bluuebunny/crossref_metadata_2025 huggingface dataset:
ADAR1-dependent editing regulates human β cell transcriptome diversity during inflammation
Authors: Szymczak Florian , Cohen-Fultheim Roni , Thomaidou Sofia , de Brachène Alexandra Coomans , Castela Angela , Colli Maikel , Marchetti Piero , Levanon Erez , Eizirik Decio , Zaldumbide Arnaud
Published: November 2022

Introduction

Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing excessive immune activation.

Methods

Using high-throughput RNA sequencing data from human islets and EndoC-βH1 cells exposed to IFNα or IFNγ/IL1β, we evaluated the role of ADAR1 in human pancreatic β cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing.

Results

We show that both IFNα and IFNγ/IL1β stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-βH1 cells as well as in primary human islets.

Discussion

We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFNα effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the β cell transcriptome under inflammatory conditions.
Exploration and validation of a combined immune and metabolism gene signature for prognosis prediction of colorectal cancer
Authors: Xiao Yitai , Zhang Guixiong , Wang Lizhu , Liang Mingzhu
Published: November 2022

Background

Colorectal cancer (CRC) is still one of the most frequently diagnosed malignancy around the world. The complex etiology and high heterogeneity of CRC necessitates the identification of new reliable signature to identify different tumor prognosis, which may help more precise understanding of the molecular properties of CRC and identify the appropriate treatment for CRC patients. In this study, we aimed to identify a combined immune and metabolism gene signature for prognosis prediction of CRC from large volume of CRC transcriptional data.

Methods

Gene expression profiling and clinical data of HCC samples was retrieved from the from public datasets. IRGs and MRGs were identified from differential expression analysis. Univariate and multivariate Cox regression analysis were applied to establish the prognostic metabolism-immune status-related signature. Kaplan-Meier survival and receiver operating characteristic (ROC) curves were generated for diagnostic efficacy estimation. Real-time polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry (IHC) was conducted to verified the expression of key genes in CRC cells and tissues.

Results

A gene signature comprising four genes (including two IRGs and two MRGs) were identified and verified, with superior predictive performance in discriminating the overall survival (OS) of high-risk and low-risk compared to existing signatures. A prognostic nomogram based on the four-gene signature exhibited a best predictive performance, which enabled the prognosis prediction of CRC patients. The hub gene ESM1 related to CRC were selected via the machine learning and prognostic analysis. RT-PCR, Western blot and IHC indicated that ESM1 was high expressed in tumor than normal with superior predictive performance of CRC survival.

Conclusions

A novel combined MRGs and IRGs-related prognostic signature that could stratify CRC patients into low-and high- risk groups of unfavorable outcomes for survival, was identified and verified. This might help, to some extent, to individualized treatment and prognosis assessment of CRC patients. Similarly, the mining of key genes provides a new perspective to explore the molecular mechanisms and targeted therapies of CRC.
Diagnostic performance of novel inflammatory biomarkers based on ratios of laboratory indicators for nonalcoholic fatty liver disease
Authors: Zhao Yanhua , Xia Junxiang , He He , Liang Shanshan , Zhang He , Gan Wei
Published: November 2022

Introduction

There is few effective biomarkers for diagnosing nonalcoholic fatty liver disease (NAFLD) in clinical practice. This study was aimed to investigate the predictive ability of novel inflammatory biomarkers, including the monocyte to high-density lipoprotein cholesterol ratio (MHR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR), for NAFLD.

Methods

A total of 4465 outpatients diagnosed with NAFLD and 3683 healthy controls were enrolled between May 2016 and November 2021 from the West China Hospital of Sichuan University, and anthropometric and laboratory examination data were collected. The two-sample Mann-Whitney U test and binary logistic regression analysis were used to evaluate the correlations between four inflammatory biomarkers and NAFLD. The areas under the curves (AUCs) of receiver operating characteristic were used to evaluate their predictive ability for NAFLD.

