bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bi-allelic amplification of ATM gene in blastoid variant of mantle cell lymphoma: a novel mechanism of inactivation due to chromoanagenesis?
Authors: Ortega Veronica , Mendiola Christina , Rodriguez Juana , Ehman William , Qian You-Wen , Velagaleti Gopalrao 
Published: February 2021

Abstract
Background
Mantle cell lymphoma (MCL) is derived from naïve CD5+ B-cells with the cytogenetic hallmark translocation 11;14. The presence of additional abnormalities is associated with blastoid variants in MCL (BMCL) and confers a poor prognosis. Many of these tumors also show deletion or loss of heterozygosity (LOH) of the ATM gene and biallelic ATM inactivation show significantly higher chromosomal imbalances.

Case presentation
Here we report a 52 year-old male who presented to the clinic with worsening dyspnea, fever, chills, diffuse lymphadenopathy, splenomegaly and leukocytosis with blastoid cells circulating in blood. The bone marrow aspirate showed about 40% abnormal blast-looking cells and biopsy revealed a remarkable lymphoid infiltrate. The patient was diagnosed with blastoid variant mantle cell lymphoma (BMCL). Chromosome analysis on bone marrow showed a complex karyotype. FISH analysis from B-cell lymphoma panel showed bi-allelic amplification of ATM gene. Other abnormalities were present including CCND1/IGH fusion, confirming the MCL diagnosis, in addition to RB1 and p53 deletion. High resolution SNP-microarray studies showed complex copy number changes, especially on chromosomes 7 and 11, consistent with chromoanagenesis. Microarray studies also showed LOH at the ATM locus indicating the amplification seen on FISH is not biallelic.

Conclusion
To the best of our knowledge, ATM gene amplification is not previously reported in BMCL and our case suggests a novel mechanism of ATM inactivation caused by chromoanagenesis resulting in mutant allele specific imbalance with copy number gain.
Actin-like protein 6A/MYC/CDK2 axis confers high proliferative activity in triple-negative breast cancer
Authors: Jian Yunting , Huang Xinjian , Fang Lishan , Wang Meng , Liu Qinghua , Xu Hongyi , Kong Lingzhi , Chen Xiangfu , Ouyang Ying , Wang Xi , Wei Weidong , Song Libing 
Published: February 2021

Abstract
Background
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high proliferative activity. TNBC tumors exhibit elevated MYC expression and altered expression of MYC regulatory genes, which are associated with tumor progression and poor prognosis; however, the underlying mechanisms by which MYC retains its high expression and mediates TNBC tumorigenesis require further exploration.

Methods
ACTL6A regulation of MYC and its target gene, CDK2, was defined using Co-IP, mass spectrometry and ChIP assays. To study the role of ACTL6A in TNBC, we performed soft-agar, colony formation, flow cytometry and tumor formation in nude mice. CDK2 inhibitor and paclitaxel were used in testing combination therapy in vitro and in vivo.

Results
ACTL6A bound MYC to suppress glycogen synthase kinase 3 beta (GSK3β)-induced phosphorylation on MYC T58, which inhibited ubiquitination of MYC and stabilized it. Moreover, ACTL6A promoted the recruitment of MYC and histone acetyltransferase KAT5 on CDK2 promoters, leading to hyperactivation of CDK2 transcription. ACTL6A overexpression promoted, while silencing ACTL6A suppressed cell proliferation and tumor growth in TNBC cells in vitro and in vivo, which was dependent on MYC signaling. Furthermore, co-therapy with paclitaxel and CDK2 inhibitor showed synergistic effects in tumor suppression. Notably, ACTL6A/MYC/CDK2 axis was specifically up-regulated in TNBC and high expression of ACTL6A was correlated to shorter survival in patients with TNBC.

Conclusions
These findings reveal a novel mechanism by which ACTL6A prolongs the retention of MYC in TNBC and suggest that pharmacological targeting ACTL6A/MYC/CDK2 axis might have therapeutic potential in patients with TNBC.
Long non-coding RNA CCDC183-AS1 acts AS a miR-589-5p sponge to promote the progression of hepatocellular carcinoma through regulating SKP1 expression
Authors: Zhu He , Zhang Hongwei , Pei Youliang , Liao Zhibin , Liu Furong , Su Chen , Liu Yachong , Dong Renshun , Song Jia , Zhang Xuewu , Fan Yawei , Liang Huifang , Zhang Bixiang , Chen Xiaoping 
Published: February 2021

Abstract
Background
Hepatocellular carcinoma (HCC) is a common type of malignant human cancer with high morbidity and poor prognosis, causing numerous deaths per year worldwide. Growing evidence has been demonstrated that long non-coding RNAs (lncRNAs) are closely associated with hepatocarcinogenesis and metastasis. However, the roles, functions, and working mechanisms of most lncRNAs in HCC remain poorly defined.

