bluuebunny/crossref_metadata_2025 huggingface dataset:
GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects
Authors: Zhao Xin , Wang Minghe , Wen Zhitong , Lu Zhihong , Cui Lijuan , Fu Chao , Xue Huan , Liu Yunfeng , Zhang Yi
Published: August 2021

Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.
(DA-DOPF): A Day-Ahead Dynamic Optimal Power Flow With Renewable Energy Integration in Smart Grids
Authors: Ilyas Muhammad Arsalan , Alquthami Thamer , Awais Muhammad , Milyani Ahmad H. , Rasheed Muhammad Babar
Published: August 2021

The performance of a power system can be measured and evaluated by its power flow analysis. Along with the penetration of renewable energies such as wind and solar, the power flow problem has become a complex optimization problem. In addition to this, constraint handling is another challenging task of this problem. The main critical problem of this dynamic power system having such variable energy sources is the intermittency of these VESs and complexity of constraint handling for a real-time optimal power flow (RT-OPF) problem. Therefore, optimal scheduling of generation sources with constraint satisfaction is the main goal of this study. Hence, a renewable energy forecasting–based, day-ahead dynamic optimal power flow (DA-DOPF) is presented in this paper with the forecasting of solar and wind patterns by using artificial neural networks. Moreover, contribution factors are calculated using triangular fuzzy membership function (T-FMF) in the sub-interval time slots. Furthermore, the superiority of feasible (SF) solution constraint handling approach is used to avoid the constraint violation of inequality constraints of optimal power flow. The IEEE 30-bus transmission network has been amended to integrate a solar photovoltaic and wind farm in different buses. In this approach, the computing program is based on MATPOWER which is a tool of MATLAB for load flow analysis which uses the Newton–Raphson technique because of its rapid convergence. Meteorological information has been gathered during the time frame January 1, 2015, to December 31, 2017, from Danyore Weather Station (DWS) at Hunza, Pakistan. A Levenberg–Marquardt calculation–based artificial neural network model is utilized to foresee the breeze speed and sunlight-based irradiance in light of its versatile nature. Finally, the results are discussed analytically to select the best generation schedule and control variable values.
Potential Analysis of the Attention-Based LSTM Model in Ultra-Short-Term Forecasting of Building HVAC Energy Consumption
Authors: Xu Yang , Gao Weijun , Qian Fanyue , Li Yanxue
Published: August 2021

Predicting system energy consumption accurately and adjusting dynamic operating parameters of the HVAC system in advance is the basis of realizing the model predictive control (MPC). In recent years, the LSTM network had made remarkable achievements in the field of load forecasting. This paper aimed to evaluate the potential of using an attentional-based LSTM network (A-LSTM) to predict HVAC energy consumption in practical applications. To evaluate the application potential of the A-LSTM model in real cases, the training set and test set used in experiments are the real energy consumption data collected by Kitakyushu Science Research Park in Japan. Pearce analysis was first carried out on the source data set and built the target database. Then five baseline models (A-LSTM, LSTM, RNN, DNN, and SVR) were built. Besides, to optimize the super parameters of the model, the Tree-structured of Parzen Estimators (TPE) algorithm was introduced. Finally, the applications are performed on the target database, and the results are analyzed from multiple perspectives, including model comparisons on different sizes of the training set, model comparisons on different system operation modes, graphical examination, etc. The results showed that the performance of the A-LSTM model was better than other baseline models, it could provide accurate and reliable hourly forecasting for HVAC energy consumption.
Driving Factors of CO2 Emissions: Further Study Based on Machine Learning
Authors: Li Shanshan , Siu Yam Wing , Zhao Guoqin
Published: August 2021

Greenhouse gases, especially carbon dioxide (CO2) emissions, are viewed as one of the core causes of climate change, and it has become one of the most important environmental problems in the world. This paper attempts to investigate the relation between CO2 emissions and economic growth, industry structure, urbanization, research and development (R&D) investment, actual use of foreign capital, and growth rate of energy consumption in China between 2000 and 2018. This study is important for China as it has pledged to peak its carbon dioxide emissions (CO2) by 2030 and achieve carbon neutrality by 2060. We apply a suite of machine learning algorithms on the training set of data, 2000–2015, and predict the levels of CO2 emissions for the testing set, 2016–2018. Employing rmse for model selection, results show that the nonlinear model of k-nearest neighbors (KNN) model performs the best among linear models, nonlinear models, ensemble models, and artificial neural networks for the present dataset. Using KNN model, sensitivity analysis of CO2 emissions around its centroid position was conducted. The findings indicate that not all provinces should develop its industrialization. Some provinces should stay at relatively mild industrialization stage while selected others should develop theirs as quickly as possible. It is because CO2 emissions will eventually decrease after saturation point. In terms of urbanization, there is an optimal range for a province. At the optimal range, the CO2 emissions would be at a minimum, and it is likely a result of technological innovation in energy usage and efficiency. Moreover, China should increase its R&D investment intensity from the present level as it will decrease CO2 emissions. If R&D reinvestment is associated with actual use of foreign capital, policy makers should prioritize the use of foreign capital for R&D investment on green technology. Last, economic growth requires consuming energy. However, policy makers must refrain from consuming energy beyond a certain optimal growth rate. The above findings provide a guide to policy makers to achieve dual-carbon strategy while sustaining economic development.
Long-Term Persistence and Relevant Therapeutic Impact of High-Titer Viral-Neutralizing Antibody in a Convalescent COVID-19 Plasma Super-Donor: A Case Report
Authors: De Rienzo Mafalda , Foddai Maria Laura , Conti Laura , Mandoj Chiara , Iaboni Stefano , Saladini Ilenia , Castilletti Concetta , Matusali Giulia , Donno Davide Roberto , Marchioni Luisa , Ianniello Stefania , Corpolongo Angela , Palange Maria , Ciliberto Gennaro , Piaggio Giulia , De Marco Federico
Published: August 2021