Results

The MHR, NLR and LMR were higher in patients with NAFLD than in healthy controls (P<0.001), whereas the PLR was remarkably lower (P<0.001). The OR values of the MHR, NLR, PLR, and LMR were 1.599 (1.543-1.658), 1.250 (1.186-1.317), 0.987(0.986-0.988) and 1.111(1.083-1.139), respectively(P<0.001). After adjusting for confounding factors, MHR was still the most relevant risk factor for NAFLD compared with other inflammatory markers (P<0.001). The AUCs of the MHR, NLR, PLR, and LMR were as follows: 0.663 (0.651-0.675), 0.524 (0.512-0.537), 0.329 (0.318-0.341), and 0.543 (0.530-0.555), respectively (P<0.001). Furthermore, the diagnostic model combining the MHR with alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, fasting blood glucose, creatinine, uric acid, and body mass index had the best AUC of 0.931 (0.925-0.936).

Conclusions

MHR was superior to NLR, PLR and LMR as an inflammatory biomarker in the prediction of NAFLD. When combined with relevant laboratory parameters, the MHR may improve the clinical noninvasive diagnosis of NAFLD.
Asymmetric effect of agriculture value added on CO2 emission: Does globalization and energy consumption matter for pakistan
Authors: Khurshid Nabila , Khurshid Jamila , Shakoor Usman , Ali Kashif
Published: November 2022

Globalization has resulted in several technical advancements, including the ability to connect people all over the world and drive the economies with higher agricultural output. With agricultural productivity expanding quickly, the negative impact of globalization on environmental degradation is being disregarded. Rapid agricultural expansion and globalization have resulted in significant increases in energy consumption and CO2 emissions. The primary purpose of this research is to assess the role of Pakistan’s massive agriculture industry in encouraging or discouraging CO2 emissions under Globalization scenario. Therefore, we applied Non-linear Autoregressive Distributive Lag Nonlinear Autoregressive Distributed Lag model from 1971 to 2021. Our results showed that in presence of globalization, agricultural production shows asymmetries in case of positive and negative shocks. A positive shock in Agricultural production increased the CO2 emissions while negative shock in agricultural production decreased CO2 emissions. Furthermore, GDP, energy consumption and economic globalization have positive association with economic globalization while on the other hand, surprisingly trade and urbanization in the presence of globalization have negative association with CO2 emissions. Environmental deterioration due to greenhouse emissions causes climatic variation in the economy and several mitigation strategies are required on sustainable basis in Pakistan. So, our study recommends that farmers of Pakistan should adopt organic farming this will help to reduce CO2 emissions.
Study on the control targets and measures for total diesel consumption from mobile sources in Beijing, China
Authors: Ai Yi , Cui Yangyang , Ge Yunshan , Wu Xuefang , Wu Tongran , Liu Xinyu , Shen Yan , Liu Mingyu , Wan Yunfei , Yi Huawei , Xue Yifeng
Published: November 2022

