bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Efficacy and Safety of Qishen Yiqi Dropping Pill Combined with Conventional Western Medicine in the Treatment of Chronic Heart Failure: A Systematic Review and Meta-Analysis
Authors: Chen Lisheng , Wang Ruilin , Liu Honghong , Wei Shizhang , Jing Manyi , Wang Min , Zhao Yanling
Published: February 2021

Objective. The systematic review was designed to evaluate the safety and efficacy of Qishen Yiqi dropping pill combined with conventional Western medicine in the treatment of chronic heart failure (CHF). Methods. Relevant randomized controlled trials (RCTs) investigating the clinical efficacy of Qishen Yiqi dropping pill combined with conventional Western medicine in treating CHF were widely searched in electronic databases, including PubMed, Cochrane Library, EMBASE, CBM, CNKI, Read-show database, VIP database, and WanFang up to December 26, 2020. The methodological quality of each trial was assessed according to the Cochrane Reviewers’ Handbook 5.0. Meta-analysis was performed by using Review Manager 5.3. Results. Twenty-one RCTs (N = 2162) that met the criteria were included in the review for the assessment of methodological quality. Meta-analysis showed that compared with the conventional Western medicine (control group), Qishen Yiqi dropping pill combined with conventional Western medicine (experience group) significantly improved clinical efficiency, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), brain natriuretic peptide level (BNP), 6 min-walk distance (6-MWD), and adverse reactions. Conclusion. Qishen Yiqi dropping pill combined with conventional Western medicine are better than conventional Western medicine alone to improve the indicators of patients with CHF, which provides a certain basis for the treatment of CHF.
Mechanism of Intestinal Flora and Proteomics on Regulating Immune Function of Durio zibethinus Rind Polysaccharide
Authors: Jiang Huimin , Wang Jinmei , Liang Qiongxin , Jiang Shengjun , Ma Changyang , Zhang Yan , Kang Wenyi
Published: February 2021

In this study, cyclophosphamide was injected intraperitoneally to establish an immunosuppressive mouse model to study the immune regulating effects of Durio zibethinus Murr rind polysaccharide (DZMP) through proteomics and intestinal flora. The results showed that the thymus and spleen indexes of the high‐dose DZMP (200 mg/kg) group were significantly increased, and the tissue structure of the spleen was improved compared with the model group (P < 0.01). The contents of IL‐2, IL‐4, IL‐6, and TNF‐α in the high‐dose group of DZMP were significantly increased (P < 0.001). Activities of acid phosphatase (ACP), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and total antioxidant capacity (T‐AOC) were increased in serum (P < 0.01). In the liver, catalase (CAT) activity was increased (P < 0.001) while the malondialdehyde (MDA) content was decreased and immune activity was increased (P < 0.001). Proteomics studies showed that the drug group could significantly increase the low‐affinity immunoglobulin gamma Fc receptor III (FcγRIII) protein and protein kinase C‐α (PKC‐α) compared with the model group (P < 0.001). In addition, the result showed that those proteins were likely involved in the regulation of the metabolic pathways of autoimmune thyroid disease, Staphylococcus aureus infection, and NF‐κB signaling pathway. Intestinal microbial studies showed that short‐chain fatty acid (SCFA) content was increased as well as the relative abundance of beneficial bacteria Akkermansia, Bacteroides, and Paraprevotella, while the relative abundance of Ruminococcus and Oscillospira was decreased compared with the model group (P < 0.001). The results showed that DZMP might play a beneficial role in immune regulation by improving intestinal flora.
Lie Symmetry Analysis and Explicit Solutions for the Time-Fractional Regularized Long-Wave Equation
Authors: Maarouf Nisrine , Maadan Hicham , Hilal Khalid
Published: February 2021

This paper systematically investigates the Lie group analysis method of the time-fractional regularized long-wave (RLW) equation with Riemann–Liouville fractional derivative. The vector fields and similarity reductions of the time-fractional (RLW) equation are obtained. It is shown that the governing equation can be transformed into a fractional ordinary differential equation with a new independent variable, where the fractional derivatives are in Erdèlyi–Kober sense. Furthermore, the explicit analytic solutions of the time-fractional (RLW) equation are obtained using the power series expansion method. Finally, some graphical features were presented to give a visual interpretation of the solutions.
Marked Rebound of Platelet Count in the Early Postpartum Period in a Patient with Essential Thrombocythemia
Authors: Hashimoto Yoshinori , Hosoda Rina , Omura Hiromi , Tanaka Takayuki
Published: February 2021

Essential thrombocythemia (ET) occurs predominantly in the elderly, but approximately 20% of patients are <40 years old. Unlike other myeloproliferative neoplasms, ET occurs more commonly in women. We encountered a 38-year-old women diagnosed with ET who exhibited elevated platelet count in early pregnancy. Her platelet count exceeded 1500 × 109/L by late pregnancy; interferon

