bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Analysis of Cutaneous CD30-Positive Lymphoproliferative Disorders
Authors: Abdulla Farah R , Zhang Weiwei , Wu Xiwei , Honda Kord , Qin Hanjun , Cho Hyejin , Querfeld Christiane , Zain Jasmine , Rosen Steven T. , Chan Wing C. , Parekh Vishwas , Song Joo Y. 
Published: November 2021

Abstract
Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPD) are the second most common cutaneous lymphomas. According to the World Health Organization (WHO), CD30+ LPD include primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP) as well as borderline lesions. pcALCL and LyP is thought to represent two ends of a spectrum of diseases that have different clinical presentations, clinical courses, and prognoses in their classic forms, but share the same histology of medium to large CD30+ atypical lymphoid cell infiltrates. Because the behavior of these entities is different clinically and prognostically, we aim to search for oncogenic genomic variants using whole exome sequencing (WES) that drive the development of LyP and pcALCL.
Clinical information, pathology, immunohistochemistry, and T-cell rearrangements on six cases of LyP and five cases of pcALCL were reviewed to confirm the rendered diagnosis prior to WES of all specimens. All cases of CD30 LPD had recurrent mutations in at least one of the epigenetic modifying genes, with the most frequent mutations found in the mixed lineage methyltransferase family involved in the methylation of H3K4: CREBBP (27%), KMT2A (36%), KMT2D (36%), SETD2 (27%), and SMARCA4 (27%) (Figure). Within the JAK/STAT pathway, mutations of STAT3 were observed in 2 cases of pcALCL (n=2, 18%), STAT5B in one case of LyP (n=1, 9%) and JAK1 mutation in one case of LyP(n=1, 9%). Lastly, mutations were also identified in the T-cell signaling pathway. 3/5 cases of pcALCL demonstrated loss of function mutations in EOMES, a T-box transcription factor important in lymphocyte development. We had two cases of C-ALCL and one case of LyP with NOTCH1 mutations supporting the importance of this gene in T-cell lymphomas.
TP53 mutations and copy number loss is more characteristic of aggressive lymphomas and these abnormalities were absent in pcALCL and LyP and may explain the indolent nature of CD30+ LPD.
While the JAK/STAT pathway, T-signaling, and epigenetic alterations possibly play a role in the pathogenesis of these diseases, genes involved in cell-cycle control and apoptosis (ie. TP53) that are characteristic of more aggressive diseases were not identified. Extending this investigation to a larger number of samples will allow us to detect additional mutations that may help distinguish between CD30+ LPDs of LyP and pcALCL as well as other histologic mimics such as systemic ALCL and large cell transformation of MF.
Figure 1 Figure 1.

Disclosures
Abdulla: Caris Life Licenses: Current Employment. Zain: Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria; Secura Bio, DaichiSankyo, Abbvie: Research Funding; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy.
Characterising Tumour and Microenvironmental Responses to R-CHOP in Immunocompetent Mouse Models of DLBCL
Authors: Maybury Bernard D , Bewicke-Copley Findlay , Johnson Peter , Fitzgibbon Jude , Calado Dinis Pedro 
Published: November 2021

