bluuebunny/crossref_metadata_2025 huggingface dataset:
Geochemistry of macrofossil, bulk rock and secondary calcite in the Early Jurassic strata of the Llanbedr (Mochras Farm) drill core, Cardigan Bay Basin, Wales, UK
Authors: Ullmann Clemens V. , Szȕcs Dominika , Jiang Mengjie , Hudson Alexander J.L. , Hesselbo Stephen P.
Published: June 2021

The Llanbedr (Mochras Farm) core (Wales, UK) yielded a >1300 m long mudrock sequence that has excellent potential for establishing an integrated stratigraphic scheme for the entire Early Jurassic Epoch. Lithological variations in the core are predominantly driven by hierarchical changes in the carbonate content. These changes also dominate – or may impact upon – many geochemical and physical properties of the core. The bulk carbonate C isotope record displays systematic fluctuations, the largest of which correspond to previously identified phases of environmental perturbation. The magnitudes of negative C isotope excursions in carbonate are inflated compared with equivalents previously described elsewhere as a result of diagenesis and the concomitant loss of primary carbonate. The marine macrofossil record of Mochras reveals biological and isotopic patterns that are generally comparable with other UK basins. Potentially significant differences between the Cleveland and Cardigan Bay basins are observed in the Pliensbachian and Toarcian fossils. This different expression may be related to different habitat structures or palaeoceanographic and water depth differences between these basins. Minima in macrofossil

δ

18
O values generally coincide with peaks in macrofossil wood abundance and sea-level lowstands inferred from sequence stratigraphic interpretation of other UK sections. This relationship suggests a possible relative sea-level control on the observed O isotope records and sediment provenance.

Supplementary material:
Analytical data for the Mochras core are available at
https://doi.org/10.6084/m9.figshare.c.5463508
The Balance of Nature: A Global Marine Perspective
Authors: Arnscheidt Constantin W. , Rothman Daniel H.
Published: June 2021

The ancient idea of the balance of nature continues to influence modern perspectives on global environmental change. Assumptions of stable biogeochemical steady states and linear responses to perturbation are widely employed in the interpretation of geochemical records. Here, we review the dynamics of the marine carbon cycle and its interactions with climate and life over geologic time, focusing on what the record of past changes can teach us about stability and instability in the Earth system. Emerging themes include the role of amplifying feedbacks in producing past carbon cycle disruptions, the importance of critical rates of change in the context of mass extinctions and potential Earth system tipping points, and the application of these ideas to the modern unbalanced carbon cycle. A comprehensive dynamical understanding of the marine record of global environmental disruption will be of great value in understanding the long-term consequences of anthropogenic change.
Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging
Authors: Clayton Zachary S. , Hutton David A. , Brunt Vienna E. , VanDongen Nicholas S. , Ziemba Brian P. , Casso Abigail G. , Greenberg Nathan T. , Mercer Amanda N. , Rossman Matthew J. , Campisi Judith , Melov Simon , Seals Douglas R.
Published: June 2021

Our study provides novel evidence that oral apigenin supplementation can reverse two clinically important indicators of arterial dysfunction with age, namely, vascular endothelial dysfunction and large elastic artery stiffening, and prevents foam cell formation in an established cell culture model of early atherosclerosis. Importantly, our results provide extensive insight into the biological mechanisms of apigenin action, including increased nitric oxide bioavailability, normalization of age-related increases in arterial ROS production and oxidative stress, reversal of age-associated aortic intrinsic mechanical wall stiffening and adverse remodeling of the extracellular matrix, and suppression of vascular inflammation. Given that apigenin is commercially available as a dietary supplement in humans, these preclinical findings provide the experimental basis for future translational studies assessing the potential of apigenin to treat arterial dysfunction and reduce cardiovascular disease risk with aging.
Cloning Method for Stress-Resistant Gene of Conringia planisiliqua under Drought Stress
Authors: Zhu Yanfei , Qu Yanying , Ayana Melkamu Teshome
Published: June 2021

The low temperature, drought, high salt, and other environments influence crop production and development directly, so the gene cloning method has become an effective biological means. In order to effectively improve the cloning effect, a gene cloning method for Conringia planisiliqua based on mRNA differential display technology was proposed. Based on mRNA differential display technology, the gene of Conringia planisiliqua was transcribed. The present study expects gene cloning to be better than the traditional method. This will lay the basis for gene cloning and functional verification of the transcription and disease-resistant proteins in Conringia planisiliqua. According to homologous identification results, the homologous drought-resistant genes were determined and screened. The data of Conringia planisiliqua in the existing biological database were used to extract ESTs data of Conringia planisiliqua. Then, the heating environment was established and the concept of integral function was introduced to express the influence of growth environment of different genomes. The mass, momentum, energy, and turbulent flow situation of stress-resistant gene of Conringia planisiliqua during the growth were satisfied. Finally, the data search was carried out in the NCBI database and gene cloning was achieved by ESTs data sequence. Experimental results show that the proposed method can effectively reduce the gene data fitting and improve the quantity of gene fragments cloned in a cycle, so the overall cloning effect is better.
Various Topologies Generated from Ej‐Neighbourhoods via Ideals
Authors: Hosny Rodyna A. , Asaad Baravan A. , Azzam A. A. , Al-Shami Tareq M.
Published: June 2021

