bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Green Tea Polyphenol Epigallocatechin Gallate (EGCG) Antagonizes the Inhibitory Effect of Bortezomib on Myeloma Cells.
Authors: Burger Renate , Czekalla Hanna , Ahrens Tanja , Richter Kathrin , Guenther Andreas , Gramatzki Martin 
Published: November 2019

Abstract
Dietary plant polyphenols are known to have antitumor, antiinflammatory, and antioxidant activity and as such may sensitize tumor cells to chemotherapeutic agents. We have evaluated the effects of the green tea polyphenol epigallocatechin gallate (EGCG) alone and in combination with other drugs on human myeloma cells. The compound is currently under investigation in several phase I/II clinical trials including for treatment of patients with early stage chronic lymphocytic leukemia. EGCG inhibited the in vitro growth of human myeloma cell lines in a time and dose-dependent manner. IC50 concentrations were between 12.5 μM and 50 μM as measured in a colorimetric tetrazolium (MTS) based assay and by trypan blue exclusion. Excess amounts of IL-6, bone marrow stromal cells, or overexpression of Mcl-1 and Bcl-xL could not protect from EGCG induced cytotoxicity. Pretreatment of INA-6 cells with EGCG resulted in a dose-dependent inhibition of IL-6 induced STAT3 tyrosine phosphorylation. In accordance with the essential role of STAT3 for INA-6 cell survival, EGCG induced apoptosis as determined by flow cytometry upon 7-amino-actinomycin D/annexin-V staining. In cell lines not dependent on exogenous IL-6, EGCG induced growth inhibition was abolished by pretreating the cells with 200 U/ml catalase, an enzyme which reduces reactive oxygen species (ROS). The combination of EGCG with doxorubicin, dexamethason, or rapamycin did not result in increased growth inhibition. In contrast, growth inhibition by bortezomib was antagonized with EGCG at concentrations that were not inhibitory when used alone (1–10 μM). In conclusion, EGCG exerts its effects on myeloma cells through several mechanisms including inhibition of IL-6 mediated signalling pathways via STAT3 and induction of oxidative stress. Notably, at pharmacologically achievable concentrations, EGCG antagonized bortezomib activity. Thus, the intake of natural polyphenols (high consumption of green tea or taking green tea extracts) may be critical during therapy with bortezomib.
Expression and Role of hERG1 Channels in Pediatric Acute Lymphoblastic Leukemias: Shortcoming of Drug Resistance by hERG1 Channel Inhibitors in Stoma-Supported Leukaemia Cell Cultures In Vitro.
Authors: Pillozzi Serena , Accordi Benedetta , Veltroni Marinella , Masselli Marika , Pancrazzi Elisa , Gaipa Giuseppe , Lippi Alma , Bernini Gabriella , Basso Giuseppe , Arcangeli Annarosa 
Published: November 2019

Abstract
Therapy resistance is still a major obstacle to successful treatment in a significant number of pediatric acute lymphoblastic leukaemia (ALL) patients. It has been previously demonstrated that children with ALL whose leukemia cells exhibit in vitro resistance to single or a combination of drugs have a significantly worse prognosis compared to patients with sensitive leukemic cells (Ramakers-van Woerden N, et al Leukemia18(3):521–9 2004). Ion channels are becoming one of the potential targets for cancer therapy and putative biochemical modulators of conventional chemotherapy (Conti M, J Exp Ther Oncol. 4(2):161–6, 2004). In particular, K+ channels belonging to the hERG1 family are attracting most attention, since they are over-expressed in a broad range of primary acute myeloid leukaemias (AML) as well as in both myeloid and lymphoid leukemic cell lines (Pillozzi S, et al Leukemia16:1791–1798, 2002; Smith GA, et al, JBC227:18528–18534, 2002). hERG1 channel expression confers a greater capacity to engraft the bone marrow and invade the bloodstream in NOD/SCID mice injected with AML cells. This fact corresponds to a greater malignancy (shorter overall survival and higher probability to relapse) in hERG1 positive AML patients (Pillozzi S, et al Blood110:1238–1250, 2007). It was also recently shown that the expression of hERG1 is related to the chemosensitivity of cancer cells to vincristine, paclitaxel, and hydroxy-camptothecin (Chen SZ, et al Cancer Chemother Pharmacol56(2):212–20, 2005). We studied the expression and role of hERG1 channels in various B lymphoid leukaemia cell lines and primary childhood B lymphoid leukaemia samples. It emerged that:
hERG1 K+ channels are expressed in both all the leukaemia cell lines and primary childhood B leukaemia samples; the N-terminus deleted, herg1b isoform was preferentially expressed in both cell lines and primary samples; in childhood leukaemia patients, the level of herg1b expression correlated with response to therapy.
B lymphoid leukaemia cell lines were co-cultured on human bone marrow stromal cells, a system known to enhance leukaemia cell survival and escape from drug-induced apoptosis. In these cultures, the addition of a specific hERG1 inhibitor, E4031, induced a significant apoptosis in leukaemia cells, bypassing the protective effect of the bone marrow microenvironment. We hypothesise that hERG1 channels can represent a novel molecular device regulating drug sensitivity in childhood acute leukaemia cells, and that targeting of hERG1 channels can restore a proper pro-apoptotic response to chemotherapy in resistant B lymphoid leukemic cells.
Targeting An Ancient Retrovirus In Tumor Using Engineered T Cells
Authors: Krishnamurthy Janani , Rabinovich Brian , Olivares Simon , Teijuan Mi , Switzer Kirsten , Plummer Joshua , Maiti Sourindra , Singh Harjeet , Huls Helen , Johanning Feng-wang , Cooper Laurence J N 
Published: November 2019