α

was administered but failed to induce an adequate response. She underwent emergency cesarean delivery at 37 weeks of gestation. Although her platelet count was 1000 × 109/L immediately after delivery, it markedly increased to 3271 × 109/L approximately 2 weeks later. Cytoreductive therapy was resumed; the subsequent course was free from complications. Several review articles have indicated that because platelet counts of patients may again increase to the pregnancy level or rebound after delivery, cytoreductive therapy should be administered if necessary. However, there is insufficient information on when therapeutic interventions are necessary and how they should be performed. It remains unknown whether the platelet count will decrease after some time without treatment if it rebounds. We hope management guidelines will be established by collecting detailed data on the postpartum course as well as during pregnancy.
A Novel Parameter‐Adaptive VMD Method Based on Grey Wolf Optimization with Minimum Average Mutual Information for Incipient Fault Detection
Authors: Xu Wang , Hu Jinfei
Published: February 2021

Recently, variational mode decomposition (VMD) has attracted wide attention on mechanical vibration signal analysis. However, there are still some dilemmas in the application of VMD, such as the determination of the number of mode decomposition K and quadratic penalty term α. In order to acquire appropriate parameters of VMD, an improved parameter‐adaptive VMD method based on grey wolf optimizer (GWO) is developed by taking the minimum average mutual information into consideration (GWOMI). Firstly, the parameters (K, α) are adaptively determined through GWOMI. Then, the vibration signal is decomposed by the developed method and effective modes are extracted according to the maximum kurtosis. Finally, the extracted modes are processed by Hilbert envelope analysis to acquire the incipient fault features. With the simulation and experimental analysis, it is clearly found that the developed method is effective and performs better than some existing ones.
Long Noncoding RNA ANPODRT Overexpression Protects Nucleus Pulposus Cells from Oxidative Stress and Apoptosis by Activating Keap1‐Nrf2 Signaling
Authors: Kang Liang , Tian Yueyang , Guo Xing , Chu Xu , Xue Yuan
Published: February 2021

Oxidative stress and subsequent nucleus pulposus (NP) cell apoptosis are important contributors to the development of intervertebral disc degeneration (IDD). Emerging evidences show that long noncoding RNAs (lncRNAs) play a role in the pathogenesis of IDD. In this study, we investigated the role of lncRNA ANPODRT (anti‐NP cell oxidative damage‐related transcript) in oxidative stress and apoptosis in human NP cells. We found that ANPODRT was downregulated in degenerative NP tissues and in NP cells treated with tert‐butyl hydroperoxide (TBHP, the oxidative stress inducer). ANPODRT overexpression alleviated oxidative stress and apoptosis in NP cells exposed to TBHP, while ANPODRT knockdown exerted opposing effects. Mechanistically, ANPODRT facilitated nuclear factor E2‐related factor 2 (Nrf2) accumulation and nuclear translocation and activated its target genes by disrupting the kelch‐like ECH‐associated protein 1‐ (Keap1‐) Nrf2 association in NP cells. Nrf2 knockdown abolished the antioxidative stress and antiapoptotic effects of ANPODRT in NP cells treated with TBHP. Collectively, our findings suggest that ANPODRT protects NP cells from oxidative stress and apoptosis, at least partially, by activating Nrf2 signaling, implying that ANPODRT may be a potential therapeutic target for IDD.
Speckle Tracking Echocardiography: Early Predictor of Diagnosis and Prognosis in Coronary Artery Disease
Authors: Pastore Maria Concetta , Mandoli Giulia Elena , Contorni Francesco , Cavigli Luna , Focardi Marta , D’Ascenzi Flavio , Patti Giuseppe , Mondillo Sergio , Cameli Matteo
Published: February 2021

Echocardiography represents a first level technique for the evaluation of coronary artery disease (CAD) which supports clinicians in the diagnostic and prognostic workup of these syndromes. However, visual estimation of wall motion abnormalities sometimes fails in detecting less clear or transient myocardial ischemia and in providing accurate differential diagnosis. Speckle tracking echocardiography (STE) is a widely available noninvasive tool that could easily and quickly provide additive information over basic echocardiography, since it is able to identify subtle myocardial damage and to localize ischemic territories in accordance to the coronary lesions, obtaining a clear visualization with a “polar map” useful for differential diagnosis and management. Therefore, it has increasingly been applied in acute and chronic coronary syndromes using rest and stress echocardiography, showing good results in terms of prediction of CAD, clinical outcome, left ventricular remodeling, presence, and quantification of new/residual ischemia. The aim of this review is to illustrate the current available evidence on STE usefulness for the assessment and follow‐up of CAD, discussing the main findings on bidimensional and tridimensional strain parameters and their potential application in clinical practice.
RBF Interpolation Algorithm for FTS Tool Path Generation
Authors: Nie Yahui , Du Yinfei , Xu Zhuo , Zhang Zimiao , Qi Yang
Published: February 2021

Freeform optics are defined as nonrotational symmetric optical surfaces in the manufacturing industry. Freeform optics are extensively applied to many areas in order to improve system performance. Fast tool servo (FTS) assisting single-point diamond turning technology has high application prospects in freeform optics machining. This paper discusses the interpolation algorithm for tool path generation of FTS through the application of a radial basis function (RBF) algorithm. For this purpose, a positive definite RBF with compact support was employed as the interpolant. The existence is mathematically proven. Numerical simulations were performed to compare the performances of the RBF algorithm and commonly used algorithms for satisfying the requirements of existence, smoothness, and accuracy. Machining experiments were also conducted to validate the applicability of the algorithm. The simulation results showed that the RBF interpolation algorithm outperformed other algorithms in terms of smoothness. The RBF algorithm also provided the highest interpolation accuracy. Furthermore, the RBF interpolation algorithm exhibited the highest accuracy for error distribution, with large errors distributed mainly in transition areas. The machining results were also in general agreement with the simulation results although obvious practical errors were observed. Overall, RBF interpolation can provide higher accuracy and better smoothness in the tool path generation of FTS.
Propionibacterium acnes Infection after Craniotomy in a Young Adult with Subdural Hematoma
Authors: El Soufi Hind , El Soufi Yahya , Bagheri Farshad
Published: February 2021

