bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development Of Methods To Perform Next Generation Sequencing (NGS)-Based Genomics Studies On Multiple Myeloma Clinical Samples
Authors: Keats Jonathan J , Kwei Kevin A , Degenhardt Jeremiah D , Allen Kristi , Kirk Christopher J. , Tuch Brian B 
Published: November 2019

Abstract
NGS is a powerful tool for interrogating genomic alterations in cancer cells from the scale of single nucleotides up to whole chromosomes. While methods for performing NGS analysis on solid tumors have been widely reported in the literature, fewer methods are available for hematological malignancies, which are often collected and stored in different conditions. Here we report our efforts to overcome the unique challenges of performing a whole exome sequencing (WES) study on hundreds of multiple myeloma (MM) patient samples.
As part of Onyx-sponsored clinical trials of the proteasome inhibitor, carfilzomib, bone marrow aspirates were collected from patients and subjected to bead-based CD138 positive selection to enrich tumor cells. The yield of CD138+ cells after enrichment varied greatly from 200,000 to >10,000,000, depending primarily on the disease state and the volume and quality of aspirate received. CD138+ cells were banked in a variety of formats that differed in their suitability for downstream DNA and RNA analysis, including as pellets or re-suspended in reagents such as TRIzol®, RNAlater and Buffer RLT. At the time of abstract submission we have performed extensive analyses of samples stored in TRIzol.
TRIzol is renowned for its excellence in preserving RNA integrity while providing a means to simultaneously extract DNA and protein. However, the standard DNA extraction method yields material that is not of sufficient quality for DNA analyses such as WES. We attempted to remedy this problem through three approaches: (1) modifying extraction conditions to improve the quality of the DNA, (2) rescuing the extracted DNA with double-stranding steps prior to library preparation, and (3) applying newer, low input and single-strand library construction methods. Our efforts to modify the extraction conditions were unsuccessful, but by combining DNA rescue and newer library construction methods, we could ultimately generate high quality exomes (as judged by comparison to exomes generated from matched, pelleted samples) from the whole range of clinical samples in our biobank. We believe these methods create new opportunities for the community to interrogate, with the latest NGS approaches, vast numbers of clinical samples banked in the era of gene-expression profiling (GEP).

Disclosures:
Kwei: Onyx Pharmaceuticals: Employment, Equity Ownership. Degenhardt:Onyx Pharmaceuticals: Employment, Equity Ownership. Kirk:Onyx Pharmaceuticals: Employment, Equity Ownership. Tuch: Onyx Pharmaceuticals: Employment, Equity Ownership.
Long-Term Results Of Allogeneic Stem Cell Transplantation In 56 Adult Patients With Philadelphia-Positive Acute Lymphoblastic Leukemia: A 20-Year Single Center Experience
Authors: Ibatici Adalberto , Guolo Fabio , Galaverna Federica , Delle Piane Clara , Dominietto Alida , Raiola Anna Maria , Lint Maria Teresa van , Di Grazia Carmen , Carella Angelo Michele , Bacigalupo Andrea 
Published: November 2019

Abstract

Background
Despite the great clinical benefit from the advent of tyrosine-kinase inhibitors (TKIs) treatment for adult patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), allogeneic hematopoietic stem cells transplantation (allo-HSCT) does not appear to be dispensable, if the optimal long-term outcome is to be achieved. However, there are only few data reported on long-term survivors with Ph+ ALL, particularly for those not receiving pre-transplant TKIs in the conventional induction therapy.
In this retrospective analysis, we report on the long term outcomes of myeloablative allo-HSCT during the past 2 decades as single center experience. Data on the use of post-transplant TKIs and molecular monitoring for minimal residual disease are being collected to investigate their predictive role.

Patients and methods
Between 1989 and 2013, we collected 56 patients who underwent myeloablative allo-HSCT from HLA-identical siblings (n: 24), unrelated donors (n: 17), alternative donors (n: 15). Median age was 41 years (16-64). Disease phase at transplant was CR1 in 30 pts (53%), >CR1 in 26 pts. Pre-transplant TKI as part of induction therapy was given in 25 pts (44%). Conditioning regimen was TBI-based in 47 pts (83%) and chemotherapy-based in 9 pts. GVHD prophylaxis was given according to Center standard practice.