Abstract
Human endogenous retroviruses (HERVs) are ancient viruses forming 8% of human genome. One subset of HERVs, the HERV-K has recently been found to be expressed on tumor cells including melanoma, breast cancer and lymphoma but not on normal body cells. Thus, targeting HERV-K protein as a tumor associated antigen (TAA) may be a potential treatment strategy for tumors that are resistant to conventional therapies. One approach to improve therapeutic outcome is by infusing T cells rendered specific for such TAAs preferentially expressed on tumor cells. Recognition of cell-surface TAAs independent of major histocompatibility complex can be achieved by introducing a chimeric antigen receptor (CAR) on T cells using gene therapy. This approach is currently being used in our clinical trials adoptively transferring CD19-specific CAR+ T cells into patients with B-lineage malignancies. Preliminary analysis of HERV-K env protein expression in 268 melanoma samples and 139 normal organ donor tissues using immunohistochemistry demonstrated antigen expression in tumor cells and absence of expression in normal organ tissues. The scFv region from a mouse monoclonal antibody to target HERV-K env was used to generate a CAR and cloned into Sleeping Beauty (SB) plasmid for stable expression in T cells. HERV-K-specific CAR+T cells were selectively propagated ex vivo on artificial antigen presenting cells (aAPC) using an approach already in our clinical trials. Indeed, after genetic modification of T cells and selection on HERV-K+ aAPC, over 95% of propagated T cells stably expressed the introduced HERV-K-specific CAR and exhibited redirected specificity for HERV-K+ melanoma (Figure 1). Further, the adoptive transfer of HERV-K-specific CAR+T cells killed metastatic melanoma in a mouse xenograph model. While we have chosen melanoma as our tumor model, this study has the potential to be applied to other malignancies, including lymphoma and myeloma due to restricted expression of HERV-K envelope (env) protein on these tumor cells. These data demonstrate that it is feasible to generate T cells expressing a HERV-K-specific CAR using a clinically-appealing approach as a treatment strategy for HERV-K env+ tumors.

Disclosures:
No relevant conflicts of interest to declare.
A case of dyskinesia after levetiracetam administration
Authors: Yim Soo Hwan , Choi Yun Ho , Heo Kyoung , Cho Kyoo ho 
Published: November 2019

Abstract
Background
Antiepileptic drug (AED) induced dyskinesia is an unusual manifestation in the medical field. In the previous case reports describing first generation-AED related involuntary movements, the authors suggested that a plausible cause is pharmacokinetic interactions between two or more AEDs. To date, development of dyskinesia after levetiracetam (LEV) has not been reported.

Case presentation
A 28-year-old woman with a history of brain metastasis from spinal cord glioblastoma presented with several generalized tonic-clonic seizures without restored consciousness. LEV was administered intravenously. Thereafter no more clinical or electroencephalographic seizures were noted on video-EEG monitoring, while chorea movement was observed in her face and bilateral upper limbs.

Discussion and conclusions
To our knowledge, there is no case report of dyskinesia after administration of LEV. Considering the temporal relationship and absence of ictal video-EEG findings, we suggest that development of choreoathetosis was closely associated with the undesirable effects of LEV. We propose that dopaminergic system dysregulation and genetic susceptibility might underlie this unusual phenomenon after LEV treatment.
Searching for optimal blood pressure targets in type 2 diabetic patients with coronary artery disease
Authors: Shen Ying , Dai Yang , Wang Xiao Qun , Zhang Rui Yan , Lu Lin , Ding Feng Hua , Shen Wei Feng 
Published: November 2019

Abstract
Background
Controversies exist regarding the optimal blood pressure (BP) level that is safe and provides cardiovascular protection in patients with type 2 diabetes mellitus (T2DM) and coexistent coronary artery disease. Several new glucose-lowering agents have been found to lower BP as well, making the interaction between BP and T2DM even more complex.

