bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genotype in Patients with Thalassemia Major Has No Impact on Risk of Liver Fibrosis
Authors: Al-Khabori Murtadha K. , Daar Shahina , Al-Zedjali Shoaib , Al Omairi Al Ghaliya , Hassan Moez , Al Rahbi Sarah , Ibnouf Abubakr , Al Busaifi Said 
Published: October 2019

Abstract
Introduction and Objectives: Patients with Thalassemia Major (TM) develop various complications related to iron overload and transfusion associated infections. It is unknown as yet if the specific genotype leading to TM has further impact on the development of liver fibrosis. Therefore, we planned to assess the impact of genotypes in patients with TM on the risk of liver fibrosis.
Methods: We included 88 patients with TM with available genotyping data in this study. These patients were followed and transfused in a single tertiary academic center. All those patients had their liver fibrosis assessed by ultrasound elastography (FibroScan device) with a cut off value of 7.8 kPa. The genotyping was done using Amplification Refractory Mutation System (ARMS)-hot start-polymerase chain reaction (PCR) technique. Iron overload was assessed using the average serum ferritin in the 5 years prior to the liver fibrosis assessment. Association was assessed using Chi-squared test and adjustment using multivariable logistic regression.
Results: A total of 88 patients were included with a median age of 27 years (Interquartile range [IQR]: 23-31). Females constituted 54% of patients and 34% of patients were splenectomised. The median alanine transaminase, aspartate transaminase, albumin and total bilirubin were 31 U/L (IQR: 20-58), 30 U/L (IQR: 18-46), 46 g/L (IQR: 43-48) and 23 µmol/L (IQR: 15-34) respectively. The median ferritin and liver iron concentration assessed by MRI T2* were 1472 µg/L (IQR: 741-2760) and 7.0 mg/gdw (IQR: 3.5-15.9) respectively. Thirty seven percent of patients had positive serology for HCV while 1% of patients had positive serology for HBV. The genotypes seen in this study included homozygous IVS-I, 5 (G-C) in 39 patients, homozygous codon 44 (-C) in 19 patients, double heterozygous IVS-I, 5 (G-C)/25 bp deletion in 5 patients and others (≤ 3 patients each) in 25 patients. The proportion of patients with fibrosis was 55%. The proportion of patients with fibrosis in the homozygous IVS-I, 5 (G-C) group was 58% compared to 52% in all other genotypes and the difference was not statistically significant (odds ratio of 1.3 with a p value of 0.6652). The impact of the genotype remained non-significant after adjustment of iron overload in the multivariable logistic regression model. The only statistically significant factor was the iron overload (p values: iron overload 0.006, genotype 0.966).
Conclusion: The risk of liver fibrosis is associated with the iron overload in patients with TM. There is no additional independent impact of the genotype. Further studies with larger sample size to study the impact of various genotypes are required to confirm these results.

Disclosures
No relevant conflicts of interest to declare.
Cardiometabolic and Hemostatic Profiles of Women Carriers of Hemoglobin Variants Using Combined Oral Contraceptives
Authors: Ferreira Junia Raquel Dutra , Guarda Caroline Conceição , Santiago Rayra Pereira , Rocha Luane , Ferreira Jessica SANTOS , Araújo Luís , Mota Barbara , Pitanga Thassila Nogueira , Milena Milena Magalhães , Carvalho Magda Seixas , Adorno Elisangela Vitoria , Goncalves Marilda Souza 
Published: October 2019

