bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel necroptosis-related lncRNA signature for predicting prognosis and anti-cancer treatment response in endometrial cancer
Authors: He Wei-Peng , Chen Yu-Ying , Wu Lin-Xiang , Guo Yun-Yun , You Ze-Shan , Yang Guo-Fen
Published: November 2022

Background

Necroptosis, a form of programmed cell death, underlies tumorigenesis and the progression of cancers. Anti-cancer strategies targeting necroptosis have increasingly been shown to present a potential cancer therapy. However, the predictive utility and anticancer sensitivity value of necroptosis-related lncRNAs (NRLs) for endometrial cancer (EC) are currently unknown.

Methods

EC patient gene expression profiles and the corresponding clinical information collected from The Cancer Genome Atlas were used to identify NRLs that constituted a predictive signature for EC. The functional pathways, immune status, clinicopathological correlation, and anticancer drug sensitivity of the patients relative to the NRLs signatures were analyzed.

Results

A signature composed of 7 NRLs (AC019080.5, BOLA3-AS1, AC022144.1, AP000345.2, LEF1-AS1, AC010503.4, and RPARP-AS1) was identified. The high-risk patient group with this signature exhibited a poorer prognosis and lower survival rate than low-risk group lacking this signature. This necroptosis-related lncRNA signature had a higher predictive accuracy compared with other clinicopathological variables (area under the receiver operating characteristic curve of the risk score: 0.717). Additionally, when patients were stratified based on other clinicopathological variables, the overall survival was significantly shorter in the high-risk versus low-risk group across all cohorts. Gene set enrichment analysis (GSEA) revealed that immune- and tumor-related signaling pathways and biological processes were enriched in the high-risk group compared to the low-risk group. Single-sample gene set enrichment analysis (ssGSEA) additionally showed that the resulting risk score was strongly correlated with EC patient immune status. Finally, patients with high-risk scores were more sensitive to the anti-cancer drugs such as Docetaxel, Mitomycin.C, Vinblastine, AZD.2281 (olaparib), AZD6244, and PD.0332991 (Palbociclib).

Conclusion

These findings reveal a novel necroptosis-related lncRNA signature for predicting EC patient prognosis and shed new light on anticancer therapy strategies for EC.
A novel costimulatory molecule gene-modified leukemia cell-derived exosome-targeted CD4+ T cell vaccine efficiently enhances anti-leukemia immunity
Authors: Li Jiaqi , Huang Fang , Jiang Yan , Zhao Jie , Wan Jiangbo , Hao Siguo
Published: November 2022

Previous studies demonstrated that CD4+ T cells can uptake tumor antigen-pulsed dendritic cell-derived exosomes (DEXO), which harbor tumor antigen peptide/pMHC I complex and costimulatory molecules and show potent effects on inducing antitumor immunity. However, in preliminary study, CD4+ T cells targeted by leukemia cell-derived exosomes (LEXs) did not show the expected effects in inducing effective anti-leukemia immunity, indicating that LEX is poorly immunogenetic largely due to an inadequate costimulatory capacity. Therefore, LEX-based anti-leukemia vaccines need to be optimized. In this study, we constructed a novel LEX-based vaccine by combining CD4+ T cells with costimulatory molecules gene-modified LEXs, which harbor upregulated CD80 and CD86, and the anti-leukemia immunity of CD80 and CD86 gene-modified LEX-targeted CD4+ T cells was investigated. We used lentiviral vectors encoding CD80 and CD86 to successfully transduced the L1210 leukemia cells, and the expression of CD80 and CD86 was remarkably upregulated in leukemia cells. The LEXs highly expressing CD80 and CD86 were obtained from the supernatants of gene-transduced leukemia cells. Our data have shown that LEX-CD8086 could promote CD4+ T cell proliferation and Th1 cytokine secretion more efficiently than control LEXs. Moreover, CD4+ TLEX-CD8086 expressed the acquired exosomal costimulatory molecules. With acquired costimulatory molecules, CD4+ TLEX-CD8086 can act as APCs and are capable of directly stimulating the leukemia cell antigen-specific CD8+ CTL response. This response was higher in potency compared to that noted by the other formulations. Furthermore, the animal study revealed that the CD4+ TLEX-CD8086 significantly inhibited tumor growth and prolonged survival of tumor-bearing mice than other formulations did in both protective and therapeutic models. In conclusion, this study revealed that CD4+ TLEX-CD8086 could effectively induce more potential anti-leukemia immunity than LEX-CD8086 alone, suggesting that the utilization of a costimulatory molecule gene-modified leukemia cell-derived exosome-targeted CD4+ T cell vaccine may have promising potential for leukemia immunotherapy.
A practical nomogram based on serum interleukin-6 for the prognosis of liver failure
Authors: Xiao Nanxi , Liu Linxiang , Zhang Yue , Nie Yuan , Zhu Xuan
Published: November 2022

Background

Liver failure (LF) is a serious liver function damage caused by various factors, mainly jaundice, hepatic encephalopathy, coagulation disorders and multiple organ failure, with the clinical characteristic of high short-term mortality. LF is often accompanied by excessive activation of inflammatory factors, and an excessive systemic inflammatory response (i.e., inflammatory storm) is considered to be the trigger of LF. However, a specific prognostic model including inflammatory factors for patients with LF has not been well established.

Aim

To establish and validate a nomogram for predicting 28-day, 90-day, and 180-day mortality in patients with LF.