Based on the current air pollution control and CO2 emission reduction policies, this study analyzed the energy structure, number of motor vehicles and nonroad mobile machinery, energy consumption and pollutant emissions in Beijing. Furthermore, the diesel consumption characteristics and challenges for emission reduction in key fields were investigated, such as medium- and heavy-duty diesel trucks, long-distance passenger and tourist diesel vehicles, and nonroad machinery, which are areas with difficult-to-reduce diesel consumption. Control targets and measures for total diesel consumption were also proposed. The results indicated that the higher diesel consumption per unit area in Beijing is related to the larger passenger car and freight truck populations. In recent decades, the number of diesel vehicles has increased, the vehicle type structure has been optimized, the proportion of vehicles with high emission standards has increased, and the absolute pollutant emissions have decreased. Among these, nitrogen oxides (NOx), fine particulate matter (PM2.5) and volatile organic compound (VOC) emissions of different models decreased by 39.5%, 75.3% and 42.8%, respectively, while carbon dioxide (CO2) emissions from diesel combustion decreased by 32%. Moreover, medium and large passenger vehicles, medium- and heavy-duty trucks and construction machinery are the main contributors to diesel consumption. These vehicle types are also difficult to control and reduce, and their replacement by new-energy vehicles is relatively limited. The main control measures for diesel consumption are as follows. First, a green transportation mode can be adopted for goods that can be converted from roads to railways. Second, fuel consumption reduction for nonroad mobile machinery can be realized by tightening fuel consumption limits, setting appropriate maximum retirement life, establishing low- or ultralow-emission zones, and establishing demonstration plots for electric vehicle (EV) substitution for mobile machinery. To improve the air quality and take the lead in carbon neutrality in the future, Beijing must further accelerate the energy structure adjustment and the development of new-energy vehicles in the transportation sector. Carbon neutralization is an important opportunity for diesel consumption reduction, and the synergistic control of atmospheric pollution and carbon emissions from diesel combustion must be strengthened.
Factors related to human-vector contact that modify the likelihood of malaria transmission during a contained Plasmodium falciparum outbreak in Praia, Cabo Verde
Authors: Stresman Gillian , DePina Adilson José , Nelli Luca , Monteiro Davidson D. S. , Leal Silvânia da Veiga , Moreira António Lima , Furtado Ullardina Domingos , Roka Jerlie C. Loko , Neatherlin John , Gomes Carolina , Tfeil Abderrahmane Kharchi , Lindblade Kimberly A.
Published: November 2022

Background

Determining the reproductive rate and how it varies over time and space (RT) provides important insight to understand transmission of a given disease and inform optimal strategies for controlling or eliminating it. Estimating RT for malaria is difficult partly due to the widespread use of interventions and immunity to disease masking incident infections. A malaria outbreak in Praia, Cabo Verde in 2017 provided a unique opportunity to estimate RT directly, providing a proxy for the intensity of vector-human contact and measure the impact of vector control measures.

Methods

Out of 442 confirmed malaria cases reported in 2017 in Praia, 321 (73%) were geolocated and informed this analysis. RT was calculated using the joint likelihood of transmission between two cases, based on the time (serial interval) and physical distance (spatial interval) between them. Log-linear regression was used to estimate factors associated with changes in RT, including the impact of vector control interventions. A geostatistical model was developed to highlight areas receptive to transmission where vector control activities could be focused in future to prevent or interrupt transmission.

Results

The RT from individual cases ranged between 0 and 11 with a median serial- and spatial-interval of 34 days [interquartile range (IQR): 17–52] and 1,347 m (IQR: 832–1,985 m), respectively. The number of households receiving indoor residual spraying (IRS) 4 weeks prior was associated with a reduction in RT by 0.84 [95% confidence interval (CI) 0.80–0.89; p-value <0.001] in the peak-and post-epidemic compared to the pre-epidemic period.

Conclusions

Identifying the effect of reduced human-vector contact through IRS is essential to determining optimal intervention strategies that modify the likelihood of malaria transmission and can inform optimal intervention strategies to accelerate time to elimination. The distance within which two cases are plausibly linked is important for the potential scale of any reactive interventions as well as classifying infections as imported or introduced and confirming malaria elimination.
Prognostic necroptosis-related gene signature aids immunotherapy in lung adenocarcinoma
Authors: Song Yuqi , Zhang Jinming , Fang Linan , Liu Wei
Published: November 2022

Background: Necroptosis is a phenomenon of cellular necrosis resulting from cell membrane rupture by the corresponding activation of Receptor Interacting Protein Kinase 3 (RIPK3) and Mixed Lineage Kinase domain-Like protein (MLKL) under programmed regulation. It is reported that necroptosis is closely related to the development of tumors, but the prognostic role and biological function of necroptosis in lung adenocarcinoma (LUAD), the most important cause of cancer-related deaths, is still obscure.

Methods: In this study, we constructed a prognostic Necroptosis-related gene signature based on the RNA transcription data of LUAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases as well as the corresponding clinical information. Kaplan-Meier analysis, receiver operating characteristic (ROC), and Cox regression were made to validate and evaluate the model. We analyzed the immune landscape in LUAD and the relationship between the signature and immunotherapy regimens.

