Diagnosis and Prognosis of Overt Disseminated Intravascular Coagulation in a General Hospital: Meaning of the ISTH Score System, Fibrin Monomers, and Lipoprotein-C Reactive Protein Complex Formation

Background: Chronic kidney disease (CKD) is characterized by structural and functional disorder of the kidney with irreversible and gradual characteristics with one of the modalities of renal replacement therapy such as hemodialysis (HD). The role of inflammation in HD patients by uremic toxin and dialysis can be assessed by the marker of High Sensitive C Reactive Protein (HsCRP). Several studies have examined the relationship between HsCRP and red cell distribution width (RDW) in regular HD patients which leads to increase patient morbidity and mortality, but until now, there has been no study in Indonesia regarding the correlation between HsCRP and RDW in regular HD patients. This study aims to determine the correlation HsCRP as a marker of inflammation and RDW values in regular HD patients. Methods: This is a cross-sectional study in Regular HD patients at Dialysis Unit-H. Adam Malik General Hospital. A total of 20 subjects were included. Bivariate and multivariate analysis was conducted to analyze the relationship of HsCRP, ureum, creatinin, hemoglobin, and eGFR to RDW. Results: There were 20 Regular HD patients analyzed. The proportion of patients with increased RDW was 80%. In pearson correlation test, there is a strong correlation between HsCRP and RDW (r= 0.667, p<0.001). Discussion: Majority of regular HD patients at H. Adam Malik General Hospital were assessed with increased RDW. Pearson correlation analysis revealed HsCRP was significantly associated with RDW. Conclusion: Increased RDW was found in 80% of regular HD patients at H. Adam malik General Hospital. From pearson correlation analysis, we found HsCRP was significantly associated with RDW. Keywords: inflammation, high sensitive c reactive protein, red blood cell distribution width, regular hemodialysis.

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Targeting WNT10B-Driven Signalling through Induction of FZD6 By Porcupine Inhibition in T Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-124871 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3956-3956

Author(s):

Adriana Cassaro ◽

Francesca Lazzaroni ◽

Giovanni Grillo ◽

Gianluigi Reda ◽

Roberto Cairoli ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Complex Formation ◽

Wnt Signaling ◽

Protein Complex ◽

Lymphoblastic Leukemia ◽

Protein Complex Formation ◽

Cell Acute Lymphoblastic Leukemia ◽

Short Hairpin ◽

Signaling Activation

Background Wnt/Fzd signaling is known to play a pervasive influence in hematopoietic stem cell maintenance, T-cell development in the thymus and function as well as an important role in T-cell acute lymphoblastic leukemia (T-ALL) establishment. We have previously described a recurrent rearrangement involving the WNT10Blocus (WNT10BR) expressing a transcript variant (WNT10BIVS1) in acute myeloid leukemia. To determine the occurrence of this rearrangement in T-ALL we analyzed retrospectively an italian cohort of patients (n=20) and detected the WNT10BRrearrangement with a high prevalence (14/20). We also confirmed the relevance of these findings to human disease, detecting the molecular circuit triggered by the WNT10B over-expression using the MOLT-4 T-ALL cell model.In this report, we examined the expression of components of the Wnt signaling cascade mediated by WNT10B and the effects of specific gene silencing by short hairpin RNA (shRNA) and exposure to the potent PORCN inhibitor (LGK974), or the TGFbRI inhibitor (A83-01) on the WNT10B-mediated Wnt signaling activation. Methods We used the T-ALL model MOLT-4 cell line to assess the WNT10B/FZD signaling axis driven by WNT10BR. In order to identify interaction between WNT10B and FZD receptors we performed in situ proximity ligation assay (PLA) a method used to visualize protein-protein interactions.MOLT4 cells were infected with WNT10B/WNT10BIVS1-shRNA silencing lentiviral vectors versus empty vector control and treated with increased concentration of LGK974 or A83-01, subsequently the effects of pharmacological inhibition on the WNT10B/FZD interactions and on Wnt effector proteins were evaluated by PLA and expression analyses. Cell proliferation and cell death were measured by EdU assay and Annexin-V/Propidium Iodide (PI) analyses. Results We found that WNT10BRdrives Wnt signaling activity in T-ALL through interaction of WNT10B with FZD6 receptor. The effects of WNT10B/FZD6 interaction on Wnt-mediated signal in MOLT-4 were interfered by short hairpin RNAs (shRNAs)-mediated gene silencing and by small molecules-mediated disruption of Wnt-dependent signaling. We performed WNT10BIVS1knockdown or pharmacological inhibition of WNT10B release by the porcupine (PORCN) inhibitor LGK974 and these in turn progressively down-modulate WNT10B/FZD6 protein complex formation and significantly impairs intracellular effectors and leukemic expansion. Finally, we induced interference to the WNT10B/FZD6 protein complex formation by exposure to the TGFbRI inhibitor A83-01 via inhibiting FZD6 expression, confirming its role in the WNT10B-mediated signaling activation. Conclusion Our study describes the molecular circuit of WNT10BR-mediated activation and highlight a strategy for a major improvement in T-ALL treatment.By altering FZD6-WNT10B complex formation, may provide the basis for therapeutic strategies to eradicate leukemic stem cells in patients selectively deployed depending on the underlying genetics of disease. Disclosures No relevant conflicts of interest to declare.

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