bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss, Gain and Altered Function of GlyR α2 Subunit Mutations in Neurodevelopmental Disorders
Authors: Chen Xiumin , Wilson Katie A. , Schaefer Natascha , De Hayr Lachlan , Windsor Mark , Scalais Emmanuel , van Rijckevorsel Germaine , Stouffs Katrien , Villmann Carmen , O’Mara Megan L. , Lynch Joseph W. , Harvey Robert J.
Published: April 2022

Glycine receptors (GlyRs) containing the α2 subunit govern cell fate, neuronal migration and synaptogenesis in the developing cortex and spinal cord. Rare missense variants and microdeletions in the X-linked GlyR α2 subunit gene (GLRA2) have been associated with human autism spectrum disorder (ASD), where they typically cause a loss-of-function via protein truncation, reduced cell-surface trafficking and/or reduced glycine sensitivity (e.g., GLRA2Δex8-9 and extracellular domain variants p.N109S and p.R126Q). However, the GlyR α2 missense variant p.R323L in the intracellular M3-M4 domain results in a gain-of-function characterized by slower synaptic decay times, longer duration active periods and increases in channel conductance. This study reports the functional characterization of four missense variants in GLRA2 associated with ASD or developmental disorders (p.V-22L, p.N38K, p.K213E, p.T269M) using a combination of bioinformatics, molecular dynamics simulations, cellular models of GlyR trafficking and electrophysiology in artificial synapses. The GlyR α2V–22L variant resulted in altered predicted signal peptide cleavage and a reduction in cell-surface expression, suggestive of a partial loss-of-function. Similarly, GlyR α2N38K homomers showed reduced cell-surface expression, a reduced affinity for glycine and a reduced magnitude of IPSCs in artificial synapses. By contrast, GlyR α2K213E homomers showed a slight reduction in cell-surface expression, but IPSCs were larger, with faster rise/decay times, suggesting a gain-of-function. Lastly, GlyR α2T269M homomers exhibited a high glycine sensitivity accompanied by a substantial leak current, suggestive of an altered function that could dramatically enhance glycinergic signaling. These results may explain the heterogeneity of clinical phenotypes associated with GLRA2 mutations and reveal that missense variants can result in a loss, gain or alteration of GlyR α2 function. In turn, these GlyR α2 missense variants are likely to either negatively or positively deregulate cortical progenitor homeostasis and neuronal migration in the developing brain, leading to changes in cognition, learning, and memory.
Classification of African Native Plant Foods Based on Their Processing Levels
Authors: Jideani Afam I. O. , Onipe Oluwatoyin O. , Ramashia Shonisani E.
Published: April 2022

With increasing advocacy for plant food consumption, the sub-Saharan Africa landscape is home to diverse plant-based food commodities. The need to leverage the advantages of unprocessed/minimally processed foods (PFs) over ultra-processed foods (UPFs) is a system that requires exploitation. Most of the crops produced in the continent are either classified as traditionally or moderately PFs. However, the rise in industrialization and formalization of markets is impacting and marginalizing traditional food processing (FP). Current FP classification frameworks are briefly discussed. The level of processing of cereals, grains, fruits, vegetables, roots, and tuber crops in the continent requires intervention from nutritionists, food scientists, and scientific and governmental bodies to gain a holistic view and tackle the issue of food insecurity in Africa. This study reviews the levels of processing of African foods, challenges, and future directions.
Degalactosylated Whey Protein Suppresses Inflammatory Responses Induced by Lipopolysaccharide in Mice
Authors: Inui Toshio , Kawamura Namiko , Nakama Riho , Inui Akio , Katsuura Goro
Published: April 2022

The effects of degalactosylated whey protein on lipopolysaccharide (LPS)-induced inflammatory responses in mice were observed in comparison with intact whey protein. Intraperitoneal administration of both intact and degalactosylated whey proteins for 5 days did not affect body weight and food intake in mice. On day 6, intraperitoneal administration of LPS induced a marked decrease in body weight 4 h later. The LPS-induced decrease in body weight was significantly suppressed by the administration of degalactosylated whey protein, but not intact whey protein. Administration of LPS also significantly increase plasma tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels, which were significantly suppressed by the administration of degalactosylated whey protein, but not intact whey protein. Moreover, the application of degalactosylated whey protein to RAW264.7 cells significantly reduced mRNA expression of toll-like receptor 4 (TLR4) and significantly increased mRNA expression of mitogen-activated protein kinase phosphatase-1 (MKP-1). The marked increased expression of TNF-α and IL-1β in response to LPS in RAW264.7 cells was significantly suppressed by the application of degalactosylated whey protein. These results suggest that degalactosylated whey protein suppresses the effects of LPS in part by decreasing in TLR4 and increasing in MKP-1.
The Obesogenic Environment: Epigenetic Modifications in Placental Melanocortin 4 Receptor Gene Connected to Gestational Diabetes and Smoking
Authors: Franzago Marica , Porreca Annamaria , D’Ardes Mario , Di Nicola Marta , Di Tizio Luciano , Liberati Marco , Stuppia Liborio , Vitacolonna Ester
Published: April 2022

Background

Maternal metabolic insults as well as Gestational Diabetes Mellitus (GDM) influence the fetal health and may affect ‘offspring’s susceptibility to chronic diseasesviaepigenetic modifications. GDM, the most common metabolic disorder in pregnancy, can be considered the result of complex interactions between genetic and environmental factors. A critical point in this view is the identification of genes which are epigenetically modified under the influence of GDM. The melanocortin 4 receptor (MC4R)gene plays a crucial role in nutritional health by suppressing appetite and participating in energy control regulation. The correlations between pregnant ‘women’s metabolic profiles and placental epigenetic modifications of this gene have been poorly investigated.

