bluuebunny/crossref_metadata_2025 huggingface dataset:
Anhedonic Type Behavior and Anxiety Profile of Wistar-UIS Rats Subjected to Chronic Social Isolation
Authors: Acero-Castillo María Camila , Ardila-Figueroa María Camila , Botelho de Oliveira Silvia
Published: May 2021

Chronic Social Isolation (CSI) is a model of prolonged stress employed in a variety of studies to induce depression and anxious behavior in rats. The present study aims to evaluate the effect of CSI on male Wistar rats in terms of “anhedonic-type” behavior in the Sucrose Preference Test (SPT) and anxiogenic profile in the elevated-plus-maze (EPM) test, as well as evaluating the effect of resocialization upon sucrose consumption. A total of 24 adolescent male Wistar rats were evaluated. The animals were housed either together (communally) or socially isolated for 21 days, and then exposed for four consecutive days to the SPT test [water vs. a 32% sucrose solution (SS)]. Four days later, they were again subjected to the SPT test (32% vs. 0.7% SS), and then tested on the EPM apparatus 3 days later. Following the completion of the anxiogenic profile of the model, the animals were resocialized for 72 h and then re-tested once again using the SPT (32% vs. 0.7% SS). Twenty-four hours after this final consumption, the animals were euthanized to record the weight of their adrenal glands (AG). It was found that exposure to CSI produces anhedonic-type behavior and an anxiogenic profile in adolescent male rats, as evidenced in both the SPT and EPM tests, as well as in the animals’ physiological stress response. It was also demonstrated that resocialization does not reverse the anhedonic-type behavior, nor the physiological response to stress.
OptiFlex: Multi-Frame Animal Pose Estimation Combining Deep Learning With Optical Flow
Authors: Liu XiaoLe , Yu Si-yang , Flierman Nico A. , Loyola Sebastián , Kamermans Maarten , Hoogland Tycho M. , De Zeeuw Chris I.
Published: May 2021

Animal pose estimation tools based on deep learning have greatly improved animal behaviour quantification. These tools perform pose estimation on individual video frames, but do not account for variability of animal body shape in their prediction and evaluation. Here, we introduce a novel multi-frame animal pose estimation framework, referred to as OptiFlex. This framework integrates a flexible base model (i.e., FlexibleBaseline), which accounts for variability in animal body shape, with an OpticalFlow model that incorporates temporal context from nearby video frames. Pose estimation can be optimised using multi-view information to leverage all four dimensions (3D space and time). We evaluate FlexibleBaseline using datasets of four different lab animal species (mouse, fruit fly, zebrafish, and monkey) and introduce an intuitive evaluation metric—adjusted percentage of correct key points (aPCK). Our analyses show that OptiFlex provides prediction accuracy that outperforms current deep learning based tools, highlighting its potential for studying a wide range of behaviours across different animal species.
Impact of Platelet Endothelial Aggregation Receptor-1 Genotypes on Long-Term Cerebrovascular Outcomes in Patients With Minor Stroke or Transient Ischemic Attack
Authors: Zhang Xiao-Guang , Gu Jing-Yu , Fu Qiang-Qiang , Chen Shi-Wu , Xue Jie , Jiang Shan-Shan , Kong Yu-Ming , Li You-Mei , Yue Yun-Hua
Published: May 2021

Background: Platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 has been reported to affect agonist-stimulated platelet aggregation, but it remains unclear whether this variant plays a role in recurrent stroke. Here we assess the clinical relevance of PEAR1 rs12041331 in acute minor ischemic stroke (AMIS) and transient ischemic attack (TIA) Chinese patients treated with dual antiplatelet therapy (DAPT).

Methods: We recruited 273 consecutive minor stroke and TIA patients, and Cox proportional hazard regression was used to model the relationship between PEAR1 rs12041331 and thrombotic and bleeding events.

Results: Genotyping for PEAR1 rs12041331 showed 49 (18.0%) AA homozygotes, 129 (47.3%) GA heterozygotes, and 95 (34.7%) GG homozygotes. No association was observed between PEAR1 rs12041331 genotype and stroke or composite clinical vascular event rates (ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, or vascular death) or bleeding events regardless if individuals carried one or two copies of the A allele. Our results suggested that rs12041331 genetic polymorphism was not an important contributor to clinical events in AMIS and TIA patients in the setting of secondary prevention.

Conclusions: Our data do provide robust evidence that genetic variation in PEAR1 rs12041331 do not contribute to atherothrombotic or bleeding risk in minor stroke and TIA patients treated with DAPT.
Levels of Fibrin Degradation Products at Admission With Acute Ischemic Stroke Correlate With the NIH Stroke Scale Score 1 h After Intravenous Thrombolysis
Authors: Zhu Bin , Zhang Limin , Du Wanliang , Yang Jie , Tian Yue , Wu Mingfen , Wu Tingxi , Ling Xi , Liu Yilin , Zhao Xingquan , Zhao Zhigang
Published: May 2021

Background: Fibrin degradation products (FDPs) are fragments released by the plasmin-mediated degradation of fibrinogen or fibrin. Whether plasma levels of these fragments can predict the thrombolytic effect of recombinant tissue plasminogen activator (r-tPA) remains unknown.