Methods
Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression level of CCDC183-AS1 in HCC tissues and cell lines. Cell proliferation, migration and invasion ability were evaluated by CCK-8 and transwell assay, respectively. Animal experiments were used to explore the role of CCDC183-AS1 and miR-589-5p in vivo. Bioinformatic analysis, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to confirm the regulatory relationship between CCDC183-AS1, miR-589-5p and SKP1.

Results
Significantly upregulated expression of CCDC183-AS1 was observed in both HCC tissues and cell lines. HCC patients with higher expression of CCDC183-AS1 had a poorer overall survival rate. Functionally, overexpression of CCDC183-AS1 markedly promoted HCC cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas the downregulation of CCDC183-AS1 exerted opposite effects. MiR-589-5p inhibitor counteracted the proliferation, migration and invasion inhibitory effects induced by CCDC183-AS1 silencing. Mechanistically, CCDC183-AS1 acted as a ceRNA through sponging miR-589-5p to offset its inhibitory effect on the target gene SKP1, then promoted the tumorigenesis of HCC.

Conclusions
CCDC183-AS1 functions as an oncogene to promote HCC progression through the CCDC183-AS1/miR-589-5p/SKP1 axis. Our study provided a novel potential therapeutic target for HCC patients.
Angiopoietin-2 outperforms other endothelial biomarkers associated with severe acute kidney injury in patients with severe sepsis and respiratory failure
Authors: Yu Wen-Kuang , McNeil J. Brennan , Wickersham Nancy E. , Shaver Ciara M. , Bastarache Julie A. , Ware Lorraine B. 
Published: February 2021

Abstract
Background
Endothelial dysfunction and injury is a major pathophysiologic feature of sepsis. Sepsis is also the most frequent cause of acute kidney injury (AKI) in critically ill patients. Though most studies of AKI in sepsis have focused on tubular epithelial injury, the role of endothelial dysfunction and injury is less well studied. The goal of this study was first to investigate whether endothelial dysfunction and injury biomarkers were associated with severe AKI in sepsis patients. The second goal was to determine the best performing biomarker for severe AKI and whether this biomarker was associated with severe AKI across different etiologies of sepsis and clinical outcomes.

Methods
We studied adults with severe sepsis and acute respiratory failure (ARF) enrolled in the prospective observational Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma endothelial dysfunction and injury biomarkers, including angiopoietin-2, soluble vascular endothelial cadherin (sVE-cadherin), endocan and syndecan-1, were measured at study enrollment. Primary analysis focused on the association between endothelial biomarker levels with severe AKI (defined as Kidney Disease: Improving Global Outcomes [KDIGO] AKI stage 2 or 3), other organ dysfunctions (defined by Brussels organ failure scores), and comparison of pulmonary versus non-pulmonary sepsis.

Results
Among 228 sepsis patients enrolled, 141 developed severe AKI. Plasma levels of angiopoietin-2, endocan, sVE-cadherin, and syndecan-1 were significantly higher in sepsis patients with severe AKI compared to those without severe AKI. Among four endothelial biomarkers, only angiopoietin-2 was independently associated with severe AKI (odds ratio 6.07 per log increase, 95% CI 2.34–15.78, p < 0.001). Plasma angiopoietin-2 levels by quartile were significantly higher in sepsis patients with hepatic, coagulation, and circulatory failure. Plasma angiopoietin-2 levels were also significantly higher in patients with non-pulmonary sepsis compared to subjects with pulmonary sepsis.

Conclusion
Among four biomarkers of endothelial dysfunction and injury, angiopoietin-2 had the most robust independent association with development of severe AKI in patients with severe sepsis and ARF. Plasma angiopoietin-2 levels were also associated with other organ dysfunctions, non-pulmonary sepsis, and death. These findings highlight the importance of early endothelial dysfunction and injury in the pathogenesis of sepsis-induced AKI.
Age-dependent VDR peak DNA methylation as a mechanism for latitude-dependent multiple sclerosis risk
Authors: Ong Lawrence T. C. , Schibeci Stephen D. , Fewings Nicole L. , Booth David R. , Parnell Grant P. 
Published: February 2021