Objective

The aim of this study was to evaluate the effect of GDM and maternal clinical parameters at the third trimester of pregnancy to DNA methylation levels in the placenta at CpG sites ofMC4Rgene.

Design and Methods

Socio-demographic and clinical characteristics, Mediterranean diet adherence, smoking habits, and physical activity were assessed at the third trimester of pregnancy of 60 Caucasian pregnant women, of which 33 with GDM. Clinical parameters of the newborns were recorded at birth.MC4RDNA methylation on maternal and fetal sides of the placenta was analyzed using bisulfite pyrosequencing.

Results

MC4RDNA methylation levels at CpG1 and CpG2 were lower on the fetal side of the placenta in GDM-affected women than in non-GDM-affected recruits (p= 0.033). Moreover, DNA methylation levels on the maternal side at CpG1 were positively related to glucose concentration at 2-h oral glucose tolerance test (OGTT). On the other hand, CpG2 DNA methylation was positively related to both 1-h and 2-h during OGTT. Maternal DNA methylation level at CpG2 was also associated with low density lipoprotein cholesterol (LDL-C) at the third trimester of pregnancy (rho = 0.340,p< 0.05), while CpG1 methylation was negatively related to maternal weight variations at delivery (rho = −0.316,p< 0.05). Significant associations betweenMC4RDNA methylation on the maternal side and lipid profile at third trimester of pregnancy in women smokers were found.

Conclusion

Our results suggest thatMC4Rmethylation profile in the placenta is related to maternal metabolic and nutritional conditions, potentially affecting fetal programming and the future metabolic health of the newborn.
Effect of Meal Texture on Postprandial Glucose Excursions and Gut Hormones After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy
Authors: Hedbäck Nora , Hindsø Morten , Bojsen-Møller Kirstine N. , Linddal Adelaide K. , Jørgensen Nils B. , Dirksen Carsten , Møller Andreas , Kristiansen Viggo B. , Hartmann Bolette , Holst Jens J. , Svane Maria S. , Madsbad Sten
Published: April 2022

Background and aims

The metabolic consequences after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are often studied using a liquid mixed meal. However, liquid meals may not be representative of the patients’ everyday diet. We therefore examined postprandial glucose and gut hormone responses using mixed meals differing only with respect to meal texture.

Methods

Twelve RYGB-operated, 12 SG-operated, and 12 unoperated individuals (controls) were enrolled in the study. Participants were matched on age, sex, and body mass index. In randomized order, each participant underwent a liquid and a solid 4-h mixed meal test on separate days. The meals were isocaloric (309 kcal), and with identical macronutrient composition (47 E% carbohydrate, 18 E% protein, 32 E% fat, and 3 E% dietary fibers). The liquid meal was blended to create a smooth liquid texture while the other meal retained its solid components.

Results

Postprandial glucose concentrations (peak and incremental area under curve, iAUC) did not differ between the two meal textures in any group. In the control group, peak C-peptide was higher after the liquid meal compared with the solid meal (p = 0.04), whereas iAUCs of C-peptide were similar between the two meals in all groups. Peak of glucagon-like peptide-1 (GLP-1) was higher after the liquid meal compared with the solid meal in RYGB- and SG-operated individuals (RYGB p = 0.02; SG p < 0.01), but iAUC of GLP-1 did not differ between meal textures within any group. Peak of glucose-dependent insulin tropic polypeptide (GIP) was higher after the liquid meal in the SG and control groups (SG p = 0.02; controls p < 0.01), but iAUCs of GIP were equal between meals. There were no differences in total AUC of ghrelin between the liquid and solid meals within any of the groups.

Conclusion

A liquid and a solid meal with identical macronutrient composition result in similar postprandial glucose responses, both in operated and unoperated individuals. Small differences were observed for the postprandial peaks of C-peptide, GLP-1, and GIP concentrations. Overall, a liquid meal is suitable for evaluating glucose tolerance, β-cell function, and gut hormones responses, both after RYGB and SG and in unoperated individuals.

Clinical Trial Registration

[www.clinicaltrials.gov], identifier [NCT04082923].
Assessment of the Novel, Practical, and Prognosis-Relevant TNM Staging System for Stage I-III Cutaneous Melanoma
Authors: Hu Di , Liu Zeming , Chen Sichao , Huang Yihui , Zeng Wen , Wei Wei , Zhang Chao , Zhou Ling , Chen Danyang , Wu Yiping , Guo Liang
Published: April 2022

Background

The clinical TNM staging system does not differ between the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging manual. A more practical TNM staging system for patients with stage I-III cutaneous melanoma are needed.

Methods

Data were accessed from the Surveillance, Epidemiology, and End Results (SEER) open database. We divided the patients into 32 groups based on the T and N categories. The Kaplan-Meier survival curves and treatment guidelines were used to proposed a new TNM staging system. Cox proportional hazards model and 1000-person-years were used to verify accuracy.

Results

This retrospective study included 68 861 patients from 2010 to 2015. The new proposed staging system was as follows: stage IA, T1aN0M0; stage IB, T1b/T2aN0M0; stage IIA, T3-4aN0M0 and T2bN0M0; stage IIB, T1-4aN1-2M0 and T3-4bN0M0; and stage III, T1-4aN3M0 and T1-4bN1-3M0. Hazard ratios for the new stages IB, IIA, IIB, and III, with stage IA as reference, were 4.311 (95% confidence interval [CI]: 3.217-5.778), 8.993 (95% CI: 6.637-12.186), 13.179 (95% CI: 9.435-18.407), and 20.693 (95% CI: 13.655-31.356), respectively (all p-values < 0.001). Cancer-specific mortality rates per 1000-person-years were 0.812 (95% CI: 0.674-0.978), 6.612 (95% CI: 5.936-7.364), 22.228 (95% CI: 20.128-24.547), 50.863 (95% CI: 47.472-54.496) and 120.318 (95% CI: 112.596-128.570) for stages IA, IB, IIA, IIB and III, respectively.

