bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Levels of Acetylated Low Density Lipoprotein Uptake and Low Tie2 Promoter Activity Distinguishes Sinusoids from Other Vessel Types in the Murine Bone Marrow
Authors: Li Xiaomiao , Hu Zhongbo , Jorgenson Marda , Slayton William 
Published: April 2020

Abstract
Background: The bone marrow contains a variety of blood vessels that have different functions in maintaining the bone marrow as the major blood producing organ in adulthood. For instance, arterioles function to control the flow of blood into bone marrow compartments, and the sinusoids serve as a conduit to the blood stream and niches for megakaryocyte development. Most current studies of the bone marrow vasculature, including studies quantifying changes in the marrow vascular by microvascular density, do not differentiate between different types of marrow vessels. Recognizing the changes in different types of blood vessels has important physiologic implications. Here we report a new method to distinguish sinusoids from arterioles in the murine bone marrow.
Methods and Results: We used transgenic mice with GFP expressed downstream of the Tie-2 promoter, combined with in vivo acetylated low-density lipoprotein (Ac-LDL) uptake method to differentiate sinusoids from arterioles. We found that Ac-LDL was specifically endocytosed by sinusoids, and Tie-2 expression was more pronounced in the arteries, arterioles, and transitional capillaries. Combining these two functional endothelial markers and using confocal microscopy to obtain three dimensional images, we identified transitional zones where arterioles emptied into the sinusoids.
Conclusions: These results demonstrate that the marrow vasculature and specific endothelial cell types are functionally heterogeneous. Methods to study changes in the marrow vasculature and particularly the vascular niche, a function of sinusoids, need to take into account this heterogeneity.
Endogenous Nitric Oxide Synthesis Inhibitor Asymmetrical Dimethyl-L-Arginine (ADMA) and Neoplasms in Children
Authors: Doroszko Adrian , Niedzielska Ewa , Wojcik Dorota , Wojcik Elzbieta , Szuba Andrzej , Andrzejak Ryszard 
Published: April 2020

Abstract
Background: Neoplasms in children are uncommon diseases however they have broad impact on the society. Despite novel therapeutic strategies for children suffering from leukemia or solid tumor, the mortality rate of the disease is still high. The endogenous nitric oxide synthesis inhibitor asymmetrical dimethyl-L-arginine (ADMA) is considered to be a strong cardirovascular risk factor and may lead to new therapeutic strategies. Our previous findings indicate that elevated plasma level of ADMA is correlated with worse prognosis in adult patients with NHL. There are no data available pointing at metabolites of NO-pathway nor clinical evidence as prognostic factor of oncological treatment in children.
Aim: To investigate the relation between elevated plasma level of NO-pathway metabolites and well established markers of clinical stage of the disease.
Material and method: 12 children with acute leukemias (ALL, AML), 13 with solid tumor (PNET, osteosarcoma, Wilms’ tumor, RMS) during hemato-oncological treatment were recruited to a pilot study and N=15 healthy children to a control group. Plasma concentrations of ADMA, SDMA, L-Arg was determined. Relationship to clinical stage of the disease, biochemical and blood markers was tested.
Results Table 1: Differences in mean plasma concentrations of arginine, ADMA and SDMA in pts with leukemia vs pts with solid tumor vs control group
Control:N=15 Mean ±SD Median ±SEM Leukemia;N=12 Mean±SD Median ±SEM Solid tumour; N=13 Mean±SD Median ±SEM P L-Arg 68,58±24,29 60,19±6,27 31,28±8,63 30,82±2,49 49,59±10,81 49,18±3,00 0,0000 ADMA 0,62±0,10 0,61±0,02 1,17±1,10 0,53±0,32 0,98±1,10 0,46±0,31 NS SDMA 0,44±0,18 0,39±0,04 1,18±1,10 0,80±0,32 1,56±1,02 1,09±0,28 0,0024 ARG/ADMA 112,8±46,28 107,4±11,94 67,40±54,31 69,48±15,68 228,82±451,44 117,35±125,21 NS
Table 2:Significant correlations in group of pts with solid tumor and in patients with leukemia
LEUKEMIA; N=12 R p ADMA & Ca 0,78 0,008 SDMA & Ca 0,75 0,011 SDMA & CRP −0,78 0,021 Arg/ADMA & K −0,72 0,019 Arg/ADMA & Ca −0,64 0,043 Arg& MONOCYTE 0,65 0,043 ADMA & TOT.BILIRUB. −0,92 0,000 ADMA & TOT.PROTEIN 0,75 0,032 SDMA & EOSINOPHILE 0,73 0,025 SDMA & TOT.BILIRUB −0,82 0,007 Arg/ADMA & TOT.BILIRUB. 0,81 0,009 SOLID TUMOR; N=15 R p Arg &RBC 0,70 0,016 Arg & Hb 0,64 0,035 Arg & LYMPHOCYTE 0,81 0,003 Arg & EOSINOPHILE 0,76 0,011 ADMA &MONOCYTE −0,78 0,008 ADMA & TOT.PROTEIN 0,62 0,040 ADMA & Hb 0,64 0,035 Arg/ADMA &MONOCYTE 0,82 0,004 Arg/ADMA & BASOPHILE 0,65 0,043
Conclusions:A lower plasma level of L-Arg was found both in pts with leukemia and solid tumors. Higher plasma concentration of SDMA was found in patients with leukemia and solid tumor compared to the control group. Further studies are necessary to clarify the significance of these findings.
Interleukin-21 Induces Cell Cycle Arrest and Apoptosis of Diffuse Large B-Cell Lymphomas (DLBCL) Via Activation of STAT3 and Upregulation of C-Myc
Authors: Sarosiek Kristopher A , Nechushtan Hovav , Avisar Eli , Lossos Izidore S 
Published: April 2020