Abstract
Introduction: Several studies reported combined contraceptives influence in hemostatic and lipid profile besides the concern about the thromboembolism and cardiovascular risks due to the steroids hormones use. As women with hemoglobin (Hb) variants have a pre-existing inflammatory condition and considering the high frequency of hemoglobin variant worldwide, this study aims to evaluate the association of hematological, lipid, glicemic, inflammatory and hemostatic profiles in women using combined oral contraceptives and carriers of hemoglobin variants.
Methods: We performed a cross-sectional study including 591 women in reproductive-age. We investigated their hemoglobin profile and COCs use. Of them, we included 60 women with HbAA, 21 with HbAC, 25 with HbAS and 7 with HbSC profiles, all of them combined oral contraceptives users. Among those combined oral contraceptives nonusers, 9 were HbAC and 19 HbSC. We evaluated fasting serum glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), C-reactive protein (CRP), fibrinogen, D-dimer and hematological profile among the studied groups. This study was conducted in accordance and approved by the Research Ethics Committee of the Fundação Oswaldo Cruz - FIOCRUZ, Brazil; and also with the Helsinki Declaration of 1975, and its revisions. Mann-Whitney U tests were used to compare two groups of values within the same variable.
Results: We observed significant differences in some hematological and cardiometabolic parameters in women carriers of different Hb variants and using COCs. We found relevant increases in CRP levels in HbSC and HbAC women that seem to be associated with different types of progestins present in combined oral contraceptives formulations. Also, combined oral contraceptives use seems to be associated with decreased HDL-c levels in HbAC women. Otherwise, D-dimer levels were increased in all women with Hb variants, independently of the contraceptive use.
Conclusions: Although combined oral contraceptive remains an important method to prevent unintended pregnancy, our data suggest that contraception in women carriers of Hb variants, including those in heterozygosis, should be carefully evaluated, especially, considering the pre-existent inflammatory and pro-thrombotic conditions that together with combined oral contraceptive use may result in additional health problems, such as cardiovascular and thromboembolic diseases.

Disclosures
No relevant conflicts of interest to declare.
Studies on the Genetic Mutations of Hereditary Fibrinogen Disorder
Authors: Zhou Rong-Fu , Na Zhou , Jian OuYang 
Published: October 2019

Abstract
Hereditary fibrinogen disorder is a rare kind of bleeding disease, which divided into two types. Type I is a kind of quantity disorder, including afibrinogenemia and hypofibrinogenemia. Type II is a kind of quality disorder, including dysfibrinogenemia. Fibrinogen is a kind of hexameric glycoprotein and consists of two pairs of three chains, which are Aα, Bβ and γchain. FGA、FGB and FGG code for the relevant glycoprotein. The mutations on these genes are responsible for this disorder. In this study, the levels of fibrinogen antigen of 12 cases with low fibrinogen activity were firstly detected. The results showed that one case had low level, and the patient definded as hypofibrinogenemia, and other 11 cases had normal level, thus these patients identified as dysfibrinogenemia. All exons and their flanks of FGA , FGB and FGG were amplified by PCR. THe PCR products were sequenced directly and blasted to normal sequence of corresponding gene to find the mutation. The result showed that among 11 cases with dysfibrinogenemia, five harbored Aα Arg16His heterozygous mutation and one of those also possessed a de novo γAsp185Asn heterozygous mutation ; one Aα Arg16Cys heterozygous mutation; four γArg275Cys heterozygous mutation and one γArg275His heterozygous mutation.The patient with hypofibrinogenemia harbored Aα Cys36Arg heterozygous mutation. Endonuclease restriction digestion was performed to exclude genetic polymorphism for the γAsp185Asn mutation. In molecular modeling, the hydrogen bonds were changed in the mutational variant of γ185Asn. Besides, a new site of glycosylation might appear after the mutation, which might lead to destroy the stability of molecular structure. The alignment of homologous sequence between different species suggested that γAsp185 was a highly conservative site. In a word, the above mutations might be the causes of dysfibrinogenemia or hypofibrinogenemia for these patients.

Disclosures
No relevant conflicts of interest to declare.
Incidence of Venous Thromboembolism in Patients with Resected Biliary Tract Cancers
Authors: Meier Anne , Khorana Alok A. , Sohal Davendra P. S. 
Published: October 2019

