bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinicopathologic Determinants of Survival in Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma (MEITL): Analysis of a Pooled Database
Authors: Haddad Philip A , Dadi Neelakanta 
Published: February 2021

Introduction:
MEITL is a rare and rapidly progressive extranodal T-cell lymphoma that arises from the intestinal intraepithelial T lymphocytes. Established in the 2016 WHO classification, this entity was carved out of what was previously known as type 2 enteropathy-associated T-cell lymphoma. MEITL usually affects the young-old and is not associated with celiac disease. We conducted this analysis to explore the clinicopathologic determinants of survival in this newly established T-cell entity.
Methods:
In order to study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 116 cases. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).
Results:
A total of 116 patients with confirmed MEITL were identified. The median age was 59.5 years with a peak incidence between ages 56 and 68. There was a male predominance with M:F ratio of 2. The jejunum was the most commonly involved site (71%). Median OS of the whole group was 11 months. The most common presentations were abdominal pain, followed by perforation, diarrhea, and weight loss. The majority presented at stages I&II (78%). The median duration of symptoms prior to diagnosis was 4 months. Compared to no treatment, combination chemotherapy and stem cell transplant (SCT) were statistically superior with a median OS of 2, 9, and 34 months respectively (p=0.0005). Further analysis revealed that surgical resection imparted a survival advantage on its own and in conjunction with combination chemotherapy and SCT. When surgical resection was incorporated in the analysis, median OS amounted to 2, 5, 7, 11, 13, 24 months for no treatment, surgery alone, chemotherapy, surgery+chemotherapy, SCT, and surgery+SCT respectively (p=0.0015). The quality of response to treatment also seemed to impact the outcome (p=0.0005) with median OS of 6, 36, and 60 months for none/transient, PR, and CR respectively. OS was not impacted by sex, presentation with obstruction or perforation, or anatomic site involvement. While older age, weight loss, and TCRγδ seemed to negatively impact OS, they did not reach statistical significance.
Conclusions:
This study presents an updated clinicopathologic data from a pooled cohort of patients with MEITL. It identifies quality of response, treatment modalities as well as surgical resection as major determinants of OS in this rare disease.

Disclosures
No relevant conflicts of interest to declare.
Assay Specificity and Sensitivity Evaluation of Cepheid GeneXpert® NPM1 Prototype for Mutation Detection in Acute Myeloid Leukemia
Authors: Yang Xi , Shridhar Krupa , Sanjeeviraman Jayashree , Day Gwo-Jen 
Published: February 2021

Background:
Mutations in thenucleophosmin1 (NPM1) are considered as founder mutations in acute myeloid leukemia (AML). NPM1 mutations in exon 12 occur in about 60% adult AML patients with normal karyotype. Among all NPM1 subtypes, type A (69.15%), type B (7.41%) and type D (7.41%) are found to be most frequent. The evaluation of minimal residual disease (MRD) has been considered critical to more precisely define AML response to clinical treatment, thereby refining disease risk stratification. Currently, AML with NPM1 gene mutations is recognized as a distinct entity, due to its unique clinical features. A large body of evidence demonstrated a significant independent prognosis factor of molecular MRD monitoring in NPM1-mutated AML.
Objectives:
Here we present GeneXpert NPM1 prototype, a fast and promising test for use in AML mutation detection (this prototype is for research use only, not for use in diagnostic procedures, and not reviewed by any regulatory body). NPM1 prototype is an easy-to-use-sample in/results out, and highly sensitive assay. The turnaround time is as fast as less than 3 hours. NPM1 prototype is designed for the quantitative detection of NPM1 mutant mRNA transcripts (types A, B and D in exon 12) and the ABL endogenous control mRNA transcript in peripheral blood of AML patients. This test is also designed for use as an aid in the monitoring of mutant NPM1 mRNA transcript levels in patients diagnosed with NPM1-mutated AML. This test does not differentiate between A, B or D type mutant NPM1 transcripts and does not detect or monitor other rare types of mutant NPM1.
Results:
Through assay optimization, we were able to reach limit of detection (LoD) within 0.05% for three NPM1 subtypes among all screened EDTA donor blood samples. Ct-copy number regression curve aligns well among three subtypes, within detection range. Our assay specificity has been above 95% among 30 screened EDTA donor blood samples.
Conclusion:
In summary, GeneXpert NPM1 prototype shows promise as a fast test for use in AML mutation detection.The presented NPM1 prototype has a great advantage covering most prevalent NPM1 mutation types up to 94% of all NPM1 subtypes. Our results demonstrated that our prototype shows satisfactory assay specificity and sensitivity. Clinical samples will be included for our clinical validation in the future.