Conclusion

We developed a more practical and prognosis-relevant staging system than that of the 8th edition AJCC manual for patients with stage I-III cutaneous melanoma. Treatments using this new model would improve the quality of life and survival rates of patients with melanoma.
Potential Predictive and Prognostic Value of Biomarkers Related to Immune Checkpoint Inhibitor Therapy of Triple-Negative Breast Cancer
Authors: Tan Qiaorui , Yin Sha , Zhou Dongdong , Chi Yajing , Man Xiaochu , Li Huihui
Published: April 2022

As an aggressive subtype of breast cancer, triple-negative breast cancer (TNBC) is associated with poor prognosis and lack of effective therapy, except chemotherapy. In recent years, immunotherapy based on immune checkpoint (IC) inhibition has emerged as a promising therapeutic strategy in TNBC. TNBC has more tumor-infiltrating lymphocytes (TILs) and higher rate of mutation and programmed cell death ligand-1 (PD-L1) expression than other subtypes of breast cancer have. However, previous studies have shown that monotherapy has little efficacy and only some TNBC patients can benefit from immunotherapy. Therefore, it is important to identify biomarkers that can predict the efficacy of IC inhibitors (ICIs) in TNBC. Recently, various biomarkers have been extensively explored, such as PD-L1, TILs and tumor mutational burden (TMB). Clinical trials have shown that PD-L1-positive patients with advanced TNBC benefit from ICIs plus chemotherapy. However, in patients with early TNBC receiving neoadjuvant therapy, PD-L1 cannot predict the efficacy of ICIs. These inconsistent conclusions suggest that PD-L1 is the best to date but an imperfect predictive biomarker for efficacy of ICIs. Other studies have shown that advanced TNBC patients with TMB ≥10 mutations/Mb can achieve clinical benefits from pembrolizumab. TILs also have potential predictive value in TNBC. Here, we select some biomarkers related to ICIs and discuss their potential predictive and prognostic value in TNBC. We hope these biomarkers could help to identify suitable patients and realize precision immunotherapy.
Is Lymph Node Dissection Necessary During Radical Nephroureterectomy for Clinically Node-Negative Upper Tract Urothelial Carcinoma? A Multi-Institutional Study
Authors: Lee Hsiang-Ying , Chang Chao-Hsiang , Huang Chi-Ping , Yu Chih-Chin , Lo Chi-Wen , Chung Shiu-Dong , Wu Wei-Che , Chen I-Hsuan Alan , Lin Jen-Tai , Jiang Yuan-Hong , Lee Yu-Khun , Hsueh Thomas Y. , Chiu Allen W. , Chen Yung-Tai , Lin Chang-Min , Tsai Yao-Chou , Chen Wei-Chieh , Chiang Bing-Juin , Huang Hsu-Che , Chen Chung-Hsin , Huang Chao-Yuan , Wu Chia-Chang , Lin Wei Yu , Tseng Jen-Shu , Ke Hung-Lung , Yeh Hsin-Chih
Published: April 2022

Purpose

This study aimed to compare the oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) without clinical lymph node metastasis (cN0) undergoing lymph node dissection (LND) during radical nephroureterectomy (NU).

Methods

From the updated data of the Taiwan UTUC Collaboration Group, a total of 2726 UTUC patients were identified. We only include patients with ≥ pT2 stage and enrolled 658 patients. The Kaplan–Meier estimator and Cox proportional hazards model were used to analyze overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS) in LND (+) and LND (−) groups.

Results

A total of 658 patients were included and 463 patients without receiving LND and 195 patients receiving LND. From both univariate and multivariate survival analysis, there are no significant difference between LND (+) and LND (-) group in survival rate. In LND (+) group, 18.5% patients have pathological LN metastasis. After analyzing pN+ subgroup, it revealed worse CSS (p = 0.010) and DFS (p < 0.001) compared with pN0 patients.

Conclusions

We found no significant survival benefit related to LND in cN0 stage, ≥ pT2 stage UTUC, irrespective of the number of LNs removed, although pN+ affected cancer prognosis. However, from the result of pN (+) subgroup of LND (+) cohort analysis, it may be reasonable to not perform LND in patients with cT2N0 stage due to low positive predictive value of pN (+). In addition, performing LND may be considered for ureter cancer, which tends to cause lymphatic and hematogenous tumor spreading. Further large prospective studies are needed to validate our findings.
Circulating Glycan Monosaccharide Composite-Based Biomarker Diagnoses Colorectal Cancer at Early Stages and Predicts Prognosis
Authors: Li Haoran , Wang Xueling , Huang Xiaodan , He Yanli , Zhang Yiran , Hao Cui , Zeng Pengjiao , Zhang Meng , Gao Yanyun , Yang Dandan , Shan Ming , Dou Huaiqian , Li Xiaoyu , Chang Xiaotian , Tian Zibin , Zhang Lijuan
Published: April 2022

Introduction

Early diagnosis could lead to a cure of colorectal cancer (CRC). Since CRC is related to aging and lifestyles, we tested if the environmental information-enriched monosaccharide composite (MC) of circulating glycans could serve as an early diagnostic biomarker for CRC. Meanwhile, we evaluated its role in predicting prognosis.