Methods

A total of 423 eligible LF patients were enrolled in this retrospective study. Independent predictors were identified using a multivariate logistic model and then integrated into a nomogram to predict 28-day, 90-day, and 180-day mortality. The concordance index, receiver operating characteristic curves, and calibration plots were used to evaluate the performance of the model.

Results

Sex, age, total bilirubin, aspartate aminotransferase, international normalized ratio, Child–Pugh score, and serum interleukin-6 were independent risk factors for death at 28, 90, and 180 days in LF patients. The nomogram showed good calibration and discrimination with an area under the receiver operating characteristic curve (AUC) of 0.927. The calibration curve fit as well, indicating that the nomogram had good clinical application value.

Conclusion

This nomogram model for predicting the 28-day, 90-day, and 180-day mortality of LF patients could help optimize treatment strategies and improve prognosis.
Clinical, imaging, and blood biomarkers to assess 1-year progression risk in fibrotic interstitial lung diseases—Development and validation of the honeycombing, traction bronchiectasis, and monocyte (HTM)-score
Authors: Shao Guangyu , Hawle Patricia , Akbari Kaveh , Horner Andreas , Hintenberger Rainer , Kaiser Bernhard , Lamprecht Bernd , Lang David
Published: November 2022

Introduction

Progression of fibrotic interstitial lung disease (ILD) leads to irreversible loss of lung function and increased mortality. Based on an institutional ILD registry, we aimed to evaluate biomarkers derived from baseline patient characteristics, computed tomography (CT), and peripheral blood for prognosis of disease progression in fibrotic ILD patients.

Methods

Of 209 subsequent ILD-board patients enregistered, 142 had complete follow-up information and were classified fibrotic ILD as defined by presence of reticulation or honeycombing using a standardized semi-quantitative CT evaluation, adding up typical ILD findings in 0–6 defined lung fields. Progression at 1 year was defined as relative loss of ≥10% in forced vital capacity, of ≥15% in diffusion capacity for carbon monoxide, death, or lung transplant. Two-thirds of the patients were randomly assigned to a derivation cohort evaluated for the impact of age, sex, baseline lung function, CT finding scores, and blood biomarkers on disease progression. Significant variables were included into a regression model, its results were used to derive a progression-risk score which was then applied to the validation cohort.

Results

In the derivation cohort, age, monocyte count ≥0.65 G/L, honeycombing and traction bronchiectasis extent had significant impact. Multivariate analyses revealed the variables monocyte count ≥0.65 G/L (1 point) and combined honeycombing or traction bronchiectasis score [0 vs. 1–4 (1 point) vs. 5–6 lung fields (2 points)] as significant, so these were used for score development. In the derivation cohort, resulting scores of 0, 1, 2, and 3 accounted for 1-year progression rates of 20, 25, 46.9, and 88.9%, respectively. Similarly, in the validation cohort, progression at 1 year occurred in 0, 23.8, 53.9, and 62.5%, respectively. A score ≥2 showed 70.6% sensitivity and 67.9% specificity, receiver operating characteristic analysis for the scoring model had an area under the curve of 71.7%.

Conclusion

The extent of honeycombing and traction bronchiectasis, as well as elevated blood monocyte count predicted progression within 1 year in fibrotic ILD patients.
Allicin shows antifungal efficacy against Cryptococcus neoformans by blocking the fungal cell membrane
Authors: Li Zhun , Li Zhengtu , Yang Jun , Lu Chun , Li Yongming , Luo Yinzhu , Cong Feng , Shi Rongmei , Wang Zhen , Chen Huaying , Li Xinxia , Yang Jinglu , Ye Feng
Published: November 2022

Allicin, which is generated by the catalytic reaction between alliin and alliinase extracted from garlic, has been shown to have a wide range of antimicrobial activities, but its anti-Cryptococcus efficacy and mechanism are not quite clear. Here, we have determined that the Conversion rate of allicin in the reaction product reached 97.5%. The minimal inhibitory concentration (MIC) of allicin against Cryptococcus neoformans (C. neoformans) H99 was 2 μg/ml, which is comparable to fluconazole (FLU, 1 μg/ml). Furthermore, allicin exhibited effective antifungal activity against 46 clinical isolates of C. neoformans, and the MICs ranged from 1 to 8 μg/ml, even for AmB-insensitive strains. Interestingly, allicin also exerted additive or synergistic effects when combined with amphotericin B (AmB) and FLU. Time-killing curves and long-term live cell imaging of H99 showed that 4 MIC of allicin had fungicide activity. Additionally, allicin (4 and 8 mg/kg) exerted a dose-dependent therapeutic effect on H99-infected mice by significantly reducing the wet pulmonary coefficient and Cryptococcus load and reducing lung damage. Even the efficacy of 8 mg/kg was comparable to FLU (20 mg/kg). Transcriptomics revealed that allicin may act on the cell membrane of H99. Subsequently, transmission electron microscopy (TEM) observations showed that allicin clearly breached the cell membrane and organelles of H99. Confocal laser scanning microscopy (CLSM) results further confirmed that allicin disrupted the permeability of the cell membranes of H99 in a dose-dependent manner. Allicin exhibits strong anti-C. neoformans activity in vitro and in vivo, mainly by destroying the permeability and related functions of Cryptococcus cell membranes.
Metabolic diversity in a collection of wild and cultivated Brassica rapa subspecies
Authors: Zheng Shuning , Szymański Jędrzej , Shahaf Nir , Malitsky Sergey , Meir Sagit , Wang Xiaowu , Aharoni Asaph , Rogachev Ilana
Published: November 2022