Abstract
IL-21, a recently discovered member of the IL-2 cytokine family, has been shown to have diverse regulatory effects on B-cells including the induction of antibody secretion, differentiation, or apoptosis depending on the cellular milieu and activation status. However, the effects of IL-21 on B-cell neoplasms such as DLBCL are largely unknown. Our research has uncovered the widespread expression of the IL-21 receptor (IL-21R) in B-cell lymphomas including DLBCL. Our results confirmed reports that IL-21R stimulation results in potent phosphorylation of STAT-1 and -3 and weak activation of STAT-5. However, our findings also show that treatment of DLBCL cell lines with IL-21 induces cell cycle arrest and apoptosis. The cell death is caspase-dependent and evident in a majority of DLBCL cell lines. To further examine the potential therapeutic applicability of IL-21, we assessed the effects of IL-21 on primary DLBCL tumor cells and in vivo DLBCL mice models. In primary tumors, IL-21 induced apoptosis in five of five DLBCLs compared to two of three follicular lymphomas, and two of seven chronic lymphocytic leukemias. No apoptosis or cell death was induced in normal peripheral B-lymphocytes. In xenograft DLBCL tumors, in situ IL-21 injections induced tumor regression and dramatically extended the overall survival of mice (P&lt;0.001). To elucidate the mechanism of IL-21-induced cell death, microarray analysis was performed on endogenously sensitive or resistant DLBCL cell lines as well as an RCK8 cell line that acquired IL-21 resistance following chronic exposure to the cytokine. The most striking difference between IL-21 sensitive and resistant cell lines was observed in the expression of c-Myc, a known target of STAT-3, which was only induced in cell lines undergoing apoptosis upon IL-21 treatment. We have shown that the cell death associated with IL-21 treatment was prevented by utilizing c-Myc specific siRNAs and shRNA. Interestingly, c-Myc upregulation and cell death was also prevented upon knockdown of STAT-3 with siRNAs. Stimulation of the STAT-3-cMYC signaling pathway led to decreases in levels of anti-apoptotic proteins Bcl-XL and Bcl-2, which are bone-fide targets of c-Myc. Our results delineate a new IL-21-induced pro-apoptotic signaling pathway involving STAT-3 and c-Myc, which are usually considered as anti-apoptotic effectors in cancer cells. Furthermore, our findings demonstrate that IL-21 is a highly potent anti-DLBCL agent in vitro and in xenograft DLBCL models and warrant initiation of clinical studies in patients.
Hematopoietic Stem Cell Gene Therapy For Wiskott- Aldrich Syndrome
Authors: Witzel Maximilian GW , Braun Christian J. , Boztug Kaan , Paruzynski Anna , Albert Michael H. , Schwarzer Adrian , Modlich Ute , Beier Rita , Göhring Gudrun , Naundorf Sonja , Kühlcke Klaus , Rose Martina , Fraser Christopher , Mathias Liesl , Ferrari Rudolf , Abboud Miguel R. , Al-Herz Waleed , Kondratenko Irina , Maródi László , Schlegelberger Brigitte , Baum Christopher , Schmidt Manfred , von Kalle Christof , Klein Christoph 
Published: April 2020