One of the considerable subjects in mathematics is the study of topology. Deducing topology from arbitrary binary relations has enticed the attention of many researchers. So, we devote this article to generate some kinds of topologies from ideals and Ej‐neighborhoods which are induced from any binary relation. We define new types of approximations and accuracy measures from these topologies and then compare them with their counterparts induced directly from Ej‐neighborhoods and ideals. Also, we show that the approximations and accuracy measures given, herein, are better than those introduced in some previous studies under any arbitrary relation.
A Case of John Cunningham Virus Induced Rhombencephalitis after Rituximab Therapy for Idiopathic Thrombocytopenic Purpura
Authors: Katragadda Silpita , Koneru Varshaa , Devany Genevieve , DeWitt Aaron S. , Tati Vasudev H.
Published: June 2021

Background. John Cunningham virus (JCV) is known to cause progressive multifocal leukoencephalopathy (PML) in immuno-compromised patients due to lytic infection of oligodendrocytes and astrocytes. Rarely, it may also present as granule cell neuronopathy (GCN), leading to degeneration of cerebellar granule cell neurons. It is described in patients with underlying conditions or medication contributing to immune compromise. Case Presentation. A 73-year-old man presented with ataxia and difficulty in speech which began 3 months after initiation of treatment for idiopathic thrombocytopenic purpura with rituximab. Neurological examination was significant for torsional nystagmus, motor aphasia, right-sided dysmetria, and dysdiadochokinesia with gait ataxia. Magnetic resonance imaging (MRI) showed right cerebellar lesion and cerebrospinal fluid (CSF) polymerase chain reaction (PCR) was positive for JC virus. Conclusion. The diagnosis of JC virus-related cerebellar disease can be missed, due to the subacute to chronic onset and challenges in detection. Clinicians should have a high degree of suspicion for development of these symptoms, even a few months after initiation of immune-modulatory therapy because the progression and outcomes can be disastrous.
Multicriteria Decision Analysis for Renewable Energy Integration Design: For an Institutional Energy System Network
Authors: Rajavelu Dharani , Madasamy Balasubramonian
Published: June 2021

The hybridization of a renewable energy generator with an existing system in a specific building plays a vital role in solving many important problems of electrical energy systems such as reliability, cost-effective, and ecological option. In this perspective, a modified energy system is proposed in an existing building with integrated renewable energy using multicriteria decision analysis (MCDA). To achieve the sustainable energy solution, the hybrid power source configurations available in the locations are analyzed to ensure reliability using the HOMER software tool. Among these, the best configuration is identified by using the Best Worst Method (BWM) based MCDA approach. The study examined the technical, economic, and environmental perspectives for the achievement of the Sustainable Development Goals (SDGs) such as affordable, reliable, sustainable, and modern energy. The results of the survey in the building show that the best optimal hybrid configuration of the proposed location is the Gird-PV-Wind-based systems for the specific location based on the key techno-economic-environmental criteria of the SDGs.
An Adaptive Industrial Control Equipment Safety Fault Diagnosis Method in Industrial Internet of Things
Authors: Zhang Hanrui , Li Qianmu , Meng Shunmei , Xu Zhuoran , Lv Chaoxian
Published: June 2021

With the rapid development of intelligent manufacturing and Industrial Internet of Things, many industrial control systems have high requirements for the security of the system itself. Failures of industrial control equipment will cause abnormal operation of industrial control equipment and waste of resources. It is very meaningful to detect and identify potential equipment abnormalities and failures in time and implement effective fault tolerance strategies. In the Industrial Internet of Things environment, the instructions and parameters of industrial control equipment often change due to changes in actual requirements. However, it is impractical to customize the learning method for each parameter value. Aiming at the problem, this paper proposes a fault diagnosis model based on ensemble learning and proposes a method of updating voting weights based on dynamic programming to assist decision-making. This method is based on Bagging strategy and combined with dynamic programming voting weight adjustment method to complete fault type prediction. Finally, this paper uses different loads as dynamic conditions; the diagnostic capability of the Bagging-based fault diagnosis integrated model in a dynamically changing industrial control system environment is verified by experiments. The fault diagnosis model of industrial control equipment based on ensemble learning effectively improves the adaptive ability of the model and makes the fault diagnosis framework truly intelligent. The voting weight adjustment method based on dynamic programming further improves the reliability of voting.
Yoga Effects on Anthropometric Indices and Polycystic Ovary Syndrome Symptoms in Women Undergoing Infertility Treatment: A Randomized Controlled Clinical Trial
Authors: Mohseni Maryam , Eghbali Mohammad , Bahrami Homa , Dastaran Farzaneh , Amini Leila
Published: June 2021

The aim of this study was to investigate the effects of yoga exercises on anthropometric parameter and clinical sign of PCOS among women undergoing infertility treatment. This clinical trial study was performed on 61 women with PCOS who have undergone infertility treatment at Sarem Hospital in Tehran, Iran. The patients were first selecting based on purposeful and then randomly assigning to the intervention and control groups. In the intervention group, yoga exercises were performed for 6 weeks and the patients in the control group only received routine care. Anthropometric parameters and clinical signs were performed and recorded. After the intervention, here was a significant reduction in hirsutism, abdominal circumference, and hip circumference scores in the intervention group compared to the control group (