Results
Median follow-up was 67 months (1- 244). There were no cases of primary graft failure. Incidence of grade II-IV acute GVHD occurred in 31 pts (55%) and extensive chronic GVHD in 18 pts (32%). Transplant-related mortality was 35% at 2 years and 7 more patients died of non-relapse causes up to 12 years after transplant. The 10-year OS was 25% and significantly better for patients in CR1 vs. >CR1 (36% VS 14% - p=0,006). The 10-year DFS was 27% with no statistical difference for pts in CR1 vs. >CR1. Age at transplant and pre-transplant TKI did not affect the outcomes.

Conclusions
In this retrospective analysis over a 20-year time period, we show that approximately one-third of adult Ph+ ALL are cured if they undergo allo-HSCT in CR1. Therefore, we confirm that disease status at transplant has a major prognostic impact on clinical outcomes. The apparent lack of benefit of pre-transplant TKI exposure may be due to the retrospective nature of the analysis.

Disclosures:
No relevant conflicts of interest to declare.
Tele Hematology/Hemostasis Clinics: Delivering Hematology/Oncology and Hemophilia Comprehensive Services To Remote Pediatric Patients In Michigan
Authors: Kulkarni Roshni , Witkop Michelle , Scott-Emuakpor Ajovi , Gera Renuka , Gualdoni Steven , Adkins Susan , Carlson Laura , Rushlow David , Saah Elna 
Published: November 2019

Abstract

Introduction
Telemedicine is the delivery of health services to patients through interactive video and /or audio who otherwise have difficulty in accessing services. Often these patients reside in remote areas and distance and cost of travel to access specialty services are limited. In addition, inclement weather often results in cancellation of these clinics. Beside diagnostic and comprehensive clinical services, teleclinics could also offer access to clinical trials for children in remote areas.

Methods
Records of patient visits seen at Marquette General Hospital (MGH) in the Michigan Upper Peninsula MI UP) and Traverse City (TC) by Michigan State University (MSU) pediatric hematologists. The types of patients and distance traveled by patients, satisfaction survey by patients regarding their telemedicine visit versus field clinic were recorded. Personnel, equipment type and cost as well as the cost savings of travel will be discussed.

Results
Since 1994, MSU hematologists have been conducting field clinics at MGH for pediatric hematology oncology services. Field clinics in TC were conducted in the 1990s but were then discontinued. The need for telehematology services arose because of distance, inclement weather and cost of travel. Since 2011, using real time telemedicine, 26 patients, ages 2- 24 years with various hematologic/hemostatic and oncologic diseases were seen at MGH. At Traverse City, primarily, patients with various bleeding disorders such as hemophilia, von Willebrand Disease, FVII deficiency and platelet function disorders were seen via telemedicine and included 11 patients, ages newborn – 23 years. Besides physicians, physician assistants, nurse practitioner, social worker, nurse, clinic staff and participated in the delivery of services such as consultations, treatment planning, disease monitoring and education. For those patients eligible for clinical trials, consent was obtained via telemedicine visit. Besides savings in costs of travel, there was considerable time savings for the health team, patients and their families.

Conclusion
Telehematology and hemostasis clinics allow comprehensive specialty services to be delivered in a cost effective manner to remote patients. Future research in telehematology is needed to measure improvement in health outcomes, including quality of life, access to state of the art and preventive therapies, and participation in disease surveillance and clinical trials.

Disclosures:
No relevant conflicts of interest to declare.
Direct stimulation of cells expressing receptors for macrophage colony- stimulating factor (CSF-1) by a plasma membrane-bound precursor of human CSF-1
Authors: Stein J , Borzillo GV , Rettenmier CW 
Published: November 2019