Methods: We performed a hospital-based study of patients with acute ischemic stroke (AIS) to explore the relationship between FDP levels at admission and the NIH Stroke Scale (NIHSS) score 1 h after thrombolysis treatment. In this retrospective, single-center study, the data of all patients with AIS who received r-tPA treatment at Beijing Tiantan Hospital from January 2019 to October 2020 were collected and analyzed. Demographic and clinical data, including laboratory examinations, were also analyzed.

Results: A total of 339 patients with AIS were included in this study. Of these, 151 showed favorable effects of r-tPA, and 188 showed unsatisfactory effects at 1 h after thrombolysis. Overall, we found an inverse relationship between the FDPs levels at admission and the NIHSS score. A significant difference was observed when using the interquartile range of the FDPs levels (1.31 μg/mL) as a cutoff value (P = 0.003, odds ratio [OR] = 1.95, 95% confidence interval [CI]: 1.26–3.01), even after adjusting for confounding factors (P = 0.003, OR = 2.23, 95% CI: 1.31–3.77). In addition, significant associations were observed in the tertile (T3) and quartile (Q3, Q4) FDP levels when compared with T1 or Q1. A nomogram was also employed to create a model to predict an unsatisfactory effect of r-tPA. We found that FDP levels, white blood cell count, age, D-dimer level, and body mass index could influence the thrombolytic effect of r-tPA.

Conclusion: In conclusion, the present study demonstrated that the levels of FDPs at admission can be used as a prognostic factor to predict the curative effect of r-tPA.
A Novel Approach to New-Onset Hemiplegic Shoulder Pain With Decreased Range of Motion Using Targeted Diagnostic Nerve Blocks: The ViVe Algorithm
Authors: Fitterer John W. , Picelli Alessandro , Winston Paul
Published: May 2021

Introduction: Hemiplegic shoulder pain (HSP) is the most common pain disorder after stroke with incidence estimates of 30–70% and associated with reductions in function, interference with rehabilitation, and a reduced quality of life. Onset may occur as soon as a week after stroke in 17% of patients. Management of HSP represents a complex treatment pathway with a lack of evidence to support one treatment. The pain has heterogeneous causes. In the acute setting, decreased range of motion in the shoulder can be due to early-onset spasticity, capsular pattern stiffness, glenohumeral pathology, or complex regional pain syndrome (CRPS). As contracture can form in up to 50% of patients after stroke, effective management of the painful shoulder and upper limb with decreased range of motion requires assessment of each possible contributor for effective treatment. The anesthetic diagnostic nerve block (DNB) is known to differentiate spasticity from contracture and other disorders of immobility and can be useful in determining an appropriate treatment pathway.

Objective: To create a diagnostic algorithm to differentiate between the causes of HSP in the stiff, painful shoulder in the subacute setting using diagnostic techniques including the Budapest Criteria for CRPS and DNB for spasticity and pain generators.

Results: Examination of each joint in the upper extremity with HSP may differentiate each diagnosis with the use of an algorithm. Pain and stiffness isolated to the shoulder may be differentiated as primary shoulder pathology; sensory suprascapular DNB or intra-articular/subacromial injection can assist in differentiating adhesive capsulitis, arthritis, or rotator cuff injury. CRPS may affect the shoulder, elbow, wrist, and hand and can be evaluated with the Budapest Criteria. Spasticity can be differentiated with the use of motor DNB. A combination of these disorders may cause HSP, and the proposed treatment algorithm may offer assistance in selecting a systematic treatment pathway.
The Neural Correlates of Effortful Cognitive Processing Deficits in Schizophrenia: An ERP Study
Authors: Jiang Chen-Guang , Wang Jun , Liu Xiao-Hong , Xue Yan-Ling , Zhou Zhen-He
Published: May 2021

Background: Individuals’ information processing includes automatic and effortful processes and the latter require sustained concentration or attention and larger amounts of cognitive “capacity.” Event-related potentials (ERPs) reflect all neural activities that are related to a certain stimulus. Investigating ERP characteristics of effortful cognitive processing in people with schizophrenia would be helpful in further understanding the neural mechanism of schizophrenia.

Methods: Both schizophrenia patients (SCZ, n = 33) and health controls (HC, n = 33) completed ERP measurements during the performance of the basic facial emotion identification test (BFEIT) and the face-vignette task (FVT). Data of ERP components (N100, P200, and N250), BFEIT and FVT performances were analyzed.

Results: Schizophrenia patients’ accuracies of face emotion detection in the BFEIT and vignette emotion detection in the FVT were both significantly worse than the performance of the HC group. Repeated-measures ANOVAs performed on mean amplitudes and latencies revealed that the interaction effect for group × experiment × site (prefrontal, frontal, central, parietal, and occipital site) was significant for N250 amplitude. In FVT experiment, N250 amplitudes at prefrontal and frontal sites in schizophrenia group were larger than those of HC group; the maximum N250 amplitude was present at the prefrontal site in both the groups. For N250 latency, the interaction effect for group × experiment was significant; N250 latencies in the schizophrenia group were longer than those of the HC group.