AbstractBackgroundThe mechanisms linking UV radiation and vitamin D exposure to the risk of acquiring the latitude and critical period-dependent autoimmune disease, multiple sclerosis, is unclear. We examined the effect of vitamin D on DNA methylation and DNA methylation at vitamin D receptor binding sites in adult and paediatric myeloid cells. This was accomplished through differentiating CD34+ haematopoietic progenitors into CD14+ mononuclear phagocytes, in the presence and absence of calcitriol.ResultsFew DNA methylation changes occurred in cells treated with calcitriol. However, several VDR-binding sites demonstrated increased DNA methylation in cells of adult origin when compared to cells of paediatric origin. This phenomenon was not observed at other transcription factor binding sites. Genes associated with these sites were enriched for intracellular signalling and cell activation pathways involved in myeloid cell differentiation and adaptive immune system regulation.ConclusionThese results suggest vitamin D exposure at critical periods during development may contribute to latitude-related differences in autoimmune disease incidence.
The role of point-of-care ultrasound in the diagnosis of pericardial effusion: a single academic center retrospective study
Authors: Hanson Matthew G. , Chan Barry 
Published: February 2021

Abstract
Background
Symptomatic pericardial effusion (PCE) presents with non-specific features and are often missed on the initial physical exam, chest X-ray (CXR), and electrocardiogram (ECG). In extreme cases, misdiagnosis can evolve into decompensated cardiac tamponade, a life-threatening obstructive shock. The purpose of this study is to evaluate the impact of point-of-care ultrasound (POCUS) on the diagnosis and therapeutic intervention of clinically significant PCE.

Methods
In a retrospective chart review, we looked at all patients between 2002 and 2018 at a major Canadian academic hospital who had a pericardiocentesis for clinically significant PCE. We extracted the rate of presenting complaints, physical exam findings, X-ray findings, ECG findings, time-to-diagnosis, and time-to-pericardiocentesis and how these were impacted by POCUS.

Results
The most common presenting symptom was dyspnea (64%) and the average systolic blood pressure (SBP) was 120 mmHg. 86% of people presenting had an effusion > 1 cm, and 89% were circumferential on departmental echocardiogram (ECHO) with 64% having evidence of right atrial systolic collapse and 58% with early diastolic right ventricular collapse. The average time-to-diagnosis with POCUS was 5.9 h compared to > 12 h with other imaging including departmental ECHO. Those who had the PCE identified by POCUS had an average time-to-pericardiocentesis of 28.1 h compared to > 48 h with other diagnostic modalities.

Conclusion
POCUS expedites the diagnosis of symptomatic PCE given its non-specific clinical findings which, in turn, may accelerate the time-to-intervention.
Toxoplasma gondii in Sheep and Goats from Central Iran
Authors: Bahreh Mojtaba , Hajimohammadi Bahador , Eslami Gilda 
Published: February 2021

Abstract
Objective
Toxoplasmosis, caused by Toxoplasma gondii, infects humans by consuming infected raw or undercooked meat and foods harboring mature oocysts. In this study, we assessed the prevalence of T. gondii in sheep and goats coming from central Iran. After completing the questionnaire, about one gram of liver or diaphragm tissue was taken as a sample from 90 sheep and 90 goats slaughtered in Yazd Province and stored at – 20 ºC. DNA extraction was done, and then T. gondii was detected using nested PCR.

Results
This study indicated that the prevalence of T. gondii in all slaughtered animals was 11.6% (21 of 180), including 14.4% (13/90) in sheep and 8.8% (8/90) in goats. The infection rates in liver and diaphragm samples were 12.2% (11/90) and 11.1% (10/90), respectively (p = 0.8163). The infection rate in animals older than one was 16.3% (15/92), and it was 6.8% (6/88) in animals under one year of age. Therefore, no significant differences were found (p = 0.475). Infection rates were 19.5% (18/92) in males and 3.4% (3/88) in females (p = 0.0007). In conclusion, the infection rates of toxoplasmosis in livestock in this area are almost high, and therefore, it is necessary to design appropriate prevention programs to control the disease.
Genome-wide DNA methylation profiling is able to identify prefibrotic PMF cases at risk for progression to myelofibrosis
Authors: Lehmann Ulrich , Stark Helge , Bartels Stephan , Schlue Jerome , Büsche Guntram , Kreipe Hans 
Published: February 2021

Abstract
Background
Patients suffering from the BCR-ABL1-negative myeloproliferative disease prefibrotic primary myelofibrosis (pre-PMF) have a certain risk for progression to myelofibrosis. Accurate risk estimation for this fibrotic progression is of prognostic importance and clinically relevant. Commonly applied risk scores are based on clinical, cytogenetic, and genetic data but do not include epigenetic modifications. Therefore, we evaluated the assessment of genome-wide DNA methylation patterns for their ability to predict fibrotic progression in PMF patients.