Abstract
Secreted forms of macrophage colony-stimulating factor (M-CSF or CSF-1) are generated by proteolytic cleavage of membrane-bound glycoprotein precursors. Alternatively spliced transcripts of the human CSF-1 gene encode at least two different transmembrane precursors that are differentially processed in mammalian expression systems. The larger precursor rapidly undergoes proteolysis to yield the secreted growth factor and does not give rise to forms of CSF-1 detected on the cell surface. By contrast, the smaller human CSF-1 precursor is stably expressed on the plasma membrane where it is inefficiently cleaved to release a soluble molecule. To determine whether the smaller precursor is biologically active on the cell surface, mouse NIH-3T3 fibroblasts expressing the different forms of human CSF-1 were killed by chemical fixation and tested for their ability to support the proliferation of cells that require this growth factor. Only fixed cells expressing human CSF-1 precursors on their surface stimulated the growth in vitro of a murine macrophage cell line or normal mouse bone marrow-derived mononuclear phagocytes. The ability of these nonviable fibroblasts to induce the proliferation of CSF-1-dependent cells was not mediated by release of soluble growth factor, required direct contact with the target cells, and was blocked by neutralizing antiserum to CSF-1. These results demonstrate that the cell surface form of the human CSF-1 precursor is biologically active and indicate that plasma membrane- bound growth factors can functionally interact with receptor-bearing targets by direct cell-cell contact.
Trends and factors affecting the US adult hematology workforce: a mixed methods study
Authors: Sharma Deva , Wallace Natalie , Levinsohn Erik A. , Marshall Ariela L. , Kayoumi Karen , Madero Johanna , Homer Morgan , Reynolds Robby , Hafler Janet , Podoltsev Nikolai A. , Lee Alfred Ian 
Published: November 2019

Key PointsA mixed methods study of surveys, interviews, and focus groups raises concerns about the state of the adult hematology workforce. Hematology/oncology fellowship program directors, fellows, and practicing clinicians offer different strategies to address these problems.
Paroxysmal cold hemoglobinuria successfully treated with complement inhibition
Authors: Lau-Braunhut Sarah A. , Stone Hannah , Collins Griffin , Berentsen Sigbjørn , Braun Benjamin S. , Zinter Matt S. 
Published: November 2019

Key PointsThis is the first-ever demonstration of successful treatment of paroxysmal cold hemoglobinuria using the complement inhibitor eculizumab.
Hawley retainer and lichenoid reaction: a rare case report
Authors: Elhadad Mahmoud Ahmed , Gaweesh Yasmine 
Published: November 2019

Abstract
Background
Oral lichenoid reaction (OLR) is a type IV cell-mediated immune response in the oral cavity. There is an established relationship between various dental materials and OLR, but few cases reports reported the occurrence of a lichenoid reaction in association with the use of a Hawley retainer.

Case presentation
A female patient (twenty years of age) has been complaining of a reddish painful area on the tongue, which started one year ago and has been increasing in size over time. The patient completed orthodontic treatment two years ago and has been using a Hawley retainer for orthodontic retention since then. After performing histological analysis and patch test, the lesion was diagnosed as a lichenoid reaction to the Hawley retainer. Topical corticosteroids were prescribed, and the patient was asked to stop using the retainer and followed for six months.

Conclusions
It is difficult to diagnose lichenoid lesions and even more challenging to differentiate between OLP and OLR, therefore it is essential to do a full intraoral and extraoral examination. OLL can occur in association with Hawley retainer, which we believe could be because it is made of an acrylic based material. Generally, OLL resolves after removal of the cause.
Bleeding in cardiac patients prescribed antithrombotic drugs: electronic health record phenotyping algorithms, incidence, trends and prognosis
Authors: Pasea Laura , Chung Sheng-Chia , Pujades-Rodriguez Mar , Shah Anoop D. , Alvarez-Madrazo Samantha , Allan Victoria , Teo James T. , Bean Daniel , Sofat Reecha , Dobson Richard , Banerjee Amitava , Patel Riyaz S. , Timmis Adam , Denaxas Spiros , Hemingway Harry 
Published: November 2019

Abstract
Background
Clinical guidelines and public health authorities lack recommendations on scalable approaches to defining and monitoring the occurrence and severity of bleeding in populations prescribed antithrombotic therapy.

Methods
We examined linked primary care, hospital admission and death registry electronic health records (CALIBER 1998–2010, England) of patients with newly diagnosed atrial fibrillation, acute myocardial infarction, unstable angina or stable angina with the aim to develop algorithms for bleeding events. Using the developed bleeding phenotypes, Kaplan-Meier plots were used to estimate the incidence of bleeding events and we used Cox regression models to assess the prognosis for all-cause mortality, atherothrombotic events and further bleeding.

