bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival Difference in Multiple Myeloma By Place of Birth
Authors: Khanal Bindu Raj , Nepal Barsha , Ghimire Krishna B 
Published: October 2019

Abstract
Introduction:
Multiple Myeloma (MM) survival has improved in last decade with better understanding of disease process and use of novel agents. There is limited data if there is survival difference in MM by place of birth. We choose United States and South Asian Association for Regional Cooperation (SAARC) countries to see if there any difference in survival among these two geographical regions. SAARC consists of 8 south Asian countries: Afghanistan, Bangladesh, Bhutan, India, Sri Lanka, Nepal, Maldives and Pakistan.
Methods:
We analyzed Surveillance Epidemiology and End Results (SEER), SEER 18 registry to compare relative survival (RS) of US born and SAARC countries born MM patients, who were diagnosed with MM during (1973-2011). We analyzed RS during three eras: pre transplant era (1973-1995), transplant era (1996-2002) and era of novel agents (2003-2011) by age (≤65 and >65 years) and sex. We used SEER*Stat software to calculate Z value.
Results:
There were 228 SAARC born and 42,629 US born MM patients diagnosed during (1973-2011). Median age of diagnosis for SAARC countries born MM patients was 64 years (range: 27-88) and 82 of them were female. Median age of diagnosis for US born MM patients was 68 years (range: 18-99) and 19,385 of them were female.
There was no significant difference in RS between SAARC born and US born MM patients during pre-transplant and transplant eras. In the era of novel agents, RS of SAARC born MM patients was significantly higher compared to US born MM patients (64±5.1% vs 47.6±0.5%, Z value 3.4) at 3 years and (47.6±6.2% vs 32.2±0.5%; Z value 3.3) at 5 years.
Analysis by sex showed, both male and female SAARC born MM patients had higher RS compared to US born MM patients at 3 and 5 years during era of novel agents.
Similarly, younger (≤65 years) SAARC born MM patients had significantly better survival than US born MM patients at 3 and 5 years. Older (>65 years) SAARC born MM patients also had significantly better survival at 3 years but there was no significant difference at 5 years.
Conclusions:
Our study showed that there is survival difference Multiple Myeloma patients by place of birth. MM patients born is SAARC countries have better survival than patients born in US. It could possibly be related to difference in disease biology, socioeconomic status and access to health care. We need more studies in future to confirm these findings and individualise treatment plan.

Disclosures
No relevant conflicts of interest to declare.
Incidence and Outcomes of Pediatric Myelodysplastic Syndrome in the US
Authors: Xavier Ana , Kutny Matthew A. , Costa Luciano J 
Published: October 2019

Background
There is lack of epidemiological data on pediatric myelodysplastic syndrome (p-MDS) in the literature. MDS became reportable to the Surveillance, Epidemiology and End Results (SEER) Program in 2001, providing an opportunity to estimate the incidence and survival of pediatric patients with MDS in the United States.
Methods
We utilized data from the National Cancer Institute SEER-18 to determine the incidence and long term overall survival (OS) of pediatric patients (ages 0 to 20 years) diagnosed with de novo MDS or therapy-related MDS. Inclusion criteria was diagnosis of MDS (International Classification of Diseases-Oncology, Third Edition, ICD-O-4 codes 9980/3, 9991/3, 9992/3, 9982/3, 9985/3, 9983/3, 9986/3, 9986/3, 9989/3, 9985/3, 9975/3, and 9987/3) between 2001 and 2011. Follow up was updated through the end of 2011 (November 2013 submission). Overall survival was estimated using the method of Kaplan-Meier. A Cox proportional hazard model was used to compare the effects of age, race, gender, histological subtype, and etiology (de novovs. therapy-related) on survival.
Results
The incidence of p-MDS was 1.16 cases/1 million population*year. A greater incidence occurred in children younger than 1 year of age possibly reflecting congenital bone marrow failure syndromes (Figure 1). A total of 314 p-MDS cases were included in the analysis with median follow up of 31 months (range 0-131). Median age of patients was 9 years; 167 (53.3%) had MDS unclassifiable (NOS), 40 (12.7%) had therapy-related MDS (t-MDS), 44 (14%) had refractory anemia with excess blasts (RAEB), 32 (10.3%) had refractory anemia (RA), 17 (5.4%) had refractory cytopenia with multilineage dysplasia (RCMD), 6 (1.9%) had refractory anemia with ring sideroblasts (RARS), 5 (1.6%) had refractory anemia with excess blasts in transformation (RAEBT), and 3 (0.9%) had MDS associated with isolated del(5q). Male patients comprised 154 (49%) of cases. Racial groups included white (218, 69.4%), 52 (15.7%) black, 37 (11.8%) of other races, and 7 (2.3%) the race was unknown.
The 5 year-OS for the entire cohort was 68% (95% C.I.=62.3-73.7). Patients with t-MDS had significantly worse 5 year-OS (41.2%; 95%C.I.=23.8-58.6) compared to those with de novo MDS (71.3%; 95%C.I.=65.3-77.2; P=0.004, Figure 2). In multivariate analysis of age, race, gender, histological subtype, and etiology (de novovs. therapy-related) utilizing Cox regression model, only t-MDS was associated with higher risk of death (HR=2.07, 95% C.I.=1.25-3.42, P=0.005).
Conclusions
Pediatric MDS is a rare disorder, with higher incidence among children younger than 1 year of age. Over two thirds of p-MDS patients will become long-term survivors, although significantly inferior outcome is seen in t-MDS.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Prevalence and Risk Factors of Complications in Patients with Thalassemia Intermedia
Authors: Tantiworawit Adisak , Winichakoon Poramed , Hantrakool Sasinee , Chai-adisaksopha Chatree , Rattarittamrong Ekarat , Norasetthada Lalita 
Published: October 2019

