bluuebunny/crossref_metadata_2025 huggingface dataset:
Extending the Applicability of In Ovo and Ex Ovo Chicken Chorioallantoic Membrane Assays to Study Cytostatic Activity in Neuroblastoma Cells
Authors: Merlos Rodrigo Miguel Angel , Casar Berta , Michalkova Hana , Jimenez Jimenez Ana Maria , Heger Zbynek , Adam Vojtech
Published: September 2021

Purpose

The chick chorioallantoic membrane (CAM) assay can provide an alternative versatile, cost-effective, and ethically less controversial in vivo model for reliable screening of drugs. In the presented work, we demonstrate that CAM assay (in ovo and ex ovo) can be simply employed to delineate the effects of cisplatin (CDDP) and ellipticine (Elli) on neuroblastoma (Nbl) cells in terms of their growth and metastatic potential.

Methods

The Nbl UKF-NB-4 cell line was established from recurrent bone marrow metastases of high-risk Nbl (stage IV, MYCN amplification, 7q21 gain). Ex ovo and in ovo CAM assays were optimized to evaluate the antimetastatic activity of CDDP and Elli. Immunohistochemistry, qRT-PCR, and DNA isolation were performed.

Results

Ex ovo CAM assay was employed to study whether CDDP and Elli exhibit any inhibitory effects on growth of Nbl xenograft in ex ovo CAM assay. Under the optimal conditions, Elli and CDDP exhibited significant inhibition of the size of the primary tumor. To study the efficiency of CDDP and Elli to inhibit primary Nbl tumor growth, intravasation, and extravasation in the organs, we adapted the in ovo CAM assay protocol. In in ovo CAM assay, both studied compounds (CDDP and Elli) exhibited significant (p < 0.001) inhibitory activity against extravasation to all investigated organs including distal CAM.

Conclusions

Taken together, CAM assay could be a helpful and highly efficient in vivo approach for high-throughput screening of libraries of compounds with expected anticancer activities.
CXCL9 Is a Potential Biomarker of Immune Infiltration Associated With Favorable Prognosis in ER-Negative Breast Cancer
Authors: Liang Yuan-ke , Deng Ze-kun- , Chen Mu-tong , Qiu Si-qi , Xiao Ying-sheng , Qi Yu-zhu , Xie Qin , Wang Zheng-hao , Jia Shi-cheng , Zeng De , Lin Hao-yu
Published: September 2021

The chemokine CXCL9 (C-X-C motif chemokine ligand 9) has been reported to be required for antitumour immune responses following immune checkpoint blockade. In this study, we sought to investigate the potential value of CXCL9 according to immune responses in patients with breast cancer (BC). A variety of open-source databases and online tools were used to explore the expression features and prognostic significance of CXCL9 in BC and its correlation with immune-related biomarkers followed by subsequent verification with immunohistochemistry experiments. The CXCL9 mRNA level was found to be significantly higher in BC than in normal tissue and was associated with better survival outcomes in patients with ER-negative tumours. Moreover, CXCL9 is significantly correlated with immune cell infiltration and immune-related biomarkers, including CTLA4, GZMB, LAG3, PDCD1 and HAVCR2. Finally, we performed immunohistochemistry with breast cancer tissue samples and observed that CXCL9 is highly expressed in the ER-negative subgroup and positively correlated with the immune-related factors LAG3, PD1, PDL1 and CTLA4 to varying degrees. These findings suggest that CXCL9 is an underlying biomarker for predicting the status of immune infiltration in ER-negative breast cancer.
Long Non-Coding RNAs as Potential Diagnostic and Prognostic Biomarkers in Breast Cancer: Progress and Prospects
Authors: Lu Cuicui , Wei Duncan , Zhang Yahui , Wang Peng , Zhang Wen
Published: September 2021

Breast cancer is the most common malignancy among women worldwide, excluding non-melanoma skin cancer. It is now well understood that breast cancer is a heterogeneous entity that exhibits distinctive histological and biological features, treatment responses and prognostic patterns. Therefore, the identification of novel ideal diagnostic and prognostic biomarkers is of utmost importance. Long non-coding RNAs (lncRNAs) are commonly defined as transcripts longer than 200 nucleotides that lack coding potential. Extensive research has shown that lncRNAs are involved in multiple human cancers, including breast cancer. LncRNAs with dysregulated expression can act as oncogenes or tumor-suppressor genes to regulate malignant transformation processes, such as proliferation, invasion, migration and drug resistance. Intriguingly, the expression profiles of lncRNAs tend to be highly cell-type-specific, tissue-specific, disease-specific or developmental stage-specific, which makes them suitable biomarkers for breast cancer diagnosis and prognosis.
Translational Potential of RNA Derived From Extracellular Vesicles in Multiple Myeloma
Authors: Reale Antonia , Khong Tiffany , Mithraprabhu Sridurga , Spencer Andrew
Published: September 2021

The cross-talk between tumour cells and stromal cells is a hallmark of multiple myeloma (MM), a blood cancer that still remains incurable despite increased knowledge of its biology and advances in its treatment. Extracellular vesicles (EVs) derived from both tumour and stromal cells have been shown to play an important role in mediating this cross-talk ultimately favouring MM progression and drug resistance. Furthermore, EVs and their content including RNA (EV-RNA) have been successfully isolated from blood and are being explored as liquid biomarkers in MM with the potential to improve diagnosis and monitoring modalities with a minimally-invasive and repeatable analysis, i.e. liquid biopsy. In this review, we describe both the role of EV-RNA in defining the biological features of MM and their potential translational relevance as liquid biomarkers, therapeutic targets and delivery systems. We also discuss the limitations and technical challenges related to the isolation and characterization of EVs and provide a perspective on the future of MM-derived EV-RNA in translational research.
Regulation of Extracellular Matrix Production in Activated Fibroblasts: Roles of Amino Acid Metabolism in Collagen Synthesis
Authors: Kay Emily J. , Koulouras Grigorios , Zanivan Sara
Published: September 2021