Results
We present electronic health record phenotyping algorithms for bleeding based on bleeding diagnosis in primary or hospital care, symptoms, transfusion, surgical procedures and haemoglobin values. In validation of the phenotype, we estimated a positive predictive value of 0.88 (95% CI 0.64, 0.99) for hospitalised bleeding. Amongst 128,815 patients, 27,259 (21.2%) had at least 1 bleeding event, with 5-year risks of bleeding of 29.1%, 21.9%, 25.3% and 23.4% following diagnoses of atrial fibrillation, acute myocardial infarction, unstable angina and stable angina, respectively. Rates of hospitalised bleeding per 1000 patients more than doubled from 1.02 (95% CI 0.83, 1.22) in January 1998 to 2.68 (95% CI 2.49, 2.88) in December 2009 coinciding with the increased rates of antiplatelet and vitamin K antagonist prescribing. Patients with hospitalised bleeding and primary care bleeding, with or without markers of severity, were at increased risk of all-cause mortality and atherothrombotic events compared to those with no bleeding. For example, the hazard ratio for all-cause mortality was 1.98 (95% CI 1.86, 2.11) for primary care bleeding with markers of severity and 1.99 (95% CI 1.92, 2.05) for hospitalised bleeding without markers of severity, compared to patients with no bleeding.

Conclusions
Electronic health record bleeding phenotyping algorithms offer a scalable approach to monitoring bleeding in the population. Incidence of bleeding has doubled in incidence since 1998, affects one in four cardiovascular disease patients, and is associated with poor prognosis. Efforts are required to tackle this iatrogenic epidemic.
Composite lymphoma of concurrent T zone lymphoma and large cell B cell lymphoma in a dog
Authors: Matsuyama Arata , Bienzle Dorothee , Richardson Danielle , Deravi Nariman , Hwang Mei-Hua , Darzentas Nikos , Keller Stefan M. 
Published: November 2019

Abstract
Background
Evolution of indolent to aggressive lymphoma has been described in dogs but is difficult to distinguish from the de novo development of a second, clonally distinct lymphoma. Differentiation of these scenarios can be aided by next generation sequencing (NGS)-based assessment of clonality of lymphocyte antigen receptor genes.

Case presentation
An 8-year-old male intact Mastiff presented with generalized lymphadenomegaly was diagnosed with nodal T zone lymphoma (TZL) based on cytology, histopathology, immunohistochemistry and flow cytometry. Thirteen months later, the dog re-presented with progressive lymphadenomegaly, and based on cytology and flow cytometry, a large B cell lymphoma (LBCL) was diagnosed. Sequencing-based clonality testing confirmed the de novo development of a LBCL and the persistence of a TZL.

Conclusions
The occurrence of two distinct lymphoid neoplasms should be considered if patient features and tumor cytomorphology or immunophenotype differ among sequential samples. Sequencing-based clonality testing may provide conclusive evidence of two concurrent and distinct clonal lymphocyte populations, termed most appropriately “composite lymphoma”.
The long noncoding RNA PCGEM1 promotes cell proliferation, migration and invasion via targeting the miR-182/FBXW11 axis in cervical cancer
Authors: Zhang Qian , Zheng Jindan , Liu Lili 
Published: November 2019

Abstract
Background
Cervical cancer (CC) is the fourth leading cause of cancer-associated death in women worldwide. Recently, long noncoding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) has been demonstrated to involve in the initiation and progression of human cancers. However, to date, the clinical and functional significance of PCGEM1 expression in CC progression remains unknown.

Methods
qRT-PCR was performed to investigate PCGEM1 expression levels in CC tissues and cell lines. The effect of PCGEM1 on CC cells was assessed by gain- and loss-of-function assays. MS2-binding sequences-MS2-binding protein-based RIP assay (MS2-RIP), RNA pull-down and Luciferase reporter assays were performed to investigate the interaction between PCGEM1 and miR-182. The association between miR-182 and F-box and WD repeat domain containing 11 (FBXW11) was verified by luciferase reporter assay. The effect of PCGEM1 on the NF-κB and β-catenin/TCF signaling pathways was determined by luciferase reporter assay.

