bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth Differentiation Factor-15 as a Biomarker for Sarcopenia in Patients With Chronic Obstructive Pulmonary Disease
Authors: Deng Mingming , Bian Yiding , Zhang Qin , Zhou Xiaoming , Hou Gang
Published: June 2022

Purpose

Sarcopenia is an important factor contributing to comorbidities in patients with chronic obstructive pulmonary disease (COPD) and is an independent risk factor for increased mortality. The diagnostic process for sarcopenia requires specific equipment and specialized training and is difficult procedurally. A previous study found that GDF15 levels are associated with skeletal muscle mass and function in patients with COPD. However, whether circulating GDF15 levels can be used for the prediction of sarcopenia in patients with COPD is unknown.

Methods

This study included 235 patients with stable COPD who were divided into a development set (n = 117) and a validation set (n = 118), and we followed the definition of sarcopenia as defined by the guidelines from the Asian Working Group for Sarcopenia. Serum concentrations of GDF15 were measured using an enzyme-linked immunosorbent assay (ELISA), and construction of a nomogram and decision curve analysis were performed using the R package “rms.”

Results

In this study, serum GDF15 levels were negatively associated with skeletal muscle mass (r = –0.204, p = 0.031), handgrip strength (r = –0.274, p = 0.004), quadriceps strength (r = –0.269, p = 0.029), and the thickness (r = –0.338, p < 0.001) and area (r = –0.335, p < 0.001) of the rectus femoris muscle in patients with COPD. Furthermore, the serum levels of GDF15 in patients with sarcopenia were significantly higher than those in controls. Importantly, serum levels of GDF15 could effectively predict sarcopenia in patients with COPD based on the development set (AUC = 0.827) and validation set (AUC = 0.801). Finally, a nomogram model based on serum GDF15 levels and clinical features showed good predictive ability (AUC > 0.89) in the development and validation sets.

Conclusion

Serum GDF15 levels could be used to accurately and easily evaluate sarcopenia in patients with COPD.
Fat Oxidation of Fatty Fish vs. Meat Meal Diets Under in vitro Standardized Semi-Dynamic Gastric Digestion
Authors: Harahap Iskandar Azmy , Sobral Maria Madalena C. , Casal Susana , Pinho Susana C. M. , Faria Miguel A. , Suliburska Joanna , Ferreira Isabel M. P. L. V. O.
Published: June 2022

Meat and fish are introduced into the diet as a source of protein, but these muscle foods present different fatty acid (FA) compositions and different lipid stabilities. Fatty fish is expected to oxidize due to its higher content of polyunsaturated FA (PUFA), whereas the higher heme-Fe content of red meat will also affect lipid stability. Combining other food ingredients within a meal also influences lipid oxidation, which will not stop after meals intake. This is due to the acidic environment of the stomach together with the presence of metallic ions, a process that is scarcely understood. The goal of this study was to evaluate the oxidation of fatty fish vs. meat meal diets under in vitro standardized semi-dynamic gastric conditions and FA release from the stomach to the duodenum. Meal diets composed by 25% beef meal (BM) or fatty fish meal (FM), 25% fried potatoes, and 50% sugar soft drink were prepared. Proximate composition, FA and amino acid profiles, and meals quality indices were evaluated. Their differences in composition led to different total gastric digestion time of 242.74 (BM) and 175.20 (FM) minutes. Using the INFOGEST semi-dynamic gastric model, 4 gastric emptying (GE) were simulated in both meals. In each GE, FA profile and lipid oxidation products (LOPs) formation were assessed. As a result, more than 50% FA release to the duodenum occurred in GE1, whose percentage decreased with the time of digestion. FM exhibited the highest LOPs formation, which corroborates the high peroxidizability index measured for this meal diet. Higher LOPs formation occurred in the later GEs, which released less FA. This suggests that higher times of residence in the stomach increase FA oxidation. This study shows a higher formation of LOPs during digestion of FM using a whole meal approach. These results relate to its richness in PUFAs compared to BM. Despite higher LOPs formation, FM digests that reached duodenum still contain higher content of unoxidized PUFAs compared with BM and a desirable ω3/ω6 PUFAs ratio of ~0.43. LOPs formation in PUFA-rich meals could be reduced if those meals have a low caloric value, avoiding large times of residence in the stomach and consequently high levels of oxidation.
Combination of Geriatric Nutritional Risk Index and Carcinoembryonic Antigen to Predict the Survival of Patients With Colorectal Cancer
Authors: Xie Hailun , Wei Lishuang , Yuan Guanghui , Liu Mingxiang , Liang Yanren , Gao Shunhui , Wang Qiwen , Lin Xin , Tang Shuangyi , Gan Jialiang
Published: June 2022

Background

This study explored the value of the combination of Geriatric Nutritional Risk Index (GNRI) and carcinoembryonic antigen (CEA) for the prognosis assessment of CRC patients.

Methods

This study retrospectively enrolled 1,014 CRC patients who underwent surgery between 2012 and 2014. Kaplan-Meier and log-rank tests were used to compare survival differences. Cox proportional hazards regression analysis was used to assess risk factors associated with progression-free survival (PFS) and overall survival (OS). Nomograms were constructed to predict the prognosis of CRC patients. Randomized internal validation was used to confirm the predictive accuracy of the prognostic nomograms.