Methods
With the reference to recent literature, this review article describes the potential mechanisms of increased risk of hypertension in T2DM and outlines the possible optimal BP levels based upon recommendations on the management of hypertension by the current guidelines, in combination with our research findings, for type 2 diabetic patients with coronary artery disease.

Results
The development of hypertension in T2DM involves multiple processes, including enhanced sympathetic output, inappropriate activation of renin-angiotensin- aldosterone system, endothelial dysfunction induced through insulin resistance, and abnormal sodium handling by the kidney. Both AGE-RAGE axis and adipokine dysregulation activate intracellular signaling pathways, increase oxidative stress, and aggravate vascular inflammation. Pancreatic β-cell specific microRNAs are implicated in gene expression and diabetic complications. Non-pharmacological intervention with lifestyle changes improves BP control, and anti-hypertensive medications with ACEI/ARB, calcium antagonists, β-blockers, diuretics and new hypoglycemic agent SGLT2 inhibitors are effective to decrease mortality and prevent major adverse cardiovascular events. For hypertensive patients with T2DM and stable coronary artery disease, control of BP < 130/80 mmHg but not < 120/70 mmHg is reasonable, whereas for those with chronic total occlusion or acute coronary syndromes, an ideal BP target may be somewhat higher (< 140/90 mmHg). Caution is advised with aggressive lowering of diastolic BP to a critical threshold (< 60 mmHg).

Conclusions
Hypertension and T2DM share certain similar aspects of pathophysiology, and BP control should be individualized to minimize adverse events and maximize benefits especially for patients with T2DM and coronary artery disease.
LncRNA SNHG8 is identified as a key regulator of acute myocardial infarction by RNA-seq analysis
Authors: Zhuo Liu-An , Wen Yi-Tao , Wang Yong , Liang Zhi-Fang , Wu Gang , Nong Mei-Dan , Miao Liu 
Published: November 2019

Abstract
Background
Long noncoding RNAs (lncRNAs) are involved in numerous physiological functions. However, their mechanisms in acute myocardial infarction (AMI) are not well understood.

Methods
We performed an RNA-seq analysis to explore the molecular mechanism of AMI by constructing a lncRNA-miRNA-mRNA axis based on the ceRNA hypothesis. The target microRNA data were used to design a global AMI triple network. Thereafter, a functional enrichment analysis and clustering topological analyses were conducted by using the triple network. The expression of lncRNA SNHG8, SOCS3 and ICAM1 was measured by qRT-PCR. The prognostic values of lncRNA SNHG8, SOCS3 and ICAM1 were evaluated using a receiver operating characteristic (ROC) curve.

Results
An AMI lncRNA-miRNA-mRNA network was constructed that included two mRNAs, one miRNA and one lncRNA. After RT-PCR validation of lncRNA SNHG8, SOCS3 and ICAM1 between the AMI and normal samples, only lncRNA SNHG8 had significant diagnostic value for further analysis. The ROC curve showed that SNHG8 presented an AUC of 0.850, while the AUC of SOCS3 was 0.633 and that of ICAM1 was 0.594. After a pairwise comparison, we found that SNHG8 was statistically significant (PSNHG8-ICAM1 = 0.002; PSNHG8-SOCS3 = 0.031). The results of a functional enrichment analysis of the interacting genes and microRNAs showed that the shared lncRNA SNHG8 may be a new factor in AMI.

Conclusions
Our investigation of the lncRNA-miRNA-mRNA regulatory networks in AMI revealed a novel lncRNA, lncRNA SNHG8, as a risk factor for AMI and expanded our understanding of the mechanisms involved in the pathogenesis of AMI.
Bee pollen and propolis improve neuroinflammation and dysbiosis induced by propionic acid, a short chain fatty acid in a rodent model of autism
Authors: Aabed Kawther , Bhat Ramesa Shafi , Al-Dbass Abeer , Moubayed Nadine , Algahtani Norah , Merghani Nada M. , Alanazi Azizah , Zayed Naima , El-Ansary Afaf 
Published: November 2019