P
<
0.05

). Given the effects of yoga exercises on the improvement of hirsutism, abdominal circumference, and hip circumference, it is suggested to use yoga as a treatment strategy in women with PCOS.
The Clinical Efficiency and the Mechanism of Sanzi Yangqin Decoction for Chronic Obstructive Pulmonary Disease
Authors: Wang Mengqi , Gu Wenwen , Kui Fuguang , Gao Fan , Niu Yuji , Li Wenwen , Zhang Yaru , Guo Lijuan , Geng Shengnan , Du Gangjun
Published: June 2021

This work is carried out to evaluate the clinical efficacy of Sanzi Yangqin decoction (SZYQD) treating chronic obstructive pulmonary disease (COPD) and to analyze its mechanism. The clinical efficacy of SZYQD treating COPD was evaluated by meta-analysis, and its mechanism was analyzed by network pharmacology. Molecular docking validation of the main active compounds and the core targets was performed by AutoDock vina software. A cigarette smoke (CS) and LPS-induced COPD model in ICR mice was constructed to confirm the effects of luteolin on COPD. Results showed that SZYQD has a greater benefit on the total effect (OR = 3.85, 95% CI [3.07, 4.83],

P
=
1

) in the trial group compared with the control group. The percentage of forced expiratory volume in one second (FEV1%) (MD = 0.5, 95% CI [0.41, 0.59],

P
<
0.00001

) and first seconds breathing volume percentage of forced vital capacity (FEV1%/FVC) were improved (MD = 5.97, 95% CI [3.23, 8.71],

P
<
0.00001

). There are 27 compounds in SZYQD targeting 104 disease targets related to COPD. PPI network analysis indicated that EGFR, MMP9, PTGS2, MMP2, APP, and ERBB2 may be the core targets for the treatment of COPD. Molecular docking demonstrated that luteolin in SZYQD showed the strongest binding activity to core targets. Experimental results revealed that the expression of COPD-related targets in lung tissue was significantly increased in the COPD group and was improved in the luteolin group. Our data indicated that SZYQD has a curative effect on COPD and luteolin is a candidate compound for COPD treatment by regulating EGFR, MMP9, PTGS2, MMP2, APP, and ERBB2.
Knowledge and Attitude of Dental Clinicians towards Light-Curing Units: A Cross-Sectional Study
Authors: Al-Senan Dana , Ageel Fatin , Aldosari Amani , Maktabi Haifa
Published: June 2021

Objectives. Light curing is crucial when applying composite resin restorations. Complete polymerization of the resin depends on delivering adequate light energy to it. Dental clinicians may be unaware of the importance of proper light-curing techniques. This study aimed at evaluating and comparing the level of knowledge of general practitioners (GPs) and specialists (SPs) regarding light-curing units. Materials and Methods. An electronic survey was conducted online among GPs and SPs of various specialties, working in the governmental sector in Riyadh, Saudi Arabia. Collected data were analyzed for statistical significance. Results. 310 dentists were included in the study. Nearly half of the GPs (45.9%) and more than half of SPs (56.8%) use light-emitting diode (LED) type light-curing units (LCUs). 36.9% of GPs and 29.6% of SPs were unsure about the type of LCUs they use in their dental clinics. 10.8% of GPs and 8.5% of SPs knew the proper term of the power output of LCU. 52.2% of the GPs and 55.7% of SPs were wrong about advancements in technology of LED LCUs. Regarding the use of radiometer, 48.2% of SPs and 35.1% of GPs had responded wrongly, and 37.7% of SPs and 52.3% of GPs were not familiar with the device, showing a statistical significance

p
=
0.040

. There was no statistical significance observed in the responses pertaining to their years of experience, expected for two questions. Conclusion. Both GPs and SPs displayed inadequate knowledge regarding the use of LCUs. Further educational programs are recommended to spread awareness about the handling of LCUs among dental clinicians.
Common Barriers to Reporting Medical Errors
Authors: Aljabari Salim , Kadhim Zuhal
Published: June 2021

Background. Medical errors are the third leading cause of death in the United States. Reporting of all medical errors is important to better understand the problem and to implement solutions based on root causes. Underreporting of medical errors is a common and a challenging obstacle in the fight for patient safety. The goal of this study is to review common barriers to reporting medical errors. Methods. We systematically reviewed the literature by searching the MEDLINE and SCOPUS databases for studies on barriers to reporting medical errors. The preferred reporting items for systematic reviews and meta-analyses guideline was followed in selecting eligible studies. Results. Thirty studies were included in the final review, 8 of which were from the United States. The majority of the studies used self-administered questionnaires (75%) to collect data. Nurses were the most studied providers (87%), followed by physicians (27%). Fear of consequences is the most reported barrier (63%), followed by lack of feedback (27%) and work climate/culture (27%). Barriers to reporting were highly variable between different centers.
Using Galileo and BDS-3 Quad-Frequency Signals for Long-Baseline Instantaneous Decimeter-Level Positioning
Authors: Gao Wang , Liu Liwei , Qiao Longlei , Pan Shuguo
Published: June 2021