Results

The GNRI-CEA score was established by combining GNRI and CEA. Compared with patients with normal GNRI-CEA scores, patients with mild/moderate/severe GNRI-CEA scores had significantly lower survival (PFS, 68.99% vs. 57.75% vs. 41.34% vs. 31.36%, p < 0.001; OS, 68.99% vs. 57.75% vs. 41.34% vs. 31.36%, p < 0.001). The GNRI-CEA score is an independent factor predicting the prognosis of CRC patients. The risk of death was twofold higher in patients with low GNRI and high CEA than in those with both normal GNRI and CEA [PFS, hazard ratio (HR), 2.339; 95% confidence interval (CI), 1.656–3.303; p < 0.001; OS, HR, 2.340; 95% CI, 1.645–3.329; p < 0.001]. Prognostic nomograms had good resolution and accuracy in predicting 1–5 year PFS and OS. Randomized internal validation showed that the nomograms were reliable.

Conclusion

The combination of GNRI and CEA can effectively stratify the prognosis of CRC patients. The nomogram established based on the two indices can provide a personalized reference for prognostic assessment and clinical decision-making for CRC patients.
Hypoglycemic Effects of Lycium barbarum Polysaccharide in Type 2 Diabetes Mellitus Mice via Modulating Gut Microbiota
Authors: Ma Qingyu , Zhai Ruohan , Xie Xiaoqing , Chen Tao , Zhang Ziqi , Liu Huicui , Nie Chenxi , Yuan Xiaojin , Tu Aobai , Tian Baoming , Zhang Min , Chen Zhifei , Li Juxiu
Published: June 2022

This study aims to explore the molecular mechanisms of Lycium barbarum polysaccharide (LBP) in alleviating type 2 diabetes through intestinal flora modulation. A high-fat diet (HFD) combined with streptozotocin (STZ) was applied to create a diabetic model. The results indicated that LBP effectively alleviated the symptoms of hyperglycemia, hyperlipidemia, and insulin resistance in diabetic mice. A high dosage of LBP exerted better hypoglycemic effects than low and medium dosages. In diabetic mice, LBP significantly boosted the activities of CAT, SOD, and GSH-Px and reduced inflammation. The analysis of 16S rDNA disclosed that LBP notably improved the composition of intestinal flora, increasing the relative abundance of Bacteroides, Ruminococcaceae_UCG-014, Intestinimonas, Mucispirillum, Ruminococcaceae_UCG-009 and decreasing the relative abundance of Allobaculum, Dubosiella, Romboutsia. LBP significantly improved the production of short-chain fatty acids (SCFAs) in diabetic mice, which corresponded to the increase in the beneficial genus. According to Spearman’s correlation analysis, Cetobacterium, Streptococcus, Ralstonia. Cetobacterium, Ruminiclostridium, and Bifidobacterium correlated positively with insulin, whereas Cetobacterium, Millionella, Clostridium_sensu_stricto_1, Streptococcus, and Ruminococcaceae_UCG_009 correlated negatively with HOMA-IR, HDL-C, ALT, AST, TC, and lipopolysaccharide (LPS). These findings suggested that the mentioned genus may be beneficial to diabetic mice’s hypoglycemia and hypolipidemia. The up-regulation of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and insulin were remarkably reversed by LBP in diabetic mice. The real-time PCR (RT-PCR) analysis illustrated that LBP distinctly regulated the glucose metabolism of diabetic mice by activating the IRS/PI3K/Akt signal pathway. These results indicated that LBP effectively alleviated the hyperglycemia and hyperlipidemia of diabetic mice by modulating intestinal flora.
Protective Mechanism of Fagopyrum esculentum Moench. Bee Pollen EtOH Extract Against Type II Diabetes in a High-Fat Diet/Streptozocin-Induced C57BL/6J Mice
Authors: Zhang Jinjin , Cao Wei , Zhao Haoan , Guo Sen , Wang Qian , Cheng Ni , Bai Naisheng
Published: June 2022

Bee pollen is known as a natural nutrient storehouse and plays a key role in many biological processes. Based on the preliminary separation, identification, and characterization of the main active components of Fagopyrum esculentum Moench. bee pollen (FBP), the protective effects of F. esculentum bee pollen extract (FBPE) on high-fat-diet (HFD) and streptozocin (STZ) induced type II diabetes mellitus (T2DM) was evaluated in this study. The results revealed that FBPE contains 10 active compounds mainly including luteolin (9.46 g/kg), resveratrol (5.25 g/kg), kaemferol (3.67 g/kg), etc. The animal experiment results showed that FBPE could improve HFD-STZ induced T2DM mice. Moreover, the underlying mechanism of the above results could be: (i) FBPE could reduce the inflammation related to phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, and (ii) the gut microbiota remodeling. The results of correlation analysis showed Candidatus Arthromitus and SMB53 indicated positive correlations to tumor necrosis factor-α (TNF-α); Coprococcus, Ruminocossus, and Odoribacteraceae reported negative correlations to transforming growth factor-β (TGF-β). That FBPE has an outstanding ability to improve T2DM and could be used as a kind of potential functional food for the prevention of T2DM.
Polyphenolics and Chemical Profiles of Domestic Norwegian Apple (Malus × domestica Borkh.) Cultivars
Authors: Fotirić Akšić Milica , Nešović Milica , Ćirić Ivanka , Tešić Živoslav , Pezo Lato , Tosti Tomislav , Gašić Uroš , Dojčinović Biljana , Lončar Biljana , Meland Mekjell
Published: June 2022