Abstract
BACKGROUND
Thalassemia intermedia (TI) or Non-transfusion dependent thalassemia (NTDT) is a mild form of thalassemia and does not require regular transfusion. Many complications can be found in this disease and different from thalassemia major(TM). Most studies mainly focus on beta thalassemia and lack of study in alpha group. This study aims to elucidate the prevalence of complications and identify predictive factors affecting complication of both alpha and beta NTDT patients.
METHODS
We retrospectively reviewed NTDT patients who attended our clinic from 1 January 2012 to 31 December 2013. Medical record was reviewed for complication and clinical data.
RESULTS
One hundred NTDT patients were included in this study, female (60%), median age 38 years (19-78). Alpha thalassemia was the majority population (54%). Interestingly, overall complications were found in 83%. The three most common were extramedullary hematopoiesis (47%), cholelithiasis (35%) and abnormal liver function (29%). The others were endocrinopathy (29%), osteoporosis (17%), pulmonary hypertension (14%), cardiomyopathy (11%), thrombosis (4%), and leg ulcer (2%), respectively. The mean ferritin level was 1,563.46 ng/ml. Forty four and seventy six percent of patients had ferritin level more than 2,500 and 800 ng/ ml, respectively.
The significant risk factors affecting complications in extramedullary hematopoiesis were female with odd ratio 2.76 (95% CI 1.046-7.294, p= 0.040) and hemoglobin level below 8 g/dL with odd ratio 3.08 (95% CI 1.113-8.521, p= 0.03) and the significant risk factors affecting complications in osteoporosis were female with odd ratio 7.64 (95% CI 1.514-38.604, p= 0.014) and age more than 40 years with odd ratio 4.66 (95% CI 1.313-16.506, p= 0.017). Iron overload (ferritin > 800 ng/ml) was the only risk factor for abnormal liver function from this study with odd ratio 3.79 (95% CI 1.033-13.919, p= 0.035), but trend to be statistical significant in other complications. Three patients were death and all of them died from sepsis.
CONCLUSION
Alpha thalassemia is the common type of NTDT in our study which is different from previous study. The complication in NTDT is also different from TM. The most common complications were extramedullary hematopoiesis, cholelithiasis and abnormal liver function. The prevalence of iron overload was high in these patients. Thus, regular iron monitoring and early investigation for complication detecting were necessary in this group of patients.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Processing of Neutrophil α-Defensins Does Not Rely on Serine Proteases in Vivo
Authors: Glenthoj Andreas , Nickles Katrin , Cowland Jack B , Borregaard Niels 
Published: October 2019

Abstract
The α-defensins human neutrophil peptides (HNPs) are the predominant antimicrobial peptides of neutrophil granules. They are synthesized in promyelocytes and myelocytes as proHNPs, but only processed and stored as mature HNPs in promyelocytes. Despite decades of search, the mechanisms underlying the posttranslational processing of neutrophil defensins remain unidentified. Thus, neither the enzyme processing proHNPs nor the localization of processing has been identified. It has long been hypothesized that proHNPs are processed by the serine proteases highly expressed in promyelocytes: Neutrophil elastase (NE), cathepsin G (CG), and proteinase 3 (PR3), all of which have shown in vitrocapability to process recombinant proHNP into HNP.
We investigated, whether serine proteases are in fact responsible for proHNP processing in human bone marrow cells and in human and murine myeloid cell lines. Subcellular fractionation of the human promyelocytic cell line PLB-985 demonstrated proHNP processing to commence in fractions containing endoplasmic reticulum. Processing of 35S-proHNP was insensitive to serine protease inhibitors. Simultaneous knockdown of NE, CG, and PR3 did not decrease proHNP processing by primary human neutrophil precursors. Furthermore, introduction of NE, CG, and PR3 into murine promyelocytic cells did not increase processing capability. Finally, two patients suffering from Papillon–Lefèvre syndrome, who lack the ability to activate neutrophil serine proteases, demonstrated normal levels of fully processed HNP in peripheral neutrophils.
Contradicting earlier assumptions, our study found serine proteases dispensable for processing of proHNPs in vivo. This calls for study of other protease classes in the search for the proHNP processing protease(s).