Disclosures
No relevant conflicts of interest to declare.
Estrogen: Friend or Foe in Monge's Disease?
Authors: Azad Priti , Villafuerte Francisco , Haddad Gabriel 
Published: February 2021

Rationale: Chronic mountain sickness (CMS), or Monge's disease, is a progressive debilitating syndrome caused by chronic (years) exposure to high altitude hypoxia, as experienced by people living in the Andean region. Excessive erythrocytosis (EE) is one of the critical traits of CMS and this excessive pathobiologic response has deleterious effects since a high hematocrit would increase blood viscosity and reduce blood flow to hypoxia-sensitive organs (brain and heart), often resulting in myocardial infarction or stroke in young adults. Within the population of Cerro de Pasco in the Andes, CMS prevalence is vastly different between males and females, being rare in females. Of interest is that there is a sharp increase in CMS incidence in females after menopause. This suggests the role of gender and sex hormones in altering disease manifestation.
Methods: In order to understand the molecular basis for polycythemia of high altitude, we have generated a disease in-the dish-model by re-programming fibroblasts and native CD34+ve cells from CMS and non-CMS subjects and converting them to RBC. Using this in-vitro platform, we are now studying the interactions between genetic factors and sex hormones (Testosterone, Estrogen and Progesterone) and their effect on RBC production in the CMS and non-CMS subjects at high altitude.
Results: While we found that testosterone increased RBC production mildly (insignificantly), estrogen in physiologic concentrations (10nM), in sharp contrast, reduced the CD235a (Glycophorin A- marker of mature RBC) remarkably (from 56% in the untreated CMS sample to 10% in the treated CMS) and eliminated the CMS EE phenotype. There is also stage-specificity and dose response effects for estrogen. This strongly suggests that estrogen has a protective role against the polycythemia phenotype. To probe further, we studied the effect of estrogen (10nM) on GATA1, a critical link with erythropoiesis. There was a sharp 5 fold decrease in GATA1 (p&lt;0.01) and its target genes such as Alas2 (p&lt;0.001) in erythroid cells. This decreased expression resulted in marked reduction (&gt;50%) in RBC production, demonstrating that estrogen constrains RBC production in females.
Conclusion: Our results demonstrate that estrogen inhibits GATA1 expression and prevents excessive erythropoiesis and Monge's disease in females at high altitude. We believe that these studies not only shed light on the role of sex hormones on hypoxia-induced excessive erythropoiesis but have a broader application in their regulation of erythropoiesis and related blood disorders.

Disclosures
No relevant conflicts of interest to declare.
Aberrant Expression of Mir-20a in Serum Exosomes of Multiple Myeloma Lead Abnormal Expression of HIF-1 Signaling Pathway Related Proteins
Authors: Zhang Zhiyao , Zhou Huixing , Geng Chuanying , Gao Wen , Chen Wenming 
Published: February 2021

Objective To determine the abnormal expression of miRNA in plasma exosomes of patients with multiple myeloma (MM) and its effect on the expression of HIF signaling pathway related proteins.
Methods Microarray analysis was performed on the exosomal miRNA analysis of 12 MM patients to determine how it might participate in MM. Then a co-expression network was performed to discover the potential role of miRNAs in regulating tumorigenesis and disease progression of MM. The expression of miR-20a in the exosomes of 48 MM patients was detected and the potential target genes were verified.
Results Differential expression of 43 miRNAs was observed in exosomes of multiple myeloma (MM) patients compared to healthy individuals. Among them, 7 miRNAs were significantly up-regulated in patients with multiple myeloma, and 35 miRNAs were significantly decreased compared with healthy controls. The results of microarray analysis showed that the seven miRNAs up-regulated in MM exosomes were mainly involved in NF-κB signaling, tumor necrosis factor-mediated signaling pathway regulation while 37 down-regulated miRNAs are mainly involved in HIF-1 signaling pathway, vascular development, cell adhesion. Decreased expression of miR-20a was associated with MM aggressiveness in the MM cohort compared with healthy individuals. We identified HIF-1 signaling pathway related proteins SENP1 and sumo as a potential target gene of miR-20a which were upregulation in MM.
Conclusion The microarray chip confirmed the differential expression of miRNA in plasma exosomes of patients with myeloma and healthy controls. Abnormally expressed miRNAs may be involved in the occurrence and development of tumors. These results may provide further evidence for exosomes as novel biomarkers for predicting MM recurrence.