As the signals of Galileo and the global BDS-3 navigation satellite system have been accessible, positioning users can use quad-frequency even five-frequency signals nowadays. With multifrequency signals, one can form some useful combinations to improve the positioning performance, e.g., the widely used extra-wide-lane (EWL)/wide-lane (WL) in triple-frequency cases. For quad-frequency or five-frequency cases, better positioning performance can be expected since additional frequencies are introduced. In this study, we systematically analyse the benefits of Galileo and BDS-3 quad-frequency signals on long-baseline instantaneous positioning. First, the theoretical analysis of EWL/WL ambiguity resolution (AR) and satellite-station range estimation with a single-satellite geometry-free and ionosphere-free model is studied, along with the comparison with triple-frequency cases. Second, using the quad-frequency advantages, an instantaneous decimeter-level positioning model is proposed, where the geometry-free model is adopted for the first two EWL AR and the geometry-based model is adopted for the third WL AR. In the end, the AR and positioning performance are evaluated using real long-baseline date containing Galileo and BDS-3 quad-frequency observations. The results indicate that, with quad-frequency observations, both Galileo and BDS-3 EWL/WL ambiguities can be fixed reliably with a single epoch. Contributed by the resolved EWL/WL ambiguities, instantaneous decimeter-level positioning can be obtained, with the accuracies of 0.116 m/0.126 m/0.351 m in north, east, and up directions, respectively.
Serum Exosomes Derived from Irritable Bowel Syndrome Patient Increase Cell Permeability via Regulating miR-148b-5p/RGS2 Signaling in Human Colonic Epithelium Cells
Authors: Xing Ying , Xue Shan , Wu Jing , Zhou Jianhong , Xing Fangfang , Li Tianxing , Nie Xiaohu
Published: June 2021

Aim. Irritable bowel syndrome (IBS) is a multifactorial functional bowel disorder characterized by disruption of the intestinal barrier. Circulating exosomal microRNAs (miRNAs) are involved in regulating epithelial barrier function, and upregulation of miR-148b-5p has been detected in IBS. However, whether exosomal miR-148-5p is involved in the IBS pathogenesis remains unclear. This study was aimed at investigating the relationship of exosomal miR-148-5p with colonic epithelial permeability. Methods. Exosomes were isolated from the serum of IBS patients and healthy controls. HT-29 cells were cultured with the IBS-derived serum exosomes (IBS-exo). Exosome uptake assay was used to evaluate whether the IBS-exo could be absorbed by HT-29 cells. FITC-Dextran flux and transepithelial/endothelial electrical resistance were measured to evaluate epithelial permeability. A luciferase reporter assay was used to determine whether the regulator of G protein signaling- (RGS-) 2 is a target gene of miR-148b-5p. Results. miR-148b-5p was obviously elevated in the IBS-exo compared to the control-exo. Upregulation of miR-148b-5p was observed in the HT-29 cells cultured with IBS-exo. Exposure to IBS-exo increased cell permeability and decreased RGS2 expression. The IBS-exo-induced alterations were obviously reversed by interfering with the miR-148b-5p expression. Mimicking the IBS-exo treatment, miR-148b-5p overexpression increased cell permeability and downregulated RGS2 expression, which were abrogated by overexpressing RGS2. The luciferase reporter assay revealed that RGS2 was a direct target of miR-148b-5p. Conclusions. Serum-derived exosomes from IBS patients increase colonic epithelial permeability via miR-148b-5p/RGS2 signaling.
Impact of Arterial Remodeling of Intermediate Coronary Lesions on Long-Term Clinical Outcomes in Patients with Stable Coronary Artery Disease: An Intravascular Ultrasound Study
Authors: Geng Liang , Du Peizhao , Yuan Yuan , Gao Liming , Wang Yunkai , Li Jiming , Zhang Qi
Published: June 2021

Background. Treatment of coronary intermediate lesions remains a controversy, and the role of arterial remodeling patterns determined by intravascular ultrasound in intermediate lesion is still not well known. The aim of this study was to investigate the impact of arterial remodeling of intermediate coronary lesions on long-term clinical outcomes. Methods. Arterial remodeling patterns were assessed in 212 deferred intermediate lesions from 162 patients after IVUS examination. Negative, intermediate, and positive remodeling was defined as a remodeling index of <0.88, 0.88∼1.0, and >1.0, respectively. The primary endpoint was the composite vessel-oriented clinical events, defined as the composition of target vessel-related cardiac death, target vessel-related myocardial infarction, and target vessel revascularization. Quantitative flow ratio was assessed for evaluating the functional significance of intermediate lesions. Results. 72 intermediate remodeling lesions were present in 66 patients, whereas 77 negative remodeling lesions were present in 71 patients, and 63 positive remodeling lesions were present in 55 patients. Negative remodeling lesions had the smallest minimum lumen area (4.16 ± 1.03 mm2 vs. 5.05 ± 1.39 mm2 vs. 4.85 ± 1.76 mm2;

P
<
0.01

), smallest plaque burden (63.45 ± 6.13% vs. 66.12 ± 6.82% vs. 71.17 ± 6.45%;

P
<
0.01

), and highest area stenosis rate (59.32% ± 10.15% vs. 54.61% ± 9.09% vs. 51.67% ± 12.96%;

P
<
0.01

). No significant difference was found in terms of quantitative flow ratio among three groups. At 5 years follow-up, negative remodeling lesions had a higher rate of composite vessel-oriented clinical event (14.3%), compared to intermediate (1.4%,

P
=
0.004

) or positive remodeling lesions (4.8%,

P
=
0.06

). After adjusting for multiple covariates, negative remodeling remained an independent determinant for vessel-oriented clinical event (HR: 4.849, 95% CI 1.542–15.251,