Using modern analytical techniques, a comprehensive study of the chemical composition of fruits from apple cultivars grown in Western Norway during 2019 and 2020 was done. Metals, sugars, organic acids, antioxidant tests, and polyphenol content have been observed. In all investigated samples, the most dominant sugars were glucose, fructose, and sucrose. Among 11 tested organic acids, the dominant was malic acid, followed by citric and maleic acid. The most common metal was potassium, followed by magnesium and zinc. The quantification of polyphenols showed that among the 11 quantified polyphenols, chlorogenic acid, quercetin 3-O-rhamnoside, quercetin 3-O-glucoside, quercetin, and phlorizin were the most abundant. A detailed study of the polyphenolic profile of nine investigated apple samples provided 30 identified polyphenolic compounds from the class of hydroxybenzoic and hydroxycinnamic acids, flavonoids, and dihydrochalcones. In addition to the identified 3-O-caffeoylquinic acid, its two isomers of 5-O-caffeoylquinic acid and three esters were also found. Present polyphenols of the tested apples provided significant data on the quality of Norwegian apples, and they contribute to the distinguishing of these apple samples.
Redefine the Role of Proton Beam Therapy for the Locally-Advanced Non-Small Cell Lung Cancer Assisting the Reduction of Acute Hematologic Toxicity
Authors: Cao Xi , Liu Peilin , Gao Xian-shu , Shang Shiyu , Liu Jiayu , Wang Zishen , Su Mengmeng , Ding Xuanfeng
Published: June 2022

Purpose

To investigate the potential clinical benefit of utilizing intensity-modulated proton therapy (IMPT) to reduce acute hematologic toxicity for locally advanced non-small cell lung cancer (LA-NSCLC) patients and explore the feasibility of a model-based patient selection approach via the normal tissue complication probability (NTCP).

Methods

Twenty patients with LA-NSCLC were retrospectively selected. Volumetric modulated arc photon therapy (VMAT) and IMPT plans were generated with a prescription dose of 60 Gy in 30 fractions. A wide range of cases with varied tumor size, location, stations of metastatic lymph nodes were selected to represent the general cancer group. Contouring and treatment planning followed RTOG-1308 protocol. Doses to thoracic vertebral bodies (TVB) and other organ at risks were compared. Risk of grade ≥ 3 acute hematologic toxicity (HT3+) were calculated based on the NTCP model, and patients with a reduction on NTCP of HT3+ from VMAT to IMPT (△NTCP_HT3+) ≥ 10% were considered to ‘significantly benefit from proton therapy.’

Results

Compared to VMAT, IMPT significantly reduced the dose to the TVB, the lung, the heart, the esophagus and the spinal cord. Tumor distance to TVB was significantly associated with △NTCP _HT3+ ≥ 10%. For the patients with tumor distance ≤ 0.7 cm to TVB, the absolute reduction of dose (mean, V30 and V40) to TVB was significantly lower than that in patients with tumor distance > 0.7 cm.

Conclusion

IMPT decreased the probability of HT3+ compared to VMAT by reducing the dose to the TVB in LA-NSCLC patients. Patients with tumor distance to TVB less than 0.7 cm are likely to benefit most from proton over photon therapy.
Rewiring of the Endocrine Network in Triple-Negative Breast Cancer
Authors: Li Kaixuan , Zong Dongjiang , Sun Jianrong , Chen Danxiang , Ma Minkai , Jia Liqun
Published: June 2022

The immunohistochemical definition of estrogen/progesterone receptors dictates endocrine feasibility in the treatment course of breast cancer. Characterized by the deficiency of estrogen receptor α, ERα-negative breast cancers are dissociated from any endocrine regimens in the routine clinical setting, triple-negative breast cancer in particular. However, the stereotype was challenged by triple-negative breast cancers’ retained sensitivity and vulnerability to endocrine agents. The interplay of hormone action and the carcinogenic signaling program previously underscored was gradually recognized along with the increasing investigation. In parallel, the overlooked endocrine-responsiveness in ERα-negative breast cancers attracted attention and supplied fresh insight into the therapeutic strategy in an ERα-independent manner. This review elaborates on the genomic and non-genomic steroid hormone actions and endocrine-related signals in triple-negative breast cancers attached to the hormone insensitivity label. We also shed light on the non-canonical mechanism detected in common hormone agents to showcase their pleiotropic effects.
Construction and Validation of a m7G-Related Gene-Based Prognostic Model for Gastric Cancer
Authors: Li Xin-yu , Wang Shou-lian , Chen De-hu , Liu Hui , You Jian-Xiong , Su Li-xin , Yang Xi-tao
Published: June 2022

Background

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system. Chinese cases of GC account for about 40% of the global rate, with approximately 1.66 million people succumbing to the disease each year. Despite the progress made in the treatment of GC, most patients are diagnosed at an advanced stage due to the lack of obvious clinical symptoms in the early stages of GC, and their prognosis is still very poor. The m7G modification is one of the most common forms of base modification in post-transcriptional regulation, and it is widely distributed in the 5′ cap region of tRNA, rRNA, and eukaryotic mRNA.

Methods

RNA sequencing data of GC were downloaded from The Cancer Genome Atlas. The differentially expressed m7G-related genes in normal and tumour tissues were determined, and the expression and prognostic value of m7G-related genes were systematically analysed. We then built models using the selected m7G-related genes with the help of machine learning methods.The model was then validated for prognostic value by combining the receiver operating characteristic curve (ROC) and forest plots. The model was then validated on an external dataset. Finally, quantitative real-time PCR (qPCR) was performed to detect gene expression levels in clinical gastric cancer and paraneoplastic tissue.

Results

The model is able to determine the prognosis of GC samples quantitatively and accurately. The ROC analysis of model has an AUC of 0.761 and 0.714 for the 3-year overall survival (OS) in the training and validation sets, respectively. We determined a correlation between risk scores and immune cell infiltration and concluded that immune cell infiltration affects the prognosis of GC patients. NUDT10, METTL1, NUDT4, GEMIN5, EIF4E1B, and DCPS were identified as prognostic hub genes and potential therapeutic agents were identified based on these genes.