Propionibacteriumacnes is a Gram-positive bacillus that can be part of the human skin flora. This bacterium infecting the subdural space postoperatively is quite a rare entity. When present, it likely reflects a true infection rather than contamination requiring urgent intervention. We are reporting a rare case of craniotomy for subdural hematoma evacuation complicated by subdural Propionibacterium acnes infection. The infection was successfully treated with surgical debridement and antibiotics.
Upregulation of Versican Associated with Tumor Progression, Metastasis, and Poor Prognosis in Bladder Carcinoma
Authors: Zhang Qi , Wu Junxiu , Chen Xinpeng , Zhao Ming , Zhang Dahong , Gao Feng
Published: February 2021

Objective. This work analyzes the role of versican (VCAN) on bladder cancer (BLCA). Versican (VCAN) is a chondroitin sulfate proteoglycan which is important for tumorigenesis and the development of cancer. However, the expression of VCAN on human bladder cancer (BLCA) has been rarely reported. Methods. The clinical significance of VCAN in BLCA has been determined by our bioinformatics tools. Then, we performed immunohistochemical staining (IHC) and analyzed the correlation between VCAN expression and clinicopathological features. Results. The bioinformatics results reveal that a high VCAN mRNA level was significantly associated with stage, histological subtype, molecular subtype, and metastasis in BLCA. Furthermore, IHC reveals that expression of VCAN was significantly correlated with the number of tumors, invasion depth, lymph node metastasis, distant metastasis, and histological grade. Kaplan‐Meier survival analysis reveals that patients with a high expression of VCAN have poor prognosis than those patients with a low expression of VCAN. According to our result from the bioinformatics database, the mechanism of VCAN in BLCA revealed that VCAN was related to FBN1 and genes of the ECM remodeling pathway (MMP1, MMP2). Conclusion. VCAN expression might be included in the process of carcinogenesis and prognosis. Hence, VCAN could be a reliable biomarker of the clinical prognosis on BLCA.
Generating Water Waves on Steady Currents Using Mass Source Wave Maker Coupled with Analytical Relaxation Wave Absorber
Authors: Feng Xing , Liu Jia , Ma Ruina
Published: February 2021

In order to numerically simulate the wave-current interaction problems frequently encountered by aquaculture structures, a two-dimensional numerical wave-current tank model was established here based on a mass source wave maker coupled with an analytical relaxation wave absorber. The wave-maker model and the wave-absorber model were embedded into a two-dimensional RANS solver, which was closed with RSM turbulence scheme. The volume of fluid (VOF) method was adapted to accurately capture the free surface between water and air. To generate a steady uniform current flow, the uniform current flow velocity was calculated at the left-hand-side (LHS) and right-had-side (RHS) outflow boundaries, respectively. Once the steady uniform current flow was generated over the whole computational domain, the target water wave was marked within a specified region by embedding the mass source function based on wave theory into the mass conservation equation and then propagated on the generated uniform current flow. To verify the accuracy of the numerical wave-current tank established here, some of the obtained numerical results were then compared with the experimental results and the analytical solutions, and they agreed well with each other, indicating that the model developed here has great ability in simulating water waves on uniform currents over constant water depth. The established numerical wave-current tank was then used to study the optimal layout of the mass source region and the effects of water current velocity on water surface wave parameters during regular wave coupling with uniform water currents. Meanwhile, the established model was extended to generate steep wave and apply in deep water conditions. Finally, the proposed methods were applied to investigate the wave-current-structure interaction problems and the propagation of solitary waves traveling with coplanar/counter currents. Model-data comparisons show that the developed model here is potentially useful and efficient for investigating the inevitable wave-current-structure interaction problems in aquaculture technologies.
Alismatis Rhizoma Triterpenes Alleviate High-Fat Diet-Induced Insulin Resistance in Skeletal Muscle of Mice
Authors: Jia Xiao-Kang , Huang Jin-Fang , Huang Xiao-Qiang , Li Xiao-Yan , Huang Ming-Qing , Zhu Huai-Chang , Li Gao-Pan , Lan Meng-Liu , Yu Zhi-Wen , Xu Wen , Wu Shui-Sheng
Published: February 2021

Alismatis rhizoma (AR), which is the dried rhizome of Alisma orientale (Sam.) Juz. (Alismataceae), is an important component of many famous Chinese formulas for hypoglycemic. This study aimed to evaluate the insulin resistance (IR) alleviating effects of AR triterpenes (ART) and ART component compatibility (ARTC, the mixture of 16-oxo-alisol A, 16-oxo-alisol A 23-acetate, 16-oxo-alisol A 24-acetate, alisol C, alisol C 23-acetate, alisol L, alisol A, alisol A 23-acetate, alisol A 24-acetate, alisol L 23-acetate, alisol B, alisol B 23-acetate, 11-deoxy-alisol B and 11-deoxy-alisol B 23-acetate) in high-fat diet-induced IR mice and plamitate-treated IR C2C12 cells, respectively. A dose of 200 mg/kg of ART was orally administered to IR mice, and different doses (25, 50, and 100 μg/ml) of ARTC groups were treated to IR C2C12 cells. IPGTT, IPITT, body weight, Hb1AC, FFA, TNF-