Results
For this purpose, the DNA methylation profile was analyzed genome-wide in a training set of 22 bone marrow trephines from patients with either fibrotic progression (n = 12) or stable disease over several years (n = 10) using the 850 k EPIC array from Illumina. The DNA methylation classifier constructed from this data set was validated in an independently measured test set of additional 11 bone marrow trephines (7 with stable disease, 4 with fibrotic progress). Hierarchical clustering of methylation β-values and linear discriminant classification yielded very good discrimination between both patient groups. By gene ontology analysis, the most differentially methylated CpG sites are primarily associated with genes involved in cell–cell and cell–matrix interactions.

Conclusions
In conclusion, we could show that genome-wide DNA methylation profiling of bone marrow trephines is feasible under routine diagnostic conditions and, more importantly, is able to predict fibrotic progression in pre-fibrotic primary myelofibrosis with high accuracy.
Unusual deletion of the maternal 11p15 allele in Beckwith–Wiedemann syndrome with an impact on both imprinting domains
Authors: Eggermann Thomas , Begemann Matthias , Pfeiffer Lutz 
Published: February 2021

Abstract
Background
Whereas duplications in 11p15.5 covering both imprinting centers (ICs) and their subordinated genes account for up to 1% of Beckwith–Wiedemann and Silver–Russell syndrome patients (BWS, SRS), the deletions in 11p15.5 reported so far only affect one of the ICs. In these cases, not only the size and gene content had an impact on the phenotype, but also the sex of the contributing parent influences the clinical signs of the deletion carrier.

Results
We here report on the first case with a heterozygous deletion within the maternal allele affecting genes which are regulated by both ICs in 11p15.5 in a BWS patient, and describe the molecular and clinical consequences in case of its maternal or paternal inheritance.

Conclusions
The identification of a unique deletion affecting both 11p15.5 imprinting domains in a BWS patient illustrates the complexity of the regulation mechanisms in these key imprinting regions.
Comprehensive analysis of allergen-specific IgE in COPD: mite-specific IgE specifically related to the diagnosis of asthma-COPD overlap
Authors: Toyota Hikaru , Sugimoto Naoya , Kobayashi Konomi , Suzuki Yuki , Takeshita Yuri , Ito Ayaka , Ujino Mariko , Tomyo Fuminori , Sakasegawa Hirokazu , Koizumi Yuta , Kuramochi Michio , Yamaguchi Masao , Nagase Hiroyuki 
Published: February 2021

Abstract
Background
Although the relationship between allergic sensitization and increased respiratory symptoms of chronic obstructive pulmonary disease (COPD) has been suggested, which allergen has a significant effect on COPD pathology is unclear. This study aimed to identify the specific IgE related to clinical features of COPD and the diagnosis of asthma-COPD overlap (ACO).

Methods
We recruited 76 patients with COPD and analyzed 39 IgE using panel IgE test (View Allergy 39®). ACO was diagnosed according to the Japanese Respiratory Society Guidelines.

Results
As for perennial aeroallergens, the positivity for moth (31.5%), Candida (23.7%), Dermatophagoides pteronyssinus (22.4%) and house dust (22.4%), and concerning pollen, Japanese cedar (35.5%) and Japanese cypress (22.2%) exceeded 20%. Only the positivity of IgE for Dermatophagoides pteronyssinus and house dust was significantly higher in ACO compared with that in non-ACO COPD. Moreover, it contributed to the diagnosis of ACO in an IgE class-dependent manner. Patients with cockroach IgE exhibited higher residual volume, whereas those with Japanese cedar IgE exhibited better diffusion capacity than negative patients. The contribution for ACO diagnosis by the receiver operating characteristic curve analysis was comparable among total IgE (cutoff value: 158 IU/mL), blood eosinophil count (234/μL), and fraction of exhaled nitric oxide (31.0 ppb).

Conclusions
The prominent role of mite-specific IgE in the diagnosis and pathology of ACO and the potentially detrimental effect of cockroach sensitization on air trapping in COPD were suggested. The finding highlights the future development of a treatment targeting IgE as a treatable trait in COPD.
Klebsiella brain abscess in an immunocompetent patient: a case report
Authors: Wu Clay , Han Semi , Baydur Ahmet , Lindgren Brett 
Published: February 2021

Abstract
Background
Klebsiella pneumoniae brain abscesses are a rare entity and typically present in immunocompromised patients. We present a case of an overall healthy patient who developed a Klebsiella pneumoniae brain abscess in the absence of liver pathology.