Conclusion: Schizophrenia patients present effortful cognitive processing dysfunctions which reflect in abnormal ERP components, especially N250 at prefrontal cortex and frontal cortex sites. These findings have important implications for further clarifying the neural mechanism of effortful cognitive processing deficits in schizophrenia.
Therapeutic Potential of Selenium in Glioblastoma
Authors: Yakubov Eduard , Eibl Thomas , Hammer Alexander , Holtmannspötter Markus , Savaskan Nicolai , Steiner Hans-Herbert
Published: May 2021

Little progress has been made in the long-term management of malignant brain tumors, leaving patients with glioblastoma, unfortunately, with a fatal prognosis. Glioblastoma remains the most aggressive primary brain cancer in adults. Similar to other cancers, glioblastoma undergoes a cellular metabolic reprogramming to form an oxidative tumor microenvironment, thereby fostering proliferation, angiogenesis and tumor cell survival. Latest investigations revealed that micronutrients, such as selenium, may have positive effects in glioblastoma treatment, providing promising chances regarding the current limitations in surgical treatment and radiochemotherapy outcomes. Selenium is an essential micronutrient with anti-oxidative and anti-cancer properties. There is additional evidence of Se deficiency in patients suffering from brain malignancies, which increases its importance as a therapeutic option for glioblastoma therapy. It is well known that selenium, through selenoproteins, modulates metabolic pathways and regulates redox homeostasis. Therefore, selenium impacts on the interaction in the tumor microenvironment between tumor cells, tumor-associated cells and immune cells. In this review we take a closer look at the current knowledge about the potential of selenium on glioblastoma, by focusing on brain edema, glioma-related angiogenesis, and cells in tumor microenvironment such as glioma-associated microglia/macrophages.
Explainable Deep Learning for Personalized Age Prediction With Brain Morphology
Authors: Lombardi Angela , Diacono Domenico , Amoroso Nicola , Monaco Alfonso , Tavares João Manuel R. S. , Bellotti Roberto , Tangaro Sabina
Published: May 2021

Predicting brain age has become one of the most attractive challenges in computational neuroscience due to the role of the predicted age as an effective biomarker for different brain diseases and conditions. A great variety of machine learning (ML) approaches and deep learning (DL) techniques have been proposed to predict age from brain magnetic resonance imaging scans. If on one hand, DL models could improve performance and reduce model bias compared to other less complex ML methods, on the other hand, they are typically black boxes as do not provide an in-depth understanding of the underlying mechanisms. Explainable Artificial Intelligence (XAI) methods have been recently introduced to provide interpretable decisions of ML and DL algorithms both at local and global level. In this work, we present an explainable DL framework to predict the age of a healthy cohort of subjects from ABIDE I database by using the morphological features extracted from their MRI scans. We embed the two local XAI methods SHAP and LIME to explain the outcomes of the DL models, determine the contribution of each brain morphological descriptor to the final predicted age of each subject and investigate the reliability of the two methods. Our findings indicate that the SHAP method can provide more reliable explanations for the morphological aging mechanisms and be exploited to identify personalized age-related imaging biomarker.
Effect of Combined Interval and Continuous Exercise Training on Gastric Emptying, Appetite, and Adaptive Responses in Men With Overweight and Obesity
Authors: Horner Katy M. , Byrne Nuala M. , King Neil A.
Published: May 2021

Background/Objectives: Characterizing compensatory and adaptive responses to exercise assists in understanding changes in energy balance and health outcomes with exercise interventions. This study investigated the effects of a short-term exercise intervention (combining high intensity interval (HII) and continuous exercise) on (1) gastric emptying, appetite and energy intake; and (2) other adaptive responses including cardiorespiratory fitness, in inactive men with overweight/obesity.

Methods: Fifteen men (BMI: 29.7 ± 3.3 kg/m−2) completed a 4-wk supervised exercise intervention, consisting of 5 exercise sessions per week alternating between HII (30 s at 100% VO2max followed by 30 s recovery) and continuous (at 50% VO2max) training on a cycle ergometer, progressing from 30 to 45 min session duration. Gastric emptying (13C-octanoic acid breath test), appetite (visual analog scale), energy intake (ad libitum lunch meal), body composition (air displacement plethysmography), non-exercise activity (accelerometery) VO2max, blood pressure, and fasting concentrations of glucose, insulin, and ghrelin were measured before and after (≥48 h) the intervention.

Results: Gastric emptying, glucose, insulin and ghrelin were unchanged, but energy intake at the ad libitum lunch test meal significantly increased at post-intervention (+171 ± 116 kcal, p < 0.01). Body weight (−0.9 ± 1.1 kg), waist circumference (−2.3 ± 3.5 cm) and percent body fat (−0.9 ± 1.1%) were modestly reduced (P < 0.05). VO2max increased (+4.4 ± 2.1 ml.kg.min−1) by 13% and systolic (−6.2 ± 8.4 mmHg) and diastolic (−5.8 ± 2.2 mmHg) blood pressure were significantly reduced (P ≤ 0.01 for all).

Conclusions: Four weeks of exercise training did not alter gastric emptying, indicating gastric emptying may only adapt to a higher volume/longer duration of exercise or changes in other characteristics associated with regular exercise. The combination of HII and continuous exercise training had beneficial effects on body composition, cardiorespiratory fitness, and blood pressure and warrants further investigation in larger randomized controlled trials.
Investigating the Effectiveness of an Educational Escape Game for Increasing Nutrition-Related Knowledge in Young Adolescents: A Pilot Study
Authors: Abdollahi Anna M. , Masento Natalie A. , Vepsäläinen Henna , Mijal Michal , Gromadzka Monika , Fogelholm Mikael
Published: May 2021

Objective: As a pilot trial under the Games of Food consortium, this study assessed the effectiveness of an educational escape game alongside a self-study method as a nutrition knowledge intervention. Furthermore, this study explored the use of an escape game as an educational tool for young adolescents.