Results: Five genes (RIPK3, MLKL, TLR2, TNFRSF1A, and ALDH2) were used to construct the prognostic signature, and patients were divided into high and low-risk groups in line with the risk score. Cox regression showed that risk score was an independent prognostic factor. Nomogram was created for predicting the survival rate of LUAD patients. Patients in high and low-risk groups have different tumor purity, tumor immunogenicity, and different sensitivity to common antitumor drugs.

Conclusion: Our results highlight the association of necroptosis with LUAD and its potential use in guiding immunotherapy.
A network meta-analysis to evaluate the efficacy of traditional Chinese medicine on intestinal flora in patients with gastrointestinal cancer
Authors: Feng Niran , Wang Shurui , Liu Chengjiang , Xu Zixin , Song Zhijie , Li Kunyang , Yu Zhifeng
Published: November 2022

Background and Purpose: Traditional Chinese medicine (TCM) can regulate intestinal flora so as to affect the occurrence, progression, and prognosis of gastrointestinal cancer. According to clinical studies, TCM oral administration, TCM external treatment, and TCM injections, can adjust intestinal flora disorders in patients with gastrointestinal cancer. This network meta-analysis aims to evaluate the effect of three treatments on the intestinal flora in gastrointestinal cancer patients.

Methods: This meta-analysis was registered in PROSPERO (CRD42022332553). Six electronic databases, namely CNKI, Wanfang, CSTJ, PubMed, Cochrane Library, and EMBASE, were searched from their inception to 1 April 2022. We identified randomized controlled trials (RCT) used to compare the efficacy of three TCM treatment methods—oral administration, external therapy and injections—on the intestinal flora in gastrointestinal cancer patients. The main outcome indicators were Bifidobacteria, Lactobacilli, Escherichia coli, and Enterococci. Stata (15.1) and the Cochrane risk of bias assessment tool were employed.

Results: We identified 20 eligible RCTs with a total of 1,774 patients. According to network meta-analysis results, TCM injection plus common treatment (CT) or oral administration of TCM plus CT was superior to CT alone for supporting Bifidobacterium. In supporting Lactobacillus, TCM injection plus CT demonstrated more obvious effect relative to oral administration of TCM plus CT; TCM injection plus CT was more effective than CT only; and oral administration of TCM plus CT was superior to CT only.The inhibitory effect of TCM injection plus CT on Escherichia coli was better compared with CT only. In terms of inhibiting Enterococci, oral administration of TCM plus CT was superior to CT only.The difference in efficacy among the above treatments was statistically significant. In the SUCRA probability ranking, TCM injection plus CT had the best ranking curve among the three treatments and was the most effective in supporting Bifidobacteria (Sucra = 90.08%), Lactobacilli (Sucra = 96.4%), and regulating Escherichia coli (Sucra = 86.1%) and Enterococci (Sucra = 87.1%).

Conclusion: TCM injections plus CT is the most effective therapy in balancing the intestinal flora of gastrointestinal cancer patients. However, the current results deserve further validation through high-quality research.

Systematic Review Registration: http://www.prisma-statement.org/, identifier 10.1136/bmj.n71.
Mitigating aflatoxin contamination in maize: Breeding for stable resistant cultivars
Authors: Oppong Allen , Appiah Jnr Kofi , Appiah-Kubi Zippora , Adu-Amoah Richard , Adu-Dapaah Hans
Published: November 2022

