bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunohistochemical Analyses on Angiogenesis in a Porcine Von Willebrand Disease Model
Authors: Von Depka Mario , Allerkamp Hanna , Ekhlasi-Hundrieser Mahnaz , Pfarrer Christiane , Detering Carsten , Lehner Stefanie 
Published: October 2019

Abstract
Objectives: Women with von Willebrand Disease (VWD) type 3 may develop miscarriage during pregnancy. There is evidence that besides its role in coagulation von Willebrand Factor (VWF) is also involved in angiogenesis and defects of this pathway could play a role in miscarriage. For this reason, VWF as well as proteins with known functions in angiogenesis were analysed by immunohistochemistry of several tissues in a pig model comprising all VWD type 3 genotypes (VWD, heterozygous carriers, wildtype).
Methods: Uterus tissue samples including the endometrium were collected from a total of 6 pigs. Of these, two were affected by VWD type 3, two were heterozygous carriers, and the remaining two were wildtype individuals, which served as controls. Hematoxylin-eosin-staining was implemented for morphological evaluation of the tissues, especially with regard to possible differences in structure and pattern of blood vessels. In a second step immunohistochemical analyses comparing the expression of angiogenic factors including VWF were performed in VWD-animals, genetic carriers and wildtype pigs.
Results: Hematoxylin-eosin-staining of histological sections of the porcine uteri comprising the different genotypes revealed differences in the vascular architecture within the lamina propria. Compared to non pregnant wild type pigs where blood vessels in the lamina propria of the endometrium usually are of smaller caliber (mostly categorized as arterioles, venules and capillaries), the lamina propria of VWD type 3 animals contained multiple large arteries and veins (of the type usually found in the uterine wall). The immunohistochemical analysis for VWF showed almost no VWF expression in the pigs affected by VWD. In wildtype and heterozygous pigs, expression was obvious in the endothelium. A narrow band of VWF expression apically on the epithel cells as well as partial expression in glands was seen only in wildtype pigs, but not in heterozygous pigs. For some, but not all further angiogenic factors analysed, expression differences were present among the porcine VWD genotypes.
Conclusion: The results of our study confirm effects of VWF on the uterine vascular architecture and on the expression of specific angiogenic factors. Pigs affected by VWD showed almost no expression of VWF and the blood vessels within the uterine lamina propria had a surprisingly high percentage of large arteries and veins indicating a crucial role of vWF for uterine angiogenesis. Expression differences among the genotypes were obvious for specific angiogenic factors.

Disclosures
Von Depka: Octapharma: Other: Study Investigator, Speakers Bureau.
A MRI Prospective Survey on Heart and Liver Iron and Cardiac Function in Thalassemia Major Patients Treated with Deferasirox Versus Deferiprone and Desferrioxamine in Monotherapy
Authors: Pepe Alessia , Pistoia Laura , Cuccia Liana , Fortini Monica , Caruso Vincenzo , Rosso Rosamaria , Campisi Saveria , Peluso Angelo , Sorrentino Francesco , Maggio Aurelio , Positano Vincenzo , Peritore Giuseppe , Meloni Antonella 
Published: October 2019

Abstract
Background: No prospective data are available about the efficacy of deferasirox versus deferiprone and desferrioxamine in monotherapy. Our study aimed to prospectively assess the efficacy of deferasirox versus deferiprone and desferrioxamine in monotherapy in a large cohort of thalassemia major (TM) patients by quantitative Magnetic Resonance (MR).
Methods: Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we selected those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans. We identified three groups of patients: 235 treated with DFX, 142 with DFP and 162 with DFO. Iron overload was measured by T2* multiecho technique. Liver T2* values were converted into liver iron concentration (LIC) values. Biventricular function parameters were quantitatively evaluated by cine images.
Results: Excellent/good levels of compliance were similar in the DFX (98.7%) vs DFP (96.3%) and DFO (97.5%) groups.
Among the patients with myocardial iron overload at baseline, in all three groups there was a significant improvement in the global heart T2* value (DFX: +4.58±5.91ms P<0.0001, DFP: 8.53±6.97ms P<0.0001 and DFO: +3.93±5.21 ms P<0.0001) and a reduction in the number of pathological segments (DFX: -4.49±4.55 P<0.0001, DFP: -8.08±5.5.84 ms P=0.001 and DFO: -3.65±3.81 ms P<0.0001). In DFP and in DFO groups there was a significant improvement in left ventricular ejection function (LVEF) (+4.86±6.99% P=0.044 and +3.87±7.48% P=0.004, respectively). Only in the DFP group there was a significant improvement in right ventricular ejection function (RVEF) (6.69±4.61% P=0.001). The improvement in the global heart T2* was significantly lower in the DFX versus the DFP group , but it was not significantly different in the DFX versus the DFO group (Figure 1). The improvement in the LVEF was significantly higher in both DFP and DFO groups than in the DFX group while the improvement in the RVEF was significantly higher in the DFP than in DFX group (Figure 2).
Among the patients with hepatic iron at baseline (LIC≥3mg/g dw) the changes were not significantly different in DFX versus the other groups.
Conclusions: Prospectively in a large clinical setting of TM patients, DFX monotherapy was significantly less effective than DFP in improving myocardial siderosis and biventricular function and it was significantly less effective than DFO in improving the LVEF.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..
Overlapping Onset and Sequential Progression of Vasculopathy in Multiple Organs in Sickle Cell Disease
Authors: Chaturvedi Shruti , Ghafuri Djamila , Kassim Adetola A. , DeBaun Michael 
Published: October 2019