A convalescent, non-severe, patient with COVID-19 was enrolled as a hyper-immune plasma voluntary donor by the Immuno-Hematology and Transfusion Unit of the Regina Elena National Cancer Institute in Rome, under the TSUNAMI national study criteria. During a nearly 6-month period (May–October 2020), the patient was closely monitored and underwent four hyperimmune plasma collections. Serum SARS-CoV-2 (anti-S + anti-N) IgG and IgM, anti-S1 IgA, and neutralizing titers (NTs) were measured. Anti-SARS-CoV-2 antibody levels steadily decreased. No correlation was found between anti-S/anti-N IgG and IgM levels and viral NT, measured by either a microneutralization test or the surrogate RBD/ACE2-binding inhibition test. Conversely, NTs directly correlated with anti-S1 IgA levels. Hyperimmune donor plasma, administered to five SARS-CoV-2 patients with persistent, severe COVID-19 symptoms, induced short-term clinical and pathological improvement. Reported data suggest that high NTs can persist longer than expected, thus widening hyperimmune plasma source, availability, and potential use. In vitro RBD/ACE2-binding inhibition test is confirmed as a convenient surrogate index for neutralizing activity and patients’ follow-up, suitable for clinical settings where biosafety level 3 facilities are not available. IgA levels may correlate with serum neutralizing activity and represent a further independent index for patient evaluation.
Experimental Research on Compressive and Shrinkage Properties of ECC Containing Ceramic Wastes Under Different Curing Conditions
Authors: Xiong Yan , Yang Yi , Fang Shuai , Wu Di , Tang Yingfeng
Published: August 2021

Engineered cementitious composites (ECCs) suffer from high shrinkage and low early strength due to large dosage of cementitious materials and slow hydration of fly ash. This study aims to improve compressive properties and reduce drying shrinkage of ECC using ceramic wastes and hydrothermal curing. Experimental results have indicated that ceramic polishing powder (CPP) and recycled ceramic sand (RCS) exert opposite effect on the compressive strength of ECC. Hydrothermal-cured ECC enhances elasticity modulus and compressive strength and reduces later drying shrinkage as compared with that under standard curing. A CPP dosage of 35% and a hydrothermal curing regime with a temperature of 70°C and age of 7 days are recommended for the engineering application of ECC.
Right Ventricular Function Predicts Adverse Clinical Outcomes in Patients With Chronic Thromboembolic Pulmonary Hypertension: A Three-Dimensional Echocardiographic Study
Authors: Li Yidan , Liang Lirong , Guo Dichen , Yang Yuanhua , Gong Juanni , Zhang Xinyuan , Zhang Di , Jiang Zhe , Lu Xiuzhang
Published: August 2021

Background: Right ventricular (RV) function plays a vital role in the prognosis of patients with chronic thromboembolic pulmonary hypertension (CTEPH). We used new machine learning (ML)-based fully automated software to quantify RV function using three-dimensional echocardiography (3DE) to predict adverse clinical outcomes in CTEPH patients.

Methods: A total of 151 consecutive CTEPH patients were registered in this prospective study between April 2015 and July 2019. New ML-based methods were used for data management, and quantitative analysis of RV volume and ejection fraction (RVEF) was performed offline. RV structural and functional parameters were recorded using 3DE. CTEPH was diagnosed using right heart catheterization, and 62 patients underwent cardiac magnetic resonance to assess right heart function. Adverse clinical outcomes were defined as PH-related hospitalization with hemoptysis or increased RV failure, including conditions requiring balloon pulmonary angioplasty or pulmonary endarterectomy, as well as death.

Results: The median follow-up time was 19.7 months (interquartile range, 0.5–54 months). Among the 151 CTEPH patients, 72 experienced adverse clinical outcomes. Multivariate Cox proportional-hazard analysis showed that ML-based 3DE analysis of RVEF was a predictor of adverse clinical outcomes (hazard ratio, 1.576; 95% confidence interval (CI), 1.046~2.372; P = 0.030).

Conclusions: The new ML-based 3DE algorithm is a promising technique for rapid 3D quantification of RV function in CTEPH patients.
Prolonged Use of Proton Pump Inhibitors, but Not Histamine-2 Receptor Antagonists, Is Associated With Lower Bone Mineral Density in Males Aged Over 70
Authors: Gao Shihua , Song Wenting , Lin Tianye , Chen Wenhuan , He Wei , Wei Qiushi , Li Ziqi
Published: August 2021

Aims: The association of acid suppressants use with bone mineral density (BMD) is still unclear, especially in older adult with prolonged use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs). In this study, our aim was to investigate the association between PPI or H2RA use and BMD in general US older adults.