P
=
0.007

). Conclusion. IVUS-derived negative remodeling is associated with adverse long-term clinical outcome in stable patients with intermediate coronary artery stenosis.
Study on Nonuniform Evolution Characteristics of Rock Friction and Sliding
Authors: Song Yimin , Ren He , Lv Xiangfeng , Xing Tongzhen , Zhang Yue
Published: June 2021

By means of experimental research and theoretical analysis, the nonuniform evolution characteristics of rock friction and sliding were studied. Using digital speckle correlation (DIC) as observation method, the whole process of friction and sliding of a granite specimen in double-sided shear experiment is studied. A spring slider model considering the microscopic characteristics of interface asperities was established to simulate the microscopic process of rock friction and sliding. By comparing the theoretical analysis results with the experimental results, the effect of interface nonuniformity on rock friction sliding instability is studied. The results demonstrated that, with the increase of nonuniformity of sliding interface, the degree of local instability before stick-slip decreases, the stick-slip period shortens, and the value of shear drop during stick-slip period decreases. The nonuniformity of sliding interface will increase after local instability.
A Weight Possibilistic Fuzzy C-Means Clustering Algorithm
Authors: Chen Jiashun , Zhang Hao , Pi Dechang , Kantardzic Mehmed , Yin Qi , Liu Xin
Published: June 2021

Fuzzy C-means (FCM) is an important clustering algorithm with broad applications such as retail market data analysis, network monitoring, web usage mining, and stock market prediction. Especially, parameters in FCM have influence on clustering results. However, a lot of FCM algorithm did not solve the problem, that is, how to set parameters. In this study, we present a kind of method for computing parameters values according to role of parameters in the clustering process. New parameters are assigned to membership and typicality so as to modify objective function, on the basis of which Lagrange equation is constructed and iterative equation of membership is acquired, so does the typicality and center equation. At last, a new possibilistic fuzzy C-means based on the weight parameter algorithm (WPFCM) was proposed. In order to test the efficiency of the algorithm, some experiments on different datasets are conducted to compare WPFCM with FCM, possibilistic C-means (PCM), and possibilistic fuzzy C-means (PFCM). Experimental results show that iterative times of WPFCM are less than FCM about 25% and PFCM about 65% on dataset X12. Resubstitution errors of WPFCM are less than FCM about 19% and PCM about 74% and PFCM about 10% on the IRIS dataset.
Phase 1 Combination Study of the CHK1 Inhibitor Prexasertib and the PARP Inhibitor Olaparib in High-grade Serous Ovarian Cancer and Other Solid Tumors
Authors: Do Khanh T. , Kochupurakkal Bose , Kelland Sarah , de Jonge Adrienne , Hedglin Jennifer , Powers Allison , Quinn Nicholas , Gannon Courtney , Vuong Loan , Parmar Kalindi , Lazaro Jean-Bernard , D'Andrea Alan D. , Shapiro Geoffrey I.
Published: June 2021

Purpose:

Checkpoint kinase 1 (CHK1) plays a central role in the response to replication stress through modulation of cell-cycle checkpoints and homologous recombination (HR) repair. In BRCA-deficient cancers with de novo or acquired PARP inhibitor resistance, the addition of the CHK1 inhibitor prexasertib to the PARP inhibitor olaparib compromises replication fork stability, as well as HR proficiency, allowing for sensitization to PARP inhibition.

Patients and Methods:

This study followed a 3+3 design with a 7-day lead-in of olaparib alone, followed by 28-day cycles with prexasertib administered on days 1 and 15 in combination with an attenuated dose of olaparib on days 1–5 and 15–19. Pharmacokinetic blood samples were collected after olaparib alone and following combination therapy. Patients enrolled to the expansion phase of the study underwent paired tumor biopsies for pharmacodynamic (PD) assessments.

Results:

Twenty-nine patients were treated. DLTs included grade 3 neutropenia and grade 3 febrile neutropenia. The MTD/recommended phase 2 dose (RP2D) was prexasertib at 70 mg/m2 i.v. with olaparib at 100 mg by mouth twice daily. Most common treatment-related adverse events included leukopenia (83%), neutropenia (86%), thrombocytopenia (66%), and anemia (72%). Four of 18 patients with BRCA1-mutant, PARP inhibitor–resistant, high-grade serous ovarian cancer (HGSOC) achieved partial responses. Paired tumor biopsies demonstrated reduction in RAD51 foci and increased expression of γ-H2AX, pKAP1, and pRPA after combination exposure.

Conclusions:

Prexasertib combined with olaparib has preliminary clinical activity in BRCA-mutant patients with HGSOC who have previously progressed on a PARP inhibitor. PD analyses show that prexasertib compromises HR with evidence of induction of DNA damage and replication stress.
Integrin β7 Inhibits Colorectal Cancer Pathogenesis via Maintaining Antitumor Immunity
Authors: Zhang Youhua , Xie Ruting , Zhang Hailong , Zheng Yajuan , Lin Changdong , Yang Lei , Huang Mengwen , Li Man , Song Feifei , Lu Ling , Yang Muqing , Liu Ying , Wei Qing , Li Jiyu , Chen Jianfeng
Published: June 2021