Maize is a major cereal crop for humans and animals. The production and consumption of maize are adversely affected by aflatoxin contamination resulting in reduced grain quality with high health risk to consumers. Unsafe aflatoxin levels above 20 ppb have been reported in maize from farmers’ fields in Ghana. A study was undertaken to evaluate the yield and aflatoxin contamination resistance stabilities of selected hybrids being developed in Ghana. Eighteen maize genotypes (14 hybrids with the following code names: GH01, GH02, GH03, GH04, GH05, GH06, GH07, GH08, GH09, GH10, GH11, GH12, GH13, and GH14 and four local checks: Etubi, Obotantim, Tintim, and Mamaba) were evaluated across six environments in two seasons. Artificial inoculation was done randomly using the side needle injection method 14 days after midsilk at a concentration of 9 × 107 conidia/ml. After the harvest levels of aflatoxin in the harvested grains were determined using high-performance liquid chromatography (HPLC). Data analysis showed that genotypic effects and environmental effects on some traits were consistently significant across environments, which mean that there was useful variation among the genotypes that could be utilized for the development of hybrids. Non-significant genotype by environment interaction effects for grain yield suggests that a promising genotype selected in one of these locations will also be suitable for production in the other locations in the same agroecological zone. GGE biplot analyses provided clear bases for determining stability and performance of the hybrids. Two hybrids have the potential for production in Ejura, Fumesua, Ohawu, Akumadan, and Kpeve and similar agroecological zones. GH04, GH10, and GH01 were lowest yielding, but GH10 was most stable. GH05 was identified as the most promising for production in Ejura, Ohawu, and Akumadan. Again, GH08 was the Vertex genotype for Wenchi environment. Ejura, located in the transition zone, was identified as the ideal testing environment for the hybrids. Most of the hybrids showed low levels of aflatoxin accumulation below 20 ppb despite artificial inoculation. The study revealed GH01, GH05, and GH08 as the most stable among the top yielding hybrids with aflatoxin levels of 11.9, 14.3, and 3.8 ppb, respectively, after artificial inoculation, which can be considered for cultivation as varieties to help mitigate aflatoxin contamination in maize in Ghana and beyond.
Assessing the efficacy of immunotherapy in lung squamous carcinoma using artificial intelligence neural network
Authors: Li Siqi , Li Wei , Ma Tianyu , Fu Siyun , Gao Xiang , Qin Na , Wu Yuhua , Zhang Xinyong , Wang Jinghui , Pan Yuanming , Liu Zhidong
Published: November 2022

Background

At present, immunotherapy is a very promising treatment method for lung cancer patients, while the factors affecting response are still controversial. It is crucial to predict the efficacy of lung squamous carcinoma patients who received immunotherapy.

Methods

In our retrospective study, we enrolled lung squamous carcinoma patients who received immunotherapy at Beijing Chest Hospital from January 2017 to November 2021. All patients were grouped into two cohorts randomly, the training cohort (80% of the total) and the test cohort (20% of the total). The training cohort was used to build neural network models to assess the efficacy and outcome of immunotherapy in lung squamous carcinoma based on clinical information. The main outcome was the disease control rate (DCR), and then the secondary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Results

A total of 289 patients were included in this study. The DCR model had area under the receiver operating characteristic curve (AUC) value of 0.9526 (95%CI, 0.9088–0.9879) in internal validation and 0.9491 (95%CI, 0.8704–1.0000) in external validation. The ORR model had AUC of 0.8030 (95%CI, 0.7437–0.8545) in internal validation and 0.7040 (95%CI, 0.5457–0.8379) in external validation. The PFS model had AUC of 0.8531 (95%CI, 0.8024–0.8975) in internal validation and 0.7602 (95%CI, 0.6236–0.8733) in external validation. The OS model had AUC of 0.8006 (95%CI, 0.7995–0.8017) in internal validation and 0.7382 (95%CI, 0.7366–0.7398) in external validation.

Conclusions

The neural network models show benefits in the efficacy evaluation of immunotherapy to lung squamous carcinoma patients, especially the DCR and ORR models. In our retrospective study, we found that neoadjuvant and adjuvant immunotherapy may bring greater efficacy benefits to patients.
Autoimmune hepatitis after COVID-19 vaccination
Authors: Zheng Han , Zhang Ting , Xu Yiyao , Lu Xin , Sang Xinting
Published: November 2022