Conclusion

The m7G-related gene-based prognostic model showed good prognostic discrimination. Understanding how m7G modification affect the infiltration of the tumor microenvironment (TME) cells will enable us to better understand the TME’s anti-tumor immune response, and hopefully guide more effective immunotherapy methods.
Comparison of the Oncological Outcomes Between Robot-Assisted and Abdominal Radical Hysterectomy for Cervical Cancer Based on the New FIGO 2018 Staging System: A Multicentre Retrospective Study
Authors: Li Pengfei , Zhan Xuemei , Lv Chifei , Lin Zhong , Yang Ying , Wang Wuliang , Wang Shaoguang , Hao Min , Zhu Bin , Bin Xiaonong , Lang Jinghe , Liu Ping , Chen Chunlin
Published: June 2022

Objective

To compare the 3-year oncological outcomes of robot-assisted radical hysterectomy (RRH) and abdominal radical hysterectomy (ARH) for cervical cancer.

Methods

Based on the clinical diagnosis and treatment for cervical cancer in the China database, patients with FIGO 2018 stage IA with lymphovascular space invasion (LVSI)-IB2 cervical cancer disease who underwent RRH and ARH from 2004 to 2018 were included. Kaplan–Meier survival analysis was used to compare the 3-year overall survival (OS) and disease-free survival (DFS) rate between patients receiving RRH and those receiving ARH. The Cox proportional hazards model and propensity score matching were used to estimate the surgical approach-specific survival.

Results

A total of 1,137 patients with cervical cancer were enrolled in this study, including the RRH group (n = 468) and the ARH group (n = 669). The median follow-up time was 45 months (RRH group vs. ARH group: 24 vs. 60 months). Among the overall study population, there was no significant difference in 3-year OS and DFS between the RRH group and the ARH group (OS: 95.8% vs. 97.6% p = 0.244). The Cox proportional hazards analysis showed that RRH was not an independent risk factor for 3-year OS (HR: 1.394, 95% CI: 0.552–3.523, p = 0.482). However, RRH was an independent risk factor for 3-year DFS (HR: 1.985, 95% CI: 1.078–3.655 p = 0.028). After 1:1 propensity score matching, there was no significant difference in 3-year OS between the RRH group and the ARH group (96.6% vs. 98.0%, p = 0.470); however, the 3-year DFS of the RRH group was lower than that of the ARH group (91.0% vs. 96.1%, p = 0.025). The Cox proportional hazards analysis revealed that RRH was not an independent risk factor for 3-year OS (HR: 1.622, 95% CI: 0.449–5.860 p = 0.461), but RRH was an independent risk factor for 3-year DFS (HR: 2.498, 95% CI: 1.123–5.557 p = 0.025).

Conclusion

Among patients with stage I A1 (LVSI +)-I B2 cervical cancer based on the FIGO 2018 staging system, RRH has a lower 3-year DFS than ARH, suggesting that RRH may not be suitable for early cervical cancer patients.
The Cognitive Effects of Radiotherapy for Brain Metastases
Authors: Lehrer Eric J. , Jones Brianna M. , Dickstein Daniel R. , Green Sheryl , Germano Isabelle M. , Palmer Joshua D. , Laack Nadia , Brown Paul D. , Gondi Vinai , Wefel Jeffrey S. , Sheehan Jason P. , Trifiletti Daniel M.
Published: June 2022

Brain metastases are the most common intracranial neoplasm and are seen in upwards of 10-30% of patients with cancer. For decades, whole brain radiation therapy (WBRT) was the mainstay of treatment in these patients. While WBRT is associated with excellent rates of intracranial tumor control, studies have demonstrated a lack of survival benefit, and WBRT is associated with higher rates of cognitive deterioration and detrimental effects on quality of life. In recent years, strategies to mitigate this risk, such as the incorporation of memantine and hippocampal avoidance have been employed with improved results. Furthermore, stereotactic radiosurgery (SRS) has emerged as an appealing treatment option over the last decade in the management of brain metastases and is associated with superior cognitive preservation and quality of life when compared to WBRT. This review article evaluates the pathogenesis and impact of cranial irradiation on cognition in patients with brain metastases, as well as current and future risk mitigation techniques.
A Novel Intergenic Gene Between SLC8A1 and PKDCC-ALK Fusion Responds to ALK TKI WX-0593 in Lung Adenocarcinoma: A Case Report
Authors: Du Jia , Wang Baoming , Li Mengxia , Wang Chunyang , Ma Tonghui , Shan Jinlu
Published: June 2022

Background

Expanding the druggable novel anaplastic lymphoma kinase (ALK) fusions list is crucial to the precise treatment of patients with cancer with positive ALK fusions. The intergenic-ALK fusions accounted for a substantial proportion of ALK fusions. However, they were typically considered of limited clinical significance due to the obscure functional partners. In this case report, a patient carrying intergenic-ALK fusion presents an excellent outcome after taking the new second-generation tyrosine kinase inhibitor (TKI) candidate, WX-0593.

Case Presentation

A 47-year-old Chinese female patient diagnosed with IVB lung adenocarcinoma was admitted to the hospital with large dimension lesions in the left lobe of the lung. After 1 week of first line chemotherapy, no response was found. A novel ALK rearrangement generated by a fusion of the intergenic region between SLC8A1 and PKDCC to the intron 19 of ALK was presented after next-generation sequencing and was further confirmed by Sanger’s sequencing. High expression of ALK was revealed by immunohistochemistry. The patient was directed to engage in phase III clinical trial (NCT04632758) and received an orally active second-generation ALK inhibitor WX-0593. Over the course of 17 months, the partial response was obtained without significant side effects.