Methods

HPAEC-PAD was used to quantify glycan monosaccharide compositions from a total of 467 serum samples including CRC patients, colorectal adenoma (CRA) patients and healthy individuals. Two diagnostic model was constructed by logistic regression analysis. The diagnostic performance of the two models was verified in the retrospective validation group and the prospective validation group. The prognostic performance of the model was assessed by survival analysis.

Results

The concentrations of monosaccharides in serum were significantly higher in CRA and CRC patients than in healthy individuals. Two diagnostic models were constructed: MC1 was used to distinguish between healthy individuals and CRC; MC2 was used to distinguish between healthy individuals and CRA. Area under receptor operating characteristic curve (AUC) of MC2 and MC1 was 0.8025 and 0.9403 respectively. However, the AUC of CEA between healthy individuals and CRC was 0.7384. Moreover, in early stage of CRC (without lymph node metastasis), the positive rates of CEA and MC1 were 28% and 80%, respectively. The follow-up data showed that the increased MC1 value was associated with poor survival in patients with CRC (p=0.0010, HR=5.30).

Discussion

The MC1 model is superior to CEA in the diagnosis of CRC, especially in the early diagnosis. MC1 can be used for predicting prognosis of CRC patients, and elevated MC1 values indicate poor survival.
COMMD2 Upregulation Mediated by an ncRNA Axis Correlates With an Unfavorable Prognosis and Tumor Immune Infiltration in Liver Hepatocellular Carcinoma
Authors: Fang Weidan , Gan Yu , Zhang Ling , Xiong Jianping
Published: April 2022

Liver hepatocellular carcinoma (LIHC) seriously endangers the health and quality of life of individuals worldwide. Increasing evidence has underscored that the copper metabolism MURR1 domain (COMMD) family plays important roles in tumorigenesis. However, the specific role, biological function, mechanism and prognostic value of COMMD2 and its correlation with immune cell infiltration in LIHC remain unknown. In this study, we first determined the expression and prognostic potential of COMMD2 in human tumors using The Cancer Genome Atlas (TCGA) data and identified COMMD2 as a potential oncogene in LIHC. High COMMD2 expression was associated with pathological tumor stage and metastasis. Subsequently, noncoding RNAs (ncRNAs) upregulating COMMD2 expression were identified by performing expression, correlation, and survival analyses in combination. The CRNDE/LINC00511/SNHG17/HCG18-miR-29c-3p axis was identified as the most likely ncRNA-associated pathway upstream of COMMD2 in LIHC. Next, the expression profiles of COMMD2 and ncRNAs were validated in LIHC tissues and adjacent normal tissues. Furthermore, COMMD2 was significantly positively correlated with tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint molecule expression. Importantly, COMMD2 potentially influenced prognosis by regulating immune cell infiltration in LIHC. Finally, COMMD2 was knocked down in LIHC cell lines using siRNAs for functional assays in vitro, resulting in suppressed cell proliferation and migration. In summary, our findings showed that the ncRNA-mediated upregulation of COMMD2 was associated with an unfavorable prognosis correlated with immune cell infiltration in LIHC.
Multi-Omic Profiling of Multi-Biosamples Reveals the Role of Amino Acid and Nucleotide Metabolism in Endometrial Cancer
Authors: Yi Runqiu , Xie Liying , Wang Xiaoqing , Shen Chengpin , Chen Xiaojun , Qiao Liang
Published: April 2022

Background

Endometrial cancer (EC) is one of the most common gynecological cancers. The traditional diagnosis of EC relies on histopathology, which, however, is invasive and may arouse tumor spread. There have been many studies aiming to find the metabolomic biomarkers of EC to improve the early diagnosis of cancer in a non-invasive or minimally invasive way, which can also provide valuable information for understanding the disease. However, most of these studies only analyze a single type of sample by metabolomics, and cannot provide a comprehensive view of the altered metabolism in EC patients. Our study tries to gain a pathway-based view of multiple types of samples for understanding metabolomic disorders in EC by combining metabolomics and proteomics.

Methods

Forty-four EC patients and forty-three controls were recruited for the research. We collected endometrial tissue, urine, and intrauterine brushing samples. Untargeted metabolomics and untargeted proteomics were both performed on the endometrial tissue samples, while only untargeted metabolomics was performed on the urine and intrauterine brushing samples.

Results

By integrating the differential metabolites and proteins between EC patients and controls detected in the endometrial tissue samples, we identified several EC-related significant pathways, such as amino acid metabolism and nucleotide metabolism. The significance of these pathways and the potential of metabolite biomarker-based diagnosis were then further verified by using urine and intrauterine brushing samples. It was found that the regulation of metabolites involved in the significant pathways showed similar trends in the intrauterine brushings and the endometrial tissue samples, while opposite trends in the urine and the endometrial tissue samples.

Conclusions

With multi-omics characterization of multi-biosamples, the metabolomic changes related to EC are illustrated in a pathway-based way. The network of altered metabolites and related proteins provides a comprehensive view of altered metabolism in the endometrial tissue samples. The verification of these critical pathways by using urine and intrauterine brushing samples provides evidence for the possible non-invasive or minimally invasive biopsy for EC diagnosis in the future.
Safety and Efficacy of Stereotactic Ablative Radiotherapy for Ultra-Central Lung Cancer
Authors: Wang Bin , Dong Yang , Yu Xuyao , Li Fengtong , Wang Jingsheng , Chen Huaming , Niu Zeqian , Song Yongchun , Yuan Zhiyong , Tao Zhen
Published: April 2022

Background

Ultra-central lung cancer (UCLC) is difficult to achieve surgical treatment. Over the past few years, stereotactic ablative radiotherapy (SABR) or stereotactic body radiotherapy (SBRT) obviously improved the clinical efficacy and survival of UCLC patients. However, the adapted scheme of radiation therapy is still controversial. For this, a single arm retrospective analysis was performed on UCLC patients treated with SBRT.