Vaccination is one of the most vigorous ways to intervene in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Cases of autoimmune hepatitis (AIH) after coronavirus disease (COVID-19) vaccination have been increasingly reported. Twenty-seven cases of AIH are summarized in this study, providing emerging evidence of autoimmune reactions in response to various COVID-19 vaccines, including in patients with special disease backgrounds such as primary sclerosing cholangitis (PSC), liver transplantation, and previous hepatitis C virus (HCV) treatment. Molecular mimicry, adjuvants, epitope spreading, bystander activation, X chromosome, and sceptical hepatotropism of SARS-CoV-2 may account for, to some extent, such autoimmune phenomena. Immunosuppressive corticosteroids perform well with or without azathioprine in such post-COVID-19-vaccination AIH. However, determination of the exact mechanism and establishment of causality require further confirmation.
Insights into prognosis and immune infiltration of cuproptosis-related genes in breast cancer
Authors: Huang Tingting , Liu Yankuo , Li Jiwei , Shi Bingbing , Shan Zhengda , Shi Zhiyuan , Yang Zhangru
Published: November 2022

Introduction

Breast cancer (BC) has been ranking first in incidence and the leading cause of death among female cancers worldwide based on the latest report. Regulated cell death (RCD) plays a significant role in tumor initiation and provides an important target of cancer treatment. Cuproptosis, a novel form of RCD, is ignited by mitochondrial stress, particularly the lipoylated mitochondrial enzymes aggregation. However, the role of cuproptosis-related genes (CRGs) in tumor generation and progression remains unclear.

Methods

In this study, the mRNA expression data of CRGs in BC and normal breast tissue were extracted from TCGA database, and protein expression patterns of these CRGs were analyzed using UALCAN. The prognostic values of CRGs in BC were explored by using KaplanMeier plotter and Cox regression analysis. Genetic mutations profiles were evaluated using the cBioPortal database. Meanwhile, we utilized CIBERSORT and TIMER 2.0 database to perform the correlation analysis between CRGs and immune cell infiltration.

Results

Our results indicated that CRGs expression is significantly different in BC and normal breast tissues. Then we found that upregulated PDHA1 expression was associated with worse endpoint of BC. Moreover, we also performed immune infiltration analysis of CRGs, and demonstrated that PDHA1 expression was closely related to the infiltration levels of CD4+ memory T cell, macrophage M0 and M1 cell and mast cell in BC.

Conclusions

Our results demonstrated the prognostic and immunogenetic values of PDHA1 in BC. Therefore, PDHA1 can be an independent prognostic biomarker and potential target for immunotherapy of BC.
Machine learning links different gene patterns of viral infection to immunosuppression and immune-related biomarkers in severe burns
Authors: Wang Peng , Zhang Zexin , Lin Rongjie , Lin Jiali , Liu Jiaming , Zhou Xiaoqian , Jiang Liyuan , Wang Yu , Deng Xudong , Lai Haijing , Xiao Hou’an
Published: November 2022

Introduction

Viral infection, typically disregarded, has a significant role in burns. However, there is still a lack of biomarkers and immunotherapy targets related to viral infections in burns.

Methods

Virus-related genes (VRGs) that were extracted from Gene Oncology (GO) database were included as hallmarks. Through unsupervised consensus clustering, we divided patients into two VRGs molecular patterns (VRGMPs). Weighted gene co-expression network analysis (WGCNA) was performed to study the relationship between burns and VRGs. Random forest (RF), least absolute shrinkage and selection operator (LASSO) regression, and logistic regression were used to select key genes, which were utilized to construct prognostic signatures by multivariate logistic regression. The risk score of the nomogram defined high- and low-risk groups. We compared immune cells, immune checkpoint-related genes, and prognosis between the two groups. Finally, we used network analysis and molecular docking to predict drugs targeting CD69 and SATB1. Expression of CD69 and SATB1 was validated by qPCR and microarray with the blood sample from the burn patient.