Brassica rapa (B. rapa) and its subspecies contain many bioactive metabolites that are important for plant defense and human health. This study aimed at investigating the metabolite composition and variation among a large collection of B. rapa genotypes, including subspecies and their accessions. Metabolite profiling of leaves of 102 B. rapa genotypes was performed using ultra-performance liquid chromatography coupled with a photodiode array detector and quadrupole time-of-flight mass spectrometry (UPLC-PDA-QTOF-MS/MS). In total, 346 metabolites belonging to different chemical classes were tentatively identified; 36 out of them were assigned with high confidence using authentic standards and 184 were those reported in B. rapa leaves for the first time. The accumulation and variation of metabolites among genotypes were characterized and compared to their phylogenetic distance. We found 47 metabolites, mostly representing anthocyanins, flavonols, and hydroxycinnamic acid derivatives that displayed a significant correlation to the phylogenetic relatedness and determined four major phylometabolic branches; 1) Chinese cabbage, 2) yellow sarson and rapid cycling, 3) the mizuna-komatsuna-turnip-caitai; and 4) a mixed cluster. These metabolites denote the selective pressure on the metabolic network during B. rapa breeding. We present a unique study that combines metabolite profiling data with phylogenetic analysis in a large collection of B. rapa subspecies. We showed how selective breeding utilizes the biochemical potential of wild B. rapa leading to highly diverse metabolic phenotypes. Our work provides the basis for further studies on B. rapa metabolism and nutritional traits improvement.
The structure of anticorrelated networks in the human brain
Authors: Martinez-Gutierrez Endika , Jimenez-Marin Antonio , Stramaglia Sebastiano , Cortes Jesus M.
Published: November 2022

During the performance of a specific task--or at rest--, the activity of different brain regions shares statistical dependencies that reflect functional connections. While these relationships have been studied intensely for positively correlated networks, considerably less attention has been paid to negatively correlated networks, a. k.a. anticorrelated networks (ACNs). Although the most celebrated of all ACNs is the default mode network (DMN), and has even been extensively studied in health and disease, for systematically all ACNs other than DMN, there is no comprehensive study yet. Here, we have addressed this issue by making use of three neuroimaging data sets: one of N = 192 healthy young adults to fully describe ACN, another of N = 40 subjects to compare ACN between two groups of young and old participants, and another of N = 1,000 subjects from the Human Connectome Project to evaluate the association between ACN and cognitive scores. We first provide a comprehensive description of the anatomical composition of all ACNs, each of which participated in distinct resting-state networks (RSNs). In terms of participation ranking, from highest to the lowest, the major anticorrelated brain areas are the precuneus, the anterior supramarginal gyrus and the central opercular cortex. Next, by evaluating a more detailed structure of ACN, we show it is possible to find significant differences in ACN between specific conditions, in particular, by comparing groups of young and old participants. Our main finding is that of increased anticorrelation for cerebellar interactions in older subjects. Finally, in the voxel-level association study with cognitive scores, we show that ACN has multiple clusters of significance, clusters that are different from those obtained from positive correlated networks, indicating a functional cognitive meaning of ACN. Overall, our results give special relevance to ACN and suggest their use to disentangle unknown alterations in certain conditions, as could occur in early-onset neurodegenerative diseases or in some psychiatric conditions.
Vascular responses of penetrating vessels during cortical spreading depolarization with ultrasound dynamic ultrafast Doppler imaging
Authors: Hsieh Bao-Yu , Kao Yu-Chieh Jill , Zhou Ning , Lin Yi-Pei , Mei Yu-Ying , Chu Sung-Yu , Wu Dong-Chuan
Published: November 2022

The dynamic vascular responses during cortical spreading depolarization (CSD) are causally related to pathophysiological consequences in numerous neurovascular conditions, including ischemia, traumatic brain injury, cerebral hemorrhage, and migraine. Monitoring of the hemodynamic responses of cerebral penetrating vessels during CSD is motivated to understand the mechanism of CSD and related neurological disorders. Six SD rats were used, and craniotomy surgery was performed before imaging. CSDs were induced by topical KCl application. Ultrasound dynamic ultrafast Doppler was used to access hemodynamic changes, including cerebral blood volume (CBV) and flow velocity during CSD, and further analyzed those in a single penetrating arteriole or venule. The CSD-induced hemodynamic changes with typical duration and propagation speed were detected by ultrafast Doppler in the cerebral cortex ipsilateral to the induction site. The hemodynamics typically showed triphasic changes, including initial hypoperfusion and prominent hyperperfusion peak, followed by a long-period depression in CBV. Moreover, different hemodynamics between individual penetrating arterioles and venules were proposed by quantification of CBV and flow velocity. The negative correlation between the basal CBV and CSD-induced change was also reported in penetrating vessels. These results indicate specific vascular dynamics of cerebral penetrating vessels and possibly different contributions of penetrating arterioles and venules to the CSD-related pathological vascular consequences. We proposed using ultrasound dynamic ultrafast Doppler imaging to investigate CSD-induced cerebral vascular responses. With this imaging platform, it has the potential to monitor the hemodynamics of cortical penetrating vessels during brain injuries to understand the mechanism of CSD in advance.
Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro
Authors: Yang Xiaohan , Xu Yuan , Gao Wenting , Wang Li , Zhao Xinnan , Liu Gang , Fan Kai , Liu Shuang , Hao Huimin , Qu Siyan , Dong Renhou , Ma Xiaokai , Ma Jianmei
Published: November 2022