Abstract

Wiskott Aldrich Syndrome (WAS) is a life-threatening primary immunodeficiency disorder characterized by susceptibility to infections, hemorrhage and malignancies. We here report the clinical, immunological, and molecular results of ten patients treated with transfusion of autologous genetically corrected hematopoietic stem cells between 2006 and 2009. After hematopoietic stem cell gene therapy with a gamma-retroviral vector, we observed phenotypical and functional reconstitution of lymphoid, myeloid cell lines and platelet numbers in 9/10 patients. Of note, patients had sustained correction of T-cell proliferation, immunological synapse formation and NK-cell mediated lysis, capacity to generate specific antibodies, and platelet production and size. All nine patients with sustained stem cell engraftment had marked clinical improvement with respect to infections, bleeding, and autoimmunity. Comprehensive analysis of retroviral insertions sites revealed a polyclonal hematopoiesis with more than 120.000 recurring loci. However, 5/10 of patients developed T-ALL (mean 1054.2d post GT; range 488-1813d post GT), each associated with a retroviral insertion in close proximity to the LMO2 locus. In 3/5 of patients with T-ALL (treatment according to AEIOP 2009 protocol) allogeneic HSCT due to poor initial response, minimal residual disease relapse, or cytological relapse was indicated. Further, one patient developed MDS like bone marrow changes and consecutively AML (1165d post GT), HSCT was performed in remission. Retrospectively, MDS1 clonal contribution to insertion sites showed a slow increase over the period of 22 month in this patient. GT has proven to revert the cellular and clinical phenotype of WAS but remains associated with considerable risk for insertional mutagenesis. Refining gene therapy strategies is an important goal for patients with WAS.

Disclosures:
Naundorf: EUFETS GmbH: Employment. Kühlcke:EUFETS GmbH: Employment.
IL-2 enhances ex vivo–expanded regulatory T-cell persistence after adoptive transfer
Authors: Furlan Scott N. , Singh Karnail , Lopez Christina , Tkachev Victor , Hunt Daniel Joel , Hibbard James , Betz Kayla M. , Blazar Bruce R. , Trapnell Cole , Kean Leslie S. 
Published: April 2020

Abstract
As regulatory T cell (Treg) adoptive therapy continues to develop clinically, there is a need to determine which immunomodulatory agents pair most compatibly with Tregs to enable persistence and stabilize suppressor function. Prior work has shown that mechanistic target of rapamycin inhibition can increase the stability of thymic Tregs. In this study, we investigated the transcriptomic signatures of ex vivo–expanded Tregs after adoptive transfer in the setting of clinically relevant immunosuppression using a nonhuman primate (NHP) model as a prelude to future transplant studies. Here, we found that adding interleukin-2 (IL-2) to rapamycin in vivo supported a logarithmic increase in the half-life of adoptively transferred carboxyfluorescein diacetate succinimidyl ester–labeled, autologous NHP Tregs, effectively doubling the number of cells in the peripheral blood Treg compartment compared with Treg infusion when rapamycin was given alone. Using single-cell transcriptomics, we found that transferred ex vivo–expanded Tregs initially exhibit a gene expression signature consistent with an activated state. Moreover, those cells with the highest levels of activation also expressed genes associated with p53-mediated apoptosis. In contrast, transferred Tregs interrogated at day +20 posttransfer demonstrated a gene signature more similar to published profiles of resting Tregs. Together, these preclinical data further support combining IL-2 and rapamycin in vivo as adjunctive therapy for ex vivo–expanded adoptively transferred Tregs and suggest that the activation status of ex vivo–expanded Tregs is critical to their persistence.
Association between incident delirium and 28- and 90-day mortality in critically ill adults: a secondary analysis
Authors: Duprey Matthew S. , van den Boogaard Mark , van der Hoeven Johannes G. , Pickkers Peter , Briesacher Becky A. , Saczynski Jane S. , Griffith John L. , Devlin John W. 
Published: April 2020