Abstract
Background: Sickle cell disease (SCD) is associated with vasculopathy in multiple vital organs, which ultimately leads to complications such as stroke, proliferative retinopathy, chronic kidney disease and pulmonary hypertension. Existing studies focus on single organ specific vasculopathy without an emphasis on shared mechanisms and simultaneous progression of vasculopathy in multiple organs. We conducted this retrospective cohort study to determine the onset and progression, as well as sequence of involvement of vasculopathy in the central nervous system (CNS), eye, kidney and lungs of adults with SCD.
Methods: Our institutional practice is to perform annual magnetic resonance imaging with magnetic resonance angiography (MRI/MRA, for CNS vasculopathy and silent cerebral infarcts), echocardiography (for tricuspidregurgitant jet velocity > 2.5 m/sec, a surrogate of pulmonary hypertension), retinal examination, and measurement of urinaryalbumin:creatinine ratio, and serum creatinine in all adults with SCD. All patients were followed until death or last clinical encounter. Data were summarized as counts and proportions. Multivariable logistic regression was used to identify associations of number of organs affected with mortality.
Results: We identified 280 adults with SCD followed for a median period of 66 months (interquartile range [IQR] 15.7 to 112 months). Median age was 31.1 (IQR 25.4 to 39.7) years and 49.6% were female. Over half (51.8%) were on hydroxyurea therapy. The prevalence of vasculopathy in different organs was: CNS, 37.8%; retinopathy 26.1%, proteinuria, 20.7% (nephropathy 5.71%); and pulmonary hypertension, 15.36%. There was no evidence of vasculopathy in 103 (36.8%) individuals. Of the remaining 177 (63.2%) adults, vasculopathy was present in one, two, three and all four end organs in100, 55, 18, and 4 individuals respectively. Median age of onset was earliest for CNS vasculopathy [25.42 (IQR 19.31, 38.85)] years followed by retinopathy [28.41 (IQR 23.04, 35.79)] years, proteinuria [31.25 (IQR 25.6, 46.0)] years, and pulmonary hypertension [33.08 (IQR 23.83, 47.17)] years (Figure 1). Mortality rate was 1.69 per 100 patient-years. Patients with vasculopathy affecting 3 or 4 organs had a significantly higher mortality rate than those with 0-2 organs affected by vasculopathy [odds ratio 5.50 (95%CI 4.49-20.35), p=0.007], adjusted for phenotype, age, sex, hydroxyurea therapy, and smoking status.
Conclusion: Vasculopathy in SCD occurs in multiple organs simultaneously, with a predisposition to affectthe CNS first. These data strongly support that multiple vasculopathy is common, and when present in at least three organs, is associated with earlier mortality.