α

, MCP-1, and IR-associated gene expression (p-AMPK, p-IRS-1, PI3K, p-AKT, p-JNK, and GLUT4) were measured in IR mice. Glucose uptake, TNF-

α

, MCP-1, and IR-associated gene expression were also measured in IR C2C12 cells. Results showed that ART alleviated high-fat diet-induced IR in the skeletal muscle of mice, and this finding was further validated by ARTC. This study demonstrated that ART presented a notable IR alleviating effect by regulating IR-associated gene expression, and triterpenes were the material basis for the IR alleviating activity of AR.
Vehicle Routing Problem with Transshipment: Mathematical Model and Algorithm
Authors: Leelertkij Thanapat , Parthanadee Parthana , Buddhakulsomsiri Jirachai
Published: February 2021

This paper presents a new variant of vehicle routing problem with paired transshipment demands (VRPT) between retail stores (customers) in addition to the regular demand from depot to retail stores. The problem originates in a real distribution network of high-end retail department stores in Thailand. Transshipment demands arise for one-order-per-season expensive items, whose inventories at the depot may become shortage after the middle of a season, while they remain available at some retail stores. A transshipment demand is a request for items that need to be picked up from a specific store that has the items and delivered to the store that requests the items. The objective of solving the VRPT is to find delivery routes that can satisfy both regular demands and transshipment demands in the same routes without incurring too much additional transportation distance. A mixed integer linear programming model is formulated to represent the VRPT. Six small problem instances are used to test the model. A hybrid threshold accepting and neighborhood search heuristic is also developed to solve large problem instances of VRPT. The heuristic is further extended to include a forbidden list of transshipment demands that should not be included in the same routes. The purpose is to prevent incurring too much additional distance from satisfying transshipment demands. With the forbidden list, the problem becomes vehicle routing problem with optional transshipment demands (VRPOT). Computational testing shows promising results that indicate effectiveness of the proposed hybrid heuristics as well as the forbidden list.
An Improved Empirical Mode Decomposition Based on Local Integral Mean and Its Application in Signal Processing
Authors: Niu Xiao-dong , Lu Li-rong , Wang Jian , Han Xing-cheng , Li Xuan , Wang Li-ming
Published: February 2021

Empirical mode decomposition (EMD) is an effective method to deal with nonlinear nonstationary data, but the lack of orthogonal decomposition theory and mode-mixing are the main problems that limit the application of EMD. In order to solve these two problems, we propose an improved method of EMD. The most important part of this improved method is to change the mean value by envelopes of signal in EMD to the mean value by the definite integral, which enables the mean value to be mathematically expressed strictly. Firstly, we prove that the signal is orthogonally decomposed by the improved method. Secondly, the Monte Carlo method of white noise is used to explain that the improved method can effectively alleviate mode-mixing. In addition, the improved method is adaptive and does not need any input parameters, and the intrinsic mode functions (IMFs) generated from it is robust to sifting. We have carried out experiments on a series of artificial and real data, the results show that the improved method is the orthogonal decomposition method and can effectively alleviate mode-mixing, and it has better decomposition performance and physical meaning than EMD, ensemble EMD (EEMD), and complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN). In addition, the improved method is generally more time-consuming than EMD, but far less than EEMD and CEEMDAN.
Valproic acid, in combination with all-trans retinoic acid and 5-aza-2′-deoxycytidine, restores expression of silenced RARβ2 in breast cancer cells
Authors: Mongan Nigel P. , Gudas Lorraine J.
Published: February 2021

Epigenetic silencing of tumor suppressor genes has been established as an important process of carcinogenesis. The retinoic acid (RA) receptor β2 (RARβ2) gene is one such tumor suppressor gene often silenced during carcinogenesis. The combined use of histone deacetylase and DNA methyltransferase inhibitors has been shown to reverse the epigenetic silencing of numerous growth regulatory genes. Valproic acid (VPA), which has long been used in the treatment of epilepsy, was shown recently to be an effective histone deacetylase inhibitor that can induce differentiation of neoplastically transformed cells. In this study, we show for the first time that VPA, in combination with RA and the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza-dC), can overcome the epigenetic barriers to transcription of a prototypical silenced tumor suppressor gene, RARβ2, in human breast cancer cells. Chromatin immunoprecipitation assays show that the combination of VPA, RA, and Aza-dC increases histone acetylation at the silenced RARβ2 promoter of MCF-7 breast cancer cells. Furthermore, reverse transcription-PCR analyses reveal cell type–specific effects in the actions of VPA on RARβ2 expression in cultured human breast cancer cells. Finally, we show that VPA, in combination with RA and Aza-dC, inhibits the proliferation of both estrogen receptor α-positive (MCF-7) and estrogen receptor α-negative (MDA-MB-231) breast cancer cell lines. These data suggest that VPA may ultimately be useful in combination therapies in the treatment of human breast cancers.
Gene expression profiling revealed novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells
Authors: Li Yiwei , Hong Xin , Hussain Maha , Sarkar Sarah H. , Li Ran , Sarkar Fazlul H.
Published: February 2021