Materials and Methods: Altogether three schools participated, one from Finland and two from the UK. Baseline questionnaires assessing knowledge were administered before intervention day. Participants from each class were randomly allocated by the researchers into either the escape game condition, where participants played a nutrition education escape game with a focus on plant-based protein sources, or the self-study condition, where participants received an educational leaflet with identical content. In addition to the knowledge post-assessment, the educational escape game condition answered an enjoyment and intrinsic motivation questionnaire to evaluate the game experience. Paired t-tests were used to determine significant changes within intervention conditions and ANCOVA was used to estimate the differences in knowledge.

Results: The participants were 130 children (11–14 years), divided into educational escape game (n = 68) and self-study (n = 62) conditions. Both the educational escape game (20.7 vs. 23, p < 0.001) and self-study (21.1 vs. 23.1, p = 0.002) had improved overall knowledge scores. No significant differences in gained knowledge existed between groups. Of the educational escape game participants, 60% reported the game as mostly enjoyable and 46% reported added use and value for learning.

Conclusion: The educational escape game condition was comparable to the self-study method for nutrition education in adolescents. However, since the educational escape game provides an enjoyable experience that may enhance intrinsic motivation to promote learning and possible behavior change, the use of escape games for nutrition education warrant further investigation.
The Efficacy and Safety of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Combined With Thymosin in Advanced Non-Small Cell Lung Cancer Patients Harboring Active Epidermal Growth Factor Receptor Mutations
Authors: Feng Yongdong , Zhu Guangkuo , Lang Song , Hao Ping , Li Guanghui , Chen Fanglin , Zhuo Wenlei , Duan Yuzhong , Zhang Anmei , Chen Zhengtang , Sun Jianguo
Published: May 2021

Objective

To explore the efficacy and safety of EGFR-TKI combined with thymosin therapy in advanced non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations.

Methods

Patients confirmed as advanced NSCLC with active EGFR mutations were recruited from August 2008 to July 2018 retrospectively. Patients treated with EGFR-TKI were classified as the EGFR-TKI group. And those received EGFR-TKI and thymosin therapy were designated as the EGFR-TKI plus thymosin group. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), tumor response and adverse effects.

Results

The median PFS was significantly longer in EGFR-TKI plus thymosin group than that in EGFR-TKI group (14.4 months vs. 9.2 months; HR=0.433, 95% CI 0.322 - 0.582, P<0.0001). The median OS was also prolonged in EGFR-TKI plus thymosin group than that in EGFR-TKI group (29.5 months vs. 19.8 months; HR=0.430, 95% CI 0.319 - 0.580, P<0.0001). The objective response rate in EGFR-TKI plus thymosin group and EGFR-TKI group were 60.0% versus 60.8% (P=0.918). The disease control rate was 96.9% in EGFR-TKI plus thymosin group and 97.7% in EGFR-TKI group (P=1.000). There were no significant differences in adverse effects between the two groups. The number of CD3+T cells in peripheral blood decreased significantly after treatment including both CD3+CD4+T and CD3+CD8+T subsets in EGFR-TKI group, but not in EGFR-TKI plus thymosin group.

Conclusions

Combination of EGFR-TKI and thymosin can significantly prolong the PFS and OS compared with EGFR-TKI monotherapy without more adverse events, which offers a new strategy in clinic.
Case Report: Clinical Experience With Avelumab in Patients With Metastatic Merkel Cell Carcinoma and Brain Metastases Treated in Europe
Authors: Fife Kate , Tétu Pauline , Prabhakaran Jessica , Lebbé Celeste , Grignani Giovanni
Published: May 2021

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that can metastasize rapidly. In patients with metastatic MCC (mMCC), brain metastases are uncommon but are associated with poor prognosis; furthermore, there is limited published literature regarding treatment of these patients, and no specific regimens are currently recommended by guidelines. Avelumab, an anti–programmed death ligand 1 monoclonal antibody, was the first approved treatment for patients with mMCC. Here, we present 4 cases of patients with mMCC and brain metastases treated with avelumab. Patient age ranged from 48 to 70 years, and all patients received avelumab as second-line therapy following disease progression with platinum-based chemotherapy. Patient cases 1 and 2 received avelumab alone and experienced rapid disease progression according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In patient case 3, avelumab alone resulted in a prolonged complete response by RECIST 1.1 of 1 brain metastasis and partial response by RECIST 1.1 of a second brain metastasis. After 11 months of avelumab treatment, the patient received concurrent stereotactic radiosurgery that resulted in complete response of the second metastasis. Patient case 4 achieved a partial response by RECIST 1.1 with avelumab plus stereotactic radiosurgery. These results suggest that avelumab followed by radiotherapy or with concurrent radiotherapy may be an effective treatment option for patients with mMCC and brain metastases.
Differences in Prostate Cancer Incidence and Mortality in Lower Saxony (Germany) and Groningen Province (Netherlands): Potential Impact of Prostate-Specific Antigen Testing
Authors: Kappen Sanny , de Bock Geertruida H. , Sirri Eunice , Vohmann Claudia , Kieschke Joachim , Winter Alexander
Published: May 2021

Background

Prostate cancer (PCa) is the most frequent cancer among men in Europe. Differences in PCa incidence around the world can be partly explained by variations in recommendations for prostate-specific antigen (PSA), particularly for early detection. For example, the PSA testing policy is more conservative in the Netherlands than in Germany. To better understand the relationship between PSA testing recommendations and PCa incidence, stage distribution, and mortality, we compared these variables over time between Lower Saxony in northwestern Germany and the neighboring province of Groningen in the Netherlands.