Disclosures
No relevant conflicts of interest to declare.
12-HETrE, a Novel 12-LOX Oxylipin, Prevents Platelet Activation in a Gαs-like Manner
Authors: Yeung Jennifer , Fernandez-Perez Pilar , Vesci Joanne , Holman Theodore R , Ren Jin , Holinstat Michael 
Published: October 2019

Abstract
Platelet-mediated thrombosis is the primary underlying mechanism leading to cardiovascular life-threatening clinical events. Control of excessive platelet responses is an essential aspect of antithrombotic therapy. A number of anti-platelet drugs have been developed to target specific signaling pathways or endpoints involved in platelet activation. Despite the effectiveness of current anti-platelet therapies, uncontrolled thrombosis or bleeding complications still persist. We had proposed a potential novel therapeutic approach by which oxylipins generated by 12-lipoxygenase (12-LOX) oxidation of ω-6 could modulate platelet reactivity. We observed 12-hydroxyeicosatrienoic acid (12-HETrE), a 12-LOX oxidized oxylipin of ω-6 polyunsaturated fatty acid, dihomo-γ-linolenic acid (DGLA), significantly attenuated human platelet activation. We then verified that DGLA oxidation to 12-HETrE depended on functional platelet 12-lipoxygenase (12-LOX) in our transgenic mouse model deficient in 12-LOX enzyme in the platelets (12-LOX-/-). To determine whether 12-HETrE could be inducing its inhibitory regulation in a GPCR-like manner by which it could potentially be behaving similarly to prostacyclin to activate adenylyl cyclase and increase cAMP through the Gs pathway, we measured cAMP level in the presence of 12-HETrE. We observed 12-HETrE significantly increased cAMP levels. We investigated a downstream effector of cAMP, such as VASP 157 phopshorylation, which is a PKA substrate. Also observed both Rap1 and GPIIbIIa activation to be attenuated in the presence 12-HETrE, confirming our aggregation result. This the first study to show the signaling mechanism of 12-HETrE which is dependent on active 12-LOX oxidation of DGLA to regulate platelet reactivity in a Gs-like manner.

Disclosures
No relevant conflicts of interest to declare.
Anti-Factor VIII C1 Domain Antibodies Are Present in the Plasmas of Patients with Hemophilia and Inhibitors
Authors: Batsuli Glaivy , Cox Courtney , Healey John F. , Lollar Pete , Meeks Shannon L 
Published: October 2019