Immune cell infiltration is important for predicting the clinical outcomes of colorectal cancer. Integrin β7 (ITGB7), which is expressed on the surface of leukocytes, plays an essential role in the homing of immune cells to gut-associated lymphoid tissue and facilitating the retention of lymphocytes in gut epithelium; however, its role in colorectal cancer pathogenesis is poorly explored. Here, we found that the number of β7+ cells decreased significantly in tumor tissue compared with adjacent normal tissue. β7 expression decreased in tumor-derived compared with normal tissue–derived CD8+ T cells. With bulk RNA expression data from public platforms, we demonstrated that higher ITGB7 expression correlated with longer patient survival, higher cytotoxic immune cell infiltration, lower somatic copy-number alterations, decreased mutation frequency of APC and TP53, and better response to immunotherapy. The possible cell–cell interactions mediated by ITGB7 and its ligands MAdCAM-1, VCAM-1, and CDH1 were investigated using public single-cell RNA sequencing data. ITGB7 deficiency led to exaggerated tumorigenesis and progression in both Apcmin/+ spontaneous and MC38 orthotopic models of colorectal cancer, which could be due to a reduced infiltration of activated CD8+ T cells, effector memory CD8+ T cells, IFNγ+ CD8+ T cells, IFNγ+ natural killer cells, CD103+ dendritic cells, and other immune cell subsets that are essential players in antitumor immunity. In conclusion, our data revealed that ITGB7 could inhibit the tumorigenesis and progression of colorectal cancer by maintaining antitumor immunity.
Early Goal-Directed Renal Replacement Therapy in Acute Decompensated Heart Failure Patients with Cardiorenal Syndrome
Authors: Xie Yeqing , Chen Jiahui , Xu Jiarui , Shen Bo , Liao Jianquan , Teng Jie , Wang Qibing , Ding Xiaoqiang
Published: June 2021

Introduction: The aim of this study was to clarify the efficacy of early goal-directed renal replacement therapy (GDRRT) for treatment of cardiorenal syndrome (CRS) patients after acute decompensated heart failure (ADHF). Methods: In the retrospective, observational study, we enrolled 54 patients in the early GDRRT group and 63 patients in the late GDRRT group. Baseline characteristics, clinical data at initiation renal replacement therapy time, and the clinical outcome were collected and several parameters were compared and analyzed between 2 groups. Results: The urine volume at GDRRT initiation time in the early group was higher than that in the late GDRRT group (1,060.3 ± 332.1 vs. 300.5 ± 148.3 mL, p < 0.001). Hemodynamic parameters such as mean artery pressure were higher (70.06 ± 32.99 vs. 54.34 ± 40.88 mm Hg, p = 0.012), the heart rate was slower (80.17 ± 15.26 vs. 99.21 ± 25.45 bpm, p = 0.002), and the diameter of inferior vena cava was narrower (22.00 ± 1.91 vs. 25.77 ± 5.5 mm, p = 0.04) in early GDRRT. Primary end point was inhospital all-cause mortality and cardiovascular mortality, which was obviously lower in the early GDRRT group (respectively 24.1 vs. 60.3%, p = 0.002 and 20.3 vs. 50.8%, p = 0.005). The second end point of kidney recovery in the early GDRRT group was much better than that in the latter GDRRT group (p = 0.018). Moreover, urine volume after GDRRT of the early group was more significant than that of the late group (1,432 ± 172 vs. 702 ± 183 mL, p = 0.005). Conclusion: This study clarified the effectiveness of the early GDRRT strategy in ADHF patients suffered from CRS, which reduced inhospital mortality and improved the urine output and clinical kidney recovery outcome.
False Memory and Alzheimer’s Disease Pathology in Patients with Amnestic Mild Cognitive Impairment: A Study with Amyloid PET
Authors: Choi Eun-Ji , Kim Bum Joon , Kim Hyung-Ji , Kwon Miseon , Han Noh Eul , Lee Sun-Mi , Jo Sungyang , Lee Sunju , Lee Jae-Hong
Published: June 2021

Introduction: False memory, observed as intrusion errors or false positives (FPs), is prevalent in patients with Alzheimer’s disease, but has yet to be thoroughly investigated in patients with amnestic mild cognitive impairment (a-MCI) with Alzheimer’s disease pathology (ADP). We analyzed false versus veridical memory in individuals with a-MCI and measured the utility of false memory for ADP discrimination. Methods: Patients with a-MCI who received neuropsychological testing and amyloid PET were included. Patients were categorized into “with” and “without ADP” groups according to PET results. Memory tests assessed veridical and false memory, and the verity of patient responses was analyzed. A logistic regression model was used to evaluate false memory efficiency in discriminating ADP, and the sensitivity and specificity at the optimal level were estimated using the receiver-operating characteristic curve. Results: Thirty-seven ADP and 46 non-ADP patients were enrolled. The ADP group made more FPs in the recognition tests, and their response verity was significantly lower in every delayed memory test. No group difference, however, was observed in the veridical memory. The logistic regression analysis demonstrated that as the FPs increased, the risk of ADP increased 1.31 and 1.36 times in the verbal and visual recognition tests, respectively. The discriminatory accuracy of the FPs was estimated “low” to “moderate” in the visual and verbal recognition, respectively, with an optimal cutoff above 2.5. Conclusion: Increased false memory was the only feature to discriminate ADP from non-ADP in individuals with a-MCI. Further studies regarding false memory and its mechanism are warranted.
Risk Factors Associated with Preterm Prelabor Rupture of Membranes after Cord Occlusion in Monochorionic Diamniotic Twins
Authors: Micheletti Talita , Eixarch Elisenda , Bennasar Mar , Torres Ximena , Martinez-Crespo Josep Maria , Deprest Jan , Gratacos Eduard
Published: June 2021