Disclosures
No relevant conflicts of interest to declare.
Allosteric Regulation of V(D)J Recombination By Active Chromatin
Authors: Bettridge John T , Na Chan-Hyun , Pandey Akhilesh , Desiderio Stephen 
Published: October 2019

Abstract
V(D)J recombination, the process by which antigen receptor genes are assembled, is implicated in the pathogenesis of lymphoid malignancies. Rearrangement is initiated by the RAG recombinase, a heterotetrameric complex consisting of two subunits each of RAG-1 and RAG-2, which cleaves participating DNA segments at conserved signal sequences. The susceptibility of gene segments to undergo recombination is positively correlated with active chromatin marks, such as tri-methylation of histone H3 at lysine 4 (H3K4me3). RAG-2 interacts directly with H3K4me3 through a plant homeodomain (PHD), and this interaction is required for efficient V(D)J recombination in vivo. Genetic and biochemical evidence suggest that H3K4me3 stimulates substrate binding and DNA cleavage by RAG through an allosteric mechanism. This predicted that H3K4me3 binding induces conformational changes in RAG-2 that are transmitted to RAG-1. To determine whether the conformation of the RAG complex is altered by H3K4me3, we mapped changes in solvent accessibility of cysteine thiols using pulse-alkylation mass spectrometry. Binding of H3K4me3 to the RAG-2 PHD induces conformational changes in RAG-1 within the DNA-binding domains and in the ZnH2 domain, which comprises part of the scaffold for the catalytic center. Our results demonstrate that engagement of the RAG-2 PHD induces dynamic conformational changes in the RAG-1 catalytic subunit, consistent with a model of allosteric control of RAG by active chromatin.

Disclosures
No relevant conflicts of interest to declare.
Yin Yang 1 (YY1) Acting Primarily As an Oncogene and Rarely As a Tumor Suppressor in Distinct Hematological Malignancies: Prognostic and Therapeutic Implications
Authors: Kaufhold Samantha , Wottrich Stephanie , Garban Hermes , Libra Massimo , Bonavida Benjamin 
Published: October 2019

Abstract
Yin Yang 1 (YY1) is a transcription factor that is ubiquitously expressed in many normal and cancerous tissues. This transcription factor was reported to have contradictory functions, consistent with its name, and it was shown to either activate and/or repress several gene products. The role of YY1 in cancer was initially reported to be overexpressed in a large number of solid cancers, and its overexpression was suggested to be of prognostic significance (Shi et al, Curr Cancer Drug Targets 2015;15:145-57). In addition, YY1 was also shown to be a pivotal factor in both drug and immune resistance, as well as it plays an important role in invasion and metastasis (Bonavida and Baritaki, Critical Reviews in Oncogenesis 2011;16:211-226). The reported protein expression and mRNA expressions derived from Oncomine datasets were examined to assess the functions of YY1 in a large number of hematological malignancies (Bonavida and Kaufhold, Pharmacol Ther 2015;150:149-68). However, YY1 expression was not reported in all cancer types. Our preliminary findings suggested that YY1 may act either as an oncogene or as a tumor suppressor in distinct types of hematological malignancies. In multiple myeloma (MM), YY1 protein overexpression was reported and shown to be complexed with the NF-κB subunit RelA. In addition, computational analysis revealed that increased YY1 transcript levels were observed in MM. These findings suggested that YY1 may act as an oncogene in MM, and the supporting data demonstrated that knockdown of YY1 resulted in cell death of MM cell lines. Further bioinformatic analyses showed that YY1 was overexpressed in AML patient-derived tumor tissues. In contrast to AML, bioinformatics analysis revealed that YY1 mRNA was not upregulated in chronic lymphocytic leukemia (CLL) and no significant differences were observed when compared to normal tissues. Clearly, these findings suggested that YY1 may be acting as an oncogene in AML but as a tumor suppressor in CLL. In B-cell non-Hodgkin lymphoma (NHL), the overexpression of YY1 at both mRNA and protein levels suggests its involvement in the malignant transformation. Overall, these data strongly support the notion of the oncogenic role played by the transcription factor YY1 in the majority of hematological malignancies. Accordingly, we suggest that YY1 may have important implications as a therapeutic target and as a prognostic biomarker in hematological malignancies.

Disclosures
No relevant conflicts of interest to declare.
Early Different Downstream Target of Glucocorticoid Receptor Contributing to Glucocorticoids Sensitivity in Kasumi-1 Cells
Authors: Gu Wenbin , Li Meng , Liang Liang , Zhang Jian , Guo Chongye , Xing Zhikai , Lan Yongqing , Li Sha , Li Yangyang , Gao Ran , Mi Shuangli 
Published: October 2019

