bluuebunny/crossref_metadata_2025 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

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

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

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.
Cytofluorometric detection of B cell clonal excess: a new approach to the diagnosis of B cell lymphoma
Authors: Weinberg DS , Pinkus GS , Ault KA
Published: November 2019

A sensitive cytofluorometric technique, the “kappa-lambda test,” permits detection of small numbers of monoclonal B lymphocytes (clonal excess). Such a method might represent a new diagnostic tool for diagnosis of non-Hodgkin’s lymphomas, potentially providing definitive evidence of lymphomatous involvement in cases equivocal by standard immunologic methods. To determine the significance of detecting B cell clonal excess in lymphoid tissues, we applied the kappa-lambda test to cell suspensions from 60 consecutive specimens suspected to involvement by malignant lymphoma. Results were correlated with the pathologic diagnosis and with standard cell marker studies in each case. B cell clonal excess was observed in 24 of the 25 cases of non-Hodgkin’s lymphoma of B cell origin, including a single case involving early detection of recurrence. None of the remaining cases, including benign reactive hyperplasia, T cell lymphoma, and Hodgkin’s disease, showed evidence of B cell clonal excess. Selective examination of cell subpopulations was also achieved using this cytofluorometric method. We conclude that the detection of B cell clonal excess by the kappa-lambda test represents a new approach to the diagnosis of B cell lymphoma, which provides certain advantages over more standard methods of cell marker analysis.
Kinetics and mechanism of the bactericidal action of human neutrophils against Escherichia coli
Authors: Hamers MN , Bot AA , Weening RS , Sips HJ , Roos D
Published: November 2019

A mutant strain of Escherichia coli (E. coli ML-35) was used to follow the kinetics of phagocytosis, perforation of the bacterial cell envelope, and inactivation of bacterial proteins by human neutrophils. This particular E. coli mutant strain has no lactose permease, but constitutively forms the cytoplasmic enzyme beta-galactosidase. This implies that the artificial substrate ortho-nitrophenyl-beta-D- galactopyranoside cannot reach the beta-galactosidase unless the bacterial cell envelope has been perforated. Thus, the integrity of the E. coli envelope can be measured simply by the activity of beta- galactosidase with this substrate. Indeed, ingestion of E. coli ML-35 by human neutrophils was followed by perforation of the bacteria (increase in beta-galactosidase activity). Subsequently, the beta- galactosidase activity decreased due to inactivation of the enzyme. With a simple mathematical model and a curve-fitting computer program, we have determined the first-order rate constants for phagocytosis, perforation, and beta-galactosidase inactivation. With 32 normal donors, we found an interdonor variation in these rate constants of 20% to 30% (SD) and an assay variance of 5%. The perforation process closely correlated with the loss of colony-forming capacity of the bacteria. This new assay measures phagocytosis and killing in a fast, simple, and accurate way; it is not hindered by extracellular bacteria. Moreover, this method also measures the postkilling event of inactivation of a bacterial protein, which permits a better detection of neutrophils deficient in this function. The assay can also be used for screening neutrophil functions without the use of a computer program. A simple calculation suffices to detect neutrophil abnormalities. Neutrophils from patients with chronic granulomatous disease (CGD) showed an impaired rate of perforation and thus also of inactivation. Neutrophils from myeloperoxidase-deficient patients or from a patient with the Chediak-Higashi syndrome only showed a retarded inactivation of beta-galactosidase, but normal ingestion and perforation. The role of myeloperoxidase in the killing process is discussed. Although myeloperoxidase does not seem to be a prerequisite for perforation, it probably plays a role in bacterial destruction by normal cells, because the inactivation of bacterial proteins seems strictly myeloperoxidase dependent.
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