Abstract
Hemophilia A is an X-linked disorder characterized by a deficiency or absence of blood coagulation protein factor VIII (fVIII). Treatment involves replacement of fVIII through infusions for acute bleeding episodes or prevention of bleeding events. Approximately 30% of individuals with severe hemophilia A will develop antibodies to fVIII. Many studies have characterized the antigenic properties of the C2 and A2 domains as these domains are considered the predominant immunogenic domains of the fVIII protein. However, there is increasing evidence that the C1 domain contributes to fVIII function and immune response to fVIII.
Our laboratory has produced and purified a murine IgG2ak anti-human C1 domain monoclonal antibody (MAb), designated 2A9. In this study, we characterized the functional properties of MAb 2A9 using standard coagulation testing including its anti-fVIII inhibitor titer by Bethesda assay and its ability to inhibit fVIII binding to von Willebrand factor (VWF) by competition ELISA. In the Bethesda assay, 2A9 has an inhibitor titer of 97 BU/mg and is a type II inhibitor. In addition, MAb 2A9 inhibits fVIII binding to VWF in an ELISA assay with a 50% inhibitory concentration (IC50) of 1 µg/ml. This is in comparison to the potent high-titer inhibitory anti-C2 MAb I89 (IC50 0.02 µg/ml) and a control non-inhibitory anti-A2 MAb ID4 (IC50 > 10 µg/ml).
We tested 11 plasma samples from patients with congenital hemophilia with inhibitors in the Emory IRB-approved inhibitor bank. The plasma samples have inhibitory titers ranging from 1 - 188 BU/ml with a median inhibitory titer of 54 BU/ml and mean inhibitory titer 59 BU/ml. The plasmas were tested for the presence of antibodies that compete with anti-C1 domain MAb 2A9 using competition ELISA with fVIII as the antigen. Biotinylated MAb 2A9 was serially diluted and the concentration of antibody required to produce an absorbance at 405 nm of 0.3 was compared between control severe hemophilia A plasma and inhibitor plasma samples. Inhibitor plasma samples that reduced the ELISA titer of MAb 2A9 were considered a competitive inhibitor. Of the 11 inhibitor plasma samples, 4 were found to compete with MAb 2A9.
Our study demonstrates that anti-C1 domain antibodies are present in the plasma of patients with hemophilia A and inhibitors. Given the increasing evidence that the C1 domain is important in fVIII function it is likely that these anti-C1 antibodies are clinically relevant. Therefore, domains other than A2 and C2 need to be included in future studies of fVIII B cell epitopes.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Prevalence of Venous and Arterial Thrombosis Among 268 Heterozygous and 111 Homozygous Factor V Leiden Carriers: a Single-Center Cross-Sectional Study
Authors: Perez Botero Juliana , Ormsby Wayne D. , Ashrani Aneel A , McBane Robert D , Wysokinski Waldemar E , Patnaik Mrinal M. , Pruthi Rajiv K , Heit John A. 
Published: October 2019

Abstract
Background: While Factor V Leiden is associated with an increased risk of thrombosis, the magnitude of that risk among homozygous carriers is uncertain.
Methods: In a cross-sectional study of Mayo Clinic patients referred to the Special Coagulation Laboratory for a thrombophilia profile (n=379) over the 18-year period, 1996-2013, the prevalence of venous and arterial thrombosis was estimated for patients found to be Factor V Leiden carriers based on leukocyte genomic DNA genotyping. T tests and chi-square tests were used for continuous and categorical variables, respectively.
Results: Among homozygous (n=111) and heterozygous (n=268) carriers, the mean age at testing (50.3 and 50.5 years, respectively; p=0.9) and the proportion of females (50% and 54%, respectively; p=0.5) did not differ significantly. Of 29 asymptomatic carriers at the time of testing, 14 were homozygotes. Of the remaining 350 carriers, the mean age at first venous or arterial thrombosis (42 vs 43.8 years; p=0.5) among homozygous and heterozygous carriers, respectively, did not differ significantly. Thirty-five (33%) and 83 (31%) homozygous and heterozygous carriers, respectively, had at least one recurrent venous or arterial thrombosis (p=0.72). The prevalence of deep venous thrombosis (DVT) was 61% and 46% in homozygous and heterozygous carriers, respectively (p=0.008); the prevalence of pulmonary embolism was 18% and 20%, respectively (p=0.69). The prevalence of arterial thrombosis (mainly stroke and/or TIA) was higher in heterozygous (23%) compared to homozygous carriers (8%).
Conclusion: In the largest sample of homozygous Factor V Leiden carriers reported to date, thrombosis penetrance and phenotype did not appear to differ among homozygous vs. heterozygous carriers with the exception of a higher prevalence of DVT among homozygous carriers. These data should be interpreted with caution due to the potential for referral bias.

Disclosures
No relevant conflicts of interest to declare.
Calr Mutants Retroviral Mouse Models Lead to a Myeloproliferative Neoplasm Mimicking an Essential Thrombocythemia Progressing to a Myelofibrosis
Authors: Marty Caroline , Harini Nivarthi , Pecquet Christian , Chachoua Ilyas , Gryshkova Vitalina , Villeval Jean-Luc , Constantinescu Stefan N. , Kralovics Robert , Vainchenker William , Plo Isabelle 
Published: October 2019