Abstract
Background
While delirium prevalence and duration are each associated with increased 30-day, 6-month, and 1-year mortality, the association between incident ICU delirium and mortality remains unclear. We evaluated the association between both incident ICU delirium and days spent with delirium in the 28 days after ICU admission and mortality within 28 and 90 days.

Methods
Secondary cohort analysis of a randomized, double-blind, placebo-controlled trial conducted among 1495 delirium-free, critically ill adults in 14 Dutch ICUs with an expected ICU stay ≥2 days where all delirium assessments were completed. In the 28 days after ICU admission, patients were evaluated for delirium and coma 3x daily; each day was coded as a delirium day [≥1 positive Confusion Assessment Method for the ICU (CAM-ICU)], a coma day [no delirium and ≥ 1 Richmond Agitation Sedation Scale (RASS) score ≤ − 4], or neither. Four Cox-regression models were constructed for 28-day mortality and 90-day mortality; each accounted for potential confounders (i.e., age, APACHE-II score, sepsis, use of mechanical ventilation, ICU length of stay, and haloperidol dose) and: 1) delirium occurrence, 2) days spent with delirium, 3) days spent in coma, and 4) days spent with delirium and/or coma.

Results
Among the 1495 patients, 28 day mortality was 17% and 90 day mortality was 21%. Neither incident delirium (28 day mortality hazard ratio [HR] = 1.02, 95%CI = 0.75–1.39; 90 day mortality HR = 1.05, 95%CI = 0.79–1.38) nor days spent with delirium (28 day mortality HR = 1.00, 95%CI = 0.95–1.05; 90 day mortality HR = 1.02, 95%CI = 0.98–1.07) were significantly associated with mortality. However, both days spent with coma (28 day mortality HR = 1.05, 95%CI = 1.02–1.08; 90 day mortality HR = 1.05, 95%CI = 1.02–1.08) and days spent with delirium or coma (28 day mortality HR = 1.03, 95%CI = 1.00–1.05; 90 day mortality HR = 1.03, 95%CI = 1.01–1.06) were significantly associated with mortality.

Conclusions
This analysis suggests neither incident delirium nor days spent with delirium are associated with short-term mortality after ICU admission.

Trial registration
ClinicalTrials.gov, Identifier NCT01785290 Registered 7 February 2013.
A molecular survey of vector-borne pathogens and haemoplasmas in owned cats across Italy
Authors: Latrofa Maria Stefania , Iatta Roberta , Toniolo Federica , Furlanello Tommaso , Ravagnan Silvia , Capelli Gioia , Schunack Bettina , Chomel Bruno , Zatelli Andrea , Mendoza-Roldan Jairo , Dantas-Torres Filipe , Otranto Domenico 
Published: April 2020

Abstract
Background
Feline vector-borne pathogens (FeVBPs) have been increasingly investigated for their impact on cat health and their zoonotic potential. The aim of the present study was to assess the prevalence of FeVBPs and haemoplasmas in cats across Italy and to identify potential risk factors linked to their occurrence.