Methods: We conducted a cross-sectional study on a sample from National Health and Nutrition Examination Survey. Association between long-term use of PPIs or H2RAs and lumber spine BMD in elderly was evaluated using weighted multivariate linear regression models. Sensitive and subgroup analysis were also performed in this study.

Results: Long-term PPI use is correlated with lower lumber spine BMD in our multivariable regression model after adjusting for known confounding factors. Further analysis showed PPI use with a duration over 1 year was negatively associated with lumber spine BMD in male, elderly aged over 70 years, and white elderly. There is no significant association between long-term H2RA use and lumber spine BMD.

Conclusions: Our results indicated that the association between long-term use of PPI and lumber spine BMD differed by gender. Long term use of PPIs would reduce lumber spine BMD in older men, while H2RA use is not significantly linked with lumber spine BMD. Patients that are at high risk of bone loss should shortened the duration of PPI use (<1 year) or use H2RAs as alternative if possible.
Glutamatergic Neurotransmission Controls the Functional Lateralization of the mPFC in the Modulation of Anxiety Induced by Social Defeat Stress in Male Mice
Authors: Santos-Costa Nathália , Baptista-de-Souza Daniela , Canto-de-Souza Lucas , Fresca da Costa Vinícius , Nunes-de-Souza Ricardo Luiz
Published: August 2021

The rodent medial prefrontal cortex (mPFC) is anatomically divided into cingulate (Cg1), prelimbic (PrL), and infralimbic (IL) subareas. The left and right mPFC (L and RmPFC) process emotional responses induced by stress-related stimuli, and LmPFC and RmPFC inhibition elicit anxiogenesis and anxiolysis, respectively. Here we sought to investigate (i) the mPFC functional laterality on social avoidance/anxiogenic-like behaviors in male mice subjected to chronic social defeat stress (SDS), (ii) the effects of left prelimbic (PrL) inhibition (with local injection of CoCl2) on the RmPFC glutamatergic neuronal activation pattern (immunofluorescence assay), and (iii) the effects of the dorsal right mPFC (Cg1 + PrL) NMDA receptor blockade (with local injection of AP7) on the anxiety induced by left dorsal mPFC inhibition in mice exposed to the elevated plus maze (EPM). Results showed that chronic SDS induced anxiogenic-like behaviors followed by the rise of ΔFosB labeling and by ΔFosB + CaMKII double-labeling bilaterally in the Cg1 and IL subareas of the mPFC. Chronic SDS also increased ΔFosB and by ΔFosB + CaMKII labeling only on the right PrL. Also, the left PrL inhibition increased cFos + CaMKII labeling in the contralateral PrL and IL. Moreover, anxiogenesis induced by the left PrL inhibition was blocked by NMDA receptor antagonist AP7 injected into the right PrL. These findings suggest the lateralized control of the glutamatergic neurotransmission in the modulation of emotional-like responses in mice subjected to chronic SDS.
Electrophysiological Screening for Children With Suspected Auditory Processing Disorder: A Systematic Review
Authors: Liu Panting , Zhu Huiqin , Chen Mingxia , Hong Qin , Chi Xia
Published: August 2021

Objective:This research aimed to provide evidence for the early identification and intervention of children at risk for auditory processing disorder (APD). Electrophysiological studies on children with suspected APDs were systematically reviewed to understand the different electrophysiological characteristics of children with suspected APDs.

Methods:Computerized databases such as PubMed, Cochrane, MEDLINE, Web of Science, and EMBASE were searched for retrieval of articles since the establishment of the database through May 18, 2020. Cohort, case-control, and cross-sectional studies that evaluated the literature for the electrophysiological assessment of children with suspected APD were independently reviewed by two researchers for literature screening, literature quality assessment, and data extraction. The Newcastle–Ottawa Scale and 11 entries recommended by the Agency for Healthcare Research and Quality were used to evaluate the quality of the literature.

Results:In accordance with the inclusion criteria, 14 articles were included. These articles involved 7 electrophysiological testing techniques: click-evoked auditory brainstem responses, frequency-following responses, the binaural interaction component of the auditory brainstem responses, the middle-latency response, cortical auditory evoked potential, mismatch negativity, and P300. The literature quality was considered moderate.

Conclusions:Auditory electrophysiological testing can be used for the characteristic identification of children with suspected APD; however, the value of various electrophysiological testing methods for screening children with suspected APD requires further study.
Gravity and Known Size Calibrate Visual Information to Time Parabolic Trajectories
Authors: Aguado Borja , López-Moliner Joan
Published: August 2021

Catching a ball in a parabolic flight is a complex task in which the time and area of interception are strongly coupled, making interception possible for a short period. Although this makes the estimation of time-to-contact (TTC) from visual information in parabolic trajectories very useful, previous attempts to explain our precision in interceptive tasks circumvent the need to estimate TTC to guide our action. Obtaining TTC from optical variables alone in parabolic trajectories would imply very complex transformations from 2D retinal images to a 3D layout. We propose based on previous work and show by using simulations that exploiting prior distributions of gravity and known physical size makes these transformations much simpler, enabling predictive capacities from minimal early visual information. Optical information is inherently ambiguous, and therefore, it is necessary to explain how these prior distributions generate predictions. Here is where the role of prior information comes into play: it could help to interpret and calibrate visual information to yield meaningful predictions of the remaining TTC. The objective of this work is: (1) to describe the primary sources of information available to the observer in parabolic trajectories; (2) unveil how prior information can be used to disambiguate the sources of visual information within a Bayesian encoding-decoding framework; (3) show that such predictions might be robust against complex dynamic environments; and (4) indicate future lines of research to scrutinize the role of prior knowledge calibrating visual information and prediction for action control.
The Brain Structure and Intrinsic Characters of Falsification Thinking in Conditional Proposition Testing
Authors: Zhang Meng , Wang Li , Zou Feng , Wang Yufeng , Wu Xin
Published: August 2021