Cancer associated fibroblasts (CAFs) are a major component of the tumour microenvironment in most tumours, and are key mediators of the response to tissue damage caused by tumour growth and invasion, contributing to the observation that tumours behave as ‘wounds that do not heal’. CAFs have been shown to play a supporting role in all stages of tumour progression, and this is dependent on the highly secretory phenotype CAFs develop upon activation, of which extracellular matrix (ECM) production is a key element. A collagen rich, stromal ECM has been shown to influence tumour growth and metastasis, exclude immune cells and impede drug delivery, and is associated with poor prognosis in many cancers. CAFs also extensively remodel their metabolism to support cancer cells, however, it is becoming clear that metabolic rewiring also supports intrinsic functions of activated fibroblasts, such as increased ECM production. In this review, we summarise how fibroblasts metabolically regulate ECM production, focussing on collagen production, at the transcriptional, translational and post-translational level, and discuss how this can provide possible strategies for effectively targeting CAF activation and formation of a tumour-promoting stroma.
The Critical Role of Tetrahydrobiopterin (BH4) Metabolism in Modulating Radiosensitivity: BH4/NOS Axis as an Angel or a Devil
Authors: Feng Yang , Feng Yahui , Gu Liming , Liu Pengfei , Cao Jianping , Zhang Shuyu
Published: September 2021

Ionizing radiation and radioactive materials have been widely used in industry, medicine, science and military. The efficacy of radiotherapy and adverse effects of normal tissues are closed related to cellular radiosensitivity. Molecular mechanisms underlying radiosensitivity are of significance to tumor cell radiosensitization as well as normal tissue radioprotection. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS) and aromatic amino acid hydroxylases, and its biosynthesis involves de novo biosynthesis and a pterin salvage pathway. In this review we overview the role of BH4 metabolism in modulating radiosensitivity. BH4 homeostasis determines the role of NOS, affecting the production of nitric oxide (NO) and oxygen free radicals. Under conditions of oxidative stress, such as UV-radiation and ionizing radiation, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation of highly oxidative free radicals. On the other hand, BH4/NOS axis facilitates vascular normalization, a process by which antiangiogenic therapy corrects structural and functional flaws of tumor blood vessels, which enhances radiotherapy efficacy. Therefore, BH4/NOS axis may serve as an angel or a devil in regulating cellular radiosensitivity. Finally, we will address future perspectives, not only from the standpoint of perceived advances in treatment, but also from the potential mechanisms. These advances have demonstrated that it is possible to modulate cellular radiosensitivity through BH4 metabolism.
The Oncogenic Role of APC/C Activator Protein Cdc20 by an Integrated Pan-Cancer Analysis in Human Tumors
Authors: Wu Fei , Sun Yang , Chen Jie , Li Hongyun , Yao Kang , Liu Yongjun , Liu Qingyong , Lu Jiaju
Published: September 2021

The landscape of CDC20 gene expression and its biological impacts across different types of cancers remains largely unknown. Here, a pan-cancer analysis was performed to analyze the role of Cdc20 in various human cancers. Our results indicated that the expression levels of the CDC20 gene were significantly elevated in bladder cancer, breast cancer, colon cancer, rectum cancer, stomach cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, prostate cancer, pancreatic cancer, and uterine cancer. In addition, the expression of CDC20 was significantly and positively correlated with the increase of clinical stages in multiple cancer types, including breast cancer, kidney cancer, and lung cancer, et al. Among 33 cancer subtypes in the TCGA dataset, the high expression of CDC20 was correlated with poor prognosis in 10 cancer types. Furthermore, the abundance of phosphorylated Cdc20 in the primary tumor was elevated and correlated with increased tumor grade. Next, we sought to elucidate the oncogenic role by analyzing its association with immune infiltration. For most cancer types, the CDC20 expression was positively correlated with the infiltration of cancer-associated fibroblasts and myeloid-derived suppressor cells. To further understand its functional activity, we explored the classic Cdc20 downstream substrates, which were found to be mutually exclusive with the expression of Cdc20. Moreover, the pan-cancer analysis of the molecular function of Cdc20 indicated that BUB1, CCNA2, CCNB1, CDK1, MAD2L1, and PLK1 might play a critical role in interaction with Cdc20. The abundance of Cdc20 was further validated at transcriptional and translational levels with a publicly available dataset and clinical tumor tissues. The knockdown of Cdc20 dramatically inhibited tumor growth both in vivo and in vitro. Therefore, our studies delineated the oncogenic role of CDC20 and its prognostic significance at the pan-cancer level and proved its functional activity in Cdc20 high expression cancer types. Our studies will merits further molecular assays to understand the potential role of Cdc20 in tumorigenesis and provide the rationale for developing novel therapeutic strategies.
Glucose Intolerance and Cancer Risk: A Community-Based Prospective Cohort Study in Shanghai, China
Authors: Ke Juzhong , Lin Tao , Liu Xiaolin , Wu Kang , Ruan Xiaonan , Ding Yibo , Liu Wenbin , Qiu Hua , Tan Xiaojie , Wang Xiaonan , Chen Xi , Li Zhitao , Cao Guangwen
Published: September 2021

Background

Cancer becomes the leading cause of premature death in China. Primary objective of this study was to determine the major risk factors especially glucose intolerance for cancer prophylaxis.