AbstractBackgroundNeuroinflammation plays a major role in the pathogenesis of autism because the cytokine levels are typically disturbed in the brain in autistic patients. Prebiotics-rich diet maintains the healthy gut microbiota and hence can regulate the neuroinflammation indirectly. The study aimed to investigate the role of bee pollen and propolis in ameliorating neuroinflammation, including cytokine levels, in an animal model of autism.MethodsHamsters were classified as four groups: Group I, control; Group II, autistic model/animals treated with 250 mg propionic acid (PPA)/kg body weight (BW)/day for 3 days; Group III, animals treated with bee pollen at a dose of 250 mg/kg BW/day for 4 weeks; and Group IV, animals treated with propolis at a dose of 250 mg/kg BW/day for 4 weeks. Neuroinflammatory responses were evaluated using the levels of interferon γ (IFN-γ), interleukin 1 alpha (IL-1α), IL-6, IL-10, IL-12 (p70), vascular endothelial growth factor (VEGF), and tumor necrosis factor α (TNFα).ResultsSignificant decrease of IL-10 (P<0.026), VEGF (P<0.005), and TNFα(P<0.005) levels and increased IL-1α (P<0.032), IL-6(P<0.028), and IFN-γ (P<0.013) levels were observed between the four studied groups. The neurotoxic effects of PPA was clearly presented as much higher IL-6, as pro-inflammatory cytokine (P<0.05), concomitant with much lower IL-10, as anti-inflammatory cytokine(P<0.015) compared to controls. Both bee pollen and propolis were effective in ameliorating the neurotoxic effects of PPA demonstrating non-significant changes of IL-6 and IL-10 when compared to control healthy hamsters.ConclusionsOur findings indicate that both bee pollen and propolis protect against neuroinflammation in the rodent model of autism. However, further studies are needed to investigate the clinical benefits of prebiotics-rich diet in neurodevelopmental disorders, such as autism.
Cervical invasion, lymphovascular space invasion, and ovarian metastasis as predictors of lymph node metastasis and poor outcome on stages I to III endometrial cancers: a single-center retrospective study
Authors: Li Min , Wu Shuwei , Xie Yangqin , Zhang Xiaohui , Wang Zhanyu , Zhu Ying , Yan Shijie 
Published: November 2019

Abstract
Background
The aim of this study is to determine pathological factors that increase the risk of LNM and indicate poor survival of patients diagnosed with endometrial cancer and treated with surgical staging.

Method
Between January 2010 and November 2018, we enrolled 874 eligible patients who received staging surgery in the First Affiliated Hospital of Anhui Medical University. The roles of prognostic risk factors, such as age, histological subtype, tumor grade, myometrial infiltration, tumor diameter, cervical infiltration, lymphopoiesis space invasion (LVSI), CA125, and ascites, were evaluated. Multivariable logistic regression models were used to identify the predictors of LNM. Kaplan–Meier and COX regression models were utilized to study the overall survival.

Results
Multivariable regression analysis confirmed cervical stromal invasion (OR 3.412, 95% CI 1.631–7.141; P < 0.01), LVSI (OR 2.542, 95% CI 1.061–6.004; P = 0.04) and ovarian metastasis (OR 6.236, 95% CI 1.561–24.904; P = 0.01) as significant predictors of nodal dissemination. Furthermore, pathological pattern (P = 0.03), myometrial invasion (OR 2.70, 95% CI 1.139–6.40; P = 0.01), and lymph node metastasis (OR 9.675, 95% CI 3.708–25.245; P < 0.01) were independent predictors of decreased overall survival.

Conclusions
Cervical invasion, lymphopoiesis space invasion, and ovarian metastasis significantly convey the risk of LNM. Pathological type, myometrial invasion, and lymph node metastasis are all important predictors of survival and should be scheduled for completion when possible in the surgical staging procedure.
Correction to: Inhaled gold nanoparticles cause cerebral edema and upregulate endothelial aquaporin 1 expression, involving caveolin 1 dependent repression of extracellular regulated protein kinase activity
Authors: Chen Ching-Yi , Liao Po-Lin , Tsai Chi-Hao , Chan Yen-Ju , Cheng Yu-Wen , Hwang Ling-Ling , Lin Kuan-Hung , Yen Ting-Ling , Li Ching-Hao 
Published: November 2019

It was highlighted that the original article [1] contained the wrong Fig. 1.
Assessment of computational methods for the analysis of single-cell ATAC-seq data
Authors: Chen Huidong , Lareau Caleb , Andreani Tommaso , Vinyard Michael E. , Garcia Sara P. , Clement Kendell , Andrade-Navarro Miguel A. , Buenrostro Jason D. , Pinello Luca 
Published: November 2019

Abstract
Background
Recent innovations in single-cell Assay for Transposase Accessible Chromatin using sequencing (scATAC-seq) enable profiling of the epigenetic landscape of thousands of individual cells. scATAC-seq data analysis presents unique methodological challenges. scATAC-seq experiments sample DNA, which, due to low copy numbers (diploid in humans), lead to inherent data sparsity (1–10% of peaks detected per cell) compared to transcriptomic (scRNA-seq) data (10–45% of expressed genes detected per cell). Such challenges in data generation emphasize the need for informative features to assess cell heterogeneity at the chromatin level.