Abstract
R-CHOP chemoimmunotherapy has been the standard of care for diffuse large B cell lymphoma (DLBCL) for 20 years. The lymphoma and microenvironment responses to R-CHOP have not been studied in detail in an experimental setting. Here we describe the early effects of R-CHOP on lymphoma cells and infiltrating T cells in novel mouse models of DLBCL. Using cre-lox recombination to induce B cell-specific overexpression of MYC, IKK2 and BLIMP1 drives the formation of unique high grade B cell lymphomas with an activated B cell (ABC) phenotype and an intact immune environment. Using flow cytometry and RNA sequencing we compare the response to R-CHOP in these mice with the response in a cell line lymphoma model. We also performed partial splenectomy prior to R-CHOP treatment to study paired samples pre-treatment and at relapse by whole-exome and RNA sequencing. Treatment with anti-CD20 alone induced very few changes in lymphoma cells in either model, but CHOP chemotherapy in combination with rituximab induced changes in lymphoma cell and T cell phenotypes. In particular, extracellular matrix and cell adhesion gene signatures were enriched in lymphoma cells after treatment, in both disease models studied. After injection of the cell line, memory populations of CD8+ T cells are expanded but this change is reversed by chemotherapy, whereas in the cre-lox conditional model 40% of CD8+ T cells are exhausted with smaller chemotherapy-associated changes. In the paired pre-treatment/relapse samples we observed clonal selection and increased mutation burden at relapse, associated with diverse transcriptional changes. Mutations were newly detected or expanded at relapse in various lymphoma-associated genes including Trp53, Samhd1 and Ubr5. Our results suggest that DLBCL responses to treatment and biology at relapse are principally driven by tumour-specific factors, but there are some commonalities across model systems which may be amenable to therapeutic modulation. The differences in T cell responses between conditional tumours and cell-line tumours demonstrate the limitations of cell lines for studying treatment responses in vivo.
Figure 1 Figure 1.

Disclosures
Johnson: Boehringer Ingelheim: Consultancy; Janssen: Consultancy; Kite Pharma: Honoraria; Oncimmune: Consultancy; Epizyme: Consultancy, Research Funding; Bristol-Myers: Honoraria; Incyte: Honoraria; Genmab: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Morphosys: Honoraria; Celgene: Honoraria; Kymera: Honoraria. Fitzgibbon: Epizyme: Research Funding. Calado: Myricx Pharma: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties: Cancer Treatments. WO patent WO 2020/128475 A1 (2020).
A Snapshot of Venous Thromboembolism (VTE): Retrospective Audit of Events at a Metropolitan Tertiary Referral Hospital
Authors: Chong Julianne , Dissanayake Rukmal K , Younan Sarah , Chan Michael V , Yang Yao , Wong Doo Nicole , Chen Vivien 
Published: November 2021

Abstract
Background
Facility-level review of hospital-acquired venous thromboembolism (HA-VTE) cases, including pulmonary embolism (PE) and deep vein thrombosis (DVT), can provide insight into the local drivers of this preventable complication.
Aim
To determine the nature of HA-VTE, patient characteristics, VTE risk assessment completion and appropriateness of prescribed VTE prophylaxis at a metropolitan tertiary referral hospital and to compare the number of HA-VTE detected by audit of imaging scans with those reported by clinical coding.
Methods
We conducted a retrospective electronic medical record audit encompassing all patients diagnosed with HA-VTE via ventilation-perfusion scan, computed tomographic pulmonary angiography and/or doppler ultrasound using a demographic and VTE risk assessment audit tool during selected months of 2017-2019. We compared the number of manually audited cases with the number of performance unit-coded cases for the same months.
Results
The months of May 2017, October 2017, April to July 2018 and April to July 2019 were included. There was a significant difference between HA-VTE detected via manual audit (147 events) and hospital coding (18 events), p=0.002. Manual audit patients were majority non-surgical (65%), female (58%), over 60 years (80%), at moderate VTE risk (71%) with reduced mobility (52%). There were 108 DVT-only (73%), 23 PE-only (16%) and 16 DVT plus PE events (11%). Notable risk factors were moderate to major surgery (30%), active malignancy or cancer treatment (24%) and active infection (27%). Most patients were prescribed appropriate VTE prophylaxis (74%) and had documented VTE risk assessment (68%). Appropriate VTE prophylaxis was significantly associated with using an electronic clinical decision support tool during VTE risk assessment (p=0.024).
Conclusion
Facility-driven HA-VTE audits provide opportunity to developed targeted initiatives for at-risk patients at a local level. Greater numbers of HA-VTE identified via manual audit suggest the need for future real-time documentation of HA-VTE to assist with efficient case review.