Wason's selection task (WST) as a representative of the field of conditional proposition testing has been explored by multiple disciplines for more than 50 years, but the neural basis of its key falsification thinking remains unclear. Considering that the accuracy of individuals in WST has stability over time, we believe that falsification thinking has a specific brain structural basis and intrinsic neural characteristics. To test this hypothesis, we studied individuals who were able to complete the WST using T1-weighted MRI (using voxel-based morphology (VBM) analysis) and resting electroencephalogram (EEG) (using microstate analysis, which can reflect stable cognitive characteristics of individuals) techniques. First, VBM analysis found that, compared with the verification group, the gray matter volume (GMV) of the left inferior temporal gyrus and the right superior temporal region of the falsification group was larger, whereas the GMV in the cerebellum of the verification group was significantly larger than that of the falsification group. Subsequently, the results of the microstate analysis of the resting EEG data showed that the contribution of class A of the falsification group, which is closely related to the language network, is significantly higher than that of the verification group. Our structural MRI and resting EEG results consistently show that the structure and intrinsic activity pattern of the temporal lobe in individuals with falsification thinking are specific. Furthermore, the findings may provide potential insights into the role of the temporal lobe (which is also a brain region of language processing) in thought.
Abnormal Topological Network in Parkinson’s Disease With Impulse Control Disorders: A Resting-State Functional Magnetic Resonance Imaging Study
Authors: Zhu Xiaopeng , Liu Langsha , Xiao Yan , Li Fan , Huang Yongkai , Han Deqing , Yang Chun , Pan Sian
Published: August 2021

In recent years, neuroimaging evidence shows that the brains of Parkinson disease (PD) with impulse control disorders (ICDs) patients have functional disconnection changes. However, so far, it is still unclear whether the topological organization is damaged in PD patients with ICD. In this study, we aimed to explore the functional brain network in 18 patients with PD with ICDs (PD-ICD) and 18 patients with PD without ICDs (PD-nICD) by using functional magnetic resonance imaging and graph theory approach. We found that the PD-ICD patients had increased clustering coefficient and characteristic path length, while decreased small-world index compared with PD-nICD patients. Furthermore, we explored the hypothesis whether the abnormality of the small-world network parameters of PD-ICD patients is accompanied by the change of nodal centrality. As we hypothesized, the nodal centralities of the default mode network, control network, and dorsal attention network were found to be significantly damaged in the PD-ICD group compared with the PD-nICD group. Our study provides more evidence for PD-ICD patients’ brain network abnormalities from the perspective of information exchange, which may be the underlying pathophysiological basis of brain abnormalities in PD-ICD patients.
Vagus Nerve Stimulation Induced Motor Map Plasticity Does Not Require Cortical Dopamine
Authors: Brougher Jackson , Sanchez Camilo A. , Aziz Umaymah S. , Gove Kiree F. , Thorn Catherine A.
Published: August 2021

Background: Vagus nerve stimulation (VNS) paired with motor rehabilitation is an emerging therapeutic strategy to enhance functional recovery after neural injuries such as stroke. Training-paired VNS drives significant neuroplasticity within the motor cortex (M1), which is thought to underlie the therapeutic effects of VNS. Though the mechanisms are not fully understood, VNS-induced cortical plasticity is known to depend on intact signaling from multiple neuromodulatory nuclei that innervate M1. Cortical dopamine (DA) plays a key role in mediating M1 synaptic plasticity and is critical for motor skill acquisition, but whether cortical DA contributes to VNS efficacy has not been tested.

Objective: To determine the impact of cortical DA depletion on VNS-induced cortical plasticity.

Methods: Rats were trained on a skilled reaching lever press task prior to implantation of VNS electrodes and 6-hydroxydopamine (6-OHDA) mediated DA depletion in M1. Rats then underwent training-paired VNS treatment, followed by cortical motor mapping and lesion validation.

Results: In both intact and DA-depleted rats, VNS significantly increased the motor map representation of task-relevant proximal forelimb musculature and reduced task-irrelevant distal forelimb representations. VNS also significantly increased tyrosine hydroxylase (TH+) fiber density in intact M1, but this effect was not observed in lesioned hemispheres.