Conclusion

In summary, a patient with non–small cell lung cancer harboring a novel intergenic-ALK fusion, whose intergenic breakpoint was located between SLC8A1 and PKDCC, benefited from a potent ALK TKI candidate WX-0593. This finding extended the scope of targetable ALK fusions. More importantly, it highlighted the advantages of next-generation sequencing in identifying rare but functional ALK fusions, which eventually benefit patients.
A Single-Center Follow-Up Study of Low-Grade Gastric Intraepithelial Neoplasia and the Screening of Key Genes of Precancerous Lesions
Authors: Jin Xiao-Xu , Xie Xiao-Li , Niu Fu , Yin Kai-Ge , Ji Chen-Guang , Cui Jin-Feng , Liu Li , Feng Zhi-Jie
Published: June 2022

Objective

The study aimed to summarize the morphological characteristics of low-grade gastric intraepithelial neoplasia (LGIN) and explore its outcomes and risk factors. Additionally, it aimed to screen the core different expression genes (DEGs) of high-grade gastric intraepithelial neoplasia (HGIN) using bioinformatics methods to identify biomarkers for early gastric cancer outcomes.

Methods

The clinical and pathological data of 449 patients with LGIN in the endoscopy center of the Second Hospital of Hebei Medical University from June 2013 to September 2018 were collected for retrospective analysis. The GSE130823 and GSE55696 data sets were selected from the Gene Expression Omnibus database, and the GEO2R tool was used to screen DEGs in HGIN and chronic gastritis tissue types. A DEG functional enrichment analysis was conducted using the Database for Annotation, Visualization, and Integrated Discovery. The STRING database was utilized to create a protein–protein interaction network, and the CytoHubba plug-in was used to screen the key genes of HGIN.

Results

The incidence of LGIN increased with age, and most of the patients were aged between 45–59 years (P = 0.048). Lesions were found mainly in the cardia, mostly in people aged 60 (P < 0.05). Progression occurred in 42 of 449 patients, with a 9.4% rate of cancer development. Foci larger than 10 mm, ulcerative lesions, and an Helicobacter pylori-positive result were factors affecting the outcome of LGIN (P < 0.05). Seven core genes of HGIN were screened, including MYC, SOX2, CDX2, TBX3, KRT7, CDKN2A, and MUC5AC.

Conclusion

The patients with LGIN reflected the potential for developing cancer. A magnifying gastroscope can contribute to the detection of early gastric cancer. Additionally, the MYC, CDX2, and TBX3 genes may act as specific biomarkers of HGIN.
Contribution of Diffusion-Weighted Imaging and ADC Values to Papillary Breast Lesions
Authors: Lv Wenjie , Zheng Dawen , Guan Wenbin , Wu Ping
Published: June 2022

This study aimed to evaluate the role of apparent diffusion coefficient (ADC) values obtained from diffusion-weighted imaging (DWI) in the differentiation of malignant from benign papillary breast lesions. The magnetic resonance imaging (MRI) data of 94 breast papillary lesions confirmed by pathology were retrospectively analyzed. The differences in ADC values of papillary lesions under different enhancements in MRI and different pathological types were investigated, and the ADC threshold was determined by the receiver operating characteristic curve for its potential diagnostic value. The mean ADC values in borderline and malignant lesions (1.01 ± 0.20 × 10-3 mm2/s) were significantly lower compared to benign lesions (1.21 ± 0.27 × 10-3 mm2/s) (P < 0.05). The optimal threshold of the ADC value could be 1.00 × 10-3 mm2/s. The ADC values were statistically significant in differentiating between benign and malignant papillary lesions whether in mass or non-mass enhancement (P < 0.05). However, there were no statistical differences in the ADC values among borderline or any other histological subtypes of malignant lesions (P > 0.05). Measuring ADC values from DWI can be used to identify benign and malignant breast papillary lesions. The diagnostic performance of the ADC value in identifying benign and malignant breast lesions is not affected by the way of lesion enhancement. However, it shows no use for differential diagnosis among malignant lesion subtypes for now. The ADC value of 1.00 × 10-3 mm2/s can be used as the most appropriate threshold for distinguishing between benign and malignant breast papillary lesions.
CircKIF5B Promotes Hepatocellular Carcinoma Progression by Regulating the miR-192 Family/XIAP Axis
Authors: Fei Zhenghua , Wang Yanfen , Gu Yuyang , Xie Rongrong , Hao Qiongyu , Jiang Yiyan
Published: June 2022

Background

The long-term prognosis of HCC (hepatocellular carcinoma) with metastasis remains extremely poor. CircRNAs are promising as critical biological markers in identifying disease mechanisms and developing new effective treatments. However, the role of the aberrant expression of circRNAs in HCC progression remains largely unknown.

Methods

CircKIF5B location was investigated by RNA fluorescence in situ hybridization (RNA-FISH). For circRNA determination, RNase R treatment and Real-Time Quantitative RT-PCR (qRT-PCR) were performed. Transwell chamber assays examined the chemotactic migration and invasion of liver cancer cells.