Methods

A cluster sampling method was applied to enroll 10,657 community-based adults aged 15-92 years in Shanghai, China in 2013. A structured questionnaire and physical examination were applied in baseline survey. Prediabetes was diagnosed using 75-g oral glucose tolerance test. After excluding 1433 subjects including 224 diagnosed with cancer before and 1 year after baseline survey, the remaining 9,224 subjects were followed-up to December 31, 2020.

Results

A total of 502 new cancer cases were diagnosed. The cancer incidence was 10.29, 9.20, and 5.95/1,000 person-years in diabetes patients, those with prediabetes, and healthy participants, respectively (p<0.001). The multivariate Cox regression analysis indicated that age, prediabetes and diabetes, were associated with an increased risk of cancer in those <65 years, the hazard ratios (95% confidence interval) for prediabetes and diabetes were, 1.49(1.09-2.02) and 1.51(1.12-2.02), respectively. Glucose intolerance (prediabetes and diabetes) were associated with increased risks of stomach cancer, colorectal cancer, and kidney cancer in those <65 years. Anti-diabetic medications reduced the risk of cancer caused by diabetes. The multivariate Cox analysis showed that age, male, <9 years of education, and current smoking were associated with increased risks of cancer in those ≥65 years independently.

Conclusions

Glucose intolerance is the prominent cancer risk factor in adults <65 years. Lifestyle intervention and medications to treat glucose intolerance help prevent cancer in this population.
Development and Validation of an Esophageal Squamous Cell Carcinoma Risk Prediction Model for Rural Chinese: Multicenter Cohort Study
Authors: Han Junming , Wang Lijie , Zhang Huan , Ma Siqi , Li Yan , Wang Zhongli , Zhu Gaopei , Zhao Deli , Wang Jialin , Xue Fuzhong
Published: September 2021

Background

There are rare prediction models for esophageal squamous cell carcinoma (ESCC) for rural Chinese population. We aimed to develop and validate a prediction model for ESCC based on a cohort study for the population.

Methods

Data of 115,686 participants were collected from esophageal cancer (EC) early diagnosis and treatment of cancer program as derivation cohort while data of 54,750 participants were collected as validation cohort. Risk factors considered included age, sex, smoking status, alcohol drinking status, body mass index (BMI), tea drinking status, marital status, annual household income, source of drinking water, education level, and diet habit. Cox proportional hazards model was used to develop ESCC prediction model at 5 years. Calibration ability, discrimination ability, and decision curve analysis were analyzed in both derivation and validation cohort. A score model was developed based on prediction model.

Results

One hundred eighty-six cases were diagnosed during 556,949.40 person-years follow-up in the derivation cohort while 120 cases from 277,302.70 in the validation cohort. Prediction model included the following variables: age, sex, alcohol drinking status, BMI, tea drinking status, and fresh fruit. The model had good discrimination and calibration performance: R2, D statistic, and Harrell’s C statistic of prediction model were 43.56%, 1.70, and 0.798 in derivation cohort and 45.19%, 1.62, and 0.787 in validation cohort. The calibration analysis showed good coherence between predicted probabilities and observed probabilities while decision curve analysis showed clinical usefulness. The score model was as follows: age (3 for 45–49 years old; 4 for 50–54 years old; 7 for 55–59 years old; 9 for 60–64 years; 10 for 65–69 years), sex (5 for men), BMI (1 for ≤25), alcohol drinking status (2 for alcohol drinkers), tea drinking status (2 for tea drinkers), and fresh fruit (2 for never) and showed good discrimination ability with area under the curve and its 95% confidence interval of 0.792 (0.761,0.822) in the deviation cohort and 0.773 (0.736,0.811) in the validation cohort. The calibration analysis showed great coherence between predicted probabilities and observed probabilities.

Conclusions

We developed and validated an ESCC prediction model using cohort study with good discrimination and calibration capability which can be used for EC screening for rural Chinese population.
An Integrated Radiomics Model Incorporating Diffusion-Weighted Imaging and 18F-FDG PET Imaging Improves the Performance of Differentiating Glioblastoma From Solitary Brain Metastases
Authors: Zhang Liqiang , Yao Rui , Gao Jueni , Tan Duo , Yang Xinyi , Wen Ming , Wang Jie , Xie Xiangxian , Liao Ruikun , Tang Yao , Chen Shanxiong , Li Yongmei
Published: September 2021

Background

The effectiveness of conventional MRI (cMRI)-based radiomics in differentiating glioblastoma (GBM) from solitary brain metastases (SBM) is not satisfactory enough. Therefore, we aimed to develop an integrated radiomics model to improve the performance of differentiating GBM from SBM.

Methods

One hundred patients with solitary brain tumors (50 with GBM, 50 with SBM) were retrospectively enrolled and randomly assigned to the training set (n = 80) or validation set (n = 20). A total of 4,424 radiomic features were obtained from contrast-enhanced T1-weighted imaging (CE-T1WI) with the contrast-enhancing and peri-enhancing edema region, T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC), and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) images. The partial least squares (PLS) regression with fivefold cross-validation is used to analyze the correlation between different radiomic features and different modalities. The cross-validity analysis was performed to judge whether a new principal component or a new feature dimension can significantly improve the final prediction effect. The principal components with effective interpretation in all radiomic features were projected to a low-dimensional space (2D in this study). The effective features of the new projection mapping were then sent to the random forest classifier to predict the results. The performance of differentiating GBM from SBM was compared between the integrated radiomics model and other radiomics models or nonradiomics methods using the area under the receiver operating characteristics curve (AUC).