Material and Methods

We retrospectively studied primary UCLC patients who were treated with SBRT of 56 Gy/6-8f between 2010 and 2018. UCLC was defined as planning target volume (PTV) touching or overlapping the proximal bronchial tree, trachea, esophagus, heart, pulmonary vein, or pulmonary artery within 2 cm around the bronchial tree in all directions.

Results

A total of 58 patients whose median age was 68 years (range, 46-85) were included in our study, 79.3% of whom did not undergo any previous therapy. The median dose of the PTV was 77.8 Gy (range, 43.3-91.8), and the median PTV of tumors was 6.2 cm3 (range, 12.9-265.0). With a median follow-up of 57 months (range, 6-90 months), the median cumulative overall survival (OS) rate was 58 months (range, 2-105). In addition, the 1-year, 2-year and 5-year OS rates were 94.7%, 75.0% and 45.0%, respectively. In our univariable analysis (p=0.020) and multivariate analysis (p=0.004), the OS rate was associated with the PTV. The 5-year OS rates for PTV <53.0 cm3 and PTV ≥53.0 cm3 were 61.6% and 37.4%, respectively. Regarding toxicity after SBRT, there were two cases (3.5%) with grade ≥3 adverse events, of which 1 case died of sudden severe unexplained hemoptysis.

Conclusions

Patients with UCLC can benefit from SBRT at a dose of 56 Gy/6-8f. On the other hand, smaller PTV was associated with superior outcomes, and the cure difference needs to be validated by prospective comparative trials.
Successful Treatment of a Patient With Brain Metastasis From Ovarian Cancer With BRCA Wild Type Using Niraparib: A Case Report and Review of the Literature
Authors: Zhang Zhenhua , Xu Muying , Sakandar Abbas , Du Xiuju , He Huailin , He Wenfeng , Li Dan , Wen Qinglian
Published: April 2022

Background

Brain metastases from ovarian cancer are extremely rare and have a very poor prognosis. A multimodal approach (surgery combined with radiotherapy and chemotherapy) yields the best results in reducing neurological symptoms and prolonging survival. Unfortunately, not every patient receives a complete multimodal treatment due to their individual factors. Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as a maintenance treatment option for recurrent ovarian cancer. Using PARPi may prolong the overall survival in patients with brain metastases and recurrent ovarian cancer.

Case Presentation

We report a case of a female patient with advanced ovarian cancer without any germline or somatic BRCA mutation. After 21 months, after reduction surgery and adjuvant chemotherapy, she was diagnosed with brain metastasis. Due to her physical fitness and economic situation, she did not receive any radiotherapy or chemotherapy but only received surgical debulking of the brain metastasis and niraparib maintenance treatment. Up to now, she has achieved a good treatment response, and the PFS is 29 months.

Conclusion

Based on the response of our patient, PARP inhibitors as a single agent can probably be considered in patients with brain metastasis from ovarian cancer without BRCA mutation who cannot tolerate radiotherapy and chemotherapy.
lncRNA PRADX is a Mesenchymal Glioblastoma Biomarker for Cellular Metabolism Targeted Therapy
Authors: Xu Can , Zhao Jixing , Song Jia , Xiao Menglin , Cui Xiaoteng , Xin Lei , Xu Jianglong , Zhang Yuhao , Yi Kaikai , Hong Biao , Tong Fei , Tian Shaohui , Tan Yanli , Kang Chunsheng , Fang Chuan
Published: April 2022

Glioblastoma (GBM) is the most common and lethal type of primary malignant central nervous system (CNS) tumor with an extremely poor prognosis, and the mesenchymal subtype of GBM has the worst prognosis. Here, we found that lncRNA PRADX was overexpressed in the mesenchymal GBM and was transcriptionally regulated by RUNX1-CBFβ complex, overexpressed PRADX suppressed BLCAP expression via interacting with EZH2 and catalyzing trimethylation of lysine 27 on histone H3 (H3K27me3). Moreover, we showed that BLCAP interacted with STAT3 and reduced STAT3 phosphorylation, overexpressed PRADX activated STAT3 phosphorylation, and promoted ACSL1 expression via suppressing BLCAP expression, accelerating tumor metabolism. Finally, we determined that combined of ACSL1 and CPT1 inhibitors could reverse the accelerated cellular metabolism and tumor growth induced by PRADX overexpression in vivo and in vitro. Collectively, PRADX/PRC2 complex activated the STAT3 pathway and energy metabolism in relation to mesenchymal GBM progression. Furthermore, our findings provided a novel therapeutic strategy targeting the energy metabolism activity of GBM.
Development of a Nomogram Based on 3D CT Radiomics Signature to Predict the Mutation Status of EGFR Molecular Subtypes in Lung Adenocarcinoma: A Multicenter Study
Authors: Zhang Guojin , Deng Liangna , Zhang Jing , Cao Yuntai , Li Shenglin , Ren Jialiang , Qian Rong , Peng Shengkun , Zhang Xiaodi , Zhou Junlin , Zhang Zhuoli , Kong Weifang , Pu Hong
Published: April 2022

Background

This study aimed to noninvasively predict the mutation status of epidermal growth factor receptor (EGFR) molecular subtype in lung adenocarcinoma based on CT radiomics features.