Methods

Population data, tumor stage- and age group-specific PCa incidence (ICD-10 C61) and mortality rates for Lower Saxony and Groningen were obtained from the Lower Saxony Epidemiological Cancer Registry, the Netherlands Comprehensive Cancer Organization, and Statistics Netherlands for 2003–2012. Incidence and mortality rates per 100,000 person-years were age-standardized (ASR, old European standard). Trends in age-standardized incidence rates (ASIR) and mortality rates (ASMR) for specific age groups were assessed using joinpoint regression.

Results

The mean annual PCa ASIR between 2003 and 2012 was on average 19.9% higher in Lower Saxony than in Groningen (120.5 vs. 100.5 per 100,000), while the mean annual ASMR was on average 24.3% lower in Lower Saxony than in Groningen (21.5 vs. 28.4 per 100,000). Between 2003 and 2012, the average annual percentage change (AAPC) in PCa incidence rates did not change significantly in either Lower Saxony (−1.8%, 95% CI −3.5, 0.0) or Groningen (0.2%, 95% CI −5.0, 5.7). In contrast, the AAPC in mortality rate decreased significantly during the same time period in Lower Saxony (−2.5%, 95% CI −3.0, −2.0) but not in Groningen (0.1%, 95% CI −2.4, 2.6).

Conclusions

Higher PCa incidence and lower PCa-related mortality was detected in Lower Saxony than in Groningen. Although recommendations on PSA testing may play a role, the assessed data could not offer obvious explanations to the observed differences. Therefore, further investigations including data on the actual use of PSA testing, other influences (e.g., dietary and ethnic factors), and better data quality are needed to explain differences between the regions.
Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine
Authors: Wang Wanyan , Cui Jiayan , Ma Hui , Lu Weiqiang , Huang Jin
Published: May 2021

Metabolic rewiring is considered as a primary feature of cancer. Malignant cells reprogram metabolism pathway in response to various intrinsic and extrinsic drawback to fuel cell survival and growth. Among the complex metabolic pathways, pyrimidine biosynthesis is conserved in all living organism and is necessary to maintain cellular fundamental function (i.e. DNA and RNA biosynthesis). A wealth of evidence has demonstrated that dysfunction of pyrimidine metabolism is closely related to cancer progression and numerous drugs targeting pyrimidine metabolism have been approved for multiple types of cancer. However, the non-negligible side effects and limited efficacy warrants a better strategy for negating pyrimidine metabolism in cancer. In recent years, increased studies have evidenced the interplay of oncogenic signaling and pyrimidine synthesis in tumorigenesis. Here, we review the recent conceptual advances on pyrimidine metabolism, especially dihydroorotate dehydrogenase (DHODH), in the framework of precision oncology medicine and prospect how this would guide the development of new drug precisely targeting the pyrimidine metabolism in cancer.
Prevalence of Growth Restriction at Birth for Newborns With Congenital Heart Defects: A Population-Based Prospective Cohort Study EPICARD
Authors: Ghanchi Ali , Rahshenas Makan , Bonnet Damien , Derridj Neil , LeLong Nathalie , Salomon Laurent J. , Goffinet Francois , Khoshnood Babak
Published: May 2021

Background and Objectives: Congenital heart defects (CHD) and growth restriction at birth are two major causes of childhood and adult morbidity and mortality. The aim of this study was to assess the overall risk of growth restriction at birth, as measured by its imperfect proxy small (< 10th percentile) for gestational age (SGA), for newborns with CHD.

Methods: Using data from a population-based cohort of children born with CHD, we assessed the risk of growth restriction at birth using SGA and severe SGA (3rd percentile). To compare the odds of SGA and severe SGA across five specific major CHD, we used ordinal logistic regression using isolated, minor (non-operated) ventricular septal defect (VSD) as the control group.

Results: The overall proportion of SGA for “isolated” CHD (i.e., those not associated with other anomalies) was 13% (95% CI, 12–15%), which is 30% higher than what would be expected in the general population (i.e., 10%). The risk of severe SGA was 5% (95% CI, 4–6%) as compared with the expected 3% in the general population. There were substantial differences in the risk of overall SGA and more so severe SGA across the different CHD. The highest risk of SGA occurred for Tetralogy of Fallot (adjusted OR 2.7, 95% CI, 1.3–5.8) and operated VSD (adjusted OR 2.1, 95% CI, 1.1–3.8) as compared with the control group of minor (non-operated) VSD.