Both docetaxel and estramustine are antimicrotubule agents with antitumor activity in various cancers including prostate cancer. Clinical trials for docetaxel and estramustine combination treatment have suggested improved antitumor activity in hormone-refractory prostate cancer. However, the molecular mechanisms involved in the combination treatment with docetaxel and estramustine have not been fully elucidated. In order to establish such molecular mechanisms in both hormone insensitive (PC-3) and sensitive (LNCaP) prostate cancer cells, gene expression profiles of docetaxel- and estramustine-treated prostate cancer cells were obtained by using Affymetrix Human Genome U133A Array. Total RNA from PC-3 and LNCaP cells untreated and treated with 2 nmol/L docetaxel, 4 μmol/L estramustine, or 1 nmol/L docetaxel plus 2 μmol/L estramustine for 6, 36, and 72 hours was subjected to microarray analysis. Real-time PCR and Western blot analysis were conducted to confirm the microarray data. Clustering analysis based on biological function showed that docetaxel and estramustine combination treatment down-regulated some genes that are known to regulate cell proliferation, transcription, translation, and oncogenesis. In contrast, docetaxel and estramustine combination treatment up-regulated some genes related to induction of apoptosis, cell cycle arrest, and tumor suppression. Docetaxel and estramustine also showed differential effects on gene expression between mono- and combination treatment. Combination treatment with docetaxel and estramustine caused alternations of a large number of genes, many of which may contribute to the molecular mechanisms by which docetaxel and estramustine inhibit the growth of prostate cancer cells. These results provide novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells. This information could be utilized for further mechanistic research and for devising optimized therapeutic strategies against prostate cancer.
Health and Fitness at the Single-Cell Level
Authors: Green Douglas R.
Published: February 2021

Genetically identical cells in a tissue can respond differently to perturbations in their environment or “stress.” Such stresses can be physicochemical, mechanical, or infectious or may come from competition with other cells in the tissue. Here, I discuss how the varying responses to stress influence the decision of a cell to repair or die, and how one cell's response can have effects on surrounding cells. Such responses control the health and fitness of single cells and how they compete with other genetically identical cells.

See related article on p. 129
Abstract PO083: Treatment of CEA-positive solid tumors with anti-CEA chimeric antigen receptor T-cells in CEA transgenic mice
Authors: Cha Seung , Yazaki Paul , Brown Christine , Shively John
Published: February 2021

Chimeric antigen receptors (CARs) combine specificity of antibody to target antigen on cancer cells with the potent cytotoxic activity of T-cells without the need for MHC recognition. Chimeric antigen receptor (CAR) T-cells that were designed to express the single chain variable fragment binding domain of human anti-CEA antibody BW431/26 on mouse splenocytes were able to reduce CEA-expressing pancreatic adenocarcinoma tumor in CEA-transgenic (CEAtg) mice without significant off-target effects (Chmielewski et al., 2012). In this study, an anti-CEA CAR construct derived from murine anti-CEA antibody (T84.66) expressed on human T-cells targeted CEA+ colon carcinoma cells (LS174T/CEA and MC38CEA) with high specificity in vitro. When co-incubated with CEA-positive or CEA-negative mouse cancer cells, anti-CEA CAR expressed on mouse T-cells also specifically targeted CEA-positive cancer cells in vitro. Compared to mock T-cells control, anti-CEA CAR T-cells injected intravenously delayed subcutaneous MC38CEA tumor growth in CEA-transgenic mice (CEAtg). Lymphodepletion via cyclophosphamide injected before anti-CEA T-cells injection further delayed subcutaneous MC38CEA tumor growth and delayed orthotopic CEA+ breast carcinoma (E0771CEA) tumor growth in CEAtg mice. To improve the therapeutic potential of anti-CEA CAR T-cells, IL2 conjugated to humanized anti-CEA antibody (M5A-IL2, ICK) was interperitoneally injected after anti-CEA CAR T-cells into lymphodepleted CEAtg mice. A single injection of ICK after anti-CEA CAR T-cells delayed subcutaneous MC38CEA tumor growth even further. Two injections of ICK after anti-CEA T-cells delayed orthotopic E0771CEA tumor growth. Four injections of ICK after anti-CEA CAR T-cells eradicated subcutaneous MC38CEA tumors. These data show the therapeutic potential of anti-CEA CAR T-cells to target CEA-positive tumors.

