receptors recognise carbohydrates, we surveyed surface glycan expression by sickle cells using a panel of 8 l...
Source: Blood - November 21, 2018 Category: Hematology Authors: Cao, H., Wassall, H. J., Forrester, M. A., Hall, L. S., Wilson, H. M., Shepherd, J., Patel, B., Masson, A., Henderson, S., Konieczny, G., Beverly, M., Tampakis, D., Antonopoulos, A., Haslam, S. M., Dell, A., Rowe, A. J., Brewin, J., Rees, D. C., Barker, R Tags: 113. Hemoglobinopathies, Excluding Thalassemia-Basic and Translational Science: Poster III Source Type: research

Concomitant Targeting of FLT3 and BTK with CG'806 Overcomes FLT3-Inhibitor Resistance through Inhibition of Autophagy
Fms-like tyrosine kinase 3 (FLT3)-targeted therapy represents an important paradigm in the management of patients with highly aggressive FLT3 mutated acute myeloid leukemia (AML). However, clinical efficacy is usually transient and followed by emergence of resistance to FLT3-inhibitors (Borthakur et al., 2011; Cortes et al., 2013; Zhang et al., 2008). Such resistance often results from acquired mutations of TKD, which are frequently identified in D835, Y842 and F691 residues (Smith et al., 2015; Smith et al., 2012; Zhang et al., 2014). It was reported that the FLT3-ITD-targeting drug sorafenib can induce autophagy in human...
Source: Blood - November 21, 2018 Category: Hematology Authors: Zhang, W., Yu, G., Zhang, H., Ly, C., Yuan, B., Ruvolo, V., Piya, S., Bhattacharya, S., Zhang, Q., Borthakur, G., Battula, V. L., Konopleva, M. Y., Rice, W. G., Andreeff, M. Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster II Source Type: research

Endoplasmic Reticulum Stress Signaling Comprises a G9a Inhibitor Tolerance Pathway and PERK Inhibition Increases Anti-Leukemia Activity of G9a Inhibitor in Leukemia Cells and Leukemia Stem-like Cells
Conclusion: These data demonstrated that PERK-eIF2α activation has a pro-survival function to G9a inhibitor in leukemia cells and mediates resistance of AML stem cells to G9a inhibitor treatment. The PERK-eIF2α phosphorylation arm may represent a suitable target for combating resistance to G9a inhibitor in AML. The mechanisms underlying the increased sensitivity of AML cells with PERK inhibition to G9a inhibitor are unclear at present and are needed to define in further studies.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Jang, J., Eom, J.-I., Jeung, H.-k., Seol, S.-Y., Chung, H., Kim, Y. R., Cheong, J.-W., Min, Y. H. Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster I Source Type: research

FoxM1-Mediated Signaling Promotes the Progression of Mantle Cell Lymphoma
ConclusionWe have shown that FoxM1 inhibition may be a potential candidate treatment for MCL based on the results of our clinicopathological assessment and in vivo studies. Therefore, exploring the role of FoxM1 in MCL disease progression and therapeutic resistance may lead to novel therapeutic breakthroughs to improve patient clinical outcomes.DisclosuresWang: MoreHealth: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Kite Pharma: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Guo, H., Yao, Y., Zhang, H., Lorence, E., Ahmed, M., Ping, L., Nomie, K., Zhang, L., Wang, M. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Poster III Source Type: research

FOXM1 and the NPM-ALK/STAT3 Axis Form a Novel Positive Feedback Loop in Promoting the Oncogenesis of ALK-Positive Anaplastic Large Cell Lymphoma
Conclusions:In conclusion, we have identified a novel oncogenic feedback loop involving FOXM1 and the NPM-ALK/STAT3 axis in ALK+ALCL. This study has revealed the first clear example in which NPM-ALK exerts important oncogenic functions in the nuclei of ALK+ALCL cells, by means of its binding to an oncogenic transcription factor so as to promote its DNA binding and transcription activity.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Wang, P., Haque, M., Li, J., Huang, Y.-H., Almowaled, M., Bargar, C., Karpf, A., Chen, W., Turner, S., Lai, R. Tags: 603. Oncogenes and Tumor Suppressors: Poster III Source Type: research

Inhibition of B-Cell Receptor Signaling Disrupts Cell Adhesion in Mantle Cell Lymphoma Via RAC2
Conclusions: Our findings uncover a novel cross-talk between BCR signaling and cell adhesion. Ibrutinib inhibits cell adhesion via down-regulation of RAC2. Our study highlights the importance of RAC2 and cell adhesion in MCL pathogenesis and new drug development.DisclosuresWang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; AstraZeneca: Consultancy, Research Funding; MoreHealth: Consultancy; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding; Dava Oncology: Honoraria; Celgene: Honoraria, Membership on an en...
Source: Blood - November 21, 2018 Category: Hematology Authors: Wang, W., Carrie, F., Guo, H., Lee, J., Li, Y., Sukhanova, M., Sheng, D., Venkataraman, G., Mei, M., Lu, P., Gao, A., Xia, C., Jia, L., Zhang, L., Wang, M., Andrade, J., Xiaoyan, Z., Wang, Y. L. L. Tags: 605. Molecular Pharmacology, Drug Resistance-Lymphoid and Other Diseases: Poster I Source Type: research

JAK-STAT3 Pathway Regulates CD38 Expression on Multiple Myeloma Cells
In this study, we evaluated the impact of bone marrow stromal cells (BMSCs) from MM patients on CD38 expression and anti-CD38 Antibody-induced ADCC.We first cultured MM cells (RPMI8226, MM.1S, MOLP8) with culture supernatant from BMSCs and measured CD38 expression by flow cytometry. A significant reduction of CD38 expression on all MM cell lines was noted in a time-dependent fashion. For example, CD38 expression (mean fluorescence intensity) was reduced 44%, 32%, and 42% on RPMI8226, MM.1S and MOLP8 cells, respectively, after 48 h culture with BMSC supernatants. To identify mediators of this effect, we next examined the ef...
Source: Blood - November 21, 2018 Category: Hematology Authors: Ogiya, D., Liu, J., Ohguchi, H., Tai, Y.-T., Hideshima, T., Anderson, K. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research

Cirmtuzumab Inhibits Non-Canonical Wnt Signaling without Enhancing Canonical Wnt/{beta}-Catenin Signaling in Chronic Lymphocytic Leukemia
In this study, we examined whether genetic silencing of ROR1 or inhibition of ROR1-signaling also could influence canonical Wnt signaling. To inhibit ROR1 signaling we used the humanized anti-ROR1 mAb cirmtuzumab, which is being evaluated in patients with CLL (Choi MY, et al, Cell Stem Cell, 22:951, 2018). Surprisingly, we found that CRISPR/Cas9 deletion of ROR1 in 293T cells also could enhance the capacity of Wnt3a to activate canonical Wnt-signaling, albeit to a lesser extent than CRISPR/Cas9 deletion of ROR2; conversely, re-introduction of ROR1 into ROR1-deleted 293T cells suppressed Wnt3a-induced activation of canonica...
Source: Blood - November 21, 2018 Category: Hematology Authors: Zhang, H., Zhang, S., Ghia, E. M., Choi, M. Y., Zhang, J., Chen, L., Widhopf II, G. F., Rassenti, L. Z., Kipps, T. J. Tags: 605. Molecular Pharmacology, Drug Resistance-Lymphoid and Other Diseases: Poster II Source Type: research