Results
Our present study showed that PCGEM1 was significantly upregulated in CC tissues and cell lines. Overexpression of PCGEM1 was correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node, distant metastasis and poor prognosis in CC patients. Functionally, PCGEM1 promoted cell proliferation, cell cycle progression, migration and invasion, while suppressed cell apoptosis in CC cells. Further mechanistic investigation revealed that PCGEM1 associated with miR-182 and suppressed its expression. PCGEM1 could act as a competing endogenous (ceRNA) of oncogene F-box and WD repeat domain containing 11 (FBXW11) for miR-182 in CC cells. Additionally, PCGEM1 was capable to activate the NF-κB and β-catenin/TCF signaling pathways, which was reversed by inhibition of FBXW11.

Conclusion
In conclusion, our findings demonstrated that PCGEM1-miR-182-FBXW11 axis play an important role in CC progression, and indicated a promising therapeutic target for CC patients.
Evaluating the impact of implementing public bicycle share programs on cycling: the International Bikeshare Impacts on Cycling and Collisions Study (IBICCS)
Authors: Hosford Kate , Winters Meghan , Gauvin Lise , Camden Andi , Dubé Anne-Sophie , Friedman Steven Marc , Fuller Daniel 
Published: November 2019

AbstractBackgroundDespite rapid expansion of public bicycle share programs (PBSP), there are limited evaluations of the population-level impacts of these programs on cycling, leaving uncertainty as to whether these programs lead to net health gains at a population level or attract those that already cycle and are sufficiently physically active. Our objective was to determine whether the implementation of PBSPs increased population-level cycling in cities across the US and Canada.MethodsWe conducted repeat cross-sectional surveys with 23,901 residents in cities with newly implemented PBSPs (Chicago, New York), existing PBSPs (Boston, Montreal, Toronto) and no PBSPs (Detroit, Philadelphia, Vancouver) at three time points (Fall 2012, 2013, 2014). We used a triple difference in differences analysis to assess whether there were increases in cycling over time amongst those living in closer proximity (< 500 m) to bicycle share docking stations in cities with newly implemented and existing PBSPs, relative to those in cities with no PBSPs.ResultsLiving in closer proximity to bicycle share predicted increases in cycling over time for those living in cities with newly implemented PBSPs at 2-year follow-up. No change was seen over time for those living in closer proximity to bicycle share in cities with existing PBSPs relative to those in cities with no PBSP.ConclusionThese findings indicate that PBSPs are associated with increases in population-level cycling for those who live near to a docking station in the second year of program implementation.
Identifying genetic variants underlying medication-induced osteonecrosis of the jaw in cancer and osteoporosis: a case control study
Authors: Lee Kye Hwa , Kim Su-Hwan , Kim Chang Hyen , Min Byung Joo , Kim Grace Juyun , Lim Younggyun , Kim Hun-Sung , Ahn Kang-Min , Kim Ju Han 
Published: November 2019

Abstract
Background
Bisphosphonate-induced osteonecrosis of the jaw (BRONJ) presents with a typical pattern of jaw necrosis in patients who have been prescribed bisphosphonates (BPs) and other antiangiogenetic drugs to treat osteoporosis or bone-related complications of cancer.

Methods
This study divided 38 patients with BRONJ into two groups according to the prescribing causes: cancer (n = 13) and osteoporosis (n = 25), and underwent whole exome sequencing and compared them with normal controls (n = 90). To identify candidate genes and variants, we conducted three analyses: a traditional genetic model, gene-wise variant score burden, and rare-variant analysis methods.

Results
The stop-gain mutation (rs117889746) of the PZP gene in the BRONJ cancer group was significantly identified in the additive trend model analysis. In the cancer group, ARIDS, HEBP1, LTBP1, and PLVAP were identified as candidate genes. In the osteoporosis group, VEGFA, DFFA, and FAM193A genes showed a significant association. No significant genes were identified in the rare-variant analysis pipeline. Biologically accountable functions related to BRONJ occurrence-angiogenesis-related signaling (VEGFA and PLVAP genes), TGF-β signaling (LTBP1 and PZP genes), heme toxicity (HEBP1) and osteoblast maturation (ARIDS)-were shown in candidate genes.

Conclusion
This study showed that the candidate causative genes contributing to the development of BRONJ differ according to the BP dose and background disease.