Methods

In total, 728 patients with lung adenocarcinoma were included, and divided into three groups according to EGFR mutation subtypes. 1727 radiomics features were extracted from the three-dimensional images of each patient. Wilcoxon test, least absolute shrinkage and selection operator regression, and multiple logistic regression were used for feature selection. ROC curve was used to evaluate the predictive performance of the model. Nomogram was constructed by combining radiomics features and clinical risk factors. Calibration curve was used to evaluate the goodness of fit of the model. Decision curve analysis was used to evaluate the clinical applicability of the model.

Results

There were three, two, and one clinical factor and fourteen, thirteen, and four radiomics features, respectively, which were significantly related to each EGFR molecular subtype. Compared with the clinical and radiomics models, the combined model had the highest predictive performance in predicting EGFR molecular subtypes [Del-19 mutation vs. wild-type, AUC=0.838 (95% CI, 0.799-0.877); L858R mutation vs. wild-type, AUC=0.855 (95% CI, 0.817-0.894); and Del-19 mutation vs. L858R mutation, AUC=0.906 (95% CI, 0.869-0.943), respectively], and it has a stable performance in the validation set [AUC was 0.813 (95% CI, 0.740-0.886), 0.852 (95% CI, 0.790-0.913), and 0.875 (95% CI, 0.781-0.929), respectively].

Conclusion

Our combined model showed good performance in predicting EGFR molecular subtypes in patients with lung adenocarcinoma. This model can be applied to patients with lung adenocarcinoma.
Magnitude and Determinants of Postnatal Mothers' Knowledge of Essential Newborn Care at Home in Rural Ethiopia
Authors: Getachew Tamirat , Dheresa Merga , Eyeberu Addis , Balis Bikila , Yadeta Tesfaye Assebe
Published: April 2022

Introduction

Globally, nearly three million children die in the neonatal period. Although there is scant information about rural mothers, the enhancement of mothers' knowledge and skills toward essential newborn care (ENC) is a vital aspect in the reduction of newborn illness and mortality. Thus, this study aimed to assess the magnitude and determinants of mothers' knowledge of ENC.

Methods

A community-based cross-sectional study was conducted among recently delivered women using a multistage sampling method in Chole woreda. Data were collected via face-to-face interviews. A multivariate logistic regression model was used to identify the determinant factors with the level of knowledge. Odds ratios with a 95% confidence interval was used to describe association and significance was determined at a P-value < 0.05.

Results

Data from 510 mothers were employed for analysis. Overall, 33.5% (95% CI: 29.4, 37.6) of the mothers had good knowledge of ENC. Antenatal care (ANC) visits [AOR: 2.42; 95% CI: (1.50, 3.88)], counseled about ENC during ANC [AOR: 5.71; 95% CI: (2.44, 13.39)], delivery at health institutions [AOR: 2.41; 95% CI: (1.30, 4.46)], religion [AOR 1.99, 95% CI: (1.25, 3.16)], and educational level [AOR = 1.64 95% CI: (1.10, 2.51)] were significantly associated with knowledge of ENC. About 74, 75, and 41% of mothers practiced appropriate cord care, breastfeeding, and thermal care, respectively.

Conclusion

Three out of 10 mothers had a good level of knowledge of ENC. Knowledge gaps identified pertained to cord care, breastfeeding, and thermal care. There is opportunity to enhance maternal knowledge of ENC through improving access to ANC and institutional delivery.
Clinical Characteristics of Congenital Atresia of the Left Main Coronary Artery in 12 Children
Authors: Jiang Xiaokun , Ye Wenqian , Xiao Yanyan , Han Ling , Ding Wenhong , Li Wenxiu , Jin Mei , Wang Xiaofang , Meng Qi
Published: April 2022

Background

Left main coronary artery atresia (LMCAA) is an extremely rare abnormality and only <100 cases have been reported worldwide. We describe the clinical manifestations, imaging features, prognosis, and treatments of LMCAA who were admitted in our department, which aimed to improve the clinical diagnosis and treatments of LMCAA in children.

Methods

A retrospective study identified 12 patients diagnosed with congenital left coronary artery atresia at Pediatric Heart Center of Beijing Anzhen Hospital from June 2010 to June 2019. The clinical characteristics, imaging data, and treatment follow-up were analyzed.

Results

Among the 12 cases, 8 were boys and 4 were girls; the age of onset was 2 months to 2 years old (median age 7 months); the age of diagnosis was 7 months to 6 years old (median age 2 years and 11 months). At the initial diagnosis, there were 4 cases of respiratory tract infection with cardiac murmur, 3 cases of cardiac shadow enlargement, 1 case of recurrent syncope, 2 cases of feeding difficulty with cardiac enlargement, and 2 cases of simple cardiac murmur. In 12 cases of electrocardiogram examination, 7 cases showed pathological Q waves of lead I, AVL and v4–v6; in 12 cases of chest X-ray examination, 8 cases showed cardiac shadow enlargement; in 12 cases of our hospital's first cardiac ultrasound examination, 4 cases were definitely diagnosed, and 8 cases showed the possibility of left coronary artery abnormality; in 5 cases of cardiac coronary CT angiography examination, 2 cases were confirmed, 2 cases reported suspected left coronary artery abnormality, and 1 case did not report abnormality; All cases were definitely diagnosed in 8 cases of angiography. Follow-up was performed from 1 to 8 years; one case died suddenly, one case of syncope after activity was treated by oral medication, 3 cases received open coronary angioplasty and mitral valvuloplasty, recovered well after operation, the rest of the children were treated by oral medication, and the symptoms are stable at present.