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 Points

A 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 Points

This is the first-ever demonstration of successful treatment of paroxysmal cold hemoglobinuria using the complement inhibitor eculizumab.
Correction to: Genetic diversity of the Thao people of Taiwan using Y-chromosome, mitochondrial DNA and HLA gene systems
Authors: Trejaut Jean A. , Muyard Frank , Lai Ying-Hui , Chen Lan-Rong , Chen Zong-Sian , Loo Jun-Hun , Huang Jin-Yuan , Lin Marie
Published: November 2019

Following publication of the original article [1], we have been notified that Additional file 3 was published with track changes.
Hawley retainer and lichenoid reaction: a rare case report
Authors: Elhadad Mahmoud Ahmed , Gaweesh Yasmine
Published: November 2019

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

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

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

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

Background

Despite 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.

Methods

We 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.

Results

Living 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.

Conclusion

These 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

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.
Astrocytic endothelin-1 overexpression promotes neural progenitor cells proliferation and differentiation into astrocytes via the Jak2/Stat3 pathway after stroke
Authors: Cheng Xiao , Yeung Patrick K. K. , Zhong Ke , Zilundu Prince L. M. , Zhou Lihua , Chung Sookja K.
Published: November 2019

Background

Endothelin-1 (ET-1) is synthesized and upregulated in astrocytes under stroke. We previously demonstrated that transgenic mice over-expressing astrocytic ET-1 (GET-1) displayed more severe neurological deficits characterized by a larger infarct after transient middle cerebral artery occlusion (tMCAO). ET-1 is a known vasoconstrictor, mitogenic, and a survival factor. However, it is unclear whether the observed severe brain damage in GET-1 mice post stroke is due to ET-1 dysregulation of neurogenesis by altering the stem cell niche.

Methods

Non-transgenic (Ntg) and GET-1 mice were subjected to tMCAO with 1 h occlusion followed by long-term reperfusion (from day 1 to day 28). Neurological function was assessed using a four-point scale method. Infarct area and volume were determined by 2,3,5-triphenyltetra-zolium chloride staining. Neural stem cell (NSC) proliferation and migration in subventricular zone (SVZ) were evaluated by immunofluorescence double labeling of bromodeoxyuridine (BrdU), Ki67 and Sox2, Nestin, and Doublecortin (DCX). NSC differentiation in SVZ was evaluated using the following immunofluorescence double immunostaining: BrdU and neuron-specific nuclear protein (NeuN), BrdU and glial fibrillary acidic protein (GFAP). Phospho-Stat3 (p-Stat3) expression detected by Western-blot and immunofluorescence staining.

Results

GET-1 mice displayed a more severe neurological deficit and larger infarct area after tMCAO injury. There was a significant increase of BrdU-labeled progenitor cell proliferation, which co-expressed with GFAP, at SVZ in the ipsilateral side of the GET-1 brain at 28 days after tMCAO. p-Stat3 expression was increased in both Ntg and GET-1 mice in the ischemia brain at 7 days after tMCAO. p-Stat3 expression was significantly upregulated in the ipsilateral side in the GET-1 brain than that in the Ntg brain at 7 days after tMCAO. Furthermore, GET-1 mice treated with AG490 (a JAK2/Stat3 inhibitor) sh owed a significant reduction in neurological deficit along with reduced infarct area and dwarfed astrocytic differentiation in the ipsilateral brain after tMCAO.

Conclusions

The data indicate that astrocytic endothelin-1 overexpression promotes progenitor stem cell proliferation and astr ocytic differentiation via the Jak2/Stat3 pathway.
Kidney transplant outcomes in HIV-positive patients: a systematic review and meta-analysis
Authors: Zheng Xin , Gong Lian , Xue Wenrui , Zeng Song , Xu Yue , Zhang Yu , Hu Xiaopeng
Published: November 2019

Background

Kidney transplantation is now a viable alternative to dialysis in HIV-positive patients who achieve good immunovirological control with the currently available antiretroviral therapy regimens. This systematic review and meta-analysis investigate the published evidence of outcome and risk of kidney transplantation in HIV-positive patients following the PRISMA guidelines.