Disclosures
No relevant conflicts of interest to declare.
Combination of Bortezomib and Venetoclax Induces Synergistic Killing of Epstein-Barr Virus-Driven Lymphoproliferative Diseases By Targeting the Pro-Survival Function of Latent Membrane Protein-1 and Epstein-Barr Nuclear Antigen-3C
Authors: Chiang Alan Kwok Shing , Tam Kam Pui , Au-Yeung Rex Kwok Him 
Published: February 2021

Epstein-Barr virus (EBV) is strongly associated with lymphoproliferative diseases (LPDs), in particular B cell, in both immunocompetent and immunocompromised hosts. The virus is able to manipulate host cell machineries such as the ubiquitin-proteasome system and regulators of Bcl-2 family to enable the persistence of the virus and the survival of the host cells through expression of various viral proteins in distinct latency patterns. Latent membrane protein-1 (LMP-1) is a constitutively active CD40 receptor homolog and activates NF-κB signaling pathways to induce Bcl-2 expression whilst Epstein-Barr nuclear antigen-3C (EBNA-3C) interacts with and mediates proteasomal degradation of Bcl-6 protein which, in turn, increases Bcl-2 expression. We hypothesize that combining a proteasome inhibitor, bortezomib, with a Bcl-2 inhibitor, venetoclax, will induce synergistic killing of EBV-driven LPDs expressing both LMP-1 and EBNA-3C in the latency III pattern. Isobologram showed that combination of bortezomib and venetoclax could synergistically induce potent apoptosis of spontaneous lymphoblastoid cell lines (sLCL), derived from patients with post-transplant lymphoproliferative disorder (PTLD), expressing LMP-1 and EBNA-3C proteins. The mechanism of killing was related to the suppression of NF-κB signaling pathway induced by LMP-1. The phosphorylation of serine 70 of Bcl-2, which enhances the anti-apoptotic activity of Bcl-2 through stabilization of its interaction with other pro-apoptotic proteins such as Bak and Bim, was decreased in the sLCL, but not in the LMP-1 or EBNA-3C knockdown LCL, upon treatment with the drug combination. Activation of DNA damage response and production of reactive oxygen species were observed in the sLCL, contributing to the synergistic cell death. Bortezomib induced the expression of pro-apoptotic initiator, NOXA, to enhance the susceptibility of the sLCL to apoptosis upon treatment with venetoclax whilst knockdown of NOXA in the sLCL led to the resistance of the cells to apoptosis induced by the drug combination. In-vivo study demonstrated that the drug combination significantly inhibited the growth of xenograft of sLCL in SCID mice (p&lt;0.001). Taken together, we conclude that the combination of bortezomib and venetoclax induces synergistic killing of EBV-driven LPDs such as PTLD by targeting the pro-survival function of LMP-1 and EBNA-3C.

Disclosures
No relevant conflicts of interest to declare.
Secreted modular calcium-binding protein 1 binds and activates thrombin to account for platelet hyperreactivity in diabetes
Authors: Delgado Lagos Fredy , Elgheznawy Amro , Kyselova Anastasia , Meyer zu Heringdorf Dagmar , Ratiu Corina , Randriamboavonjy Voahanginirina , Mann Alexander W. , Fisslthaler Beate , Siragusa Mauro , Fleming Ingrid 
Published: February 2021