Citation Format: Seung Cha, Paul Yazaki, Christine Brown, John Shively. Treatment of CEA-positive solid tumors with anti-CEA chimeric antigen receptor T-cells in CEA transgenic mice [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO083.
CT and MRI Image Fusion Error: An Analysis of Co-Registration Error Using Commercially Available Deep Brain Stimulation Surgical Planning Software
Authors: Burke John F. , Tanzillo Dominic , Starr Philip A. , Lim Daniel A. , Larson Paul S.
Published: February 2021

Introduction: During deep brain stimulation (DBS) surgery, computed tomography (CT) and magnetic resonance imaging (MRI) scans need to be co-registered or fused. Image fusion is associated with the error that can distort the location of anatomical structures. Co-registration in DBS surgery is usually performed automatically by proprietary software; the amount of error during this process is not well understood. Here, our goal is to quantify the error during automated image co-registration with FrameLink™, a commonly used software for DBS planning and clinical research. Methods: This is a single-center retrospective study at a quaternary care referral center, comparing CT and MR imaging co-registration for a consecutive series of patients over a 12-month period. We collected CT images and MRI scans for 22 patients with Parkinson’s disease requiring placement of DBS. Anatomical landmarks were located on CT images and MRI scans using a novel image analysis algorithm that included a method for capturing the potential error inherent in the image standardization step of the analysis. The distance between the anatomical landmarks was measured, and the error was found by averaging the distances across all patients. Results: The average error during co-registration was 1.25 mm. This error was significantly larger than the error resulting from image standardization (0.19 mm) and was worse in the anterior-posterior direction. Conclusions: The image fusion errors found in this analysis were nontrivial. Although the estimated error may be inflated, it is sig­nificant enough that users must be aware of this potential inaccuracy, and developers of proprietary software should provide details about the magnitude and direction of co-registration errors.
Multiparametric MRI Lesion Classified as Prostate Imaging-Reporting and Data System 5 but Histopathologically Described as Benign: A Case Report and Review of Literature
Authors: Apfelbeck Maria , Schlenker Boris , Chaloupka Michael , Stief Christian G. , Clevert Dirk-André
Published: February 2021

Introduction: Prostate cancer (PCa) is the most common malignancy in men. The multiparametric MRI (mpMRI) significantly improved the diagnostic approach of PCa. Although PCa is highly likely to be present in prostate imaging-reporting and data system (PI-RADS) 5 lesions, there are up to 18% of PI-RADS 5 lesions with benign histopathology after targeted biopsy. Case Description: We present the case of a 66-year-old man who was referred to our hospital for MRI/ultrasound fusion-based targeted biopsy due to an elevated PSA and a PI-RADS 5 lesion described in the mpMRI. After 2 consecutive biopsies, the mpMRI target showed no malignancy. The lesion was described as PI-RADS 2 two years later. Conclusion: This case demonstrates the risk of false-positive classified PI-RADS 5 lesions in the mpMRI and the challenge in some cases to distinguish between BPH nodules and cancer. Until today, a limited amount of studies exists concerning this issue. However, further studies are required to evaluate further characteristics associated with a higher possibility of histopathologically benign findings in PI-RADS 5 lesions.
Pyridoxamine and Caloric Restriction Improve Metabolic and Microcirculatory Abnormalities in Rats with Non-Alcoholic Fatty Liver Disease
Authors: Pereira Evelyn Nunes Goulart da Silva , Silvares Raquel Rangel , Rodrigues Karine Lino , Flores Edgar Eduardo Ilaquita , Daliry Anissa
Published: February 2021

Introduction: This study aims to examine the effect of a diet intervention and pyridoxamine (PM) supplementation on hepatic microcirculatory and metabolic dysfunction in nonalcoholic fatty liver disease (NAFLD). Methods: NAFLD in Wistar rats was induced with a high-fat diet for 20 weeks (NAFLD 20 weeks), and control animals were fed with a standard diet. The NAFLD diet intervention group received the control diet between weeks 12 and 20 (NAFLD 12 weeks), while the NAFLD 12 weeks + PM group also received PM. Fasting blood glucose (FBG) levels, body weight (BW), visceral adipose tissue (VAT), and hepatic microvascular blood flow (HMBF) were evaluated at the end of the protocol. Results: The NAFLD group exhibited a significant increase in BW and VAT, which was prevented by the diet intervention, irrespective of PM treatment. The FBG was elevated in the NAFLD group, and caloric restriction improved this parameter, although additional improvement was achieved by PM. The NAFLD group displayed a 31% decrease in HMBF, which was partially prevented by caloric restriction and completely prevented when PM was added. HMBF was negatively correlated to BW, FBG, and VAT content. Conclusion: PM supplementation in association with lifestyle modifications could be an effective intervention for metabolic and hepatic vascular complications.
Mobility Performance in Community-Dwelling Older Adults: Potential Digital Biomarkers of Concern about Falling
Authors: Wang Changhong , Patriquin Michelle , Vaziri Ashkan , Najafi Bijan
Published: February 2021