Results

This study identified the circRNA circKIF5B originating from exons 1, 2, and 3 of the KIF5B gene. Importantly, we found that circKIF5B circRNA, rather than KIF5B linear mRNA, was notably upregulated in liver cancer cell lines and tissues. Moreover, we found that silencing circKIF5B markedly reduced the proliferation, invasion, and metastasis of liver cancer cells by sponging the miR-192 family, thus decreasing the expression of X-linked inhibitor of apoptosis (XIAP).

Conclusion

Our data demonstrate that circKIF5B can regulate XIAP expression by sponging miR-192 and miR-215 competing for the ceRNA mechanism, indicating that circKIF5B may act as an essential upstream regulator and providing mechanistic evidence to support the view that circKIF5B/miR-192s/XIAP is a promising therapeutic target for treating liver cancer.
Current Use of Asparaginase in Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
Authors: Maese Luke , Rau Rachel E.
Published: June 2022

Pediatric Acute Lymphoblastic Leukemia (ALL) cure rates have improved exponentially over the past five decades with now over 90% of children achieving long-term survival. A direct contributor to this remarkable feat is the development and expanded understanding of combination chemotherapy. Asparaginase is the most recent addition to the ALL chemotherapy backbone and has now become a hallmark of therapy. It is generally accepted that the therapeutic effects of asparaginase is due to depletion of the essential amino acid asparagine, thus occupying a unique space within the therapeutic landscape of ALL. Pharmacokinetic and pharmacodynamic profiling have allowed a detailed and accessible insight into the biochemical effects of asparaginase resulting in regular clinical use of therapeutic drug monitoring (TDM). Asparaginase's derivation from bacteria, and in some cases conjugation with a polyethylene glycol (PEG) moiety, have contributed to a unique toxicity profile with hypersensitivity reactions being the most salient. Hypersensitivity, along with several other toxicities, has limited the use of asparaginase in some populations of ALL patients. Both TDM and toxicities have contributed to the variety of approaches to the incorporation of asparaginase into the treatment of ALL. Regardless of the approach to asparagine depletion, it has continually demonstrated to be among the most important components of ALL therapy. Despite regular use over the past 50 years, and its incorporation into the standard of care treatment for ALL, there remains much yet to be discovered and ample room for improvement within the utilization of asparaginase therapy.
Naltrexone-Induced Cardiac Function Improvement is Associated With an Attenuated Inflammatory Response and Lipid Perioxidation in Volume Overloaded Rats
Authors: Dehe Lukas , Mousa Shaaban A. , Shaqura Mohammed , Shakibaei Mehdi , Schäfer Michael , Treskatsch Sascha
Published: June 2022

In previous studies, upregulation of myocardial opioid receptors as well as the precursors of their endogenous ligands were detected in the failing heart due to chronic volume overload. Moreover, opioid receptor blockade by naltrexone improved left ventricular function. In parallel, inflammatory processes through cytokines have been confirmed to play an important role in the pathogenesis of different forms of heart failure. Thus, the present study examined the systemic and myocardial inflammatory response to chronic volume overload and its modulation by chronic naltrexone therapy. Chronic volume overload was induced in male Wistar rats by applying an infrarenal aortocaval fistula (ACF) for 28 days during which the selective opioid receptor antagonist naltrexone (n = 6) or vehicle (n = 6) were administered via a subcutaneously implanted Alzet minipump. The ultrastructural, morphometric and hemodynamic characterization of ACF animals were performed using an intraventricular conductance catheter in vivo and electron microscopy in vitro. Co-localization of mu-, delta- and kappa-opioid receptor subtypes (MOR, DOR, and KOR respectively) with the voltage gated L-type Ca2+ channel (Cav1.2), the ryanodine receptor (RyR), and mitochondria in cardiomyocytes as well as IL-6, IL-12, TNF-alpha, and Malondialdehyde (MDA) were determined using double immunofluorescence confocal microscopy, RT-PCR and ELISA, respectively. In rat left ventricular myocardium, three opioid receptor subtypes MOR, DOR, and KOR colocalized with Cav1.2, RyR and mitochondria suggesting a modulatory role of the excitation-contraction coupling. In rats with ACF-induced volume overload, signs of heart failure and myocardial ultrastructural damage, chronic naltrexone therapy improved cardiac function and reversed the systemic and myocardial inflammatory cytokine expression as well as lipid peroxidation. In conclusion, antagonism of the cardiodepressive effects of the myocardial opioid system does not only improve left ventricular function but also blunts the inflammatory response and lipid peroxidation.
Integration of Non-Targeted Metabolomics and Targeted Quantitative Analysis to Elucidate the Synergistic Antidepressant Effect of Bupleurum Chinense DC-Paeonia Lactiflora Pall Herb Pair by Regulating Purine Metabolism
Authors: Chen Jiajun , Li Tian , Qin Xuemei , Du Guanhua , Zhou Yuzhi
Published: June 2022