Numerous studies have demonstrated that type 2 diabetes (T2D) is closely linked to the occurrence of Alzheimer’s disease (AD). Nevertheless, the underlying mechanisms for this association are still unknown. Insulin resistance (IR) hallmarked by hyperinsulinemia, as the earliest and longest-lasting pathological change in T2D, might play an important role in AD. Since hyperinsulinemia has an independent contribution to related disease progressions by promoting inflammation in the peripheral system, we hypothesized that hyperinsulinemia might have an effect on microglia which plays a crucial role in neuroinflammation of AD. In the present study, we fed 4-week-old male C57BL/6 mice with a high-fat diet (HFD) for 12 weeks to establish IR model, and the mice treated with standard diet (SD) were used as control. HFD led to obesity in mice with obvious glucose and lipid metabolism disorder, the higher insulin levels in both plasma and cerebrospinal fluid, and aberrant insulin signaling pathway in the whole brain. Meanwhile, IR mice appeared impairments of spatial learning and memory accompanied by neuroinflammation which was characterized by activated microglia and upregulated expression of pro-inflammatory factors in different brain regions. To clarify whether insulin contributes to microglial activation, we treated primary cultured microglia and BV2 cell lines with insulin in vitro to mimic hyperinsulinemia. We found that hyperinsulinemia not only increased microglial proliferation and promoted M1 polarization by enhancing the production of pro-inflammatory factors, but also impaired membrane translocation of glucose transporter 4 (GLUT4) serving as the insulin-responding glucose transporter in the processes of glucose up-taking, reduced ATP production and increased mitochondrial fission. Our study provides new perspectives and evidence for the mechanism underlying the association between T2D and AD.
The differential role of magnetic resonance imaging in predicting surgical outcomes between children versus adults with temporal lobe epilepsy
Authors: Xu Ke , Wang Xiongfei , Zhou Jian , Guan Yuguang , Li Tianfu , Luan Guoming
Published: November 2022

Objective

This study aims to investigate the clinical discrepancies and the different predictors of anterior temporal lobectomy (ATL) in children (<18 years at surgery) and adults (>18 years at surgery) with temporal lobe epilepsy (TLE).

Materials and methods

A total of 262 patients (56 children and 206 adults) with TLE who underwent ATL were included in this study. The clinical variables, including patients’ characteristics, preoperative evaluations, pathology, surgical prognosis, and surgical predictors were assessed the discrepancies between TLE children versus adults using univariate and multivariate analyses. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom and AEDs withdrawal after ATL, and the difference between TLE children and adults was analyzed using the Log-Rank test.

Results

There were significant differences including semiology, magnetic resonance imaging (MRI) examinations, numbers of preoperative AEDs, and pathologies between TLE children and adults (P < 0.05, Q < 0.05). The MRI-detected epileptic focus was the only independent predictor of seizure freedom (P = 0.002, Q = 0.036) in TLE children, and the concordance of MRI-detected focus with video-electroencephalography (video-EEG)-detected epileptic zone was the only variable associated with seizure freedom in TLE adults (OR = 2.686, 95% CI = 1.014–7.115, P = 0.047). The TLE children experienced a higher probability of AEDs withdrawal than adults after surgery (P = 0.005).

Significance

There were remarkable differences in clinical manifestations, MRI examinations, number of preoperative AEDs, and pathologies between TLE children versus adults. TLE children had a higher possibility of AEDs withdrawal than adults after surgery. The favorable seizure outcome of ATL depended on the early complete resection of MRI-detected epileptogenic focus in TLE children, while the concordance of MRI-detected focus with EEG-detected epileptogenic zone was the only predictor of favorable seizure outcomes in TLE adults.
Linear discriminant analysis of phenotypic data for classifying autism spectrum disorder by diagnosis and sex
Authors: Jacokes Zachary , Jack Allison , Sullivan Catherine A. W. , Aylward Elizabeth , Bookheimer Susan Y. , Dapretto Mirella , Bernier Raphael A. , Geschwind Daniel H. , Sukhodolsky Denis G. , McPartland James C. , Webb Sara J. , Torgerson Carinna M. , Eilbott Jeffrey , Kenworthy Lauren , Pelphrey Kevin A. , Van Horn John D. ,   The GENDAAR Consortium
Published: November 2022