Disclosures
No relevant conflicts of interest to declare.
Neutrophil Extracellular Traps Promote Joint Injury in Hemophilia
Authors: Kaminski Tomasz W. , Brzoska Tomasz , Tutuncuoglu Egemen , Ragni Margaret V. , Sundd Prithu 
Published: November 2021

Abstract

Epidemiological evidence suggests that recurring episodes of joint-bleeding contribute to the development of hemophilic arthropathy (H) in 70-85% of hemophilia patients. Despite major advances in the treatment to prevent joint bleeding, HA continues to be a major morbidity affecting hemophilia patients and the etiological mechanism contributing to the progression of HA remains poorly understood. Recent evidence suggests that the accumulation of blood in the joints may lead to the release of erythrocyte-derived DAMPs (eDAMPs) such as heme and hemoglobin that can promote sterile inflammation, however, the innate immune pathways contributing to this pathophysiology remain unknown.
In the study, we used a model of puncture-induced knee joint injury in FVIII-total knockout (F8TKO) mice and blood samples from hemophilia-A patients diagnosed with HA. Intravital multi-photon-excitation fluorescence intravital (in vivo) microscopy of injured synovium in live F8TKO or control mice was conducted to assess neutrophil-platelet aggregation and NETs generation in the knee-joint. Imaging-flow-cytometry and ELISA assays were used to estimate the number of circulating NETs in plasma of patients diagnosed with HA and mice after the knee-injury procedure. Scoring of the bleeding severity, histology, IHC and confocal imaging of joints were conducted to quantify the joint injury in mice.
F8TKO but not control mice manifested knee-joint injury and severity of bleeding 5-days post knee-injury. Progression of knee-joint injury was associated with increased neutrophil accumulation and NETs shedding within the synovium of F8TKO mice. Circulating NETs were significantly abundant in the plasma of hemophilia patients diagnosed with HA and F8TKO mice following knee-injury but not plasma of control humans or mice.
These findings are the first to suggest that NETs contribute to pathogenesis of HA in hemophilia. Currently, experiments are underway to identify the innate immune pathways that promote NETs shedding, leading to joint-damage in hemophilia.

Disclosures
Ragni: Takeda Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioverativ (Sanofi): Membership on an entity's Board of Directors or advisory committees; BioMarin Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Alnylam (Sanofi): Membership on an entity's Board of Directors or advisory committees; University of Pittsburgh: Research Funding; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sundd: CSL Behring Inc: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding.
Screening Chest CT Prior to Allogenic Transplantation - High Rates of Occult Abnormalities
Authors: Alhomoud Mohammad , Gomez-Arteaga Alexandra , Mayer Sebastian A. , Hsu Jingmei , Phillips Adrienne A. , Shore Tsiporah B. , van Besien Koen 
Published: November 2021

Abstract
Introduction: Pulmonary complications constitute a major cause of morbidity and mortality in the post-hematopoietic cell transplant (HCT) period. While Chest X-ray (CXR) is customarily used for screening, we have utilized chest computed tomography (CT) within one month of transplant. Here we aim to characterize the prevalence of abnormalities and their impact on the eligibility for allogenic (allo) HCT and outcomes post-transplant.

Methodology: We conducted a single center retrospective study of all patients who were evaluated for allogenic HCT from January 2013 through December 2020 in New York Presbyterian Hospital - Weill Cornell Medicine (NYP-WCM). All patients who had chest CT as part of their pre-transplant evaluation were included for analysis.
Results: We identified 478 patients who had Chest CT screening. In 396 CT chest was normal or confirmed previous abnormalities. Eighty-two patients (17%) had previously undetected abnormalities (Figure 1). The most frequent abnormalities were pulmonary nodules (defined as nodules of 4 mm or greater) in 27 patients (31%), ground-glass opacities (GGO) in 21 patients (25%), Pneumonia in 18 patients (21%). Miscellaneous findings not related to the primary disease were found in 12 patients (14%) including thyroid nodules, breast nodules and hemangioma of the liver. A new malignancy was found in 6 patients (7%) and incidental pulmonary embolism (PE) in 2 patients (2%) (Figure 2). There were 5 (6%) patients who were ultimately excluded from transplant due to CT chest findings (simultaneous CXR showed abnormalities in only 1 out of 5). Three of those patients were found to have invasive fungal infection, and the other two had unrecognized metastatic lung cancer. For 19 patients (23%), transplant was delayed for diagnostic procedure and/or treatment of pulmonary findings (CXR showed abnormalities in only 3 patients out of 19). The most common reason for delay was lung infection requiring treatment. Thirty-two patients (41%) out of 77 patients with abnormal CT scan who eventually underwent transplant, have died . Sixteen died after relapse, and 16 from non-relapse mortality (NRM) with pulmonary complications playing a role in 13 patients (Figure 3).
Conclusion: 17% of patients who had a pre-transplant CT chest had abnormalities that warranted further evaluation. In 23% of these patients, these findings led to a delay in transplant for further optimization. Six percent were deemed ineligible for transplant due to absolute contraindications that were incidentally discovered on chest CT. Initial screening CXR failed to identify a significant number of abnormalities. Our data suggests that chest CT imaging should be part of the routine pre-transplant evaluation.

Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Neutrophil Metabolic Rewiring in Severe and Mild COVID-19
Authors: Li Yafeng , Hook Jessica S , Ding Qing , Chung Stephen , Moreland Jessica , Agathocleous Michalis 
Published: November 2021

Abstract

SARS-CoV-2 infection can cause severe respiratory disease resulting in hospitalization and death in some people, but in others it causes a mild disease or is asymptomatic. The causes of severe COVID-19 are of profound public health importance. Severe COVID-19 is marked by an exacerbated innate immune response leading to hyperinflammation which damages host tissues. Broad inhibition of hyperinflammation by dexamethasone is a mainstay of severe COVID-19 treatment. However, more targeted therapeutic approaches to dampen hyperinflammation are lacking. Patients typically exhibit increased neutrophil numbers in the blood and lung, and increased formation of neutrophil extracellular traps. Previous work profiled the metabolome of plasma in severe COVID-19 patients and found several metabolic aberrations as compared to mild COVID-19 patients or healthy controls. However, the metabolome of immune cell populations in COVID-19 has not been characterized to our knowledge. In addition, it is not known if metabolic changes observed in severe COVID-19 mechanistically contribute to hyperinflammation and host tissue damage or if they are simply markers of pathology.
To understand how metabolism can regulate the innate immune system in COVID-19 and to explore possible therapeutic targets, we carried out a comprehensive metabolomic study of neutrophils purified from healthy controls, mild/moderate COVID-19 patients, and severe COVID-19 patients. Severe COVID-19 patients were defined as having Acute Respiratory Distress and being treated in the intensive care unit. Plasma from the same patients and healthy controls was also collected and metabolomics was performed to study how COVID-19 impacts the neutrophil and plasma metabolome in tandem.
Several metabolic pathways were significantly different between mild COVID-19 patients, severe COVID-19 patients, and healthy controls, consistent with rewired neutrophil and plasma metabolome in severe COVID-19. Differentially abundant metabolites belonged to central carbon metabolism, nucleotide metabolism, amino acid metabolism and other pathways. Variation in the PMN metabolome was largely independent from variation in the plasma metabolome. This suggests that processes internal to neutrophils drive changes in neutrophil metabolism. Metabolomics in 3 mouse models of hyperinflammation showed common or distinct metabolic features that change in inflammation compared to metabolomics of severe COVID-19 patients. Therefore changes in some metabolites comprise a general hyperinflammatory metabolic signature while others are more specific to severe COVID-19. Isotope tracing experiments were carried out to understand how nutrients were utilized in neutrophils in context of inflammation. We will describe mechanistic work testing whether metabolic features we observe in severe COVID-19 patients regulate the inflammatory response of human neutrophils.