Results

Through the cross-validity analysis of partial least squares, hundreds of radiomic features were projected into a new two-dimensional space to complete the construction of radiomics model. Compared with the combined radiomics model using DWI + 18F-FDG PET (AUC = 0.93, p = 0.014), cMRI + DWI (AUC = 0.89, p = 0.011), cMRI + 8F-FDG PET (AUC = 0.91, p = 0.015), and single radiomics model using cMRI (AUC = 0.85, p = 0.018), DWI (AUC = 0.84, p = 0.017), and 18F-FDG PET (AUC = 0.85, p = 0.421), the integrated radiomics model (AUC = 0.98) showed more efficient diagnostic performance. The integrated radiomics model (AUC = 0.98) also showed significantly better performance than any single ADC, SUV, or TBR parameter (AUC = 0.57–0.71, p < 0.05). The integrated radiomics model showed better performance in the training (AUC = 0.98) and validation (AUC = 0.93) sets than any other models and methods, demonstrating robustness.

Conclusions

We developed an integrated radiomics model incorporating DWI and 18F-FDG PET, which improved the performance of differentiating GBM from SBM greatly.
Identification of Glycolysis-Related lncRNAs and the Novel lncRNA WAC-AS1 Promotes Glycolysis and Tumor Progression in Hepatocellular Carcinoma
Authors: Xia Xigang , Zhang Hao , Xia Peng , Zhu Yimin , Liu Jie , Xu Kequan , Yuan Yufeng
Published: September 2021

Background

High glycolysis efficiency in tumor cells can promote tumor growth. lncRNAs play an important role in the proliferation, metabolism and migration of cancer cells, but their regulation of tumor glycolysis is currently not well researched.

Methods

We analyzed the co-expression of glycolysis-related genes and lncRNAs in The Cancer Genome Atlas (TCGA) database to screen glycolysis-related lncRNAs. Further prognostic analysis and differential expression analysis were performed. We further analyzed the relationship between lncRNAs and tumor immune infiltration. Since WAC antisense RNA 1 (WAC-AS1) had the greatest effect on the prognosis among all screened lncRNAs and had a larger coefficient in the prognostic model, we chose WAC-AS1 for further verification experiments and investigated the function and mechanism of action of WAC-AS1 in hepatocellular carcinoma.

Results

We screened 502 lncRNAs that have co-expression relationships with glycolytic genes based on co-expression analysis. Among them, 112 lncRNAs were abnormally expressed in liver cancer, and 40 lncRNAs were related to the prognosis of patients. Eight lncRNAs (WAC-AS1, SNHG3, SNHG12, MSC-AS1, MIR210HG, PTOV1-AS1, AC145207.5 and AL031985.3) were used to established a prognostic model. Independent prognostic analysis (P<0.001), survival analysis (P<0.001), receiver operating characteristic (ROC) curve analysis (AUC=0.779) and clinical correlation analysis (P<0.001) all indicated that the prognostic model has good predictive power and that the risk score can be used as an independent prognostic factor (P<0.001). The risk score and lncRNAs in the model were found to be related to a variety of immune cell infiltration and immune functions. WAC-AS1 was found to affect glycolysis and promote tumor proliferation (P<0.01). WAC-AS1 affected the expression of several glycolysis-related genes (cAMP regulated phosphoprotein 19 (ARPP19), CHST12, MED24 and KIF2A) (P<0.01). Under hypoxic conditions, WAC-AS1 regulated ARPP19 by sponging miR-320d to promote glucose uptake and lactate production (P<0.01).

Conclusion

We constructed a model based on glycolysis-related lncRNAs to evaluate the prognostic risk of patients. The risk score and lncRNAs in the model were related to immune cell infiltration. WAC-AS1 can regulate ARPP19 to promote glycolysis and proliferation by sponging miR-320d.
Frequency Dependent Electrical Stimulation of PFC and ACC for Acute Pain Treatment in Rats
Authors: Liu Yaling , Xu Helen , Sun Guanghao , Vemulapalli Bharat , Jee Hyun Jung , Zhang Qiaosheng , Wang Jing
Published: September 2021

As pain consists of both sensory and affective components, its management by pharmaceutical agents remains difficult. Alternative forms of neuromodulation, such as electrical stimulation, have been studied in recent years as potential pain treatment options. Although electrical stimulation of the brain has shown promise, more research into stimulation frequency and targets is required to support its clinical applications. Here, we studied the effect that stimulation frequency has on pain modulation in the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC) in acute pain models in rats. We found that low-frequency stimulation in the prelimbic region of the PFC (PL-PFC) provides reduction of sensory and affective pain components. Meanwhile, high-frequency stimulation of the ACC, a region involved in processing pain affect, reduces pain aversive behaviors. Our results demonstrate that frequency-dependent neuromodulation of the PFC or ACC has the potential for pain modulation.
Associations Between Movement Behaviors and Emotional Changes in Toddlers and Preschoolers During Early Stages of the COVID-19 Pandemic in Chile
Authors: Aguilar-Farias Nicolas , Toledo-Vargas Marcelo , Miranda-Marquez Sebastian , Cortinez-O'Ryan Andrea , Martino-Fuentealba Pia , Cristi-Montero Carlos , Rodriguez-Rodriguez Fernando , Guarda-Saavedra Paula , Del Pozo Cruz Borja , Okely Anthony D.
Published: September 2021

Background: There is limited evidence about emotional and behavioral responses in toddlers and preschoolers during the novel coronavirus (COVID-19) pandemic, particularly in Latin America.

Objective: To assess associations between changes in movement behaviors (physical activity, screen time and sleeping) and emotional changes in toddlers and preschoolers during early stages of the pandemic in Chile.