Conclusion: Our results reveal that though VNS likely upregulates catecholaminergic signaling in intact motor cortices, DA itself is not required for VNS-induced plasticity to occur. As DA is known to critically support M1 plasticity during skill acquisition, our findings suggest that VNS may engage a unique set of neuromodulatory signaling pathways to promote neocortical plasticity.
An Inhibitory Medial Preoptic Circuit Mediates Innate Exploration
Authors: Ryoo Jia , Park Seahyung , Kim Daesoo
Published: August 2021

Animals have an innate motivation to explore objects and environments with unknown values. To this end, they need to activate neural pathways that enable exploration. Here, we reveal that photostimulation of a subset of medial preoptic area (MPA) neurons expressing the vesicular-GABA transporter gene (vgat+) and sending axonal projections to the ventrolateral periaqueductal gray (vPAG) increases exploration in a chamber but causes no place preference when tested there without photostimulation. Photoinhibition of MPAvgat–vPAG projections leads to no emotional changes as measured by normal activity in an open field assay. Electrophysiological recordings revealed that most GABAergic vPAG neurons are inhibited by MPAvgat neurons. In contrast to a previous report that suggested that MPAvgat–vPAG neurons may impart positive valence to induce place preference, our results suggest that these neurons can increase innate exploration.
Evaluation of the Oncogene Function of GOLPH3 and Correlated Regulatory Network in Lung Adenocarcinoma
Authors: Zhang Tong , Wang Yue , Chen Yangyang , Jin Shuo , Gao Ying , Zhang Dan , Wu Yonghui
Published: August 2021

Background

Golgi phosphoprotein 3 (GOLPH3) is an oncoprotein localized in the Golgi apparatus. Abnormal GOLPH3 expression is potentially related to carcinogenesis. However, the potential biological regulation network of GOLPH3 in lung adenocarcinoma (LUAD) remains to be determined.

Methods

Expression of GOLPH3 was identified in LUAD via TIMER, Oncomine, Lung Cancer Explorer (LCE), Human Protein Atlas (HPA), and UALCAN database. Survival analysis was performed using the Kaplan–Meier plotter. GOLPH3 alterations were analyzed through cBioPortal. LinkedOmics was used to perform functional analysis and predict interacted targets. The protein–protein interaction network was constructed by GeneMANIA. In addition, candidate miRNAs and lncRNAs targeting GOLPH3 were generated to construct competing endogenous RNA (ceRNA) network, and survival analysis of ceRNA was performed using LnCeVar. The mRNA or protein expression of TUG1, miR-142-5p, and GOLPH3 in Beas-2B and LUAD cells was verified using qPCR or Western blotting. CCK-8 assay, wound healing assay, and transwell assay were used to detect the ability of cell proliferation, migration, and invasion.

Results

Overexpression of GOLPH3 was identified in LUAD. UALCAN analysis showed that upregulated GOLPH3 was linked to different pathological features of LUAD patients. Importantly, high GOLPH3 expression indicated a negative correlation with the first progression (FP) in LUAD patients. GOLPH3 alterations were also found. Moreover, co-expressed genes with GOLPH3 were analyzed; and they were involved in ribosome and oxidative phosphorylation pathways. Functional network analysis indicated GOLPH3 regulated T-cell receptor signaling pathway and interferon signaling pathway with kinase and transcription factor targets. Notably, TUG1/miR-142-5p/GOLPH3 affected overall survival of LUAD patients. GOLPH3 expression was decreased in the cells with overexpression of miR-142-5p and TUG1 knockdown. GOLPH3 reduction inhibited cell proliferation, migration, and invasion.

Conclusions

Upregulation of GOLPH3 has a positive correlation with clinicopathological subtypes and poor FP in LUAD. GOLPH3 promoted LUAD progression. Moreover, TUG1 may act as ceRNA to regulate GOLPH3 expression by competitive binding miR-142-5p.
Ascorbate Inhibits Proliferation and Promotes Myeloid Differentiation in TP53-Mutant Leukemia
Authors: Smith-Díaz Carlos C. , Magon Nicholas J. , McKenzie Judith L. , Hampton Mark B. , Vissers Margreet C. M. , Das Andrew B.
Published: August 2021

Loss-of-function mutations in the DNA demethylase TET2 are associated with the dysregulation of hematopoietic stem cell differentiation and arise in approximately 10% of de novo acute myeloid leukemia (AML). TET2 mutations coexist with other mutations in AML, including TP53 mutations, which can indicate a particularly poor prognosis. Ascorbate can function as an epigenetic therapeutic in pathological contexts involving heterozygous TET2 mutations by restoring TET2 activity. How this response is affected when myeloid leukemia cells harbor mutations in both TET2 and TP53 is unknown. Therefore, we examined the effects of ascorbate on the SKM-1 AML cell line that has mutated TET2 and TP53. Sustained treatment with ascorbate inhibited proliferation and promoted the differentiation of these cells. Furthermore, ascorbate treatment significantly increased 5-hydroxymethylcytosine, suggesting increased TET activity as the likely mechanism. We also investigated whether ascorbate affected the cytotoxicity of Prima-1Met, a drug that reactivates some p53 mutants and is currently in clinical trials for AML. We found that the addition of ascorbate had a minimal effect on Prima-1Met–induced cytotoxicity, with small increases or decreases in cytotoxicity being observed depending on the timing of treatment. Collectively, these data suggest that ascorbate could exert a beneficial anti-proliferative effect on AML cells harboring both TET2 and TP53 mutations whilst not interfering with targeted cytotoxic therapies such as Prima-1Met.
Prognostic Biomarkers and Immunotherapeutic Targets Among CXC Chemokines in Pancreatic Adenocarcinoma
Authors: Huang Jiacheng , Chen Zhitao , Ding Chenchen , Lin Shengzhang , Wan Dalong , Ren Kuiwu
Published: August 2021

Background

Pancreatic cancer is one of the principal causes of tumor-related death worldwide. CXC chemokines, a subfamily of functional chemotactic peptides, affect the initiation of tumor cells and clinical outcomes in several human malignant tumors. However, the specific biological functions and clinical significance of CXC chemokines in pancreatic cancer have not been clarified.