Methods
Blood samples from 958 owned cats living in the North (n = 556), Centre (n = 173) and South (n = 229) of Italy were tested for Babesia spp., Hepatozoon spp., Ehrlichia spp., Anaplasma spp. and filarioids by conventional PCR (cPCR) and for haemoplasmas and Bartonella spp. by SYBR green real-time PCR. Cats included in the study represent a sub-sample from a larger number of animals enrolled in a previous study, which were selected based on the geographical origin. Data on cats’ positivity for Leishmania infantum, feline leukaemia virus (FeLV) and for feline immunodeficiency virus (FIV), available from the previous study, were included and examined. Potential risk factors for pathogen infection were assessed in relationship to categorical variables including sex, geographical origin, breed, neutering status and age of cats.

Results
Out of the 958 cats, 194 (20.2%) were positive for at least one of the tested pathogens, 89 (16%) from the North, 32 (18.5%) from the Centre and 73 (31.9%) from the South of Italy. A high prevalence of FeVBPs was detected in male cats (n = 125, 27.8%), living in the southern part of the country (n = 73, 31.9%), younger than 18 months of age (n = 24, 22.4%) and not neutered (n = 39; 27.5%). In particular, 24 cats (2.5%) tested PCR-positive for Bartonella spp., of which 1.6% for B. henselae and 0.9% for B. clarridgeiae. A total of 111 cats scored PCR-positive for haemoplasmas (11.6%), specifically “Candidatus Mycoplasma haemominutum” (n = 95, 9.9%), M. haemofelis (n = 14, 1.5%) and “Candidatus Mycoplasma turicensis” (n = 2, 0.2%). Moreover, 39, 31 and 8 cats were positive for FeLV (4.1%), L. infantum (3.2%) and FIV (0.8%), respectively. Co-infections were registered for 19 (9.8%) cats.

Conclusions
These results confirm the occurrence of haemoplasmas and FeVBPs throughout Italy. Preventive measures to protect both animal and human health should be carried out also for owned cats, even if no health status of animals has been assessed in this study.
A new piroplasmid species infecting dogs: morphological and molecular characterization and pathogeny of Babesia negevi n. sp.
Authors: Baneth Gad , Nachum-Biala Yaarit , Birkenheuer Adam Joseph , Schreeg Megan Elizabeth , Prince Hagar , Florin-Christensen Monica , Schnittger Leonhard , Aroch Itamar 
Published: April 2020

Abstract
Introduction
Babesiosis is a protozoan tick-borne infection associated with anemia and life-threatening disease in humans, domestic and wildlife animals. Dogs are infected by at least six well-characterized Babesia spp. that cause clinical disease. Infection with a piroplasmid species was detected by light microscopy of stained blood smears from five sick dogs from Israel and prompted an investigation on the parasite’s identity.

Methods
Genetic characterization of the piroplasmid was performed by PCR amplification of the 18S rRNA and the cytochrome c oxidase subunit 1 (cox1) genes, DNA sequencing and phylogenetic analysis. Four of the dogs were co-infected with Borrelia persica (Dschunkowsky, 1913), a relapsing fever spirochete transmitted by the argasid tick Ornithodoros tholozani Laboulbène & Mégnin. Co-infection of dogs with B. persica raised the possibility of transmission by O. tholozani and therefore, a piroplasmid PCR survey of ticks from this species was performed.

Results
The infected dogs presented with fever (4/5), anemia, thrombocytopenia (4/5) and icterus (3/5). Comparison of the 18S rRNA and cox1 piroplasmid gene sequences revealed 99–100% identity between sequences amplified from different dogs and ticks. Phylogenetic trees demonstrated a previously undescribed species of Babesia belonging to the western group of Babesia (sensu lato) and closely related to the human pathogen Babesia duncani Conrad, Kjemtrup, Carreno, Thomford, Wainwright, Eberhard, Quick, Telfrom & Herwalt, 2006 while more moderately related to Babesia conradae Kjemtrup, Wainwright, Miller, Penzhorn & Carreno, 2006 which infects dogs. The piroplasm forms detected included tetrads (Maltese cross), merozoite and trophozoite stages whose average size was larger than stages of other canine Babesia spp. belonging to the Babesia (s.l.) and B. gibsoni Patton, 1910, and smaller than other canine Babesia (sensu stricto) spp. Of 212 O. tholozani ticks surveyed, 11 (5.2%) harbored DNA of the new species of Babesia.