Results
We present a benchmarking framework that is applied to 10 computational methods for scATAC-seq on 13 synthetic and real datasets from different assays, profiling cell types from diverse tissues and organisms. Methods for processing and featurizing scATAC-seq data were compared by their ability to discriminate cell types when combined with common unsupervised clustering approaches. We rank evaluated methods and discuss computational challenges associated with scATAC-seq analysis including inherently sparse data, determination of features, peak calling, the effects of sequencing coverage and noise, and clustering performance. Running times and memory requirements are also discussed.

Conclusions
This reference summary of scATAC-seq methods offers recommendations for best practices with consideration for both the non-expert user and the methods developer. Despite variation across methods and datasets, SnapATAC, Cusanovich2018, and cisTopic outperform other methods in separating cell populations of different coverages and noise levels in both synthetic and real datasets. Notably, SnapATAC is the only method able to analyze a large dataset (> 80,000 cells).
Canine cutaneous and renal glomerular vasculopathy in the Republic of Ireland: a description of three cases
Authors: Hope Aimee , Martinez Carlos , Cassidy Joseph P. , Gallagher Barbara , Mooney Carmel T. 
Published: November 2019

AbstractBackgroundCutaneous and renal glomerular vasculopathy (CRGV) is a condition of unknown aetiology involving microvascular thrombosis. It has recently been described in over 160 dogs in the United Kingdom and usually has a grave prognosis. To date, this condition has not been described in dogs residing in the Republic of Ireland.Case presentationThree dogs presented to University College Dublin Veterinary Hospital (UCDVH) for investigation of rapidly progressive skin lesions. All dogs were diagnosed with CRGV on post-mortem examination. All three dogs had azotaemia on presentation or rapidly developed azotaemia, and all were euthanased because of progression of clinical signs and likelihood of CRGV. One dog was affected by seizure-like episodes and had thrombotic microangiopathy evident within the cerebrum.ConclusionsCRGV occurs in dogs residing in the Republic of Ireland and is a differential for cases presenting with skin lesions and azotaemia. The histopathological lesions of CRGV can also affect the brain leading to neurological signs such as seizures. Owners and veterinarians should be aware that this condition can occur in dogs in Ireland.
Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes
Authors: Shimazawa Rumiko , Ikeda Masayuki 
Published: November 2019

Abstract
Background
Glycated hemoglobin (HbA1c) is accepted as the most reliable marker for assessing chronic glycemia. The present study aimed to investigate glycemic control in cardiovascular outcome trials (CVOTs) performed by pharmaceutical sponsors, at the request of the United States Food and Drug Administration (FDA) to ensure that newer hypoglycemic agents do not increase cardiovascular risk for patients with type 2 diabetes.

Methods
We chose ClinicalTrials.gov as a data source to identify randomized, double-blind, placebo-controlled non-inferiority trials of newer hypoglycemic agents for which the FDA 2008 guidance required a CVOT involving patients with type 2 diabetes.

Results
We identified 12 CVOTs, all of which were performed in accordance with the FDA guidance and published as of December 2018. Participants received either active treatment or placebo in addition to their existing therapy. On the assumption that HbA1c concentrations would be higher in the placebo group than in the treatment group, the use of open-label glucose lowering agents was encouraged as required to help all patients reach appropriate HbA1c targets according to local guidelines. As a result, the number of patients who received additional hypoglycemic agents during the trial was greater in the placebo group than in the treatment group in 10 of the CVOTs. Although the CVOTs were designed to avoid any imbalance in glycemic control between the groups, HbA1c concentrations were substantially higher in the placebo group than in the treatment group in all CVOTs throughout the observational period. The inferior glycemic control in the placebo groups was not considered in analyzing the outcomes in any of the CVOTs.

Conclusions
The safety and efficacy of new hypoglycemic agents are potentially inflated because the participants in the placebo groups unexpectedly exhibited inferior glycemic control throughout the trial compared with the outcomes in the treatment groups. This imbalance may distort data interpretation and mask potential risks of the drugs. Re-analysis with adjustment for HbA1c concentrations would determine whether the results of these CVOTs were biased by the difference in glycemic control between the treatment and placebo groups and reveal potential effects of the test drugs independent of glycemic control.