Methods

Searches of PubMed, the Cochrane Library and EMBASE identified 27 cohort studies and 1670 case series evaluating the survival of HIV-positive kidney transplant patients published between July 2003 and May 2018. The regimens for induction, maintenance therapy and highly active antiretroviral therapy, acute rejection, patient and graft survival, CD4 count and infectious complications were recorded. We evaluated the patient survival and graft survival at 1 and 3 years respectively, acute rejection rate and also other infectious complications by using a random-effects analysis.

Results

At 1 year, patient survival was 0.97 (95% CI 0.95; 0.98), graft survival was 0.91 (95% CI 0.88; 0.94), acute rejection was 0.33 (95% CI 0.28; 0.38), and infectious complications was 0.41 (95% CI 0.34; 0.50), and at 3 years, patient survival was 0.94 (95% CI 0.90; 0.97) and graft survival was 0.81 (95% CI 0.74; 0.87).

Conclusions

With careful selection and evaluation, kidney transplantation can be performed with good outcomes in HIV-positive patients.
Correction to: Contour analysis for interpretable leaf shape category discovery
Authors: Victorino Jorge , Gómez Francisco
Published: November 2019

Unfortunately, the original version of the article [1] contained an error in figure 7. The names of species Umus minor and Acer campestre were interchanged. The corrected figure 7 is given below:
Sensory assessment of Cercospora beticola sporulation for phenotyping the partial disease resistance of sugar beet genotypes
Authors: Oerke Erich-Christian , Leucker Marlene , Steiner Ulrike
Published: November 2019

Background

Due to its high damaging potential, Cercospora leaf spot (CLS) caused by Cercospora beticola is a continuous threat to sugar beet production worldwide. Breeding for disease resistance is hampered by the quantitative nature of resistance which may result from differences in penetration, colonization, and sporulation of the pathogen on sugar beet genotypes. In particular, problems in the quantitative assessment of C. beticola sporulation have resulted in the common practice to assess field resistance late in the growth period as quantitative resistance parameter. Recently, hyperspectral sensors have shown potential to assess differences in CLS severity. Hyperspectral microscopy was used for the quantification of C. beticola sporulation on sugar beet leaves in order to characterize the host plant suitability / resistance of genotypes for decision-making in breeding for CLS resistance.

Results

Assays with attached and detached leaves demonstrated that vital plant tissue is essential for the full potential of genotypic mechanisms of disease resistance and susceptibility. Spectral information (400 to 900 nm, 160 wavebands) of CLSs recorded before and after induction of C. beticola sporulation allowed the identification of sporulating leaf spot sub-areas. A supervised classification and quantification of sporulation structures was possible, but the necessity of genotype-specific reference spectra restricts the general applicability of this approach. Fungal sporulation could be quantified independent of the host plant genotype by calculating the area under the difference reflection spectrum from hyperspectral imaging before and with sporulation. The overall relationship between sensor-based and visual quantification of C. beticola sporulation on five genotypes differing in CLS resistance was R2 = 0.81; count-based differences among genotypes could be reproduced spectrally.

Conclusions

For the first time, hyperspectral imaging was successfully tested for the quantification of sporulation as a fungal activity depending on host plant suitability. The potential of this non-invasive and non-destructive approach for the quantification of fungal sporulation in other host–pathogen systems and for the phenotyping of crop traits complex as sporulation resistance is discussed.
A child with a novel ACAN missense variant mimicking a septic arthritis
Authors: Florio Angelo , Papa Riccardo , Caorsi Roberta , Consolaro Alessandro , Gastaldi Roberto , Gattorno Marco , Picco Paolo
Published: November 2019