Abstract
The t(8;21) chromosome translocation frequently occurs in acute myeloid leukemia (AML), resulting in an in-frame fusion between the DNA-binding domain of AML1 and almost the entire of ETO gene. The fusion AML1-ETO protein is thought to play a critical role in the abnormal proliferation and differentiation of myeloid leukemia cells, such as Kasumi-1 and SKNO-1 cells. Glucocorticoids (GC) can induce apoptosis in these cells at low concentrations, whereas most other myeloid leukemia cell lines are resistant to glucocorticoid-induced apoptosis. To experimentally address possible sensitive mechanisms in leukemia cells with AML1-ETO translocation, we generated aGC-resistant Kasumi-1 cell line by induction of 10-6 M dexamethasone (Dex) for three weeks. The IC50 of Dex to cells is increased from 2.5×10-8 M for original GC-sensitive Kasumi-1 cell line ( K-S cell line) to more than 1×10-5 M for induced GC-resistant Kasumi-1 cell line (K-R cell line). Since GC resistance often results from mutations in the glucocorticoid receptor (GR), all the exons of GR gene were sequenced and no mutation was found in K-R cells. Comparing to those in K-S cells, the GR protein level didn't decrease in K-R cells after 2h, 4h, 8h, 12h and 24h exposure to dexamethasone. Given that the difference of direct GR downstream genes between K-S and K-R cells may play a key role in the GC sensitivity, we systematically analyzed the changes of gene expression induced by Dex versus ethanol vehicle for 8h in K-S and K-R cells by high throughput RNA sequencing. The time point of 8h was selected according to the expression peaks of several foregone GR target genes after Dex induction. There were found 32 genes conversely regulated in K-S and K-R cells, including 14 mRNAs and 18 long non-coding RNAs. Pathway analysis indicated that the upregulated genes in K-S cells might promote the AML1-ETO fusion protein degradation by proteasomes, while the component genes of this pathway were downregulated in K-R cells. Further validation and function studies of these mRNAs and long non-coding RNAs are ongoing. Our data suggested that the downstream targets of GR among GC-sensitive and -resistant Kasumi-1 cells were significant different and they may contribute to the GC sensitivity and resistance by degradation or reservation of AML-ETO fusion protein and the regulation of apoptosis in t(8;21) leukemia cell subtype.

Disclosures
No relevant conflicts of interest to declare.
Expression of DDIT4 Is Correlated with NOTCH1 and High Molecular Risk in Acute Myeloid Leukemias
Authors: Pinto Joseph A , Bravo Leny , Chirinos Luis A. , Vigil Carlos E 
Published: October 2019

Abstract
In a meta-analysis, our team identified previously that DDIT4 expression is related with a worse outcome of several cancer types, including acute myeloid leukemia (AML). DDIT4 gene product is a repressor of mTOR activity and recent findings in the triple negative breast cancer model suggest that mTOR pathway inhibition lead to the enrichment of cancer stem cells, explaining indirectly the relationship between DDIT4 and the outcome and suggesting that a high DDIT4 expression could be related with expression of stem-cells markers, such as NOTCH1.
We evaluated 200 AML patients from the TCGA dataset. Clinical features and level 2 data of gene expression were retrieved from the website cbioportal.org for mTOR pathway and stem cell markers including ALDH genes. Gene Set Enrichment Analysis (GSEA) for biological processes was done comparing patients with high risk vs low risk determined by molecular abnormalities.
GSEA analysis found not differences in the mTOR pathway. DDIT4 is not included in none gene ontology datasets. NOTCH1 and DDIT4 expression was enriched in patients with high molecular risk and statistical differences were found mainly between good and poor prognostic groups (score -0.45 and -0.46, respectively). We next compared the correlation between DDIT4 and NOTCH1 in the entire cohort. The correlation was significant (R2=0.121; P<0.0001). NOTCH1 was over expressed in the M0 FAB subtype while the lowest expression was found in M3, M4, M5 and M7 subtypes.
This work shows the relevance of DDIT4 and NOTCH1 in the biology of AML and his association with most undifferentiated subtypes. Association between DDIT4 with NOTCH1 should be evaluated with the intention of explore therapeutic opportunities.