Methods: A cross-sectional study conducted from March 30th to April 27th, 2020. Main caregivers of 1- to 5-year-old children living in Chile answered an online survey that included questions about sociodemographic characteristics, changes in the child's emotions and behaviors, movement behaviors and caregivers' stress during the pandemic. Multiple linear regressions were used to assess the association between different factors and emotional changes in toddlers and preschoolers.

Results: In total, 1727 caregivers provided complete data on emotional changes for children aged 2.9 ± 1.36 years old, 47.9% girls. A large proportion of toddlers and preschoolers in Chile experienced emotional and behavioral changes. Most caregivers reported that children “were more affectionate” (78.9%), “more restless” (65.1%), and ‘more frustrated' (54.1%) compared with pre-pandemic times. Apart from changes in movement behaviors, factors such as child age, caregivers' age and stress, and residential area (urban/rural) were consistently associated with changes in emotions and behaviors.

Conclusion: The pandemic substantially affected the emotions and behaviors of toddlers and preschoolers in Chile. The findings suggest that supportive actions for caregivers may have a positive impact not only on adults but also on children. Mental health promotion programs should consider multilevel approaches in which the promotion of movement behaviors and support for caregivers should be essential pieces for future responses.
Maintenance of Elective Patient Care at Berlin University Children's Hospital During the COVID-19 Pandemic
Authors: Terliesner Nicolas , Rosen Alexander , Kaindl Angela M. , Reuter Uwe , Lippold Kai , Mall Marcus A. , Bernuth Horst von , Gratopp Alexander
Published: September 2021

Background: In Germany, so far the COVID-19 pandemic evolved in two distinct waves, the first beginning in February and the second in July, 2020. The Berlin University Children's Hospital at Charité (BCH) had to ensure treatment for children not infected and infected with SARS-CoV-2. Prevention of nosocomial SARS-CoV-2 infection of patients and staff was a paramount goal. Pediatric hospitals worldwide discontinued elective treatments and established a centralized admission process.

Methods: The response of BCH to the pandemic adapted to emerging evidence. This resulted in centralized admission via one ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatment during the first wave, but maintenance of elective care and decentralized admissions during the second wave. We report numbers of patients treated and of nosocomial SARS-CoV-2 infections during the two waves of the pandemic.

Results: During the first wave, weekly numbers of inpatient and outpatient cases declined by 37% (p < 0.001) and 29% (p = 0.003), respectively. During the second wave, however, inpatient case numbers were 7% higher (p = 0.06) and outpatient case numbers only 6% lower (p = 0.25), compared to the previous year. Only a minority of inpatients were tested positive for SARS-CoV-2 by RT-PCR (0.47% during the first, 0.63% during the second wave). No nosocomial infection of pediatric patients by SARS-CoV-2 occurred.

Conclusion: In contrast to centralized admission via a ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatments, maintenance of elective care and decentralized admission allowed the almost normal use of hospital resources, yet without increased risk of nosocomial infections with SARS-CoV-2. By this approach unwanted sequelae of withheld specialized pediatric non-emergency treatment to child and adolescent health may be avoided.
Association of Maternal Gestational Weight Gain With Left Ventricle Geometry and Function in Offspring at 4 Years of Age: A Prospective Birth Cohort Study
Authors: Wang Jian , Du Bowen , Wu Yujian , Li Zhuoyan , Chen Qian , Zhang Xi , Zhang Lin , Ye Yujiao , Wu Yurong , Chen Sun , Sun Kun
Published: September 2021

Background: Maternal gestational weight gain (GWG) may be associated with cardiovascular diseases in the offspring from childhood to adulthood. We aimed to investigate the association between maternal GWG and the left ventricle (LV) geometry and function in the offspring, and explore the influence of the intrauterine environment on early childhood cardiac change.

Methods: Data of 981 mother-offspring pairs from the Shanghai Birth Cohort was used. Maternal pre-pregnancy weight and height, weight in the first trimester (≤ 12 weeks), and before delivery were measured. The echocardiography, blood pressure, and anthropometry assessment were evaluated in the offspring at 4 years of age.

Results: Interventricular septal thickness during diastole had a significantly positive correlation with total GWG [β = 0.009, (0.001, 0.017)]. In the second and third trimesters, LV mass index [β = 0.149, (0.015,0.282)], interventricular septal thickness in systole [β = 0.027, (0.011,0.043)], and in diastole [β = 0.014, (0.005,0.023)] were positively associated with GWG. The risks of eccentric [OR = 1.115, (1.232, 1.010)] and concentric hypertrophy [OR = 1.133, (1.259,1.018)] increased with the elevation of maternal GWG.

Conclusions: This study suggested that the excessive maternal GWG was associated with the thickening of the interventricular septum in the offspring, especially during the second and third trimesters. Excessive GWG in the second and third trimesters was a risk factor for LV eccentric and concentric hypertrophy in the offspring.
Clinical Outcomes of Single vs. Two-Strain Probiotic Prophylaxis for Prevention of Necrotizing Enterocolitis in Preterm Infants
Authors: Priyadarshi Archana , Lowe Gemma , Saddi Vishal , Trivedi Amit , Luig Melissa , Tracy Mark
Published: September 2021

Background: The administration of live microbiota (probiotic) via enteral route to preterm infants facilitates intestinal colonization with beneficial bacteria, resulting in competitive inhibition of the growth of pathogenic bacteria preventing gut microbiome dysbiosis. This dysbiosis is linked to the pathogenesis of necrotizing enterocolitis (NEC), an acquired multi-factorial intestinal disease characterized by microbial invasion of the gut mucosa, particularly affecting preterm infants. Probiotic prophylaxis reduces NEC; however, variations in strain-specific probiotic effects, differences in administration protocols, and synergistic interactions with the use of combination strains have all led to challenges in selecting the optimal probiotic for clinical use.