Methods

Bioinformatics analysis tools and databases, including ONCOMINE, GEPIA2, the Human Protein Atlas, DAVID, GeneMANIA, cBioPortal, STRING, DGidb, MethSurv, TRRUST, SurvExpress, SurvivalMeth, and TIMER, were utilized to clarify the clinical significance and biological functions of CXC chemokine in pancreatic cancer.

Results

Except for CXCL11/12, the transcriptional levels of other CXC chemokines in PAAD tissues were significantly elevated, and the expression level of CXCL16 was the highest among these CXC chemokines. Our findings also suggested that all of the CXC chemokines were linked to tumor-immune dysfunction involving the abundance of immune cell infiltration, and the Cox proportional hazard model confirmed that dendritic and CXCL3/5/7/8/11/17 were significantly associated with the clinical outcome of PAAD patients. Furthermore, increasing expressions of CXCL5/9/10/11/17 were related to unfavorable overall survival (OS), and only CXCL17 was a prognostic factor for disease-free survival (DFS) in PAAD patients. The expression pattern and prognostic power of CXC chemokines were further validated in the independent GSE62452 dataset. For the prognostic value of single CpG of DNA methylation of CXC chemokines in patients with PAAD, we identified 3 CpGs of CXCL1, 2 CpGs of CXCL2, 2 CpGs of CXCL3, 3 CpGs of CXCL4, 10 CpGs of CXCL5, 1 CpG of CXCL6, 1 CpG of CXCL7, 3 CpGs of CXCL12, 3 CpGs of CXCL14, and 5 CpGs of CXCL17 that were significantly associated with prognosis in PAAD patients. Moreover, the prognostic value of CXC chemokine signature in PAAD was explored and tested in two independent cohort, and results indicated that the patients in the low-risk group had a better OS compared with the high-risk group. Survival analysis of the DNA methylation of CXC chemokine signature demonstrated that PAAD patients in the high-risk group had longer survival times.

Conclusions

These findings reveal the novel insights into CXC chemokine expression and their biological functions in the pancreatic cancers, which might serve as accurate prognostic biomarkers and suitable immunotherapeutic targets for patients with pancreatic cancer.
LncRNA DCST1-AS1 Promotes Endometrial Cancer Progression by Modulating the MiR-665/HOXB5 and MiR-873-5p/CADM1 Pathways
Authors: Wang Jie , Shi Pingping , Teng Huaixiang , Lu Lixiang , Guo Hailong , Wang Xiuqin
Published: August 2021

Dysregulation of long noncoding RNA (lncRNA) is implicated in the initiation and progression of various tumors, including endometrial cancer (EC). However, the mechanism of lncRNAs in EC tumorigenesis and progression remains largely unexplored. In this work, we identified a novel lncRNA DC-STAMP domain-containing 1-antisense 1 (DCST1-AS1), which is highly upregulated and correlated with poor survival in EC patients. Overexpression of DCST1-AS1 significantly enhanced EC cell proliferation, colony formation, migration, and invasion in vitro and promoted tumor growth of EC in vivo. Mechanistically, DCST1-AS1 mediated EC progression by inducing the expression of homeobox B5 (HOXB5) and cell adhesion molecule 1 (CADM1), via acting as a competing endogenous RNA for microRNA-665 (miR-665) and microRNA-873-5p (miR-873-5p), respectively. In addition, we found that the expression of miR-665 and miR-873-5p was significantly downregulated, while HOXB5 and CADM1 expression levels were increased in EC tissues. Taken together, our findings support the important role of DCST1-AS1 in EC progression, and DCST1-AS1 may be used as a prognostic biomarker as well as a potential therapeutic target for EC.
SARS-CoV-2 Vaccination in Children and Adolescents—A Joint Statement of the European Academy of Paediatrics and the European Confederation for Primary Care Paediatricians
Authors: Dembiński Łukasz , Vieira Martins Miguel , Huss Gottfried , Grossman Zachi , Barak Shimon , Magendie Christine , del Torso Stefano , Dornbusch Hans Jürgen , Mazur Artur , Albrecht Katarzyna , Hadjipanayis Adamos
Published: August 2021

Stopping the COVID-19 pandemic and its socio-economic consequences is only possible with a multifaceted strategy, including mass vaccination. Studies have been conducted mainly in adults, and data on the pediatric population is relatively limited. However, it appears that vaccination in children and adolescents is highly effective and safe. Despite the apparent benefits of vaccinating this age group, there are some medical and ethical concerns. Based on the above considerations, the European Academy of Paediatrics (EAP) and the European Confederation of Primary Care Pediatricians (ECPCP) assessed the current situation and presented recommendations for international and national authorities, pediatricians, and pediatric societies regarding vaccination against SARS-CoV-2 in children and adolescents.
Development of a Nomogram for Moderate-to-Severe Bronchopulmonary Dysplasia or Death: Role of N-Terminal Pro-brain Natriuretic Peptide as a Biomarker
Authors: Song Min , Lei Mengyuan , Luo Chenghan , Shi Zanyang , Cheng Xinru , Ding Wenqian , Cao Wenjun , Zhang Jingdi , Ge Jian , Wang Mengmeng , Xia Peige , Mao Fengxia , Wang Li , Zhang Qian
Published: August 2021

Objectives: This study aimed to explore the clinical value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in predicting moderate-to-severe bronchopulmonary dysplasia (BPD)/death, and to establish an effective clinical predictive nomogram.