Abstract
Secreted modular calcium-binding protein 1 (SMOC1) is an osteonectin/SPARC-related matricellular protein, whose expression is regulated by microRNA-223 (miR-223). Given that platelets are rich in miR-223, this study investigated the expression of SMOC1 and its contribution to platelet function. Human and murine platelets expressed SMOC1, whereas platelets from SMOC1+/− mice did not present detectable mature SMOC1 protein. Platelets from SMOC1+/− mice demonstrated attenuated responsiveness to thrombin (platelet neutrophil aggregate formation, aggregation, clot formation, Ca2+ increase, and β3 integrin phosphorylation), whereas responses to other platelet agonists were unaffected. SMOC1 has been implicated in transforming growth factor-β signaling, but no link to this pathway was detected in platelets. Rather, the SMOC1 Kazal domain directly bound thrombin to potentiate its activity in vitro, as well as its actions on isolated platelets. The latter effects were prevented by monoclonal antibodies against SMOC1. Platelets from miR-223–deficient mice expressed high levels of SMOC1 and exhibited hyperreactivity to thrombin that was also reversed by preincubation with monoclonal antibodies against SMOC1. Similarly, SMOC1 levels were markedly upregulated in platelets from individuals with type 2 diabetes, and the SMOC1 antibody abrogated platelet hyperresponsiveness to thrombin. Taken together, we have identified SMOC1 as a novel thrombin-activating protein that makes a significant contribution to the pathophysiological changes in platelet function associated with type 2 diabetes. Thus, strategies that target SMOC1 or its interaction with thrombin may be attractive therapeutic approaches to normalize platelet function in diabetes.
Excretable, ultrasmall hexagonal NaGdF4:Yb50% nanoparticles for bimodal imaging and radiosensitization
Authors: Damasco Jossana A. , Ohulchanskyy Tymish Y. , Mahajan Supriya , Chen Guanying , Singh Ajay , Kutscher Hilliard L. , Huang Haoyuan , Turowski Steven G. , Spernyak Joseph A. , Singh Anurag K. , Lovell Jonathan F. , Seshadri Mukund , Prasad Paras N. 
Published: February 2021

Abstract
Background
In this study, we report on the synthesis, imaging, and radiosensitizing properties of ultrasmall β-NaGdF4:Yb50% nanoparticles as a multifunctional theranostic platform. The synthesized nanoparticles act as potent bimodal contrast agents with superior imaging properties compared to existing agents used for magnetic resonance imaging (MRI) and computed tomography (CT). Clonogenic assays demonstrated that these nanoparticles can act as effective radiosensitizers, provided that the nanoparticles are taken up intracellularly.

Results
Our ultrasmall β-NaGdF4:Yb50% nanoparticles demonstrate improvement in T1-weighted contrast over the standard clinical MR imaging agent Gd-DTPA and similar CT signal enhancement capabilities as commercial agent iohexol. A 2 Gy dose of X-ray induced ~ 20% decrease in colony survival when C6 rat glial cells were incubated with non-targeted nanoparticles (NaGdF4:Yb50%), whereas the same X-ray dose resulted in a ~ 60% decrease in colony survival with targeted nanoparticles conjugated to folic acid (NaGdF4:Yb50%-FA). Intravenous administration of nanoparticles resulted in clearance through urine and feces within a short duration, based on the ex vivo analysis of Gd3+ ions via ICP-MS.

Conclusion
These biocompatible and in vivo clearable ultrasmall NaGdF4:Yb50% are promising candidates for further evaluation in image-guided radiotherapy applications.
The heritable landscape of near-infrared and Raman spectroscopic measurements to improve lipid content in Atlantic salmon fillets
Authors: Difford Gareth F. , Horn Siri S. , Dankel Katinka R. , Ruyter Bente , Dagnachew Binyam S. , Hillestad Borghild , Sonesson Anna K. , Afseth Nils K. 
Published: February 2021