Conclusion: The overall risks of both SGA and severe SGA were higher in isolated CHD than what would be expected in the general population with substantial differences across the subtypes of CHD. These results may provide a clue for understanding the underlying mechanisms of the relation between alterations in fetal circulation associated with different types of CHD and their effects on fetal growth.
Pharmacokinetic Characteristics, Tissue Bioaccumulation and Toxicity Profiles of Oral Arsenic Trioxide in Rats: Implications for the Treatment and Risk Assessment of Acute Promyelocytic Leukemia
Authors: Liu Wensheng , Wang Bin , Zhao Yilei , Wu Zhiqiang , Dong Andi , Chen Hongzhu , Lin Liwang , Lu Jing , Hai Xin
Published: May 2021

Oral arsenic trioxide (ATO) has demonstrated a favorable clinical efficiency in the treatment of acute promyelocytic leukemia (APL). However, the pharmacokinetic characteristics, tissue bioaccumulation, and toxicity profiles of arsenic metabolites in vivo following oral administration of ATO have not yet been characterized. The present study uses high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) to assess the pharmacokinetics of arsenic metabolites in rat plasma after oral and intravenous administration of 1 mg kg−1 ATO. In addition, the bioaccumulation of arsenic metabolites in blood and selected tissues were evaluated after 28 days oral administration of ATO in rats at a dose of 0, 2, 8, and 20 mg kg−1 d−1. The HPLC-HG-AFS analysis was complemented by a biochemical, hematological, and histopathological evaluation conducted upon completion of ATO treatment. Pharmacokinetic results showed that arsenite (AsIII) reached a maximum plasma concentration rapidly after initial dosing, and the absolute bioavailability of AsIII was 81.03%. Toxicological results showed that the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and white blood cells (WBC) in the 20 mg kg−1 d−1 ATO group were significantly increased compared to the control group (p < 0.05). The distribution trend of total arsenic in the rat was as follows: whole blood > kidney > liver > heart. Dimethylated arsenic (DMA) was the predominant bioaccumulative metabolite in the whole blood, liver, and heart, while monomethylated arsenic (MMA) was the predominant one in the kidney. Collectively, these results revealed that oral ATO was rapidly absorbed, well-tolerated, and showed organ-specific and dose-specific bioaccumulation of arsenic metabolites. The present study provides preliminary evidence for clinical applications and the long-term safety evaluation of oral ATO in the treatment of APL.
Combination of AZD3463 and DZNep Prevents Bone Metastasis of Breast Cancer by Suppressing Akt Signaling
Authors: He Wenxin , Cao Xiankun , Rong Kewei , Chen Xiaojun , Han Shuai , Qin An
Published: May 2021

Osteolysis resulting from osteoclast overactivation is one of the severe complications of breast cancer metastasis to the bone. Previous studies reported that the anti-cancer agent DZNep induces cancer cell apoptosis by activating Akt signaling. However, the effect of DZNep on breast cancer bone metastasis is unknown. We previously found that DZNep enhances osteoclast differentiation by activating Akt. Therefore, we explored the use of the anti-cancer agent AZD3463 (an Akt inhibitor) along with DZNep, as AZD3463 can act as an anti-cancer agent and can also potentially ameliorate bone erosion. We evaluated osteoclast and breast cancer cell phenotypes and Akt signaling in vitro by treating cells with DZNep and AZD3463. Furthermore, we developed a breast cancer bone metastasis animal model in mouse tibiae to further determine their combined effects in vivo. Treatment of osteoclast precursor cells with DZNep alone increased osteoclast differentiation, bone resorption, and expression of osteoclast-specific genes. These effects were ameliorated by AZD3463. The combination of DZNep and AZD3463 inhibited breast cancer cell proliferation, colony formation, migration, and invasion. Finally, intraperitoneal injection of DZNep and AZD3463 ameliorated tumor progression and protected against bone loss. In summary, DZNep combined with AZD3463 prevented skeletal complications and inhibited breast cancer progression by suppressing Akt signaling.
Rhoifolin Ameliorates Osteoarthritis via Regulating Autophagy
Authors: Yan Jiyuan , Ni Bowei , Sheng Gaohong , Zhang Yingchi , Xiao Yifan , Ma Yongzhuang , Li Hao , Wu Hua , Tu Chang
Published: May 2021

Osteoarthritis (OA) is a common age-related joint disease. Its development has been generally thought to be associated with inflammation and autophagy. Rhoifolin (ROF), a flavanone extracted from Rhus succedanea, has exhibited prominent anti-oxidative and anti-inflammatory properties in several diseases. However the exact role of ROF in OA remains unclear. Here, we investigated the therapeutic effects as well as the underlying mechanism of ROF on rat OA. Our results indicated that ROF could significantly alleviate the IL-1β–induced inflammatory responses, cartilage degradation, and autophagy downregulation in rat chondrocytes. Moreover, administration of autophagy inhibitor 3-methyladenine (3-MA) could reverse the anti-inflammatory and anti-cartilage degradation effects of ROF. Furthermore, P38/JNK and PI3K/AKT/mTOR signal pathways were involved in the protective effects of ROF. In vivo, intra-articular injection of ROF could notably ameliorate the cartilage damage in rat OA model. In conclusion, our work elucidated that ROF ameliorated rat OA via regulating autophagy, indicating the potential role of ROF in OA therapy.
Network Pharmacology-Based Validation of the Efficacy of Huiyangjiuji Decoction in the Treatment of Experimental Colitis
Authors: Yu Wei , Cheng Hongju , Zhu Baoliang , Yan Jing
Published: May 2021