Autism Spectrum Disorder (ASD) is a developmental condition characterized by social and communication differences. Recent research suggests ASD affects 1-in-44 children in the United States. ASD is diagnosed more commonly in males, though it is unclear whether this diagnostic disparity is a result of a biological predisposition or limitations in diagnostic tools, or both. One hypothesis centers on the ‘female protective effect,’ which is the theory that females are biologically more resistant to the autism phenotype than males. In this examination, phenotypic data were acquired and combined from four leading research institutions and subjected to multivariate linear discriminant analysis. A linear discriminant model was trained on the training set and then deployed on the test set to predict group membership. Multivariate analyses of variance were performed to confirm the significance of the overall analysis, and individual analyses of variance were performed to confirm the significance of each of the resulting linear discriminant axes. Two discriminant dimensions were identified between the groups: a dimension separating groups by the diagnosis of ASD (LD1: 87% of variance explained); and a dimension reflective of a diagnosis-by-sex interaction (LD2: 11% of variance explained). The strongest discriminant coefficients for the first discriminant axis divided the sample in domains with known differences between ASD and comparison groups, such as social difficulties and restricted repetitive behavior. The discriminant coefficients for the second discriminant axis reveal a more nuanced disparity between boys with ASD and girls with ASD, including executive functioning and high-order behavioral domains as the dominant discriminators. These results indicate that phenotypic differences between males and females with and without ASD are identifiable using parent report measures, which could be utilized to provide additional specificity to the diagnosis of ASD in female patients, potentially leading to more targeted clinical strategies and therapeutic interventions. The study helps to isolate a phenotypic basis for future empirical work on the female protective effect using neuroimaging, EEG, and genomic methodologies.
Eliminate the hardware: Mobile terminals-oriented food recognition and weight estimation system
Authors: Zhang Qinqiu , He Chengyuan , Qin Wen , Liu Decai , Yin Jun , Long Zhiwen , He Huimin , Sun Ho Ching , Xu Huilin
Published: November 2022

Food recognition and weight estimation based on image methods have always been hotspots in the field of computer vision and medical nutrition, and have good application prospects in digital nutrition therapy and health detection. With the development of deep learning technology, image-based recognition technology has also rapidly extended to various fields, such as agricultural pests, disease identification, tumor marker recognition, wound severity judgment, road wear recognition, and food safety detection. This article proposes a non-wearable food recognition and weight estimation system (nWFWS) to identify the food type and food weight in the target recognition area via smartphones, so to assist clinical patients and physicians in monitoring diet-related health conditions. In addition, the system is mainly designed for mobile terminals; it can be installed on a mobile phone with an Android system or an iOS system. This can lower the cost and burden of additional wearable health monitoring equipment while also greatly simplifying the automatic estimation of food intake via mobile phone photography and image collection. Based on the system’s ability to accurately identify 1,455 food pictures with an accuracy rate of 89.60%, we used a deep convolutional neural network and visual-inertial system to collect image pixels, and 612 high-resolution food images with different traits after systematic training, to obtain a preliminary relationship model between the area of food pixels and the measured weight was obtained, and the weight of untested food images was successfully determined. There was a high correlation between the predicted and actual values. In a word, this system is feasible and relatively accurate for one automated dietary monitoring and nutritional assessment.
Impact of SOX2 function and regulation on therapy resistance in bladder cancer
Authors: Chen Guodong , Chen Yan , Xu Ruiquan , Zhang Guoxi , Zou Xiaofeng , Wu Gengqing
Published: November 2022

Bladder cancer (BC) is a malignant disease with high rates of recurrence and mortality. It is mainly classified as non-muscle-invasive BC and muscle-invasive BC (MIBC). Often, MIBC is chemoresistant, which, according to cancer stem cells (CSCs) theory, is linked to the presence of bladder cancer stem cells (BCSCs). Sex-determining region Y- (SRY) Box transcription factor 2 (SOX2), which is a molecular marker of BCSCs, is aberrantly over-expressed in chemoresistant BC cell lines. It is one of the standalone prognostic factors for BC, and it has an inherently significant function in the emergence and progression of the disease. This review first summarizes the role of SRY-related high-mobility group protein Box (SOX) family genes in BC, focusing on the SOX2 and its significance in BC. Second, it discusses the mechanisms relevant to the regulation of SOX2. Finally, it summarizes the signaling pathways related to SOX2 in BC, suggests current issues to be addressed, and proposes potential directions for future research to provide new insights for the treatment of BC.
Case report: Solitary fibrous tumor of the kidney with a NAB2-STAT6 fusion gene
Authors: Ji Wen-Tong , Hu Yu , Wang Yao
Published: November 2022

Background

Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm that mostly originates from the pleura, and accounts for only 2% of all soft tissue tumors. Moreover, the cases of SFT of the kidney are rarely reported. Here, we report a typical case of kidney SFT, which was consistent with other reported cases. This case further expands on existing diagnostic methods of SFT and explains the importance of STAT6 mutations in SFT.

Case Summary

We report a typical case of SFT of the kidney. A 34-year-old woman presented to the urinary surgery department after physical examinations were suggestive of a urologic neoplasm. Further relevant imaging investigations suggested a renal tumor with benign behaviors. The patient was diagnosed with a kidney tumor suspected to be SFT and underwent laparoscopic radical left nephrectomy. Postoperative pathological immunohistochemical tests showed positivity for Signal Transducer and Activator of Transcription 6(STAT6), CD-34, CD-99, and Bcl-2, thus confirming the diagnosis of SFT. Combined with the results of genetic testing of the patient, the tumor was indicated to carry NGFI-A-Binding protein 2(NAB2): exon 6—STAT6: exon 16 mutation sites, which confirmed our diagnosis. The patient recovered quickly without any clinical evidence of incomplete resection. She has been followed-up for more than a year and will continue to be reviewed every three months to observe the final outcomes.