Bupleurum chinense DC (Chaihu)-Paeonia lactiflora Pall (Baishao) is among the most accepted herb pairs in many classic antidepressant prescriptions. Our previous study has shown that the Chaihu–Baishao herb pair (CBHP) had a better antidepressant effect than Chaihu or Baishao. Nevertheless, the synergistic antidepressant mechanism of this herb pair was not clearly understood. This study aimed to investigate the compatibility mechanism of Chaihu and Baishao for treating depression through a strategy of non-targeted metabolomics combined with targeted quantitative analysis and molecular biology techniques. First, the compatibility effects of CBHP were assessed by the chronic unpredictable mild stress (CUMS) rat model. Next, cortex metabolomics based on ultra-high-performance liquid chromatography combined with quadrupole orbitrap mass spectrometry (UPLC-Q-Orbitrap/MS) was used to discover the metabolic pathway that was synergistically regulated by CBHP. Based on the results of metabolomics analysis, metabolites were quantitatively validated by UPLC-MS/MS combined with the MRM mode in the crucial metabolic pathway. In addition, the signaling pathway associated with this metabolic pathway was detected by molecular biology techniques to further identify the biological meaning of the crucial metabolite on the synergistic antidepressant effect of CBHP. The antidepressant effect of CBHP was significantly better than that of Chaihu or Baishao single administrated in the behavioral test. According to cortex metabolomics, a total of 21 differential metabolites were screened out, and purine metabolism was selected as the crucial metabolic pathway by the enrichment analysis of differential metabolites. Subsequently, purine metabolism was confirmed as disorder in the CUMS group by targeted quantitative analysis, CBHP regulated more purine metabolites (six) than individual administration (two and two). The results showed that purine metabolism was modulated by CBHP through synergistically decreasing xanthine levels and inhibiting the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XOD). Finally, the synergistic regulation effect of CBHP on xanthine synthesis was found to be related to inhibition of malondialdehyde (MDA) production, Nod-like receptor protein 3 (NLRP3) inflammasome expression, and interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α secretion. The present study demonstrated that the regulation of purine metabolism, the suppression of oxidative stress, and inflammatory responses in the cortex were involved in the synergistic antidepressant effect of CBHP.
Structural Insights Into the High Selectivity of the Anti-Diabetic Drug Mitiglinide
Authors: Wang Mengmeng , Wu Jing-Xiang , Chen Lei
Published: June 2022

Mitiglinide is a highly selective fast-acting anti-diabetic drug that induces insulin secretion by inhibiting pancreatic KATP channels. However, how mitiglinide binds KATP channels remains unknown. Here, we show the cryo-EM structure of the SUR1 subunit complexed with mitiglinide. The structure reveals that mitiglinide binds inside the common insulin secretagogue-binding site of SUR1, which is surrounded by TM7, TM8, TM16, and TM17. Mitiglinide locks SUR1 in the NBD-separated inward-facing conformation. The detailed structural analysis of the mitiglinide-binding site uncovers the molecular basis of its high selectivity.
Insights Into the Properties, Biological Functions, and Regulation of USP21
Authors: An Tao , Lu Yanting , Yan Xu , Hou Jingjing
Published: June 2022

Deubiquitylating enzymes (DUBs) antagonize ubiquitination by removing ubiquitin from their substrates. The role of DUBs in controlling various physiological and pathological processes has been extensively studied, and some members of DUBs have been identified as potential therapeutic targets in diseases ranging from tumors to neurodegeneration. Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease family, the largest subfamily of DUBs. Although USP21 was discovered late and early research progress was slow, numerous studies in the last decade have gradually revealed the importance of USP21 in a wide variety of biological processes. In particular, the pro-carcinogenic effect of USP21 has been well elucidated in the last 2 years. In the present review, we provide a comprehensive overview of the current knowledge on USP21, including its properties, biological functions, pathophysiological roles, and cellular regulation. Limited pharmacological interventions for USP21 have also been introduced, highlighting the importance of developing novel and specific inhibitors targeting USP21.
Acylation, a Conductor of Ghrelin Function in Brain Health and Disease
Authors: Thomas Alanna S. , Sassi Martina , Angelini Roberto , Morgan Alwena H. , Davies Jeffrey S.
Published: June 2022

Acyl-ghrelin (AG) is an orexigenic hormone that has a unique octanoyl modification on its third serine residue. It is often referred to as the “hunger hormone” due to its involvement in stimulating food intake and regulating energy homeostasis. The discovery of the enzyme ghrelin-O-acyltransferase (GOAT), which catalyses ghrelin acylation, provided further insights into the relevance of this lipidation process for the activation of the growth hormone secretagogue receptor (GHS-R) by acyl-ghrelin. Although acyl-ghrelin is predominantly linked with octanoic acid, a range of saturated fatty acids can also bind to ghrelin possibly leading to specific functions. Sources of ghrelin acylation include beta-oxidation of longer chain fatty acids, with contributions from fatty acid synthesis, the diet, and the microbiome. In addition, both acyl-ghrelin and unacyl-ghrelin (UAG) have feedback effects on lipid metabolism which in turn modulate their levels. Recently we showed that whilst acyl-ghrelin promotes adult hippocampal neurogenesis and enhances memory function, UAG inhibits these processes. As a result, we postulated that the circulating acyl-ghrelin:unacyl-ghrelin (AG:UAG) ratio might be an important regulator of neurogenesis and cognition. In this review, we discuss emerging evidence behind the relevance of ghrelin acylation in the context of brain physiology and pathology, as well as the current challenges of identifying the provenance of the acyl moiety.
Protein Quality Control at the Sarcomere: Titin Protection and Turnover and Implications for Disease Development
Authors: Kötter Sebastian , Krüger Martina
Published: June 2022

Sarcomeres are mainly composed of filament and signaling proteins and are the smallest molecular units of muscle contraction and relaxation. The sarcomere protein titin serves as a molecular spring whose stiffness mediates myofilament extensibility in skeletal and cardiac muscle. Due to the enormous size of titin and its tight integration into the sarcomere, the incorporation and degradation of the titin filament is a highly complex task. The details of the molecular processes involved in titin turnover are not fully understood, but the involvement of different intracellular degradation mechanisms has recently been described. This review summarizes the current state of research with particular emphasis on the relationship between titin and protein quality control. We highlight the involvement of the proteasome, autophagy, heat shock proteins, and proteases in the protection and degradation of titin in heart and skeletal muscle. Because the fine-tuned balance of degradation and protein expression can be disrupted under pathological conditions, the review also provides an overview of previously known perturbations in protein quality control and discusses how these affect sarcomeric proteins, and titin in particular, in various disease states.
Pentaploidization Enriches the Genetic Diversity of Wheat by Enhancing the Recombination of AB Genomes
Authors: Yang Fan , Wan Hongshen , Li Jun , Wang Qin , Yang Ning , Zhu Xinguo , Liu Zehou , Yang Yumin , Ma Wujun , Fan Xing , Yang Wuyun , Zhou Yonghong
Published: June 2022