Ulcerative colitis (UC) is the major type of inflammatory bowel disease (IBD) characterized by an overactive immune responses and destruction of the colorectal epithelium with intricate pathological factors. In China, Huiyangjiuji decoction (HYJJ) has been widely administered against inflammation, but the underlying mechanical mechanisms are not known. A murine model of colitis was established by orally feeding 4% dextran sodium sulfate for 5 days. Intestinal organoids (IOs) were treated with TNFα (Tumor necrosis factor-α) as an ex-vivo UC model. A scratch assay combined with a co-culture system that incubated murine epithelial cell line (IEC-6) with macrophages (Mφs) was utilized to assess epithelial recovery under inflammatory conditions. Network pharmacology analysis was performed to elucidate the mechanism of HYJJ decoction. In the present study, we confirmed that HYJJ considerably alleviated of DSS-induced colitis, as evidenced by the improved intestinal injury and fecal albumin, as well as feces blood. Network pharmacology analysis identified the active components in HYJJ formula, and KEGG enrichment analysis indicated that HYJJ-target genes were enriched in pathogen-induced infections, cancer-related as well as inflammatory pathways. Consistently, RNA-sequencing demonstrated that HYJJ treated inhibited cytokine-cytokine interaction, IBD as well as TNF signaling pathways, confirming the anti-inflammatory and anti-neoplastic role of HYJJ decoction. In-vitro experimental evidence confirmed the suppression of pro-interleukins by HYJJ, including IL-2, IL-10 and IL-12. Moreover, the contribution of HYJJ to mucosal healing was corroborated by ex-vivo experiments, in which HYJJ rescued TNFα-compromised IOs functions, i.e., elevated mitochondrial stress (MOS) and impaired regeneration capacity. IEC-6 cells co-culture with Mφs from HYJJ-treated experimental colitis mice showed an improved migration capacity as compared to those incubated with Mφs from untreated colitis mice. We conclude that HYJJ re-establishes homeostasis of the gut epithelium during colitis by suppressing inflammation and orchestrating cytokines interaction.
Traditional Herbal Medicines, Bioactive Metabolites, and Plant Products Against COVID-19: Update on Clinical Trials and Mechanism of Actions
Authors: Alam Safaet , Sarker Md. Moklesur Rahman , Afrin Sadia , Richi Fahmida Tasnim , Zhao Chao , Zhou Jin-Rong , Mohamed Isa Naina
Published: May 2021

SARS-CoV-2 is the latest worldwide pandemic declared by the World Health Organization and there is no established anti-COVID-19 drug to combat this notorious situation except some recently approved vaccines. By affecting the global public health sector, this viral infection has created a disastrous situation associated with high morbidity and mortality rates along with remarkable cases of hospitalization because of its tendency to be high infective. These challenges forced researchers and leading pharmaceutical companies to find and develop cures for this novel strain of coronavirus. Besides, plants have a proven history of being notable wellsprings of potential drugs, including antiviral, antibacterial, and anticancer therapies. As a continuation of this approach, plant-based preparations and bioactive metabolites along with a notable number of traditional medicines, bioactive phytochemicals, traditional Chinese medicines, nutraceuticals, Ayurvedic preparations, and other plant-based products are being explored as possible therapeutics against COVID-19. Moreover, the unavailability of effective medicines against COVID-19 has driven researchers and members of the pharmaceutical, herbal, and related industries to conduct extensive investigations of plant-based products, especially those that have already shown antiviral properties. Even the recent invention of several vaccines has not eliminated doubts about safety and efficacy. As a consequence, many limited, unregulated clinical trials involving conventional mono- and poly-herbal therapies are being conducted in various areas of the world. Of the many clinical trials to establish such agents as credentialed sources of anti-COVID-19 medications, only a few have reached the landmark of completion. In this review, we have highlighted and focused on plant-based anti-COVID-19 clinical trials found in several scientific and authenticated databases. The aim is to allow researchers and innovators to identify promising and prospective anti-COVID-19 agents in clinical trials (either completed or recruiting) to establish them as novel therapies to address this unwanted pandemic.
Effects of Methanolic Extract Based-Gel From Saudi Pomegranate Peels With Enhanced Healing Potential on Excision Wounds in Diabetic Rats
Authors: Karim Shahid , Alkreathy Huda M. , Ahmad Aftab , Khan Mohammad Imran
Published: May 2021

Introduction: Current study was designed to evaluate the wound healing activity of a Saudi pomegranate peel extract on excision wound healing in experimentally induced diabetes in rats.

Methodology: Animals were divided into three groups: diabetic excision wound with no treatment, diabetic excision wound with gel alone and diabetic excision wound with Saudi pomegranate peel extract in gel. Animals were monitored for clinical signs, weekly body weight, morbidity and mortality during entire study period. The efficacy parameters evaluated were percent wound contraction, Hydroxyproline content, estimation of Transforming Growth Factor ß1 (TGF-ß1), Vascular Endothelial Growth Factor (VEGF), and Epidermal Growth Factor (EGF) in wound lysates by ELISA, mRNA expression of TGF-ß1, VEGF, and EGF in wound lysates by qPCR, Estimation of nitric oxide (NO) and NO synthase (NOS) in Wound Lysates and histopathology of skin for reepithelization, neovascularization, and inflammation.