Heterozygous mutations of the ACAN gene have been associated with a broad spectrum of non-lethal skeletal dysplasias, called Aggrecanopathies. We report a case of a child with severe inflammatory elbow involvement mimicking septic arthritis who carried the new ACAN missense variant c.6970 T > C, p.Trp2324Arg. The comprehensive clinical evaluation of the patient and his family, focused on the associated clinical features (facial dysmorphisms, short stature, brachydactily), led us to suspect a hereditary condition. Our findings suggest that Aggrecanopathies should be considered in children with familial short stature, poor growth spurt and joint involvement.
Structural variant calling: the long and the short of it
Authors: Mahmoud Medhat , Gobet Nastassia , Cruz-Dávalos Diana Ivette , Mounier Ninon , Dessimoz Christophe , Sedlazeck Fritz J.
Published: November 2019

Recent research into structural variants (SVs) has established their importance to medicine and molecular biology, elucidating their role in various diseases, regulation of gene expression, ethnic diversity, and large-scale chromosome evolution—giving rise to the differences within populations and among species. Nevertheless, characterizing SVs and determining the optimal approach for a given experimental design remains a computational and scientific challenge. Multiple approaches have emerged to target various SV classes, zygosities, and size ranges. Here, we review these approaches with respect to their ability to infer SVs across the full spectrum of large, complex variations and present computational methods for each approach.
DOD-ETL: distributed on-demand ETL for near real-time business intelligence
Authors: Machado Gustavo V. , Cunha Ítalo , Pereira Adriano C. M. , Oliveira Leonardo B.
Published: November 2019

The competitive dynamics of the globalized market demand information on the internal and external reality of corporations. Information is a precious asset and is responsible for establishing key advantages to enable companies to maintain their leadership. However, reliable, rich information is no longer the only goal. The time frame to extract information from data determines its usefulness. This work proposes DOD-ETL, a tool that addresses, in an innovative manner, the main bottleneck in Business Intelligence solutions, the Extract Transform Load process (ETL), providing it in near real-time. DOD-ETL achieves this by combining an on-demand data stream pipeline with a distributed, parallel and technology-independent architecture with in-memory caching and efficient data partitioning. We compared DOD-ETL with other Stream Processing frameworks used to perform near real-time ETL and found DOD-ETL executes workloads up to 10 times faster. We have deployed it in a large steelworks as a replacement for its previous ETL solution, enabling near real-time reports previously unavailable.
Electrical transient modeling for appliance characterization
Authors: Nait-Meziane Mohamed , Ravier Philippe , Abed-Meraim Karim , Lamarque Guy , Bunetel Jean-Charles Le , Raingeaud Yves
Published: November 2019

Transient signals are characteristic of the underlying phenomenon generating them, which makes their analysis useful in many fields. Transients occur as a sudden change between two steady state regimes, subsist for a short period, and tend to decay over time. Hence, superimposed damped sinusoids (SDS) were extensively used for transients modeling as they are adequate for describing decaying phenomena. However, SDS are not adapted for modeling the turn-on transient current of electrical appliances as it tends to decay to a steady state that is different from the one preceding it. In this paper, we propose a new and more suitable model for these signals for the purpose of characterizing appliances. We also propose an algorithm for the model parameter estimation and validate its performance on simulated and real data. Moreover, we give an example on the use of the model parameters as features for the classification of appliances using the Controlled On/Off Loads Library (COOLL) dataset. The results show that the proposed algorithm is efficient and that for real data the network fundamental frequency must be estimated to account for its variations around the nominal value. Finally, real data experiments showed that the model parameters used as features yielded a classification accuracy of 98%.
Second-order control of complex systems with correlated synthetic data
Authors: Raimbault Juste
Published: November 2019