Abstract
Background:
Venous thromboembolism (VTE) is an important complication of cancer, with adverse impact on morbidity and mortality. In biliary tract cancer (BTC), there is a paucity of data on incidence of VTE and any prognostic markers that may correlate with VTE.
Objectives:
To determine the incidence of VTE events in patients with resected BTC, as well as identify predictors of VTE.
Methods:
We conducted a retrospective cohort study of consecutive patients with BTC undergoing surgical resection with a curative intent at the Cleveland Clinic between 1/1/2006-6/30/2014. Electronic medical records and tumor registry were reviewed for baseline demographic and laboratory data, the incidence of VTE after initial diagnosis, including deep venous thrombosis (DVT) of the extremities, pulmonary emboli (PE), or intra-abdominal thrombi. Rates of VTE are reported.
Results:
The study population comprised 142 patients with a median age of 62 (range 31-84) years; 53% were women. Location of the tumors included extrahepatic (21%), intrahepatic (45%), hilar (9%), and gallbladder (25%). During follow-up, 33 (23.2%) patients had documented VTE. Twenty-five patients had 1 event each, 6 had 2 events each, 1 had 3 events, and 1 patient had 4 events, for a total of 44 events. Of these 44 events, 19 (43.2%) were lower extremity DVTs, 9 (20.4%) were upper extremity DVTs, 7 (16%) were PE, and 9 (20.4%) were visceral (intra-abdominal) thrombi. Four (12.1%) of the 33 patients experienced VTE prior to surgical resection. Univariable analyses did not reveal any association with clinical variables - including age, sex, race, baseline hemoglobin, white blood cell or platelet counts, albumin, location of the tumor, chemotherapy or radiation, and smoking.
Conclusion:
Nearly one in four patients with biliary tract cancers who have undergone surgical resection develop VTE. Larger prospective studies focusing on risk factors and novel biomarkers are warranted.

Disclosures
Khorana: Sanofi: Consultancy, Honoraria; Leo: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding.
Current Management of Blood Donors with Positive Anti-Hbc in Saudi Arabia
Authors: Al-Momen Abdul Kareem M , Alghamdi Essam , Al-Humaidan Hind , Al-Mishari Mai , Suhaibani Omar , Alnowaiser Abdullah 
Published: October 2019

Abstract
Background: Transfusion Services in Saudi Arabia are mainly hospital-based, where each major hospital recruit donors, test for Hepatitis B service antigen (HBs Ag), Hepatitis C antibody (Anti-HCV), Human Immune Deficiency Virus antibody (Anti-HIV), and Nucleic Acid Testing (NAT) for HBV-DNA, HCV-RNA, and HIV-RNA. In addition, Anti-HBc and Anti-HBs titer are tested for those who are negative for HBs Antigen and NAT, so that blood products from donors with high Anti-HBs titer (>100 u/ml) can be used. The aim of this limited retrospective study is to find out the prevalence of Anti-HBc among blood donors in different blood donation centers in Riyadh city, Saudi Arabia and current policies regarding blood utilization from donors with positive Anti-HBc.
Materials and Methods: We reviewed blood donor records in 4 large hospitals in Riyadh between 2011-2015. Hospital names are not disclosed for confidentiality reasons. Instead, they were named A, B, C, and D
Results: (see Table)
1- The overall prevalence of Anti-HBc positive blood donors is 6.2%, however, there is a significant variation among institutions ranging from 2.8 % to 11.1 % (which needs to be investigated to explain reasons for this variation).
2- Some institutions defer all donors with positive anti-HBc (although they carry out all tests), while others carry out anti-HBs and NAT testing and use blood with high titer anti-HBs (> 100 u/ml).
Conclusion: There is a need for an expert consensus opinion regarding the cost-effectiveness of anti-HBc for either donor deferral or proceeding to NAT and anti-HBs titer testing. Such a consensus is practiced in many countries, based on the prevalence of anti-HBc and the availability of NAT testing

Disclosures
No relevant conflicts of interest to declare.
Lpxn Regulates Proliferation, Adhesion and Invasion of Acute Myeloid Leukemic Cells
Authors: Dai Haiping , Zhu Guohua , Shen Qun , Wu Lili , Wang Qian , Wang Qinrong , Wen Lijun , Yao Hong , Qiu Huiying , Chen Suning , Wu Depei 
Published: October 2019