Aim: To compare any differences in NEC rates, feeding outcomes, co-morbidities in preterm infants receiving single or two-strain probiotics over a 4-year period. The two-strain probiotic prophylaxis was sequentially switched over after 2 years to the single strain probiotic within this 4-year study period, in similar cohort of preterm infants.

Methods: During two consecutive equal 2-year epochs, preterm infants (<32 weeks and or with birth weight <1,500 g) receiving two-strain (Lactobacillus acidophilus and Bifidobacterium bifidum) and single strain (Bifidobacterium breve M-16 V,) probiotic prophylaxis for prevention of NEC were included in this retrospective, observational study. The primary outcome included rates of NEC; secondary outcomes included prematurity related co-morbidities and feeding outcomes. Time to reach full enteral feeds was identified as the first day of introducing milk feeds at 150 ml/kg/day.

Results: There were 180 preterm infants in the two-strain, 196 in the single strain group from the two equal consecutive 2-year epochs. There were no differences in the NEC rates, feeding outcomes, all-cause morbidities except for differences in rates of retinopathy of prematurity.

Conclusion: In our intensive-care setting, clinical outcomes of single vs. two—strain probiotic prophylaxis for prevention of NEC were similar. Although our study demonstrates single strain probiotic may be equally effective than two-strain in the prevention of NEC, small sample size and low baseline incidence of NEC in our unit were not sufficiently powered to compare single vs. two-strain probiotic prophylaxis in preventing NEC. Further clustered randomized controlled trials are required to study the effects of single vs. multi-strain probiotic products for NEC prevention in preterm infants.
Sitagliptin Reduces Endothelial Dysfunction and Apoptosis Induced by High-Fat Diet and Palmitate in Thoracic Aortas and Endothelial Cells via ROS-ER Stress-CHOP Pathway
Authors: Cao Qiongqiong , Xu Dongmei , Chen Yong , Long Yueming , Dai Fang , Gui Li , Lu Yunxia
Published: September 2021

Macrovascular disease is tightly associated with obesity-induced metabolic syndrome. Sitagliptin (SIT), an orally stable selective inhibitor of Dipeptidyl peptidase-4 (DPP-4), has protective effects on endothelium. However, the mechanisms enabling SIT to exhibit resistance to diet-induced obesity (DIO) related with reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress in the aorta and endothelial cells have not been reported yet. Therefore, the present study was conducted to determine if SIT exerts protective role in the thoracic aortas isolated from the high-fat diet (HFD)-treated rats and palmitate (PA)-treated endothelial cells by alleviating ROS and ER stress. Male Sprague Dawley rats were randomly divided into standard chow diet (SCD), HFD and HFD plus sitagliptin administration (HFD + SIT) groups. The rats of latter two groups were given HFD fodder for 12 weeks, then the HFD + SIT rats were treated with SIT (10 mg/kg/d) by intragastric administration for another 8 weeks. The body mass, vascular tension, serum oxidative stress indices and inflammatory parameters, pathological changes, protein expression of endothelial nitric oxide synthase (eNOS), the genes associated with ER stress and apoptosis in the thoracic aorta were measured. Furthermore, cell proliferation, ROS and the protein expression associated with ER stress (especially CHOP) and apoptosis were assessed in human umbilical vein endothelial cells (HUVECs) incubated with SIT and PA. Compared to the SCD rats, the HFD rats had higher serum lipid levels, decreased vascular tension, increased inflammation, oxidative and ER stress, and apoptosis of endothelial cells. PA promoted ROS generation, ER stress and apoptosis, inhibited cell proliferation in HUVECs. SIT treatment obviously ameliorated apoptosis via alleviating ROS and ER stress in the thoracic aortas isolated from HFD-fed rats and PA-treated HUVECs. The results suggest that SIT improved endothelial function via promoting cell proliferation and alleviating ROS-ER stress-CHOP pathway both in vivo and in vitro.
Safety Assessment of Acer tegmentosum Maxim. Water Extract: General Toxicity Studies in Sprague–Dawley Rats and Beagle Dogs With Re-evaluation of Genotoxic Potentials
Authors: Park Jin-Sung , Kwon Euna , Kim Yun-Soon , Kim Sang-Moo , Kim Dae-Sun , Jang Ja-June , Yun Jun-Won , Kang Byeong-Cheol
Published: September 2021

Acer tegmentosum Maxim., commonly known as Manchurian stripe maple, is a deciduous tree belonging to the family of Aceraceae and has been traditionally used in folk medicine for its remedial effects in liver diseases and traumatic bleedings. With a growing body of experimental evidence for its pharmacological efficacies, such as neuroprotective, hepatoprotective, antioxidant, and anti-inflammatory activities, A. tegmentosum has gradually gained popularity as a health supplement and functional food. However, the large part of essential toxicity information still remained lacking despite the possibility of mutagenic potentials as previously suggested, posing safety concerns for human consumption. In this study, we evaluated 90-day repeated oral toxicity of A. tegmentosum Maxim. water extract (ATWE) in SD rats with acute toxicity assessment in beagle dogs, and reevaluated genotoxicity using a combination of in vitro and in vivo assays. During the oral study period, ATWE did not cause toxicity-related clinical signs and mortality in rodents without adverse effects observed in the analysis of hematology, serum biochemistry, and histopathology, establishing >5,000 mg/kg BW as the NOAEL. In addition, doses up to 5,000 mg/kg BW did not cause acute toxicity in beagle dogs. When assessed for genotoxicity using bacterial reverse mutation, chromosome aberration, and micronucleus formation, ATWE showed lack of mutagenicity and clastogenicity. These results demonstrated that AWTE was safe in the present preclinical study for systemic toxicity and genotoxicity at the tested doses, providing a guideline for safe use in humans.
Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability
Authors: Zhou Bo , Yuan Yaxia , Shi Le , Hu Sheng , Wang Dong , Yang Yang , Pan Yuanhu , Kong Dexin , Shikov Alexander N. , Duez Pierre , Jin Moonsoo , Li Xiaohua , Hu Xuebo
Published: September 2021