Abstract
Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocytemia (ET) and Primary Myelofibrosis (PMF). They are malignant homeopathies resulting from the transformation of a multipotent hematopoietic stem cell (HSC). The common mechanism of transformation is the constitutive activation of the cytokine receptor/JAK2 pathway that leads to the myeloproliferation. The acquired point mutation JAK2V617F is the most prevalent (95% of PV and 60% of ET or PMF). In addition, other mutations affecting the same signaling pathway have been described such as JAK2 exon 12 mutations, mutations of MPL affecting W515, and loss-of-function mutations of LNK and also mutations of c-Cbl in 3% of PMF. Recently, whole exome sequencing allowed identifying a new recurrent genetic abnormalities in the exon 9 of the calreticulin gene (CALR) in about 30% of ET and PMF patients. All CALR mutants induce a frameshift of the same alternative reading frame and generate a novel C-terminus tail.
To address the role of these new mutants in the pathophysiology of MPN, the goal of this study was to investigate the effect of the CALR mutant (del52 and ins5) expression by a retroviral mouse modeling.
For that purpose, we transduced bone marrow cells with retrovirus expressing either CALRdel52, CALRins5, CALRWT or CALRDexon9 and performed a transplantation in lethally irradiated recipient mice (10 mice / group), which were then followed over one year.
CALRdel52 expressing mice showed a rapid and strong increased in platelet counts (over 5 x106/mL) without any other changes in blood parameters during 6 months. In contrast, CALRins5 expressing mice presented platelet counts much lower than CALRdel52 but significantly higher than CALRWT or CALRDexon9 expressing mice. After 6 months, CALRdel52 expressing mice showed a decreased in platelets count associated with anemia and development of splenomegaly suggesting the progression to a myelofibrosis. Importantly, the disease was transplantable to secondary recipient for both CALRdel52 and CALRins5 mutants. The bone marrow and spleen were also analyzed over time. We observed a progressive increased in immature progenitors (SLAM cells) as well as a hypersensitivity of the megakaryocytic progenitors (CFU-MK) to thrombopoietin.
Altogether, these results demonstrate that CALR mutants are able and sufficient to induce a thrombocytosis progressing to myelofibrosis in retroviral mouse model, thus mimicking the natural history of MPN patients. It will offer a good in vivo model to investigate therapeutic approaches for CALR-positive MPN.

Disclosures
No relevant conflicts of interest to declare.
Microrna-374b Suppresses Proliferation and Promotes Apoptosis in T-Cell Lymphoblastic Lymphoma By Repressing Wnt-16 and AKT1 and Is a Promising Predictive Biomarker for Patients Survival
Authors: Cai Qingqing , Qian Dong , Chen Kailin , Xie Dan , Rao Huilan , Huang Huiqiang , Sun Xiaofei 
Published: October 2019

Abstract
Background: De-regulation of microRNA (miRNA) has been extensively investigated in both Hodgkin (HL) and non-Hodgkin lymphomas (NHL), however, little is known about the roles of miRNAs in T-cell lymphoblastic lymphoma (T-LBL). To understand the involvement of miRNAs in the development and treatment of (T-LBL), miRNA profiles were compared between tumor and corresponding non-tumor tissues.
Methods: miRCURY LNA array was used to generate miRNA expressing profile. Real-time quantitative PCR and immunohistochemistry (IHC) were applied to detect the expression of miR-374b, AKT1 and Wnt16 in T-LBL samples. Dual-luciferase reporter assay was conducted to confirm target associations of miR-374b. The tumor suppressive effect of miR-374b was determined by both in-vitro and in-vivo studies.
Results: The expression of 380 miRNAs was evaluated in five human T-LBL tissues and correspondence normal peripheral blood T-cells by microRNA microarrays. The down-regulation of miR-374b was frequently detected in primary T-LBL tissues, which was significantly associated with patients worse overall survival (P<0.001) and increasing risk of recurrence (P=0.012). Functional assays demonstrated that miR-374b could suppress T-NHL cells proliferation in vitro and in vivo. Furthermore, miR-374b could also sensitize cells to both serum starvation- and chemotherapeutic agent-induced apoptosis. Significantly, subsequent investigation characterized two AKT pathway associated molecules, AKT1 and Wnt16, as direct targets of miR-374b and account for the effect of miR-374b in T-NHL cells. Consistently, in tissues of our T-LBL patients, AKT1 and Wnt16 expression was inversely correlated with miR-374b levels, and could also be independent predictors of recurrence and survival of these patients.
Conclusions: Our data highlight the molecular etiology and clinical significance of miR-374b in T-LBL. Targeting miR-374b may represent a new therapeutic strategy to improve the therapy effect and survival for T-LBL patients.
Figure 1: Down-regulation of miR-374b is associated with poor prognosis of T-LBL Figure 1:. Down-regulation of miR-374b is associated with poor prognosis of T-LBL
Figure 2: ectopic expression of miR-374b suppress T-NHL cells proliferation and sensitize cells to both serum starvation- and chemotherapeutic agent-induced apoptosis Figure 2:. ectopic expression of miR-374b suppress T-NHL cells proliferation and sensitize cells to both serum starvation- and chemotherapeutic agent-induced apoptosis
Figure 3: Wnt16 and AKT1 are direct targets of miR-374b Figure 3:. Wnt16 and AKT1 are direct targets of miR-374b

Disclosures
No relevant conflicts of interest to declare.