The generation of synthetic data is an essential tool to study complex systems, allowing for example to test models of these in precisely controlled settings, or to parametrize simulation models when data is missing. This paper focuses on the generation of synthetic data with an emphasis on correlation structure. We introduce a new methodology to generate such correlated synthetic data. It is implemented in the field of socio-spatial systems, more precisely by coupling an urban growth model with a transportation network generation model. We also show the genericity of the method with an application on financial time-series. The simulation results show that the generation of correlated synthetic data for such systems is indeed feasible within a broad range of correlations, and suggest applications of such synthetic datasets.
Mapping actionable pathways and mutations in brain tumours using targeted RNA next generation sequencing
Authors: Lenting Krissie , van den Heuvel Corina N. A. M. , van Ewijk Anne , ElMelik Duaa , de Boer Remco , Tindall Elizabeth , Wei Ge , Kusters Benno , te Dorsthorst Maarten , ter Laan Mark , Huynen Martijn A. , Leenders William P.
Published: November 2019

Many biology-based precision drugs are available that neutralize aberrant molecular pathways in cancer. Molecular heterogeneity and the lack of reliable companion diagnostic biomarkers for many drugs makes targeted treatment of cancer inaccurate for many individuals. Identifying actionable hyperactive biological pathways in individual cancers may improve this situation.

To achieve this we applied a novel targeted RNA next generation sequencing (t/RNA-NGS) technique to surgically obtained glioma tissues. The test combines mutation detection with analysis of biological pathway activities that are involved in tumour behavior in many cancer types (e.g. tyrosine kinase signaling, angiogenesis signaling, immune response, metabolism), via quantitative measurement of transcript levels and splice variants of hundreds of genes. We here present proof of concept that the technique, which uses molecular inversion probes, generates a histology-independent molecular diagnosis and identifies classifiers that are strongly associated with conventional histopathology diagnoses and even with patient prognosis. The test not only confirmed known glioma-associated molecular aberrations but also identified aberrant expression levels of actionable genes and mutations that have so far been considered not to be associated with glioma, opening up the possibility of drug repurposing for individual patients. Its cost-effectiveness makes t/RNA-NGS to an attractive instrument to aid oncologists in therapy decision making.
Gemcitabine-incorporated polyurethane films for controlled release of an anticancer drug
Authors: Choi Seong Hoon , Cho Il-Hoon , Park Sangsoo
Published: November 2019

Background

Local delivery of anti-cancer drugs through a stent is a very promising and anticipated treatment modality for patients who have obstructions in their gastrointestinal tract with malignant tumors. Anticancer drug release via stents, however, needs to be optimized with respect to drug delivery behavior for the stents to be effective for prolonged containment of tumor proliferation and stent re-obstruction. Local stent-based drug delivery has been tested using an effective anti-cancer drug, gemcitabine, but the release from the stent-coated polyurethane films is often too fast and the drug is depleted from the coated film virtually in a day.

Methods

To moderate the drug release from a polyurethane film, a gemcitabine-incorporated polyurethane film was enveloped with a pure polyurethane film, with no drug loading, and with a silicone film by solution casting after activation of the silicone film surface with plasma treatment.

Results

The pure polyurethane barrier film was effective; the interface of the two were indistinguishable on scanning electron microscopy, and the initial burst, i.e., the cumulative release in a day, decreased from 90 to 26%. The silicone film barrier, on the other hand, was defective as voids were seen using a scanning electron microscope, and micro-separation of the two layers was observed after the film was immersed in phosphate-buffered saline for 1 day during the in vitro drug release study.

Conclusions

Enveloping a gemcitabine-releasing polyurethane film with a homo-polymer barrier film was quite effective for moderating the initial burst of gemcitabine, thus, prolonging the release time of the drug. Enveloping the polyurethane film with a silicone film was also possible after plasma treatment of the silicone film surface, but the two films eventually separated in the aqueous environment. More studies are needed to tune the drug release behavior of gemcitabine from the stent covering film before attempting a clinical application of an anti-cancer drug releasing stent.
Barrier bucket and transversely split beams for loss-free multi-turn extraction in synchrotrons
Authors: Vadai M. , Alomainy A. , Damerau H. , Gilardoni S. , Giovannozzi M. , Huschauer A.
Published: November 2019