Conclusion

Solitary fibrous tumor is difficult to differentiate from other renal tumors. CT imaging, STAT6 immunostaining and gene profiling are valid investigations to establish the diagnosis.
Risk and prognosis of secondary malignant neoplasms after radiation therapy for bladder cancer: A large population-based cohort study
Authors: Chen Ru , Zhan Xiangpeng , Jiang Haoxin , Liu Yang , Jiang Zhi , Jiang Ming , Deng Wen , Liu Xiaoqiang , Chen Guoxian , Fu Bin
Published: November 2022

Objective

To investigate the association between radiotherapy and the risk of second malignant neoplasm (SMN) development among patients with bladder cancer (BC). Overall survival (OS) is compared among patients developing SMN and without.

Method

We identified patients diagnosed with BC from the Surveillance, Epidemiology, and End Results (SEER) database. The development of an SMN is defined as any SMN occurring more than 5 years after the diagnosis of BC. The Fine-Gray competing risk regression is used to estimate the probability of SMN. The radiotherapy-associated risk (RR) for SMNs is assessed by Poisson regression. The Kaplan–Meier method was used to evaluate the OS of patients with SMNs. Propensity score matching (PSM) is performed.

Results

A total of 76575 BC patients are enrolled in our study. The probability of SMNs in the radiotherapy cohort is statistically higher than in the non-radiotherapy cohort. In competing risk regression analysis, radiotherapy is proven to be associated with a higher risk of SMN (Hazard ratio: 1.23; 95% CI: 1.102–1.368). The radiotherapy-associated risks significantly increase in the radiotherapy cohort (RR: 1.28; 95% CI: 1.14–1.43). In site-specific analysis, statistically significant results are observed in lung and bronchus (LAB) cancer and hematological malignancies. The OS rate in patients developing SMN is significantly lower than that among matched patients with primary BC.

Conclusion

Radiotherapy for BC is associated with SMN. Radiotherapy increases the risk of secondary low-dose area cancer development, including LAB cancer or hematological malignancies. Notably, this effect is not observed in the high-dose area involving pelvic tumors. Patients developing SMN showed poorer OS.
Integrative proteomics and m6A microarray analyses of the signatures induced by METTL3 reveals prognostically significant in gastric cancer by affecting cellular metabolism
Authors: Peng Guisen , Chen Shuran , Zheng Ni , Tang Yuan , Su Xu , Wang Jing , Dong Rui , Wu Di , Hu Mingjie , Zhao Yunli , Liu Mulin , Wu Huazhang
Published: November 2022

METTL3-mediated RNA N6-methyladenosine (m6A) is the most prevalent modification that participates in tumor initiation and progression via governing the expression of their target genes in cancers. However, its role in tumor cell metabolism remains poorly characterized. In this study, m6A microarray and quantitative proteomics were employed to explore the potential effect and mechanism of METTL3 on the metabolism in GC cells. Our results showed that METTL3 induced significant alterations in the protein and m6A modification profile in GC cells. Gene Ontology (GO) enrichment indicated that down-regulated proteins were significantly enriched in intracellular mitochondrial oxidative phosphorylation (OXPHOS). Moreover, the protein-protein Interaction (PPI) network analysis found that these differentially expressed proteins were significantly associated with OXPHOS. A prognostic model was subsequently constructed based on the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, and the high-risk group exhibited a worse prognosis in GC patients. Meanwhile, Gene Set Enrichment Analysis (GSEA) demonstrated significant enrichment in the energy metabolism signaling pathway. Then, combined with the results of the m6A microarray analysis, the intersection molecules of DEPs and differential methylation genes (DMGs) were significantly correlated with the molecules of OXPHOS. Besides, there were significant differences in prognosis and GSEA enrichment between the two clusters of GC patients classified according to the consensus clustering algorithm. Finally, highly expressed and highly methylated molecules regulated by METTL3 were analyzed and three (AVEN, DAZAP2, DNAJB1) genes were identified to be significantly associated with poor prognosis in GC patients. These results signified that METTL3-regulated DEPs in GC cells were significantly associated with OXPHOS. After combined with m6A microarray analysis, the results suggested that these proteins might be implicated in cell energy metabolism through m6A modifications thus influencing the prognosis of GC patients. Overall, our study revealed that METTL3 is involved in cell metabolism through an m6A-dependent mechanism in GC cells, and indicated a potential biomarker for prognostic prediction in GC.
Liquid biopsy for children with central nervous system tumours: Clinical integration and technical considerations
Authors: Stankunaite Reda , Marshall Lynley V. , Carceller Fernando , Chesler Louis , Hubank Michael , George Sally L.
Published: November 2022

Circulating cell-free DNA (cfDNA) analysis has the potential to revolutionise the care of patients with cancer and is already moving towards standard of care in some adult malignancies. Evidence for the utility of cfDNA analysis in paediatric cancer patients is also accumulating. In this review we discuss the limitations of blood-based assays in patients with brain tumours and describe the evidence supporting cerebrospinal fluid (CSF) cfDNA analysis. We make recommendations for CSF cfDNA processing to aid the standardisation and technical validation of future assays. We discuss the considerations for interpretation of cfDNA analysis and highlight promising future directions. Overall, cfDNA profiling shows great potential as an adjunct to the analysis of biopsy tissue in paediatric cancer patients, with the potential to provide a genetic molecular profile of the tumour when tissue biopsy is not feasible. However, to fully realise the potential of cfDNA analysis for children with brain tumours larger prospective studies incorporating serial CSF sampling are required.
Pharmacological basis of bergapten in gastrointestinal diseases focusing on H+/K+ ATPase and voltage-gated calcium channel inhibition: A toxicological evaluation on vital organs
Authors: Aslam Huma , Khan Arif-ullah , Qazi Neelum Gul , Ali Fawad , Hassan Syed Shams ul , Bungau Simona
Published: November 2022

Aim and objectives: This study aimed to establish a pharmacological basis for evaluating the effects of bergapten (5-methoxypsoralen) in gastrointestinal diseases and assessment of its toxicological profile.