Obesity is characterized by an excessive body mass, but is also closely associated with metabolic syndrome. And, so far, only limited pharmacological treatments are available for obesity management. Celastrol, a pentacyclic triterpenoid from a traditional Chinese medicine (Tripterygium wilfordii Hook.f.), has shown remarkable potency against obesity, inflammation and cancer, but its high toxicity, low natural abundance and tedious chemical synthesis hindered its translation into clinics. In the present work, a triterpenoid library was screened for compounds with both high natural abundance and structural similarity to celastrol; from this library, glycyrrhetinic acid (GA), a compound present in extremely high yields in Glycyrrhiza uralensis Fisch. ex DC., was selected as a possible scaffold for a celastrol mimic active against obesity. A simple chemical modification of GA resulted in GA-02, a derivative that suppressed 68% of food intake in diet-induced obesity mice and led to 26.4% weight loss in 2 weeks. GA-02 plays a role in obesity treatment by re-activating leptin signaling and reducing systemic and, more importantly, hypothalamic inflammation. GA-02 was readily bioavailable with unnoticeable in vitro and in vivo toxicities. The strategy of scaffold search and modification on the basis of bio-content and structural similarity has proved to be a green, economic, efficient and practical way of widening the medicinal applications of “imperfect” bioactive natural compounds.
Selective Myeloid Depletion of Galectin-3 Offers Protection Against Acute and Chronic Lung Injury
Authors: Humphries Duncan C. , Mills Ross , Dobie Ross , Henderson Neil C. , Sethi Tariq , Mackinnon Alison C.
Published: September 2021

Rationale:Galectin-3 (Gal-3) is an immune regulator and an important driver of fibrosis in chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Previous work has shown that global deletion of galectin-3 reduces collagen deposition in a bleomycin-induced pulmonary fibrosis model (MacKinnon et al., Am. J. Respir. Crit. Care Med., 2012, 185, 537–46). An inhaled Gal-3 inhibitor, GB0139, is undergoing Phase II clinical development for idiopathic pulmonary fibrosis (IPF). This work aims to elucidate the role of Gal-3 in the myeloid and mesenchymal compartment on the development of acute and chronic lung injury.

Methods:LgalS3fl/flmice were generated and crossed with mice expressing the myeloid (LysM) and mesenchymal (Pdgfrb) cre drivers to yieldLysM-cre+/-/LgalS3fl/flandPdgfrb-cre+/-/LgalS3fl/flmice. The response to acute (bleomycin or LPS) or chronic (bleomycin) lung injury was compared to globally deficientGal-3−/−mice.

Results:Myeloid depletion of Gal-3 led to a significant reduction in Gal-3 expression in alveolar macrophages and neutrophils and a reduction in neutrophil recruitment into the interstitium but not into the alveolar space. The reduction in interstitial neutrophils corelated with decreased levels of pulmonary inflammation following acute bleomycin and LPS administration. In addition, myeloid deletion decreased Gal-3 levels in bronchoalveolar lavage (BAL) and reduced lung fibrosis induced by chronic bleomycin. In contrast, no differences in BAL Gal-3 levels or fibrosis were observed inPdgfrb-cre+/-/LgalS3fl/flmice.

Conclusions:Myeloid cell derived Galectin-3 drives acute and chronic lung inflammation and supports direct targeting of galectin-3 as an attractive new therapy for lung inflammation.
Enhanced Bioavailability of Dihydrotanshinone I–Bovine Serum Albumin Nanoparticles for Stroke Therapy
Authors: Ren Yanru , Feng Yicheng , Xu Kunyao , Yue Saisai , Yang Tiantian , Nie Kaili , Xu Man , Xu Haijun , Xiong Xin , Körte Fabian , Barbeck Mike , Zhang Peisen , Liu Luo
Published: September 2021

Dihydrotanshinone I (DHT) is a natural component in Salvia miltiorrhiza and has been widely researched for its multiple bioactivities. However, poor solubility and biocompatibility of DHT limit its desirable application for clinical purposes. Herein, DHT was encapsulated with bovine serum albumin (BSA) to enhance bioavailability. Compared to free DHT, DHT–BSA NPs (nanoparticles) showed an improved solubility in normal saline and increased protection against hydrogen peroxide–induced oxidative damage in PC12 cells. In addition, DHT–BSA NPs administered by intravenous injection displayed a significant efficacy in the middle cerebral artery occlusion/reperfusion models, without any impact on the cerebral blood flow. In summary, DHT–BSA NPs show an enhanced bioavailability compared with free DHT and a successful penetration into the central nervous system for stroke therapy, demonstrating their application potential in cardio–cerebrovascular diseases.
AICAR, an AMP-Activated Protein Kinase Activator, Ameliorates Acute Pancreatitis-Associated Liver Injury Partially Through Nrf2-Mediated Antioxidant Effects and Inhibition of NLRP3 Inflammasome Activation
Authors: Kong Lijun , Zhang Hewei , Lu Chaosheng , Shi Keqing , Huang Hongjian , Zheng Yushu , Wang Yongqiang , Wang Dan , Wang Hongwei , Huang Wei
Published: September 2021