A special radio-frequency manipulation has been studied and successfully implemented at the CERN Proton Synchrotron for the first time. This technique aims at depleting a well-defined fraction of a continuous longitudinal beam distribution by creating a so-called barrier bucket. In addition to the intrinsic interest for its originality, this approach has an immediate application at CERN in combination with the Multi-Turn Extraction scheme. The combination of these two exotic techniques into a single, highly sophisticated process allows to dramatically reduce the beam loss at PS extraction, thus opening the door to the production of high-intensity proton beams for future fixed-target experiments at the CERN Super Proton Synchrotron.
Dynamics of activating and repressive histone modifications in Drosophila neural stem cell lineages and brain tumors
Authors: Abdusselamoglu Merve Deniz , Landskron Lisa , Bowman Sarah K. , Eroglu Elif , Burkard Thomas , Kingston Robert E. , Knoblich Jürgen A.
Published: November 2019

During central nervous system development, spatiotemporal gene expression programs mediate specific lineage decisions to generate neuronal and glial cell types from neural stem cells (NSCs). However, little is known about the epigenetic landscape underlying these highly complex developmental events. Here, we perform ChIP-seq on distinct subtypes of Drosophila FACS-purified NSCs and their differentiated progeny to dissect the epigenetic changes accompanying the major lineage decisions in vivo. By analyzing active and repressive histone modifications, we show that stem cell identity genes are silenced during differentiation by loss of their activating marks and not via repressive histone modifications. Our analysis also uncovers a new set of genes specifically required for altering lineage patterns in type II neuroblasts (NBs), one of the two main Drosophila NSC identities. Finally, we demonstrate that this subtype specification in NBs, unlike NSC differentiation, requires Polycomb-group-mediated repression.
Antibiotics for Aspiration Pneumonia in Neurologically Impaired Children
Authors: Thomson Joanna , Hall Matt , Ambroggio Lilliam , Berry Jay G , Stone Bryan , Srivastava Rajendu , Shah Samir S
Published: November 2019

OBJECTIVE

To compare hospital outcomes associated with commonly used antibiotic therapies for aspiration pneumonia in children with neurologic impairment (NI).

DESIGN/METHODS

A retrospective study of children with NI hospitalized with aspiration pneumonia at 39 children's hospitals in the Pediatric Health Information System database. Exposure was empiric antibiotic therapy classified by antimicrobial activity. Outcomes included acute respiratory failure, intensive care unit (ICU) transfer, and hospital length of stay (LOS). Multivariable regression evaluated associations between exposure and outcomes and adjusted for confounders, including medical complexity and acute illness severity.

RESULTS

In the adjusted analysis, children receiving Gram‐negative coverage alone had two‐fold greater odds of respiratory failure (odds ratio [OR] 2.15; 95% CI: 1.41‐3.27), greater odds of ICU transfer (OR 1.80; 95% CI: 1.03‐3.14), and longer LOS [adjusted rate ratio (RR) 1.28; 95% CI: 1.16‐1.41] than those receiving anaerobic coverage alone. Children receiving anaerobic and Gram‐negative coverage had higher odds of respiratory failure (OR 1.65; 95% CI: 1.19‐2.28) than those receiving anaerobic coverage alone, but ICU transfer (OR 1.15; 95% CI: 0.73‐1.80) and length of stay (RR 1.07; 95% CI: 0.98‐1.16) did not statistically differ. For children receiving anaerobic, Gram‐negative, and P. aeruginosa coverage, LOS was shorter (RR 0.83; 95% CI: 0.76‐0.90) than those receiving anaerobic coverage alone; odds of respiratory failure and ICU transfer rates did not significantly differ.

CONCLUSIONS

Anaerobic therapy appears to be important in the treatment of aspiration pneumonia in children with NI. While Gram‐negative coverage alone was associated with worse outcomes, its addition to anaerobic therapy may not yield improved outcomes.