Conclusions

Left main coronary artery atresia is difficult to diagnose and can result in heart failure early in life. Timely diagnosis and reasonable treatment are the keys to improve the prognosis.
The Natural Product Andrographolide Ameliorates Calcific Aortic Valve Disease by Regulating the Proliferation of Valve Interstitial Cells via the MAPK-ERK Pathway
Authors: Huang Yuming , Liu Ming , Liu Chungeng , Dong Nianguo , Chen Liang
Published: April 2022

Calcific aortic valve disease (CAVD) is an active pathobiological process that involves fibrosis and calcification of aortic valve leaflets, thereby causing cardiac hemodynamic changes and eventually heart failure. Cell proliferation changes at the initial stage of CAVD are an important target for pharmaceutical intervention. This study aimed to investigate whether andrographolide (AGP) could inhibit the proliferation of valve interstitial cells (VICs) in vitro and in vivo to delay the process of CAVD. Cell proliferative factors were tested in both healthy and CAVD aortic valve samples. Cell cycle, cell growth, and calcification of VICs were assessed using flow cytometry, CCK8 assay, EdU staining, and Alizarin Red S staining. The expression of cell proliferative factors and osteogenic factors were quantified by qRT-PCR or immunofluorescence staining. The interaction between AGP and ERK (extracellular regulated protein kinases) was detected by molecular docking. In addition, a high-fat diet-fed animal model was used to verify the effect of AGP on CAVD in vivo. In conclusion, we found that AGP ameliorates aortic valve incrassation by inhibiting cell proliferation via the MAPK-ERK signaling pathway. Therefore, AGP is a promising drug that prevents the occurrence of CAVD via regulating cell proliferation.
Qinghao-Biejia Herb Pair Alleviates Pristane-Induced Lupus-Like Disease and Associated Renal and Aortic Lesions in ApoE−/− Mice
Authors: Hong Jiaze , Zhang Miao , He Yuanfang , Jin Yi , He Qiaoqi , Zhang Yi , Shi Xiaowei , Tian Weiyu , Wen Chengping , Chen Juan
Published: April 2022

Backgroud: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple systems with a high prevalence of nephritis and atherosclerosis. Jieduquyuziyin prescription is a famous prescription with immune modulating and inflammation controlling effects, which is efficacious in the treatment of SLE. The most critical herbs in this prescription are Qinghao and Biejia. The aim of this study was to evaluate the therapeutic effect of Qinghao-Biejia herb hair (QB) on mice with SLE combined with atherosclerosis.

Materials and Methods: The effect of QB (identification using UPLC-TOF-MS) was assessed in female ApoE−/− mice intraperitoneally injected with 0.5 ml of pristane. Serum autoantibodies and lipid metabolic parameters were tested every 4 weeks, and spleen index, serum inflammatory biomarkers, renal injury, and aortic injury were observed after 16 weeks. The expression of signaling pathway in kidney tissues was observed by RT-qPCR and Western blot.

Results: The mice of QB-treated group exhibited a significant reduced serum autoantibodies level, urine protein, and renal immune complex deposition. QB treatment reduced the levels of inflammatory cytokines and improved the renal pathological changes. In addition, there was a reduction in aortic atheromatous plaque and some improvement in dyslipidemia. Moreover, QB suppressed the expression of HMGB1, TLR4, and MyD88 to some extent.

Conclusion: The present study implied that QB has clear efficacy for the treatment of SLE combined with atherosclerosis, and that inhibition of the HMGB1/TLR4 signaling pathway may be one of the therapeutic targets of QB for SLE combined with atherosclerosis.
The Qubit Fidelity Under Different Error Mechanisms Based on Error Correction Threshold
Authors: Li Kai
Published: April 2022

Quantum error correction is a crucial step to realize large-scale universal quantum computing, and the condition for realizing quantum error correction is that the error probability of each operation step must below some threshold. This requires that the qubits’ quality and the quantum gates precision can reach a certain level experimentally. We firstly discuss the mechanism of quantum errors: the precision of quantum gates corresponds to unitary operator errors, and the quality of qubits is attributed to decoherence. Then, according to the threshold of the surface code error correction, we proved the minimum of quantum gate fidelity should not be less than 1 − p with the error probability p, and found the natural decoherence time of qubits that can be used for error correction. This provides some kind of theoretical supports for qubits preparation and performing quantum operations experimentally.
Cerebral Microvascular Senescence and Inflammation in Diabetes
Authors: Phoenix Ashley , Chandran Raghavendar , Ergul Adviye
Published: April 2022

Stress-induced premature senescence can contribute to the accelerated metabolic aging process in diabetes. Progressive accumulation of senescent cells in the brain, especially those displaying the harmful inflammatory senescence-associated secretory phenotype (SASP), may lead to cognitive impairment linked with metabolic disturbances. In this context, the senescence within the neurovascular unit (NVU) should be studied as much as in the neurons as emerging evidence shows that neurogliovascular communication is critical for brain health. It is also known that cerebrovascular dysfunction and decreased cerebral blood flow (CBF) precede the occurrence of neuronal pathologies and overt cognitive impairment. Various studies have shown that endothelial cells, the major component of the NVU, acquire a senescent phenotype via various molecular mediators and pathways upon exposure to high glucose and other conditions mimicking metabolic disturbances. In addition, senescence in the other cells that are part of the NVU, like pericytes and vascular smooth cells, was also triggered upon exposure to diabetic conditions. The senescence within the NVU may compromise functional and trophic coupling among glial, vascular, and neuronal cells and the resulting SASP may contribute to the chronic neurovascular inflammation observed in Alzheimer’s Disease and Related Dementias (ADRD). The link between diabetes-mediated cerebral microvascular dysfunction, NVU senescence, inflammation, and cognitive impairment must be widely studied to design therapeutic strategies.
Effects of Heat Stress on Production Performance, Redox Status, Intestinal Morphology and Barrier-Related Gene Expression, Cecal Microbiome, and Metabolome in Indigenous Broiler Chickens
Authors: Liu Wen-Chao , Pan Zi-Yi , Zhao Yue , Guo Yan , Qiu Sheng-Jian , Balasubramanian Balamuralikrishnan , Jha Rajesh
Published: April 2022