Acute pancreatitis (AP) is a highly fatal acute inflammation and is often accompanied by multiple organ dysfunction syndrome (MODS). The liver, one of the most vulnerable extrapancreatic organs in AP, is the major organ involved in the evolution of the disease and correlates strongly with the occurrence of MODS. However, the etiology of pancreatitis-associated liver injury (PALI) has not been clarified and currently lacks an effective treatment. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is a cell permeable nucleoside with pleiotropic effects on anti-inflammatory and antioxidant stress that binds with adenosine monophosphate protein kinase (AMPK) and induces AMPK activation. However, the role of AICAR in PALI remains elusive. Here, we show that activation of AMPK by AICAR, a direct AMPK agonist, significantly ameliorates sodium taurocholate-induced PALI in rats, whereas treatment of PALI rats with the AMPK antagonist Compound C profoundly exacerbates the degree of liver injury, suggesting that hepatic AMPK activation exerts an essential protective role in PALI. Mechanistically, AICAR induces AMPK activation, which in turn activates nuclear factor erythroid 2-related factor 2(Nrf2) -regulated hepatic antioxidant capacity and inhibits NLRP3 inflammasome-mediated pyrolysis, protecting rats from sodium taurocholate-induced PALI. In addition, Nrf2 deficiency strikingly weakens the beneficial effects of AICAR on alleviation of liver injury, oxidative stress and NLRP3 inflammasome activation in L-arginine-induced PALI mice. Thus, AICAR protects against PALI in rodents by triggering AMPK, which is mediated at least in part by Nrf2-modulated antioxidant effects and NLRP3 inflammasome activation.
Current Molecular Therapeutic Agents and Drug Candidates for Mycobacterium abscessus
Authors: Quang Nguyen Thanh , Jang Jichan
Published: September 2021

Mycobacterium abscessus has been recognised as a dreadful respiratory pathogen among the non-tuberculous mycobacteria (NTM) because of misdiagnosis, prolonged therapy with poor treatment outcomes and a high cost. This pathogen also shows extremely high antimicrobial resistance against current antibiotics, including the anti-tuberculosis agents. Therefore, current chemotherapies require a long curative period and the clinical outcomes are not satisfactory. Thus, there is an urgent need for discovering and developing novel, more effective anti-M. abscessus drugs. In this review, we sum the effectiveness of the current anti-M. abscessus drugs and drug candidates. Furthermore, we describe the shortcomings and difficulties associated with M. abscessus drug discovery and development.
Is Targeting Nerve Growth Factor Antagonist a New Option for Pharmacologic Treatment of Low Back Pain? A Supplemental Network Meta-Analysis of the American College of Physicians Guidelines
Authors: Cao Ziqin , Li Qiangxiang , Guo Jia , Li Yajia , Wu Jianhuang
Published: September 2021

Objective: It has been found that targeting nerve growth factor antagonists (ANGF) have excellent effects in the treatment of chronic pain, and the current pharmacologic treatments have very limited effects on low back pain (LBP). Thus we conducted this network meta-analysis (NMA) to study the efficacy and safety of ANGF for the treatment of LBP, and to guide for clinical practice and further research.

Method: PubMed, Scopus, Embase, CNKI, and the Cochrane Library were searched from January 1980 to March 2021. A frequentist framework network meta-analysis with a random-effect model was performed. Ranking effects were calculated by surface under the cumulative ranking analysis (SUCRA) and clusterank analysis.

Results: This NMA identified 30 studies, involving 9,508 patients with LBP. ANGF reported both superior effect on pain relief {SUCRA 82.1%, SMD 0.89, 95% CI [(0.26,1.51)]} and function improvement {SUCRA 77.3%, SMD 0.93, 95% CI [(0.27,1.58)]} than placebo, and did not showed any higher risk of treatment-emergent adverse effects {RR 1.11, 95% CI [(0.97,1.27)]} or serious adverse effects {RR 1.03, 95% CI [(0.54,1.97)]}, but it was associate with a special risk of rapidly progressive osteoarthritis. ANGF displayed the greatest potential to be the most effective and safest treatment (cluster-rank value for function improvement and safety: 4266.96, for pain relief and safety: 4531.92).

Conclusion: ANGF could relieve pain and improve function effectively and are superior to other traditional drugs recommended by guidelines. Although no significant difference in tolerability and safety between ANGFs and placebo was found, the rapid progression of original osteoarthritis which may be related to the use of ANGFs still needs special attention and furtherly verification by clinical trials.

Systematic Review Registration: PROSPERO, identifier [CRD42021258033].
Tristetraprolin Gene Single-Nucleotide Polymorphisms and mRNA Level in Patients With Rheumatoid Arthritis
Authors: Yang Xiaoke , Chen Bo , Zhang Mingyue , Xu Shengqian , Shuai Zongwen
Published: September 2021

To observe and evaluate the correlation between single-nucleotide polymorphisms (SNPs) and messenger RNA (mRNA) level related to tristetraprolin (TTP) in Chinese rheumatoid arthritis (RA). TapMan SNP was used for genotyping analysis in 580 RA patients and 554 healthy people. Association between TTP gene polymorphisms (rs251864 and rs3746083) and RA was obtained. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) technology was applied for the detection of TTP mRNA level in peripheral blood mononuclear cells (PBMCs) in 36 RA patients and 37 healthy people. We observed that the allele T of TTP rs3746083 increased RA susceptibility (p = 0.019). A significant difference was found under the dominant model of rs3746083 (p = 0.037). Further analysis showed the allele distribution of rs3746083 was nominally correlated with RF phenotype of RA patients (p = 0.045). Nevertheless, the association between TTP rs251864 and the incidence of RA was no statistically significant (p > 0.05). The TTP expression level in PBMCs of RA patients was significantly reduced (p < 0.001). In conclusion, the results of this experiment support that TTP may be involved in the pathogenesis of RA.