Methods: The pharmacokinetic profile was evaluated using the SwissADME tool. AUTODOCK and PyRx were used for evaluating the binding affinities. The obtained results were further investigated for a post-dock analysis using Discovery Studio Visualizer 2016. The Desmond software package was used to conduct molecular dynamic simulations of best bound poses. Bergapten was further investigated for antidiarrheal, anti-secretory, charcoal meal transit time, anti-ulcer, anti-H. pylori activity.

Results: Bergapten at a dose of 50, 100, and 200 mg/kg was proved effective in reducing diarrheal secretions, intestinal secretions, and distance moved by charcoal meal. Bergapten at the aforementioned doses acts as a gastroprotective agent in the ethanol-induced ulcer model that can be attributed to its effectiveness against H. pylori. Bergapten shows concentration-dependent relaxation of both spontaneous and K+ (80 mM)-induced contractions in the isolated rabbit jejunum model; the Ca2+ concentration–response curves (CRCs) were shifted to the right showing potentiating effect similar to papaverine. For molecular investigation, the H+/K+ ATPase inhibitory assay indicated inhibition of the pump comparable to omeprazole. Oxidative stress markers GST, GSH, and catalase showed increased expression, whereas the expression of LPO (lipid peroxidation) was reduced. Histopathological examination indicated marked improvement in cellular morphology. ELISA and western blot confirmed the reduction in inflammatory mediator expression. RT-PCR reduced the mRNA expression level of H+/K+ ATPase, confirming inhibition of the pump. The toxicological profile of bergapten was evaluated by an acute toxicity assay and evaluated for behavioral analysis, and the vital organs were used to analyze biochemical, hematological, and histopathological examination.

Conclusion: Bergapten at the tested doses proved to be an antioxidant, anti-inflammatory, anti-ulcer, and antidiarrheal agent and relatively safe in acute toxicity assay.
Mechano-growth factor E-domain modulates cardiac contractile function through 14-3-3 protein interactomes
Authors: Solís Christopher , Thompson Walter C. , Peña James R. , McDermott-Roe Christopher , Langa Paulina , Warren Chad M. , Chrzanowska Magdalena , Wolska Beata M. , Solaro R. John , Pieter Detombe  , Goldspink Paul H.
Published: November 2022

In the heart, alternative splicing of the igf-I gene produces two isoforms: IGF-IEa and IGF-IEc, (Mechano-growth factor, MGF). The sequence divergence between their E-domain regions suggests differential isoform function. To define the biological actions of MGF’s E-domain, we performed in silico analysis of the unique C-terminal sequence and identified a phosphorylation consensus site residing within a putative 14-3-3 binding motif. To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E18) and phospho-null (S/A18) peptides were delivered to mice at different doses for 2 weeks. Cardiovascular function was measured using echocardiography and a pressure-volume catheter. At the lowest (2.25 mg/kg/day) and highest (9 mg/kg/day) doses, the peptides produced a depression in systolic and diastolic parameters. However, at 4.5 mg/kg/day the peptides produced opposing effects on cardiac function. Fractional shortening analysis also showed a similar trend, but with no significant change in cardiac geometry. Microarray analysis discovered 21 genes (FDR p < 0.01), that were expressed accordant with the opposing effects on contractile function at 4.5 mg/kg/day, with the nuclear receptor subfamily 4 group A member 2 (Nr4a2) identified as a potential target of peptide regulation. Testing the regulation of the Nr4a family, showed the E-domain peptides modulate Nr4a gene expression following membrane depolarization with KCl in vitro. To determine the potential role of 14-3-3 proteins, we examined 14-3-3 isoform expression and distribution. 14-3-3γ localized to the myofilaments in neonatal cardiac myocytes, the cardiac myocytes and myofilament extracts from the adult heart. Thermal shift analysis of recombinant 14-3-3γ protein showed the S/A18 peptide destabilized 14-3-3γ folding. Also, the S/A18 peptide significantly inhibited 14-3-3γ’s ability to interact with myosin binding protein C (MYPC3) and phospholamban (PLN) in heart lysates from dobutamine injected mice. Conversely, the S/E18 peptide showed no effect on 14-3-3γ stability, did not inhibit 14-3-3γ’s interaction with PLN but did inhibit the interaction with MYPC3. Replacing the glutamic acid with a phosphate group on Ser 18 (pSer18), significantly increased 14-3-3γ protein stability. We conclude that the state of Ser 18 phosphorylation within the 14-3-3 binding motif of MGF’s E-domain, modulates protein-protein interactions within the 14-3-3γ interactome, which includes proteins involved in the regulation of contractile function.
Pigment epithelium-derived factor is an interleukin-6 antagonist in the RPE: Insight of structure-function relationships
Authors: Bernardo-Colón Alexandra , Lerner Miriam , Becerra S. Patricia
Published: November 2022