Introduction: Concern about falling is a prevalent worry among community-dwelling older adults and may contribute to a decline in physical and mental health. This study aimed to examine the association between mobility performance and concern about falling. Methods: Older adults aged 65 years and older, with Mini-Mental State Examination score ≥24, and ambulatory (with or without the assistive device) were included. Concern about falling was evaluated with Falls Efficacy Scale-International (FES-I) scores. Participants with high concern about falling were identified using the cutoff of FES-I ≥23. Participants’ motor capacity was assessed in standardized walking tests under single- and dual-task conditions. Participants’ mobility performance was measured based on a 48-h trunk accelerometry signal from a wearable pendant sensor. Results: No significant differences were observed at participant characteristics across groups with different levels of concern about falling (low: N = 64, age = 76.3 ± 7.2 years, female = 46%; high: N = 59, age = 79.3 ± 9.1 years, female = 47%), after propensity matching with BMI, age, depression, and cognition. With adjustment of motor capacity (stride velocity and stride length under single- and dual-task walking conditions), participants with high concern about falling had significantly poorer mobility performance than those with low concern about falling, including lower walking quantity (walking bouts, steps and time per day, and walking bout average, walking bout variability, and longest walking bout, p ≤ 0.013), and poorer daily-life gait (stride velocity and gait variability, p ≤ 0.023), and poorer walking quality (frontal gait symmetry, and trunk acceleration and velocity intensity, p ≤ 0.041). The selected mobility performance metrics (daily steps and frontal gait symmetry) could significantly contribute to identifying older adults with high concern about falling (p ≤ 0.042), having better model performance (p = 0.036) than only walking quantity (daily steps) with adjustment of confounding effects from the motor capacity (stride length under dual-task walking condition). Conclusion: There is an association between mobility performance and concern about falling in older adults. Mobility performance metrics can serve as predictors to identify older adults with high concern about falling, potentially providing digital biomarkers for clinicians to remotely track older adults’ change of concern about falling via applications of remote patient monitoring.
T2-FLAIR Mismatch Sign and Response to Radiotherapy in Diffuse Intrinsic Pontine Glioma
Authors: Yamasaki Fumiyuki , Nishibuchi Ikuno , Karakawa Shuhei , Kaichi Yoko , Kolakshyapati Manish , Takano Motoki , Yonezawa Ushio , Imano Nobuki , Taguchi Akira , Shimomura Maiko , Taniguchi Maki , Onishi Shumpei , Okada Satoshi , Awai Kazuo , Sugiyama Kazuhiko , Nagata Yasushi
Published: February 2021

Purpose: The T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign was previously reported as a diagnostic indicator of diffuse astrocytoma, isocitrate dehydrogenase-mutant, and 1p/19q noncodeletion. Subsequently, it was reported that the same findings were observed in diffuse intrinsic pontine glioma (DIPG). We investigated the clinical significance of T2-FLAIR mismatch sign in DIPG. Methods: Twenty-one patients with DIPG (Male: Female = 12:9) were treated at our institute between 2004 and 2019. All patients were treated with local radiotherapy of 54 Gy/30 fractions. The positive T2-FLAIR mismatch sign was defined if it fulfilled the following criteria: (1) T2-FLAIR mismatch volume was >50% of T2 high volume at nonenhanced area, (2) the FLAIR low lesion is not associated with gadolinium enhancement (inside of enhancement or just outside of enhancement defined as edema), and (3) signal-intensity of FLAIR lowest lesion at tumor is lower than the normal cerebellar cortex. Results: In our patient series, T2-FLAIR mismatch sign was found in 5 out of 21 patients. Objective response rate of radiotherapy was 100% in patients positive for T2-FLAIR mismatch, while it was 25.0% in patients negative for T2-FLAIR mismatch, and this difference was statistically significant (p < 0.01, Fisher’s exact test). In patients under the age of 18-years, T2-FLAIR mismatch positive had a slightly better prognosis (p < 0.05, Wilcoxon test). Conclusion: T2-FLAIR mismatch sign in DIPG may be an indicator for better response to radiotherapy and a better prognostic factor.
How an Oncologist’s Intuition Compares to a Geriatric Assessment
Authors: Ertl Sebastian Willy , Heuer Hans-Christoph , Stahl Michael Konrad
Published: February 2021

Background: A geriatric assessment (GA) is recommended before treating older cancer patients. The goal of this study was to investigate if the additional information from a GA and discussion by a multidisciplinary board (MB) change the treatment recommendations. Patients and Methods: Older cancer patients (n = 421) were prospectively assessed by an oncologist for eligibility for chemotherapy. A multidimensional GA was performed and a discussion about each patient was held by a MB including a geriatrician. Differences between the judgment made by the oncologist, that of the MB, and the Balducci classification were examined. A statistical model of the MB decision-making process was established and evaluated. Results: The treating oncologist and the MB judged 12 and 15% of the patients as frail, 41 and 38% as vulnerable, and 46 and 47% as fit. Overall, 83% agreement was observed. Based on the Balducci classification, 55% of the patients were frail, 30% were vulnerable, and 15% were fit. Only 34% of congruency with the oncologist’s judgment was observed. In a 2-stage logistics model, activities of daily living and the Mini-Mental-State Examination (MMSE) proved most suitable for identifying frail patients. Tinetti’s test, age, Charlson Comorbidity Index, living alone, the MMSE, and the Mini-Nutritional Assessment fitted best to distinguish between vulnerable and fit. Conclusions: Regarding the decision of systemic treatment for older patients, the judgment by an experienced oncologist was comparable to that of an MB and both were significantly different from the Balducci classification. For some patients, the additional discussion of GA data in an MB may change treatment decisions.
Efficacy and Safety of Sacubitril/Valsartan in High-Risk Patients in the PIONEER-HF Trial
Authors: Berg David D. , Samsky Marc D. , Velazquez Eric J. , Duffy Carol I. , Gurmu Yared , Braunwald Eugene , Morrow David A. , DeVore Adam D.
Published: February 2021

Background:

In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile.

Methods:

PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m
2
(n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219).

Results:

The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (
P
interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (
P
interaction=NS for each).