Allohexaploidization and continuous introgression play a key role in the origin and evolution of bread wheat. The genetic bottleneck of bread wheat resulting from limited germplasms involved in the origin and modern breeding may be compensated by gene flow from tetraploid wheat through introgressive hybridization. The inter-ploidy hybridization between hexaploid and tetraploid wheat generates pentaploid hybrids first, which absorbed genetic variations both from hexaploid and tetraploid wheat and have great potential for re-evolution and improvement in bread wheat. Therefore, understanding the effects of the pentaploid hybrid is of apparent significance in our understanding of the historic introgression and in informing breeding. In the current study, two sets of F2populations of synthetic pentaploid wheat (SPW1 and SPW2) and synthetic hexaploid wheat (SHW1 and SHW2) were created to analyze differences in recombination frequency (RF) of AB genomes and distorted segregation of polymorphic SNP markers through SNP genotyping. Results suggested that (1) the recombination of AB genomes in the SPW populations was about 3- to 4-fold higher than that in the SHW populations, resulting from the significantly (P< 0.01) increased RF between adjacent and linked SNP loci, especially the variations that occurred in a pericentromeric region which would further enrich genetic diversity; (2) the crosses of hexaploid × tetraploid wheat could be an efficient way to produce pentaploid derivatives than the crosses of tetraploid × hexaploid wheat according to the higher germination rate found in the former crosses; (3) the high proportion of distorted segregation loci that skewed in favor of the female parent genotype/allele in the SPW populations might associate with the fitness and survival of the offspring. Based on the presented data, we propose that pentaploid hybrids should increasingly be used in wheat breeding. In addition, the contribution of gene flow from tetraploid wheat to bread wheat mediated by pentaploid introgressive hybridization also was discussed in the re-evolution of bread wheat.
Ectomycorrhizal Networks in the Anthropocene: From Natural Ecosystems to Urban Planning
Authors: Authier Louise , Violle Cyrille , Richard Franck
Published: June 2022

Trees acquire hydric and mineral soil resources through root mutualistic associations. In most boreal, temperate and Mediterranean forests, these functions are realized by a chimeric structure called ectomycorrhizae. Ectomycorrhizal (ECM) fungi are highly diversified and vary widely in their specificity toward plant hosts. Reciprocally, association patterns of ECM plants range from highly specialist to generalist. As a consequence, ECM symbiosis creates interaction networks, which also mediate plant–plant nutrient interactions among different individuals and drive plant community dynamics. Our knowledge of ECM networks essentially relies on a corpus acquired in temperate ecosystems, whereas the below-ground facets of both anthropogenic ECM forests and inter-tropical forests remain poorly investigated. Here, we successively (1) review the current knowledge of ECM networks, (2) examine the content of early literature produced in ECM cultivated forests, (3) analyze the recent progress that has been made in understanding the place of ECM networks in urban soils, and (4) provide directions for future research based on the identification of knowledge gaps. From the examined corpus of knowledge, we reach three main conclusions. First, the emergence of metabarcoding tools has propelled a resurgence of interest in applying network theory to ECM symbiosis. These methods revealed an unexpected interconnection between mutualistic plants with arbuscular mycorrhizal (AM) herbaceous plants, embedding ECM mycelia through root-endophytic interactions. This affinity of ECM fungi to bind VA and ECM plants, raises questions on the nature of the associated functions. Second, despite the central place of ECM trees in cultivated forests, little attention has been paid to these man-made landscapes and in-depth research on this topic is lacking. Third, we report a lag in applying the ECM network theory to urban soils, despite management initiatives striving to interconnect motile organisms through ecological corridors, and the highly challenging task of interconnecting fixed organisms in urban greenspaces is discussed. In particular, we observe a pauperized nature of resident ECM inoculum and a spatial conflict between belowground human pipelines and ECM networks. Finally, we identify the main directions of future research to make the needed link between the current picture of plant functioning and the understanding of belowground ECM networks.
The Plant V-ATPase
Authors: Seidel Thorsten
Published: June 2022

V-ATPase is the dominant proton pump in plant cells. It contributes to cytosolic pH homeostasis and energizes transport processes across endomembranes of the secretory pathway. Its localization in the trans Golgi network/early endosomes is essential for vesicle transport, for instance for the delivery of cell wall components. Furthermore, it is crucial for response to abiotic and biotic stresses. The V-ATPase’s rather complex structure and multiple subunit isoforms enable high structural flexibility with respect to requirements for different organs, developmental stages, and organelles. This complexity further demands a sophisticated assembly machinery and transport routes in cells, a process that is still not fully understood. Regulation of V-ATPase is a target of phosphorylation and redox-modifications but also involves interactions with regulatory proteins like 14-3-3 proteins and the lipid environment. Regulation by reversible assembly, as reported for yeast and the mammalian enzyme, has not be proven in plants but seems to be absent in autotrophic cells. Addressing the regulation of V-ATPase is a promising approach to adjust its activity for improved stress resistance or higher crop yield.