Retinal and choroidal inflammatory lesions increase the levels of the pro-inflammatory cytokine interleukin-6 (IL-6). Pigment epithelium-derived factor (PEDF) has anti-inflammatory properties, but it is not known if it can prevent the production of IL-6 by the retinal pigment epithelium. To investigate the anti-inflammatory effects of PEDF in the RPE, we used human ARPE-19 cells stimulated with human recombinant tumor necrosis factor-alpha (TNF-α) to induce overexpression of the IL6 gene. We found that the viability of ARPE-19 cells decreased by 22% with TNF-α at 10 ng/ml, being drastically decreased at ≥50 ng/ml. TNF-α at 5–100 ng/ml elevated the production and secretion of IL-6 protein, as measured by ELISA. To challenge the TNF-α-mediated stimulation of IL-6, we used recombinant human PEDF protein. PEDF at 100 nM recovered the TNF-α-mediated loss of cell viability and repressed IL-6 gene expression as determined by RT-PCR. PEDF at 10–100 nM attenuated the IL-6 protein secretion in a dose dependent fashion (IC50 = 65 nM), being abolished with 100 nM PEDF. To map the region that confers the IL-6 blocking effect to the PEDF polypeptide, we used chemically synthesized peptides designed from its biologically active domains, pro-death 34-mer, and pro-survival 44-mer and 17-mer (H105A), to challenge the IL-6 overproduction. The pro-survival peptides recovered the TNF-α-mediated cell viability loss, and inhibited IL-6 secretion, while the 34-mer did not have an effect, suggesting a role for the pro-survival domain in blocking TNF-α-mediated cell death and IL-6 stimulation. Our findings position PEDF as a novel antagonistic agent of IL-6 production in RPE cells, underscoring its use for the management of retinal disease-related inflammation.
Genome-guided comparative in planta transcriptome analyses for identifying cross-species common virulence factors in bacterial phytopathogens
Authors: Park Jungwook , Jung Hyejung , Mannaa Mohamed , Lee Seung Yeup , Lee Hyun-Hee , Kim Namgyu , Han Gil , Park Dong-Soo , Lee Sang-Won , Lee Seon-Woo , Seo Young-Su
Published: November 2022

Plant bacterial disease is a complex outcome achieved through a combination of virulence factors that are activated during infection. However, the common virulence factors across diverse plant pathogens are largely uncharacterized. Here, we established a pan-genome shared across the following plant pathogens: Burkholderia glumae, Ralstonia solanacearum, and Xanthomonas oryzae pv. oryzae. By overlaying in planta transcriptomes onto the pan-genome, we investigated the expression profiles of common genes during infection. We found over 70% of identical patterns for genes commonly expressed by the pathogens in different plant hosts or infection sites. Co-expression patterns revealed the activation of a signal transduction cascade to recognize and respond to external changes within hosts. Using mutagenesis, we uncovered a relationship between bacterial virulence and functions highly conserved and shared in the studied genomes of the bacterial phytopathogens, including flagellar biosynthesis protein, C4-dicarboxylate ABC transporter, 2-methylisocitrate lyase, and protocatechuate 3,4-dioxygenase (PCD). In particular, the disruption of PCD gene led to attenuated virulence in all pathogens and significantly affected phytotoxin production in B. glumae. This PCD gene was ubiquitously distributed in most plant pathogens with high homology. In conclusion, our results provide cross-species in planta models for identifying common virulence factors, which can be useful for the protection of crops against diverse pathogens.
Effect of intermittent shade on nitrogen dynamics assessed by 15N trace isotopes, enzymatic activity and yield of Brassica napus L.
Authors: Javed Hafiz Hassan , Hu Yue , Asghar Muhammad Ahsan , Brestic Marian , Abbasi Majid Ali , Saleem Muhammad Hamzah , Peng Xiao , Ghafoor Abu Zar , Ye Wen , Zhou Jing , Guo Xiang , Wu Yong-Cheng
Published: November 2022

Modern era of agriculture is concerned with the environmental influence on crop growth and development. Shading is one of the crucial factors affecting crop growth considerably, which has been neglected over the years. Therefore, a two-year field experiment was aimed to investigate the effects of shading at flowering (S1) and pod development (S2) stages on nitrogen (N) dynamics, carbohydrates and yield of rapeseed. Two rapeseed genotypes (Chuannong and Zhongyouza) were selected to evaluate the effects of shading on 15N trace isotopes, enzymatic activities, dry matter, nitrogen and carbohydrate distribution and their relationship with yield. The results demonstrated that both shading treatments disturbed the nitrogen accumulation and transportation at the maturity stage. It was found that shading induced the downregulation of the N mobilizing enzymes (NR, NiR, GS, and GOGAT) in leaves and pods at both developmental stages. Shading at both growth stages resulted in reduced dry matter of both varieties but only S2 exhibited the decline in pod shell and seeds dry weight in both years. Besides this, carbohydrates distribution toward economic organs was declined by S2 treatment and its substantial impact was also experienced in seed weight and seeds number per pod which ultimately decreased the yield in both genotypes. We also revealed that yield is positively correlated with dry matter, nitrogen content and carbohydrates transportation. In contrast to Chuannong, the Zhongyouza genotype performed relatively better under shade stress. Overall, it was noticed that shading at pod developmental stage considerable affected the transportation of N and carbohydrates which led to reduced rapeseed yield as compared to shading at flowering stage. Our study provides basic theoretical support for the management techniques of rapeseed grown under low light regions and revealed the critical growth stage which can be negatively impacted by low light.