Methods: We retrospectively analyzed very low birth weight infants (VLBWs) with gestational age ≤ 32 weeks. The NT-proBNP values were determined on the 1st, 3rd, 7th, 14th, 21st, and 28th days after birth. The correlation between NT-proBNP level and moderate-to-severe BPD/death was evaluated. Receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction ability. Then, we used multivariable logistic regression to build the prediction model and nomogram, and calibration of the model was assessed by calibration curve.

Results: In total, 556 VLBWs were involved, among whom 229 developed BPD (mild: n = 109; moderate: n = 68; severe: n = 52) and 18 died. The NT-proBNP level in the moderate-to-severe BPD/death group was significantly higher than that in the no-to-mild BPD group from the 3rd to 28th day (P < 0.001). When the natural logarithm of the serum NT-ProBNP level increased by 1 unit at day 7 (±2 days) of life, the risk of moderate and severe BPD/death was the highest (OR = 3.753; 95% CI: 2.984~4.720), and ROC analysis identified an optimal cutoff point of 3360 ng/L (sensitivity: 80.0%; specificity: 86.2%; AUC: 0.861). After adjusting for confounding factors, the level of NT-proBNP at day 7 (±2 days) of life still had important predictive value for the development of moderate-to-severe BPD/death, significantly improving the predictive ability of the model.

Conclusion: The level of NT-proBNP at day 7 (±2 days) of life can be used as an early promising biomarker for VLBWs to develop moderate-to-severe BPD/death. We constructed an early predictive nomogram to help clinicians identify high-risk populations.
Validation of Point-of-Care Ultrasound to Measure Perioperative Edema in Infants With Congenital Heart Disease
Authors: Persson Jessica N. , Holstein Jacqueline , Silveira Lori , Irons Aimee , Rajab Taufiek Konrad , Jaggers James , Twite Mark D. , Scahill Carly , Kohn Mary , Gold Christine , Davidson Jesse A.
Published: August 2021

Purpose: Fluid overload is a common post-operative issue in children following cardiac surgery and is associated with increased morbidity and mortality. There is currently no gold standard for evaluating fluid status. We sought to validate the use of point-of-care ultrasound to measure skin edema in infants and assess the intra- and inter-user variability.

Methods: Prospective cohort study of neonates (≤30 d/o) and infants (31 d/o to 12 m/o) undergoing cardiac surgery and neonatal controls. Skin ultrasound was performed on four body sites at baseline and daily post-operatively through post-operative day (POD) 3. Subcutaneous tissue depth was manually measured. Intra- and inter-user variability was assessed using intraclass correlation coefficient (ICC).

Results: Fifty control and 22 surgical subjects underwent skin ultrasound. There was no difference between baseline surgical and control neonates. Subcutaneous tissue increased in neonates starting POD 1 with minimal improvement by POD 3. In infants, this pattern was less pronounced with near resolution by POD 3. Intra-user variability was excellent (ICC 0.95). Inter-user variability was very good (ICC 0.82).

Conclusion: Point-of-care skin ultrasound is a reproducible and reliable method to measure subcutaneous tissue in infants with and without congenital heart disease. Acute increases in subcutaneous tissue suggests development of skin edema, consistent with extravascular fluid overload. There is evidence of skin edema starting POD 1 in all subjects with no substantial improvement by POD 3 in neonates. Point-of-care ultrasound could be an objective way to measure extravascular fluid overload in infants. Further research is needed to determine how extravascular fluid overload correlates to clinical outcomes.
Dl-3-n-Butylphthalide Ameliorates Diabetic Nephropathy by Ameliorating Excessive Fibrosis and Podocyte Apoptosis
Authors: Xu Jingyu , Tang Zonghao , He Youwu , Cai Shufang , Wang Beini , Zhang Susu , Wu Man , Qian Kai , Zhang Kailun , Chai Bo , Chen Guorong , Xu Ke , Ji Hao , Xiao Jian , Wu Yanqing
Published: August 2021

Diabetic nephropathy (DN) is a common diabetes associated complication. Thus, it is important to understand the pathological mechanism of DN and find the appropriate therapeutic strategy for it. Dl-3-n-Butylphthalide (DL-NBP) has anti-inflammatory and antioxidant effects, and been widely used for the treatment of stroke and cardiovascular diseases. In this study, we selected three different doses (20, 60, and 120 mg⋅kg−1 d−1) of DL-NBP and attempted to elucidate its role and molecular mechanism underlying DN. We found that DL-NBP, especially at the dose of 60 or 120 mg⋅kg−1 d−1, could significantly ameliorate diabetes-induced elevated blood urea nitrogen (BUN) and creatinine level, and alleviate renal fibrosis. Additionally, the elevated expressions of collagen and α-smooth muscle actin (α-SMA) in the kidney from db/db mice were found to be significantly suppressed after DL-NBP treatment. Furthermore, mechanistic studies revealed that DL-NBP inhibits pro-inflammatory cytokine levels, thereby ameliorating the development of renal fibrosis. Moreover, we found that DL-NBP could not only reduce the endoplasmic reticulum stress (ERS), but also suppress activation of the renin-angiotensin system to inhibit vascular endothelial growth factor (VEGF) level, which subsequently reduces the podocyte apoptosis in kidney of db/db mice. In a word, our findings suggest that DL-NBP may be a potential therapeutic drug in the treatment of DN.
mTOR-Inhibition and COVID-19 in Kidney Transplant Recipients: Focus on Pulmonary Fibrosis
Authors: Granata Simona , Carratù Pierluigi , Stallone Giovanni , Zaza Gianluigi
Published: August 2021