Introduction: Preterm prelabor rupture of membranes (PPROM) is a common complication after fetal surgeries. The aim of this study was to assess risk factors for and outcomes after PPROM following cord occlusion (CO) in monochorionic diamniotic (MCDA) pregnancies. Methods: This was a retrospective cohort study of 188 consecutive MCDA pregnancies treated by bipolar or laser CO, either primarily because of discordant malformation (dMF) or severe selective fetal growth restriction (sFGR), or secondarily when complete bichorionization was not possible in case of twin-to-twin transfusion syndrome (TTTS) or sFGR. Intentional septostomy was performed when needed. The procedure-related PPROM was defined as rupture of membranes <32 weeks’ gestation (PROM <32 weeks). Selected pre-, intra-, and early postoperative variables were analyzed by univariate and binomial logistic regression to determine they are correlated to PROM <32 weeks after CO. Results: Between 2006 and 2017, 188 cases underwent CO. Diagnosis was TTTS in 28.2% (n = 53), severe sFGR in 49.5% (n = 93), and dMF in 22.3% (n = 42). PROM <32 weeks occurred in 21.3% (n = 40), resulting in worse perinatal outcomes, as preterm birth <32 weeks occurred in 80.7% (vs. 8.3%, p = 0.000), procedure-to-delivery interval was 47.5 days (vs. 125, p = 0.000), gestational age (GA) at birth 30.0 weeks (vs. 37.7 weeks, p = 0.000), and survival 65.0% (vs. 91.1%, p = 0.000). In univariate analysis, indication, anterior placenta, cervical length, GA at surgery, operation time, amniodistention and drainage fluid volumes, chorioamniotic membrane separation, and septostomy were selected as relevant factors to be included in the regression model. In a multivariate analysis, TTTS was the only factor associated to PROM <32 weeks (OR 3.5 CI 95% 1.5–7.9). Conclusions: PROM <32 weeks after CO increases the risk of preterm delivery. In this cohort, the membrane rupture was more likely when CO was done in the context of TTTS.
From Proteinuria to Fibrosis: An Update on Pathophysiology and Treatment Options
Authors: Sharma Sonia , Smyth Brendan
Published: June 2021

Background: Proteinuria is a key biomarker in nephrology. It is central to diagnosis and risk assessment and the primary target of many important therapies. Etiologies resulting in pathological proteinuria include congenital and acquired disorders, as well as both glomerular (immune/non-immune mediated) and tubular defects. Summary: Untreated proteinuria is strongly linked to progressive loss of kidney function and kidney failure. Excess protein reaching the renal tubules is ordinarily resorbed by the tubular epithelium. However, when these mechanisms are overwhelmed, a variety of inflammatory and fibrotic pathways are activated, causing both interstitial fibrosis and glomerulosclerosis. Nevertheless, the specific mechanisms underlying this are complex and remain incompletely understood. Recently, a number of treatments, in addition to angiotensin system blockade, have been shown to effectively slow the progression of proteinuric chronic kidney disease. However, additional therapies are clearly needed. Key message: This review provides an update on the pathophysiology of proteinuria, the pathways leading to fibrosis, and an overview of current and emerging therapies.
Condutas relativas à redução do risco desenvolvidas pelos profissionais de saúde na unidade de terapia intensiva: uma scoping review
Authors: Nóbrega Thamirys Dantas , Salviano Ítalo Pereira , Dantas Polyana Lins , Pereira Bruno Oliveira Almeida , Barbosa Mayara Lima , Leal Adriana Amorim de Farias
Published: June 2021

Objetivo: Mapear e identificar as condutas relativas à redução do risco desenvolvidas pelos profissionais de saúde na unidade de terapia intensiva. Método: Scoping review segundo o JBI Institute Reviewer’s Manual. Na busca inicial foram utilizados os descritores encontrados no MeSH: health personnel, risk management e Intensive care unit, para delimitar a estratégia final de busca, composta por uma combinação de duzentas e vinte e duas palavras-chave, realizada em bases de dados científicas e cinzentas, sem limite temporal. Foram extraídas informações sobre o ano, país de origem, objetivo da publicação, condutas realizadas, condutas negligenciadas, protocolos desenvolvidos, profissionais envolvidos, aspectos do método, resultados e conclusões relacionados ao tema proposto neste artigo de scoping review. Resultados: A seleção primária foi de 10.349.624 textos que tiveram seus títulos e resumos avaliados e, de acordo com os critérios de inclusão estabelecidos, foram selecionados 94 para leitura na íntegra. Posteriormente excluímos 79 (40 não responderam ao objetivo, 38 eram indisponíveis e 1 foi escrito em francês). Assim, a seleção final foi composta por 15 artigos. Entre as principais condutas realizadas pelos profissionais de saúde, a que mais se destacou foi a higienização das mãos, no entanto, ainda é muito negligenciada nesse meio, o que gera maior risco para pacientes e profissionais das UTI’s. Além disso, a elevada carga de trabalho, falta de discussão sobre erros e falta de capacitação, são ações muito citadas que afetam diretamente a qualidade do serviço de saúde. Conclusões e implicações para a prática: É fundamental que o gerenciamento de risco no ambiente de UTI seja feito de forma prioritária, eficiente e com qualidade, a fim de evitar ou minimizar os eventos adversos, culminando, portanto, em uma assistência integral, qualificada e responsável da evolução do quadro clínico de cada paciente.
TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy
Authors: Ostriker Allison C. , Xie Yi , Chakraborty Raja , Sizer Ashley J. , Bai Yalai , Ding Min , Song Wen-Liang , Huttner Anita , Hwa John , Martin Kathleen A.
Published: June 2021

Background:

Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown.