Results: The Saudi pomegranate peel extract in gel (5.0 g extract per 100 g gel) showed significant wound healing activity when compared to the vehicle control [p < 0.05] following 21 days of treatment. Animals in the control and treatment groups were apparently normal through the study with no significant differences in body weights between groups. Expression of mRNA of TGFβ1, EGF and VEGF in wounds was the highest on day 14 post treatment 4.3, 3.5 and 0.9 fold higher respectively in the treatment group when compared to vehicle control, and on day 21, the values were 0.12, 0.3 and 0.83, respectively. No statistically significant differences were observed in TGF-ß1 levels in wounds on days 4, 7, 14 and 21 post treatment when compared to the vehicle control (p > 0.05). Significantly higher levels of VEGF were observed in treatment group on day 7 and 21 when compared to vehicle control (p < 0.05). Significantly higher levels of EGF were observed in treatment group on day 7 and 21 when compared to vehicle control (p < 0.05). Mean hydroxyproline levels were higher in treatment group on days 4 and 7 when compared to vehicle control. NO levels in treatment group were significantly lower on days 7, 14 and 21 when compared to vehicle control (p < 0.05). NOS activity in treatment group were significantly lower on days 4 and 7 when compared to vehicle control (p < 0.05). Histopathological changes in skin wound in the treatment group were consistent with wound healing when compared to the vehicle group.

Conclusion: This study’s findings suggest that topical application of SPPE gel effectively enhanced wound healing in experimentally induced diabetic conditions.
Olbert’s Kappa Fermi and Bose Distributions
Authors: Treumann R. A. , Baumjohann Wolfgang
Published: May 2021

The quantum version of Olbert’s kappa distribution applicable to fermions is obtained. Its construction is straightforward but requires recognition of the differences in the nature of states separated by Fermi momenta. Its complement, the bosonic version of the kappa distribution is also given, as is the procedure of how to construct a hypothetical kappa-anyon distribution. At very low temperature the degenerate kappa Fermi distribution yields a kappa-modified version of the ordinary degenerate Fermi energy and momentum. We provide the Olbert-generalized expressions of the Olbert-Fermi partition function and entropy which may serve determining all relevant statistical mechanical quantities. Possible applications are envisaged to condensed matter physics, possibly quantum plasmas, and dense astrophysical objects like the interior state of terrestrial planets, neutron stars, magnetars where quantum effects come into play and dominate the microscopic scale but may have macroscopic consequences.
Modeling the Consequences of Social Distancing Over Epidemics Spreading in Complex Social Networks: From Link Removal Analysis to SARS-CoV-2 Prevention
Authors: Bellingeri M. , Turchetto M. , Bevacqua D. , Scotognella F. , Alfieri R. , Nguyen Q. , Cassi D.
Published: May 2021

In this perspective, we describe how the link removal (LR) analysis in social complex networks may be a promising tool to model non-pharmaceutical interventions (NPIs) and social distancing to prevent epidemics spreading. First, we show how the extent of the epidemic spreading and NPIs effectiveness over complex social networks may be evaluated with a static indicator, that is, the classic largest connected component (LCC). Then we explain how coupling the LR analysis and type SIR epidemiological models (EM) provide further information by including the temporal dynamics of the epidemic spreading. This is a promising approach to investigate important aspects of the recent NPIs applied by government to contain SARS-CoV-2, such as modeling the effect of the social distancing severity and timing over different network topologies. Further, implementing different link removal strategies to halt epidemics spreading provides information to individuate more effective NPIs, representing an important tool to offer a rationale sustaining policies to prevent SARS-CoV-2 and similar epidemics.
Protective Renal Effects of Atrial Natriuretic Peptide: Where Are We Now?
Authors: Choi Marcelo Roberto , Fernández Belisario Enrique
Published: May 2021

Atrial natriuretic peptide belongs to the family of natriuretic peptides, a system with natriuretic, diuretic, and vasodilator effects that opposes to renin-angiotensin system. In addition to its classic actions, atrial natriuretic peptide exerts a nephroprotective effect given its antioxidant and anti-inflammatory properties, turning it as a beneficial agent against acute and chronic kidney diseases. This minireview describes the most relevant aspects of atrial natriuretic peptide in the kidney, including its renal synthesis, physiological actions through specific receptors, the importance of its metabolism, and its potential use in different pathological scenarios.
A Machine Learning Approach to Prioritizing Functionally Active F-box Members in Arabidopsis thaliana
Authors: Li Yang , Yapa Madhura M. , Hua Zhihua
Published: May 2021

Protein degradation through the Ubiquitin (Ub)-26S Proteasome System (UPS) is a major gene expression regulatory pathway in plants. In this pathway, the 76-amino acid Ub proteins are covalently linked onto a large array of UPS substrates with the help of three enzymes (E1 activating, E2 conjugating, and E3 ligating enzymes) and direct them for turnover in the 26S proteasome complex. The S-phase Kinase-associated Protein 1 (Skp1), CUL1, F-box (FBX) protein (SCF) complexes have been identified as the largest E3 ligase group in plants due to the dramatic number expansion of the FBX genes in plant genomes. Since it is the FBX proteins that recognize and determine the specificity of SCF substrates, much effort has been done to characterize their genomic, physiological, and biochemical roles in the past two decades of functional genomic studies. However, the sheer size and high sequence diversity of the FBX gene family demands new approaches to uncover unknown functions. In this work, we first identified 82 known FBX members that have been functionally characterized up to date in Arabidopsis thaliana. Through comparing the genomic structure, evolutionary selection, expression patterns, domain compositions, and functional activities between known and unknown FBX gene members, we developed a neural network machine learning approach to predict whether an unknown FBX member is likely functionally active in Arabidopsis, thereby facilitating its future functional characterization.