Conclusions
Babesia negevi n. sp. is described based on morphological and genetic characterization and phylogenetic analyses. The species is named after the Negev desert of southern Israel, where the first infected dog originated from. Despite co-infection in four dogs, the fifth dog had fatal disease attesting that B. negevi n. sp. infection requires clinical attention. Incriminating O. tholozani or another tick species as the vector of Babesia negevi n. sp., would require additional studies.
Sedimentary organic matter from a cored Early Triassic succession, Georgetown (Idaho, USA)
Authors: Schneebeli-Hermann Elke , Bagherpour Borhan , Vennemann Torsten , Leu Marc , Bucher Hugo 
Published: April 2020

AbstractThe plant fossil record from Lower Triassic sedimentary successions of the Western USA is extremely meager. In this study, samples from a drill core taken near Georgetown, Idaho, were analyzed for their palynological content as well as their stable carbon isotope composition. The concentration of palynomorphs is generally low. The lowermost part of the drilled succession represents Dinwoody/Woodside Formation and contains spore and pollen assemblages with Permian and Early Triassic affinity. Representatives of lycophytes (Densoisporites spp., Lundbladisporites spp.) were found in the overlying Meekoceras Limestone, in agreement with middle Smithian assemblages elsewhere. Ammonoids and conodonts are extremely rare, but confirm a middle Smithian age. Bulk organic and carbonate carbon isotope composition provide a stratigraphic framework. Carbonate carbon isotope compositions are compatible with the Smithian–Spathian global trend, with a middle Smithian shift towards lower δ13C values followed by a late Smithian shift towards higher values. Bulk organic carbon isotope compositions have been influenced by changes in the constitution of organic matter. A comparison with other paired carbon isotope datasets from the same basin is difficult due to lithostratigraphic inconsistencies (Hot Springs, ID) or biochemical mediated disturbance of isotope signals (Mineral Mountains, UT).
Health and well-being literacy initiatives focusing on immigrant communities: an environmental scan protocol to identify "what works and what does not"
Authors: Turin Tanvir C. , Chowdhury Nashit , Ferdous Mahzabin , Vaska Marcus , Rumana Nahid , Dahal Rudra , Rahman Nafiza , Chowdhury Mohammad Z. I. 
Published: April 2020

Abstract
Introduction
Most of the major cities in the developed western countries are characterized by an increasing multiculturalism brought by the immigrant population. The immigrant communities face challenges in the new environment with their health and wellness related unmet needs. It is imperative to find sustainable ways to empower these diverse communities to champion their health and wellness. Community-based health and wellness literacy initiatives (CBHWLI) focusing on immigrant communities can be an important step towards citizen empowerment in this regard. The aim of the present environmental scan is to identify the key factors that might impact a CBHWLI in immigrant communities in Canada in order to facilitate the process in practice and identify the competencies and training required for its implementation.

Methods
This study will gather information from existing literature and online sources as well as will capture expert and lay perspectives on the factors that can impact the effectiveness and sustainability of CBHWLIs through conducting a comprehensive environmental scan: (i) a systematic scoping review of published literature and grey literature, (ii) a comprehensive Internet search, (iii) key informant interviews, and (iv) community consultation. Specific methodological and analytical frameworks will guide each step.

Ethics and dissemination
This study is the first step in establishing a practical base for developing CBHWLI implementation research. Once the initial findings have been generated, the second step will involve inviting experts to provide their input. We first plan to disseminate the results of our scoping review and Internet scan through meetings with key stakeholders, to be followed by journal publications and conference or workshop presentations. Ethical approval is not required for the scoping review or Internet scan; however, approval to conduct interviews with key informants and community consultations in the second stage of the study will be sought from the Conjoint Health Research Ethics Board.