Disclosures
No relevant conflicts of interest to declare.
The Investigation of Hepatitis Virus Infection in Different Subtypes of B-Cell Non Hodgkin Lymphoma in China: High Infection of Both HBV and HCV in Splenic Marginal Lymphoma
Authors: Xiong Wenjie , Yi Shuhua , Li Heng , Li Zengjun , Lv Rui , Liu Wei , Xu Yan , Zou Dehui , Qiu Lugui 
Published: October 2019

Abstract
Background: The hepatitis virus infection is considered as one of the important pathogens in the pathogenesis of lymphomas. But the divergence of hepatitis infection between aggressive and indolent B cell Non-Hodgkin Lymphoma (B-NHL) has rare been investigated and dates for the subtypes of different lymphomas are limited too.
Methods: 733 new diagnosed indolent B-NHL patients and 148 aggressive B-NHL patients from January 1994 to January 2014 at institute of Hematology&Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College were retrospectively investigated. The data of general population were from large scale of national epidemiological survey in China.
Results: Compared with general population, the HCV positive rate was significantly higher in the whole B-NHL group and the indolent group (1.8% vs 0.4%, 1.9% vs 0.4% respectively, both p=0.000). While it had no significant difference in the aggressive group (1.35% vs 0.4%, p=0.068). The HCV-positive patients was similar in the indolent group and the aggressive one (1.9% vs 1.35%, P=0.639). In different indolent subtypes , the HCV-Ab positive rate of CLL、WM、SMZL、HCL, NMZL group was significantly higher than the general population. The HBs-Ag positive rate in the whole B-NHL group and the aggressive group was 9.0% and 14.2% respectively, which was significantly higher than the general population (9.0% vs 7.2%, p=0.044; 14.2% vs 7.2%, p=0.001). While it had no significantly difference between the indolent group and the general population (7.9% vs 7.2%, p=0.548).However, in the indolent B-NHL subtypes, the SMZL group had the highest HBs-Ag positive rate, which was significantly higher than the general population (18.8% vs 7.2%,p=0.002).
Conclusion: The hepatitis virus infection rate varied from different subtypes of lymphoma. In different indolent B-NHL subtypes, SMZL had the highest HBs-Ag and anti-HCV positive rate, which were significantly higher than the general population and other B-NHL. This result may suggest that the infection of hepatitis virus may play an etiologic role in SMZL.

Disclosures
No relevant conflicts of interest to declare.
A Prospective Study of Thyomosin α1 and Intravenous Immunoglobulin Role to Prevent the Infectious Pneumonia Related to Rituximab Based Immuno-Chemotherapy for B Cell Lymphoma
Authors: Lin Tongyu , Prem Raj Shrestha , Huang He , Li Xueying , Hong Huangming , Zhang Mengping , Fang Xiaojie , Wang Zhao , Guo Chengcheng , Xia Zhongjun 
Published: October 2019

Abstract
Background: Rituximab (Rtx) with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) regimen could improve the survivalship in treatment of B cell lymphoma, however, also increases the possibilities of infectious disease including pulmonary pneumonia.
Methods and materials: A prospective study was conducted in Sun Yat-sen University Cancer Center from Feb 2008 to Oct 2015 to analyze the addition of thyomosin (Th α1) and intravenous immunoglobulin (IVIG) supportive therapy impact in preventive role of pulmonary adverse effect (PAE) incidence rate related to Rtx based immuno-chemotherapy.
Results: Out of 379 cases, 215 in Th α1 and IVIG (study) group and 164 in non Th α1 and IVIG (control) group compared; 80 (21.1%) of them developed PAE: 39 Rtx immuno-chemotherapy induced interstitial pulmonary disease (IPD) and 41 infectious pneumonia (IP) cases were developed after the 4rth median cycles (2.8 months) of R-CHOP regimen from the first exposure until prior to induced PAE and 11 cases of IP were isolated with etiology. In comparing the role of Th α1 and IVIG vs. control group; out of 41 R-CHOP induced pneumonia cases: 9 (2.4%) vs. 32 (8.4%) with p <0.001, respectively found. In multivariate analysis, Th α1 and IVIG (p <0.001) was the independent highly significant factors related to decrease infectious pneumonia prevalence rate. Furthermore chemotherapy disruption rate due to pneumonia was 4.2% vs. 38.5%, in study and control group (p = 0.005), respectively. Incidence of pneumonia was found significantly lower in study group than control group in account of high risk advanced stages (Fisher's Exact Test, p <0.001) and age≥60 (Fisher's Exact Test, p = 0.002) group. 6 years of event free survival (EFS) was found higher in study group 73.2% in compare to control group 52.6% with p<0.001.
Conclusions: The B cell lymphoma patients with high risk factors along with the risk of developing infectious pneumonia may be substantially decreased by the regular implication of Th α1 and IVIG along the Rtx based chemotherapy that may result effective in improving EFS too.

Disclosures
No relevant conflicts of interest to declare.