AbstractBackgroundProduct quality and production efficiency of Atlantic salmon are, to a large extent, influenced by the deposition and depletion of lipid reserves. Fillet lipid content is a heritable trait and is unfavourably correlated with growth, thus genetic management of fillet lipid content is needed for sustained genetic progress in these two traits. The laboratory-based reference method for recording fillet lipid content is highly accurate and precise but, at the same time, expensive, time-consuming, and destructive. Here, we test the use of rapid and cheaper vibrational spectroscopy methods, namely near-infrared (NIR) and Raman spectroscopy both as individual phenotypes and phenotypic predictors of lipid content in Atlantic salmon.ResultsRemarkably, 827 of the 1500 individual Raman variables (i.e. Raman shifts) of the Raman spectrum were significantly heritable (heritability (h2) ranging from 0.15 to 0.65). Similarly, 407 of the 2696 NIR spectral landscape variables (i.e. wavelengths) were significantly heritable (h2= 0.27–0.40). Both Raman and NIR spectral landscapes had significantly heritable regions, which are also informative in spectroscopic predictions of lipid content. Partial least square predicted lipid content using Raman and NIR spectra were highly concordant and highly genetically correlated with the lipid content values ($${r}_{\text{g}}$$rg= 0.91–0.98) obtained with the reference method using Lin’s concordance correlation coefficient (CCC = 0.63–0.90), and were significantly heritable ($${h}^{2}$$h2= 0.52–0.67).ConclusionsBoth NIR and Raman spectral landscapes show substantial additive genetic variation and are highly genetically correlated with the reference method. These findings lay down the foundation for rapid spectroscopic measurement of lipid content in salmonid breeding programmes.
GMO Genetic Elements Thesaurus (GMO-GET): a controlled vocabulary for the consensus designation of introduced or modified genetic elements in genetically modified organisms
Authors: Adamse Paulien , Dagand Emilie , Bohmert-Tatarev Karen , Wahler Daniela , Miranda Manoela , Kok Esther J. , Bendiek Joachim 
Published: February 2021

Abstract
Background
Various databases on genetically modified organisms (GMOs) exist, all with their specific focus to facilitate access to information needed for, e. g., the assistance in risk assessment, the development of detection and identification strategies or inspection and control activities. Each database has its unique approach towards the subject. Often these databases use different terminology to describe the GMOs. For adequate GMO addressing and identification and exchange of GMO-related information it is necessary to use commonly agreed upon concepts and terminology.

Result
A hierarchically structured controlled vocabulary describing the genetic elements inserted into conventional GMOs, and GMOs developed by the use of gen(om)e-editing is presented: the GMO genetic element thesaurus (GMO-GET). GMO-GET can be used for GMO-related documentation, including GMO-related databases. It has initially been developed on the basis of two GMO databases, i.e. the Biosafety Clearing-House and the EUginius database.

Conclusion
The use of GMO-GET will enable consistent and compatible information (harmonisation), also allowing an accurate exchange of information between the different data systems and thereby facilitating their interoperability. GMO-GET can also be used to describe genetic elements that are altered in organisms obtained through current targeted genome-editing techniques.
Eosinophil-to-monocyte ratio is a potential biomarker in the prediction of functional outcome among patients with acute ischemic stroke
Authors: Yu Shuhong , Luo Yi , Zhang Tan , Huang Chenrong , Fu Yu , Zhang Qiang , Zeng Fangyue , Huang Hao , Zhang Chunyuan , Guo Zhiliang 
Published: February 2021

Abstract
Background
It has been shown that eosinophils are decreased and monocytes are elevated in patients with acute ischemic stroke (AIS), but the impact of eosinophil-to-monocyte ratio (EMR) on clinical outcomes among AIS patients remains unclear. We aimed to determine the relationship between EMR on admission and 3-month poor functional outcome in AIS patients.

Methods
A total of 521 consecutive patients admitted to our hospital within 24 h after onset of AIS were prospectively enrolled and categorized in terms of quartiles of EMR on admission between August 2016 and September 2018. The endpoint was the poor outcome defined as modified Rankin Scale score of 3 to 6 at month 3 after admission.

Results
As EMR decreased, the risk of poor outcome increased (p < 0.001). Logistic regression analysis revealed that EMR was independently associated with poor outcome after adjusting potential confounders (odds ratio, 0.09; 95% CI 0.03–0.34; p = 0.0003), which is consistent with the result of EMR (quartile) as a categorical variable (odds ratio, 0.23; 95% CI 0.10–0.52; ptrend < 0.0001). A non-linear relationship was detected between EMR and poor outcome, whose point was 0.28. Subgroup analyses further confirmed these associations. The addition of EMR to conventional risk factors improved the predictive power for poor outcome (net reclassification improvement: 2.61%, p = 0.382; integrated discrimination improvement: 2.41%, p < 0.001).

Conclusions
EMR on admission was independently correlated with poor outcome in AIS patients, suggesting that EMR may be a potential prognostic biomarker for AIS.