Abstract
Leupaxin (LPXN) belongs to the focal adhesion-associated adaptor protein family, participating in regulating cell adhesion and metastasis. LPXN is a recurrent fusion partner in translocations identified in AML, namely t(11;12) and t(11;21), highlights its potential leukemogenic role in acute myeloid leukemia (AML). However, the precise mechanisms by which LPXN participate in the pathogenesis and progression of AML remains unknown. In the present study, we found that LPXN had a wide expression among a variety of hematological malignancies, including AML. Stable overexpression of LPXN in K-562 cells highlighted the proliferation advantage induced by this gene observed via colony-forming-assay and nude mice models. Proliferation was believed to be induced by LPXN-driven upregulation of ERK1/2 and pERK1/2 in K562-LPXN cells. Moreover, LPXN-expressing K-562 cells were less inhibited by arsenic trioxide, as compared with control cells, which might due to downregulation of BAX, FAS and upregulation of BCL-2. Adhesion to fibronectin and invasion across matrigel were modulated by overexpression and knockdown of LPXN, respectively. Similarly, activity of MMP-9 and MMP-2, and expression of integrin α4, α5 and β1, correlated with overexpression or silencing of LPXN, respectively. Expression of pP38 also showed a positive correlation with LPXN. In general, our data suggests that LPXN promotes proliferation in vitro and in vivo via the MAPK pathway, as well as enhances adhesion and invasion of AML cells through modulating expression of integrin α4, α5, β1 and MMP-9/MMP-2.

Disclosures
No relevant conflicts of interest to declare.
HSP90 Stabilizes B-Cell Receptor Kinases in a Multi-Client Interactome: PU-H71 Induces CLL Apoptosis in a Cytoprotective Microenvironment
Authors: Wang Yue Lynn , Lu Pin , Lee Jimmy , Zhen Chao Jie , Chiosis Gabriela , Guo Ailin 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B-cells in the hematopoietic system and lymphoid tissues. Although inhibitors targeting the B-cell receptor (BCR) pathway have been successful in the treatment of the disease, the underlying mechanisms leading to BCR over-activity in CLL are not fully understood. In this study, we found that HSP90, a highly conserved molecular chaperone, is overexpressed in CLL compared to resting B-cells. HSP90 overexpression is accompanied by the over-expression of several BCR kinases including LYN, SYK, BTK and AKT. Chemical and immune-precipitation demonstrated that these BCR constituents are present in a multi-client chaperone complex with HSP90. Inhibition of HSP90 with PU-H71 destabilized the BCR kinases and caused apoptosis of CLL cells through the mitochondrial apoptotic pathway. Further, PU-H71 induced apoptosis in the presence of stromal co-culture or cytoprotective survival signals. Finally, genetic knock-down of HSP90 client AKT, but not BTK, reduced CLL viability. Overall, our study suggests that the chaperone function of HSP90 contributes to the over-activity of the BCR signaling in CLL and inhibition of HSP90 has the potential to achieve a multi-targeting effect. Thus, HSP90 inhibition may be explored to prevent or overcome drug resistance to single targeting agents.

Disclosures
No relevant conflicts of interest to declare.
A Novel Role of PALB2 in Lymphoid Tumour Development
Authors: Stankovic Tatjana , Byrd Philip J , Stewart Grant S , Taylor Alexander J , Smith Anna , Fooks Peggy , Horsley Robert , Last James I , Janic Dragana , Dokmanovic Lidija , Oliver Antony W , Taylor A.Malcolm R 
Published: October 2019