Case presentation
A 46-year-old Vietnamese man with past medical history significant for hypertension presented to the hospital with acute on chronic worsening of altered mental status, personality changes, and gait dysfunction. Initial vitals revealed temperature of 37.1 °C, heart rate 87 beats/minute, blood pressure 150/87 mmHg, respiratory rate 18/minute, and oxygen saturation 99% on room air. Physical exam was notable for altered mental status, Glasgow Coma Scale (GCS) score of 14, and right lower facial droop. Cardiopulmonary exam was within normal limits. Head computed tomography (CT) showed a left frontotemporal mass, with subsequent brain magnetic resonance imaging (MRI) revealing a ring-enhancing lesion concerning for a brain abscess. The abscess was urgently drained; however, there was intraoperative spillage into the ventricles. Intraoperative cultures grew Klebsiella pneumoniae, and the patient was maintained on appropriate antibiotics. He developed worsening mental status, septic shock, and cerebral edema requiring decompressive left hemicraniectomy. Computed tomography of the abdomen and pelvis revealed no hepatic lesions. The patient did not improve, and the family elected for comfort measures.

Conclusion
High mortality is associated with Klebsiella pneumoniae (as opposed to Klebsiella oxytoca) brain abscesses, especially in the setting of intraventricular spread. This case illustrates the need for early detection, and an aggressive medical and surgical treatment approach is required for a potential favorable outcome.
The therapeutic applications of mesenchymal stromal cells from human perinatal tissues in autoimmune diseases
Authors: Yang Chao , Wu Mingjun , You Min , Chen Yu , Luo Maowen , Chen Qiang 
Published: February 2021

AbstractThe autoimmune diseases are characterized by overactivation of immune cells, chronic inflammation, and immune response to self-antigens, leading to the damage and dysfunction of multiple organs. Patients still do not receive desired clinical outcomes while suffer from various adverse effects imparted by current therapies. The therapeutic strategies based on mesenchymal stromal cell (MSC) transplantation have become the promising approach for the treatment of autoimmune diseases due to the immunomodulation property of MSCs. MSCs derived from perinatal tissues are collectively known as perinatal MSCs (PMSCs), which can be obtained via painless procedures from donors with lower risk of being contaminated by viruses than those MSCs from adult tissue sources. Therefore, PMSCs may be the ideal cell source for the treatment of autoimmune diseases. This article summarizes recent progress and possible mechanisms of PMSCs in treating autoimmune diseases in animal experiments and clinical studies. This review also presents existing challenges and proposes solutions, which may provide new hints on PMSC transplantation as a therapeutic strategy for the treatment of autoimmune diseases.
KAT6A regulates stemness of aging bone marrow-derived mesenchymal stem cells through Nrf2/ARE signaling pathway
Authors: Fei Dongdong , Wang Yazheng , Zhai Qiming , Zhang Xige , Zhang Yang , Wang Yang , Li Bei , Wang Qintao 
Published: February 2021

Abstract
Background
This study aimed to explore the effect of KAT6A on the decreased stemness of aging bone marrow-derived mesenchymal stem cells (BMSCs) and its potential mechanism.

Methods
The acetylation level and KAT6A expression of BMSCs from the young (YBMSCs) and the old (OBMSCs) were examined. Gain- and loss-of-function experiments were performed to determine the effect of KAT6A on BMSC proliferation, colony formation, and osteogenic differentiation. The effect of KAT6A on Nrf2/ARE signaling pathway was investigated after KAT6A inhibition in YBMSCs or overexpression in OBMSCs, and the role of Nrf2/ARE signaling pathway on stemness was examined by investigating proliferation, colony formation, and osteogenic differentiation. Further in vivo study was performed to explore osteogenesis ability of OBMSCs after modulation of KAT6A and Nrf2/ARE pathway through cell sheet technology.

Results
The acetylation level and KAT6A expression of OBMSCs were decreased, and KAT6A downregulation resulted in decreased proliferation, colony formation, and osteogenic differentiation of OBMSCs. Mechanically, KAT6A was found to regulate Nrf2/ARE signaling pathway and inhibit ROS accumulation in OBMSCs, thus promoting proliferation, colony formation, and osteogenic differentiation of OBMSCs. Further study demonstrated that KAT6A could promote osteogenesis of OBMSCs by regulating Nrf2/ARE signaling pathway.

Conclusions
Downregulation of KAT6A resulted in the decreased stemness of OBMSCs by inhibiting the Nrf2/ARE signaling pathway.

Graphical abstract
KAT6A was downregulated in aging bone marrow-derived mesenchymal stem cells (BMSCs), and downregulation of KAT6A resulted in Nrf2/ARE signaling pathway inhibition and ROS accumulation, thus leading to decreased stemness of aging BMSCs.