Kidney transplant recipients are at high risk of developing severe COVID-19 due to the coexistence of several transplant-related comorbidities (e.g., cardiovascular disease, diabetes) and chronic immunosuppression. As a consequence, a large part of SARS-CoV-2 infected patients have been managed with a reduction of immunosuppression. The mTOR-I, together with antimetabolites, have been often discontinued in order to minimize the risk of pulmonary toxicity and to antagonize pharmacological interaction with antiviral/anti-inflammatory drugs. However, at our opinion, this therapeutic strategy, although justified in kidney transplant recipients with severe COVID-19, should be carefully evaluated in asymptomatic/paucisymptomatic patients in order to avoid the onset of acute allograft rejections, to potentially exploit the mTOR-I antiviral properties, to reduce proliferation of conventional T lymphocytes (which could mitigate the cytokine storm) and to preserve Treg growth/activity which could reduce the risk of progression to severe disease. In this review, we discuss the current literature regarding the therapeutic potential of mTOR-Is in kidney transplant recipients with COVID-19 with a focus on pulmonary fibrosis.
Sacubitril/Valsartan as a Therapeutic Tool Across the Range of Heart Failure Phenotypes and Ejection Fraction Spectrum
Authors: Gallo Giovanna , Volpe Massimo , Battistoni Allegra , Russo Domitilla , Tocci Giuliano , Musumeci Maria Beatrice
Published: August 2021

Heart failure (HF) is a complex syndrome caused by a variety of structural or functional cardiac abnormalities as a consequence of several involved pathophysiological pathways. In the last decades, left ventricular ejection fraction (LVEF) has represented the principal criterion used to stratify HF, to interpret ventricular function and to identify therapeutic strategies. However, this chimeric parameter oversimplifies the multiple pathways and mechanisms underlying the progression of HF. Indeed, HF should be more appropriately considered as the final stage of multiple disease states, characterized by distinct phenotypes on the basis of key clinical and molecular variables, such as underlying etiologies and conditions, demographic and structural features and specific biomarkers. Accordingly, HF should be viewed as a continuous spectrum in which the specific phenotypes need to be accurately identified with the aim to improve the disease management with a more tailored approach. In such a complex and heterogeneous scenario, the clinical benefits of an angiotensin receptor neprilysin inhibition strategy, namely in the single pill sacubitril/valsartan (S/V), have been shown across the entire HF continuum, representing a fundamental therapeutic strategy, although with different magnitudes depending on the severity and the stage of the clinical syndrome. In this viewpoint paper we have reconsidered the role of S/V in the light of different HF phenotypes and on the basis of HF considered as a whole spectrum.
Evolution of Lactase Persistence: Turbo-Charging Adaptation in Growth Under the Selective Pressure of Maternal Mortality?
Authors: Wells Jonathan C. K. , Pomeroy Emma , Stock Jay T.
Published: August 2021

The emergence of the capacity to digest milk in some populations represents a landmark in human evolution, linking genetic change with a component of niche construction, namely dairying. Alleles promoting continued activity of the enzyme lactase through the life-course (lactase persistence) evolved in several global regions within the last 7,000 years. In some European regions, these alleles underwent rapid selection and must have profoundly affected fertility or mortality. Elsewhere, alleles spread more locally. However, the functional benefits underlying the rapid spread of lactase persistence remain unclear. Here, we set out the hypothesis that lactase persistence promoted skeletal growth, thereby offering a generic rapid solution to childbirth complications arising from exposure to ecological change, or to new environments through migration. Since reduced maternal growth and greater neonatal size both increase the risk of obstructed labour, any ecological exposure impacting these traits may increase maternal mortality risk. Over many generations, maternal skeletal dimensions could adapt to new ecological conditions through genetic change. However, this adaptive strategy would fail if ecological change was rapid, including through migration into new niches. We propose that the combination of consuming milk and lactase persistence could have reduced maternal mortality by promoting growth of the pelvis after weaning, while high calcium intake would reduce risk of pelvic deformities. Our conceptual framework provides locally relevant hypotheses to explain selection for lactase persistence in different global regions. For any given diet and individual genotype, the combination of lactase persistence and milk consumption would divert more energy to skeletal growth, either increasing pelvic dimensions or buffering them from worsening ecological conditions. The emergence of lactase persistence among dairying populations could have helped early European farmers adapt rapidly to northern latitudes, East African pastoralists adapt to sudden climate shifts to drier environments, and Near Eastern populations counteract secular declines in height associated with early agriculture. In each case, we assume that lactase persistence accelerated the timescale over which maternal skeletal dimensions could change, thus promoting both maternal and offspring survival. Where lactase persistence did not emerge, birth weight was constrained at lower levels, and this contributes to contemporary variability in diabetes risk.