Abstract
PALB2 is DNA damage response protein that acts in Homologous recombination Repair (HRR) pathway and promotes recruitment of principal HRR components such as BRCA1, BRCA2 and Rad51. Biallelic PALB2 inactivation is associated with the severe form of Fanconi anemia (FA-N), characterised by severe developmental abnormalities and occurrence of embryonal tumours in infancy. Given the rarity of reported patients with biallelic PALB2 inactivation, the full extent of phenotypes associated with PALB2 mutations is still unknown.
Here we describe a family with two inherited PALB2 mutations where the affected individuals presented with few of the clinical features typically exhibited by FA-N patients. The patients, age 19 and 15 were lacking severe developmental abnormalities and displayed impaired growth and mild learning difficulties. Interestingly, however, both individuals developed B cell Non-Hodgkin lymphoma (NHL) at the early age of 12 and 3.5 years respectively, responded well to intensive chemotherapy and stayed in complete remission. Their cellular phenotype included a high level of spontaneous chromosomal damage suggestive of DNA repair defect, but otherwise deviated from the classic FA phenotype revealing an intermediate sensitivity to mitomycin C (MMC) by colony forming assay but an unusually high chromosomal radiosensitivity in G2.
We addressed the possibility that this atypical clinical and cellular phenotype could be related to the functional properties of the mutant PALB2 protein(s) expressed from the affected alleles. Indeed, we demonstrated that the PALB2 protein (T839_K862del) produced from one of the mutant alleles carried by these patients retained both its N- and C-terminal domain required to interact with BRCA1 and BRCA2 respectively. We also showed that this mutant protein preserved some function compared with previously identifiedpatient-associated mutant PALB2 proteins and allowed low level recruitment of Rad51 foci at sites of DNA damage. We propose that the presence of this mutant protein accounts for the milder MMC hyper-sensitivity exhibited by cells from these patients and the lack of FA defining clinical characteristics.
Finally, the shift in tumour spectrum from embryonal tumours towards B cell NHL observed in this family implies PALB2 as a potential suppressor of lymphoid tumourigenesis and raises the possibility that somatic mutations in this gene may contribute to the development of sporadic lymphoid tumours.

Disclosures
Janic: Baxter: Other: Paid Instructor, Research Funding; Pfizer: Other: Paid Instructor, Research Funding; Bayer: Other: Paid Instructor, Research Funding; Octopharma: Research Funding; Novo Nordisk: Other: Paid Instructor, Research Funding.
Role of miRNA in Micro-Environment Mediated Drug Resistance in Acute Promyelocytic Leukemia to Arsenic Trioxide
Authors: Ganesan Saravanan , Lakshmanan Vairavan , Palani Hamenth Kumar , Balasundaram Nithya , Alex Ansu Abu , David Sachin , Korula Anu , George Biju , Balasubramanian Poonkuzhali , Gowda Harsha , Vyas Neha , Palakodeti Dasaradhi , Mathews Vikram 
Published: October 2019

Abstract
Role of stromal microenvironment in drug resistance has been extensively reported for several cancers. We have demonstrated earlier that there is significant micro-environment mediated drug resistance (EM-DR) to arsenic trioxide (ATO) in acute promyelocytic leukemia (APL) and that this was predominantly driven by upregulation of the NF-ⱪB pathway in the malignant cell. In our current study we have probed the molecular mechanism of ATO resistance in further detail. The role of microRNA (miRNA) in mediating this cross talk, if any, has not been reported on. We undertook a study to evaluate the potential role played by miRNA in EM-DR to ATO in APL.
Using NGS based small RNA sequencing we identified two miRNA's that were differentially regulated in NB4 cells upon co-culture with HS-5 stromal cells (FDR corrected p values < 0.05). The two miRNAs were hsa-miR-23a-5p (downregulated) and hsa-miR-125a-3p (upregulated)](Fig 1a). These miRNAs have also been previously reported to be involved in NF-kB regulation, specifically miR125a-3p has been reported to be involved in activation of the NF-kB pathway and miR-23a- 5p can be repressed by the same pathway. These results were consistent with our earlier reported observations that NF-kB pathway is dysregulated and enhances drug resistance to ATO. We also observed miR-23a-5p mimics were able to restore the sensitivity of NB4 cells to ATO even in the presence of stromal cells (Fig 1b).
Consistent with the above small RNA sequencing and our previously reported microarray data, using quantitative proteomics approach we have identified that both NFkB signaling and metallothionein 2A (MT-2A) levels are upregulated in leukemic cells upon stromal co-culture. MT 2A is a known target for hsa-mir-23a-5p. MT's are known to sequester heavy metals such as arsenic and could potentially reduce their cytotoxic effect. The role of metallothionein in ATO resistance in APL and possibly other leukemia's needs further evaluation. This data along with that reported earlier by us illustrates multiple levels of regulation of the NF-kB pathway and resistance to ATO by stromal cell co-culture.

Disclosures
No relevant conflicts of interest to declare.