Conclusions:

In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.
MK2‐Deficient Mice Are Bradycardic and Display Delayed Hypertrophic Remodeling in Response to a Chronic Increase in Afterload
Authors: Ruiz Matthieu , Khairallah Maya , Dingar Dharmendra , Vaniotis George , Khairallah Ramzi J. , Lauzier Benjamin , Thibault Simon , Trépanier Joëlle , Shi Yanfen , Douillette Annie , Hussein Bahira , Nawaito Sherin Ali , Sahadevan Pramod , Nguyen Albert , Sahmi Fatiha , Gillis Marc‐Antoine , Sirois Martin G. , Gaestel Matthias , Stanley William C. , Fiset Céline , Tardif Jean‐Claude , Allen Bruce G.
Published: February 2021

Background

Mitogen‐activated protein kinase–activated protein kinase‐2 (MK2) is a protein serine/threonine kinase activated by p38α/β. Herein, we examine the cardiac phenotype of pan MK2‐null (MK2
−/−
) mice.

Methods and Results

Survival curves for male MK2
+/+
and MK2
−/−
mice did not differ (Mantel‐Cox test,
P
=0.580). At 12 weeks of age, MK2
−/−
mice exhibited normal systolic function along with signs of possible early diastolic dysfunction; however, aging was not associated with an abnormal reduction in diastolic function. Both R‐R interval and P‐R segment durations were prolonged in MK2‐deficient mice. However, heart rates normalized when isolated hearts were perfused ex vivo in working mode. Ca
2+
transients evoked by field stimulation or caffeine were similar in ventricular myocytes from MK2
+/+
and MK2
−/−
mice. MK2
−/−
mice had lower body temperature and an age‐dependent reduction in body weight. mRNA levels of key metabolic genes, including
Ppargc1a
,
Acadm
,
Lipe
, and
Ucp3,
were increased in hearts from MK2
−/−
mice. For equivalent respiration rates, mitochondria from MK2
−/−
hearts showed a significant decrease in Ca
2+
sensitivity to mitochondrial permeability transition pore opening. Eight weeks of pressure overload increased left ventricular mass in MK2
+/+
and MK2
−/−
mice; however, after 2 weeks the increase was significant in MK2
+/+
but not MK2
−/−
mice. Finally, the pressure overload–induced decrease in systolic function was attenuated in MK2
−/−
mice 2 weeks, but not 8 weeks, after constriction of the transverse aorta.

Conclusions

Collectively, these results implicate MK2 in (1) autonomic regulation of heart rate, (2) cardiac mitochondrial function, and (3) the early stages of myocardial remodeling in response to chronic pressure overload.
Risk of QTc Interval Prolongation Associated With Circulating Anti‐Ro/SSA Antibodies Among US Veterans: An Observational Cohort Study
Authors: Lazzerini Pietro Enea , Cevenini Gabriele , Qu Yongxia Sarah , Fabris Frank , El‐Sherif Nabil , Acampa Maurizio , Cartocci Alessandra , Laghi‐Pasini Franco , Capecchi Pier Leopoldo , Boutjdir Mohamed , Lazaro Deana
Published: February 2021

Background

Anti‐Sjögren's syndrome‐related antigen A‐antibodies (anti‐Ro/SSA‐antibodies) are responsible for a novel form of acquired long‐QT syndrome, owing to autoimmune‐mediated inhibition of cardiac human ether‐a‐go‐go‐related gene‐potassium channels. However, current evidence derives only from basic mechanistic studies and relatively small sample‐size clinical investigations. Hence, the aim of our study is to estimate the risk of QTc prolongation associated with the presence of anti‐Ro/SSA‐antibodies in a large population of unselected subjects.

Methods and Results

This is a retrospective observational cohort study using the Veterans Affairs Informatics and Computing Infrastructure. Participants were veterans who were tested for anti‐Ro/SSA status and had an ECG. Descriptive statistics and univariate and multivariate logistic regression analyses were performed to identify risk factors for heart rate‐corrected QT interval (QTc) prolongation. The study population consisted of 7339 subjects (61.4±12.2 years), 612 of whom were anti‐Ro/SSA‐positive (8.3%). Subjects who were anti‐Ro/SSA‐positive showed an increased prevalence of QTc prolongation, in the presence of other concomitant risk factors (crude odds ratios [OR], 1.67 [1.26–2.21] for QTc >470/480 ms; 2.32 [1.54–3.49] for QTc >490 ms; 2.77 [1.66–4.60] for QTc >500 ms), independent of a connective tissue disease history. Adjustments for age, sex, electrolytes, cardiovascular risk factors/diseases, and medications gradually attenuated QTc prolongation estimates, particularly when QT‐prolonging drugs were added to the model. Nevertheless, stepwise‐fully adjusted OR for the higher cutoffs remained significantly increased in anti‐Ro/SSA‐positive subjects, particularly for QTc >500 ms (2.27 [1.34–3.87]).

Conclusions

Anti‐Ro/SSA‐antibody positivity was independently associated with an increased risk of marked QTc prolongation in a large cohort of US veterans. Our data suggest that within the general population individuals who are anti‐Ro/SSA‐positive may represent a subgroup of patients particularly predisposed to ventricular arrhythmias/sudden cardiac death.