Disclosures
No relevant conflicts of interest to declare.
Central Line Associated Bloodstream Infection Rate Among Hematologic Malignant Patients Who Received Antimicrobial Prophylaxis in the Inpatient Setting
Authors: Abbagoni Sujith , Le Thuy , Bryan Locke J. , Mian Mohammad A. H. , Bradshaw Danielle , Fox Ashley D , Jillella Anand P , Okereke Chijioke , Kolhe Ravindra , Savage Natasha M. , Kota Vamsi 
Published: November 2021

Abstract
Introduction:
Patients with hematological malignancies are at increased risk of infections which leads to increased morbidity and mortality. Particularly, they are at an increased risk of developing central line associated bloodstream infection (CLABSI) since they frequently require central venous catheters for various essential reasons including chemotherapy, blood transfusions, and parenteral nutrition. Prophylaxis with antibiotics is the key in the management for these patients but is not always effective and sometimes associated with complications. Hence, the main objective of the study is to examine the rate of developing CLABSI in patients with hematological malignancies receiving antimicrobial prophylaxis and in those who did not receive prophylaxis.
Methods
We conducted a retrospective study involving patients diagnosed with a hematological malignancy admitted to the Augusta University Medical Center from 2002 to 2019. IRB approval was obtained to review the patients' charts. Patients who developed CLABSI are defined as those who had positive blood cultures after central venous catheter had been placed. Percentage of patients who received prophylaxis and those who didn't get antimicrobial prophylaxis were calculated. The difference between the two percentages was examined to determine whether or not it is statistically significant.
Results
The charts of 268 patients admitted for hematological malignancies were reviewed. Among 173 patients receiving antibiotic prophylaxis (65.0%), 78 (45.1%) developed CLABSI. Among the patients who didn't receive prophylaxis, 64 (68.8%) developed CLABSI. The difference between the two groups was statistically significant (p&lt;0.01), and the relative risk of developing CLABSI in patients who did not receive prophylaxis is 0.57 (95% confidence interval 0.41 - 0.79).
Conclusion
Patients who had been diagnosed with a hematologic malignancy and admitted at the academic institution from 2002 to 2019 were analyzed for the risk of developing CLABSI that was associated with the use of antibiotic prophylaxis. We found that the non-prophylactic group has statistically significant higher risk of developing CLABSI than the prophylactic group. Thus prophylaxis with antibiotics may play a major role in decreasing the rate of CLABSI in patients admitted with hematological malignancy.

Disclosures
No relevant conflicts of interest to declare.
Systematic analysis of CCCH zinc finger family in Brassica napus showed that BnRR-TZFs are involved in stress resistance
Authors: Pi Boyi , Pan Jiao , Xiao Mu , Hu Xinchang , Zhang Lei , Chen Min , Liu Boyu , Ruan Ying , Huang Yong 
Published: November 2021

AbstractBackgroundCCCH zinc finger family is one of the largest transcription factor families related to multiple biotic and abiotic stresses.Brassica napusL., an allotetraploid oilseed crop formed by natural hybridization between two diploid progenitors,Brassica rapaandBrassica oleracea. A systematic identification of rapeseed CCCH family genes is missing and their functional characterization is still in infancy.ResultsIn this study, 155CCCHgenes, 81 from its parentB. rapaand 74 fromB. oleracea, were identified and divided into 15 subfamilies inB. napus. Organization and syntenic analysis explained the distribution and collinearity relationship ofCCCHgenes, the selection pressure and evolution of duplication gene pairs inB. napusgenome. 44 diploid duplication gene pairs and 4 triple duplication gene groups were found inB. napusof CCCH family and the segmental duplication is attributed to mostCCCHgene duplication events inB. napus. Nine types of CCCH motifs exist inB. napusCCCH family members, and motif C-X7/8-C-X5-C-X3-H is the most common and a new conserved CCH motif (C-X5-C-X3-H) has been identified. In addition, abundant stress-related cis-elements exist in promoters of 27 subfamily IX (RR-TZF) genes and their expression profiles indicated thatRR-TZFgenes could be involved in responses to hormone and abiotic stress.ConclusionsThe results provided a foundation to understand the basic characterization and genes evolution ofCCCHgene family inB. napus, and provided potential targets for genetic engineering in Brassicaceae crops in pursuit of stress-tolerant traits.