Methods:

We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle–specific
Tet2
knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression.

Results:

In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner.

Conclusions:

TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.
Nanoparticle Delivery of STAT3 Alleviates Pulmonary Hypertension in a Mouse Model of Alveolar Capillary Dysplasia
Authors: Sun Fei , Wang Guolun , Pradhan Arun , Xu Kui , Gomez-Arroyo Jose , Zhang Yufang , Kalin Gregory T. , Deng Zicheng , Vagnozzi Ronald J. , He Hua , Dunn Andrew W. , Wang Yuhua , York Allen J. , Hegde Rashmi S. , Woods Jason C. , Kalin Tanya V. , Molkentin Jeffery D. , Kalinichenko Vladimir V.
Published: June 2021

Background:

Pulmonary hypertension (PH) is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the
FOXF1
gene. Although the loss of alveolar microvasculature causes PH in patients with ACDMPV, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy.

Methods:

We used echocardiography, RV catheterization, immunostaining, and biochemical methods to examine lung and heart remodeling and RV output in
Foxf1

WT/S52F

mice carrying the
S52F Foxf1
mutation (identified in patients with ACDMPV). The ability of
Foxf1

WT/S52F

mutant embryonic stem cells to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a nonintegrating
Stat3
expression vector was used to improve neonatal pulmonary angiogenesis in
Foxf1

WT/S52F

mice and determine its effects on PH and RV hypertrophy.

Results:

Foxf1

WT/S52F

mice developed PH and RV hypertrophy after birth. The severity of PH in
Foxf1

WT/S52F

mice directly correlated with mortality, low body weight, pulmonary artery muscularization, and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse embryonic stem cells carrying the
S52F Foxf1
mutation were used to produce chimeras through blastocyst complementation and to demonstrate that
Foxf1

WT/S52F

embryonic stem cells have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying
Stat3
cDNA protected
Foxf1

WT/S52F

mice from RV hypertrophy and PH, improved survival, and decreased fibrotic lung remodeling.

Conclusions:

Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.
Lack of Reperfusion Rather Than Number of Passes Defines Futility in Stroke Thrombectomy: A Matched Case-Control Study
Authors: Mohammaden Mahmoud H. , Haussen Diogo C. , Pisani Leonardo , Al-Bayati Alhamza R. , Bianchi Nicolas , Liberato Bernardo , Bhatt Nirav , Jillella Dinesh , Frankel Michael R. , Nogueira Raul G.
Published: June 2021

Background and Purpose:

There is a robust relationship between the duration of ischemia and functional outcomes after mechanical thrombectomy. Higher number of mechanical thrombectomy passes strongly correlate with lower chances of favorable outcomes. Indeed, previous studies have suggested that after multiple passes the procedure may be futile. However, using uncontrolled thresholds to define thrombectomy futility might be misleading. We aim to compare the outcome of successful reperfusion after 4 to 5 passes and ≥6 passes with those of failed reperfusion.

Methods:

A prospectively acquired mechanical thrombectomy database from January 2012 to October 2019 was reviewed. Patients were included if they had intracranial internal carotid artery or middle cerebral artery-M1/M2 occlusions and either achieved successful reperfusion after ≥4 passes or failed reperfusion. Reperfused patients (mTICI2b-3) were divided into 2 subgroups; (1) 4 to 5 passes and (2) ≥6 passes. Each subgroup was compared with a matched group of mechanical thrombectomy failure (mTICI0-2a). The primary outcome was the shift in the degree of disability at 90-day as measured by the modified Rankin Scale.

Results:

A total of 273 patients were included. As compared with matched failed reperfusion patients (n=62), those reperfused after 4 to 5 passes (n=62) had a favorable shift in the overall modified Rankin Scale score distribution (adjusted odds ratio, 3.992 [95% CI, 1.807–8.512],
P
=0.001] and higher rates of functional independence (31% versus 8.9%,
P
=0.004, adjusted odds ratio; 9.860 [95% CI, 2.323–41.845],
P
=0.002) at 90 days. Similarly, when compared with a matched group of failed reperfusion (n=42), patients reperfused after ≥6 passes (n=42) demonstrated a favorable shift in the overall modified Rankin Scale score distribution (adjusted odds ratio, 2.640 [95% CI, 1.073–6.686],
P
=0.037) and had higher rates of functional independence (36.8% vs 11.1%,
P
=0.004, adjusted odds ratio, 5.392 [95% CI, 1.185–24.530],
P
=0.029) at 90 day. Rates of parenchymal hematoma type-2 and 90-day mortality were comparable in the reperfused and nonreperfused groups.

Conclusions:

Achieving reperfusion despite multiple passes leads to improved outcomes compared with failed procedures. Arbitrary uncontrolled thresholds for a maximum number of passes to predict futile recanalization may lead to inappropriate early termination of procedures.