This study was done to evaluate the effects of heat stress (HS) on production performance, redox status, small intestinal barrier-related parameters, cecal microbiota, and metabolome of indigenous broilers. A total of forty female indigenous broilers (56-day-old) were randomly and equally divided into normal treatment group (NT group, 21.3 ± 1.2°C, 24 h/day) and HS group (32.5 ± 1.4°C, 8 h/day) with five replicates of each for 4 weeks feeding trial. The results showed that the body weight gain (BWG) of broilers in HS group was lower than those in NT group during 3–4 weeks and 1–4 weeks (p < 0.05). The HS exposure increased the abdominal fat rate (p < 0.05) but decreased the thigh muscle rate (p < 0.01). Besides, broilers in HS group had higher drip loss of breast muscle than NT group (p < 0.01). Broilers exposed to HS had lower total antioxidant capacity (T-AOC) in serum and jejunum, activities of total superoxide dismutase (T-SOD) in the jejunum, glutathione peroxidase (GSH-Px) in the thigh muscle, duodenum, and jejunum; and catalase (CAT) in breast muscle, duodenum, and jejunum (p < 0.05). Whereas the malondialdehyde (MDA) contents in breast muscle, duodenum, and jejunum was elevated by HS exposure (p < 0.05). Moreover, the relative mRNA expression of Occludin and ZO-1 in the duodenum, Occludin, Claudin-1, Claudin-4, ZO-1, Mucin-2 in the jejunum, and the Claudin-4 and Mucin-2 in the ileum was down-regulated by HS exposure (p < 0.05). The 16S rRNA sequencing results showed that the HS group increased the relative abundance of Anaerovorax in the cecum at the genus level (p < 0.05). Cecal metabolomics analysis indicated 19 differential metabolites between the two groups (p < 0.10, VIP >1). The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the differential metabolites mainly enriched in 10 signaling pathways such as the Citrate cycle (TCA cycle) (p < 0.01). In summary, chronic HS exposure caused a decline of production performance, reduced antioxidant capacity, disrupted intestinal barrier function, and negatively affected cecal microbiota and metabolome in indigenous broilers.
NeuralLasso: Neural Networks Meet Lasso in Genomic Prediction
Authors: Mathew Boby , Hauptmann Andreas , Léon Jens , Sillanpää Mikko J.
Published: April 2022

Prediction of complex traits based on genome-wide marker information is of central importance for both animal and plant breeding. Numerous models have been proposed for the prediction of complex traits and still considerable effort has been given to improve the prediction accuracy of these models, because various genetics factors like additive, dominance and epistasis effects can influence of the prediction accuracy of such models. Recently machine learning (ML) methods have been widely applied for prediction in both animal and plant breeding programs. In this study, we propose a new algorithm for genomic prediction which is based on neural networks, but incorporates classical elements of LASSO. Our new method is able to account for the local epistasis (higher order interaction between the neighboring markers) in the prediction. We compare the prediction accuracy of our new method with the most commonly used prediction methods, such as BayesA, BayesB, Bayesian Lasso (BL), genomic BLUP and Elastic Net (EN) using the heterogenous stock mouse and rice field data sets.
Astragalus sinicus Incorporated as Green Manure for Weed Control in Corn
Authors: Liu Silin , Ma Zhiyi , Zhang Ying , Chen Zhongwen , Du Xiao , Mu Yinghui
Published: April 2022

Astragalus sinicus L. (milk vetch), one of the most widespread green manure species, is widely planted in the temperate zone. Eleusine indica L. (goosegrass), a serious annual weed in the world, has evolved resistance to some non-selective herbicides. The use of milk vetch as green manure for weed control in paddy fields was proposed. Aqueous extracts of milk vetch are known to exert a different level of phytotoxicity on weeds and crops. Phytotoxic substances contained in green manure were released into the soil by leaching at the initial stage and decomposition at the later stage after the return of green manure. Considering the need for searching new sustainable strategies for weed control, a question arises: “if milk vetch could be applied in goosegrass control, which stage is the most important to control goosegrass after milk vetch returned to the field, and at the same time, will the subsequent crop, corn (Zea mays L.), be affected by the side effects from milk vetch phytotoxicity?” In this study, the potential of milk vetch for goosegrass control was approached by repeated laboratory experiments, which include the aqueous extract experiment, decomposed experiment, and pot experiment. The effects of milk vetch returning to the field on maize were simulated by a pot experiment. The extract of milk vetch could significantly inhibit the germination of goosegrass at 2% concentration, and the inhibition enhanced with the increase of concentration. In the decomposed liquid experiment, decay time within 15 days, with the increase of decay days or concentration, goosegrass inhibition effect of decomposed liquid was enhanced. When decay time was more than 15 days, the inhibition ability of the decomposed liquid to goosegrass decreased. According to the RI accumulated value, aqueous extract and decomposed liquid have a “hormesis effect” on the germination and growth of goosegrass. Pot experiment proved that the addition of 1–10% (w/w) of milk vetch significantly reduced the germination and growth of goosegrass. On the contrary, the comprehensive analysis showed that the participation of milk vetch was conducive to the growth of corn. Our results constitute evidence that the incorporation of milk vetch into the soil could be a feasible practice to reduce weed infarctions in the corn-based cropping system.