Results

We established two VRGMPs, which differed in monocytes, neutrophils, dendritic cells, and T cells. In WGCNA, genes were divided into 14 modules, and the black module was correlated with VRGMPs. A total of 65 genes were selected by WGCNA, STRING, and differential expression analysis. The results of GO enrichment analysis were enriched in Th1 and Th2 cell differentiation, B cell receptor signaling pathway, alpha-beta T cell activation, and alpha-beta T cell differentiation. Then the 2-gene signature was constructed by RF, LASSO, and LOGISTIC regression. The signature was an independent prognostic factor and performed well in ROC, calibration, and decision curves. Further, the expression of immune cells and checkpoint genes differed between high- and low-risk groups. CD69 and SATB1 were differentially expressed in burns.

Discussion

This is the first VRG-based signature (including 2 key genes validated by qPCR) for predicting survival, and it could provide vital guidance to achieve optimized immunotherapy for immunosuppression in burns.
Case report: Complete response to pembrolizumab in a liver metastatic colon adenocarcinoma patient with a novel likely pathogenic germline MSH2 mutation
Authors: Xu Yanjie , Li Qin , Zhao Jiemin , Ni Xuefeng , Li Ping , Hu Wenwei
Published: November 2022

Lynch syndrome (LS) is a genetic disorder mainly caused by germline mutations in mismatched repair (MMR) genes (MSH2, MLH1, MSH6, and PMS2) or deletions of the epithelial cell adhesion molecule gene (EPCAM). A 43-year-old Chinese male patient underwent radical surgery and was pathologically confirmed to have stage IIIB colon adenocarcinoma. After four cycles of standard adjuvant chemotherapy, the tumor reoccurred in situ with intestinal obstruction. The patient received secondary colectomy. Immunohistochemistry analysis revealed a loss of MSH2 protein expression in the surgical specimen. Noticing that the patient’s mother and grandfather all were diagnosed with LS-related cancers, we collected the patient’s and his mother’s peripheral blood for genetic testing, and the result showed a six-base deletion of MSH2. Thus, we concluded that our patient had LS. Subsequently, the patient accepted pembrolizumab as the first-line systemic therapy after liver metastases. He achieved clinical complete response (cCR) within 2 months and remained progression-free for more than 2 years. The case report showed that MSH2 mutation (c.489_494deTGGGTA) is a likely pathogenic mutation, and immunotherapy (pembrolizumab) is effective for this patient.
The evolutionary diversification of the Salmonella artAB toxin locus
Authors: Ojiakor Adaobi , Gibbs Rachel N. , Chen Zhe , Gao Xiang , Fowler Casey C.
Published: November 2022

Salmonella enterica is a diverse species of bacterial pathogens comprised of >2,500 serovars with variable host ranges and virulence properties. Accumulating evidence indicates that two AB5-type toxins, typhoid toxin and ArtAB toxin, contribute to the more severe virulence properties of the Salmonella strains that encode them. It was recently discovered that there are two distinct types of artAB-like genetic elements in Salmonella: those that encode ArtAB toxins (artAB elements) and those in which the artA gene is degraded and the ArtB homolog, dubbed PltC, serves as an alternative delivery subunit for typhoid toxin (pltC elements). Here, we take a multifaceted approach to explore the evolutionary diversification of artAB-like genetic elements in Salmonella. We identify 7 subtypes of ArtAB toxins and 4 different PltC sequence groups that are distributed throughout the Salmonella genus. Both artAB and pltC are encoded within numerous diverse prophages, indicating a central role for phages in their evolutionary diversification. Genetic and structural analyses revealed features that distinguish pltC elements from artAB and identified evolutionary adaptations that enable PltC to efficiently engage typhoid toxin A subunits. For both pltC and artAB, we find that the sequences of the B subunits are especially variable, particularly amongst amino acid residues that fine tune the chemical environment of their glycan binding pockets. This study provides a framework to delineate the remarkably complex collection of Salmonella artAB/pltC-like genetic elements and provides a window into the mechanisms of evolution for AB5-type toxins.
Forest succession improves the complexity of soil microbial interaction and ecological stochasticity of community assembly: Evidence from Phoebe bournei-dominated forests in subtropical regions
Authors: He Gongxiu , Peng Tieshuang , Guo Yi , Wen Shizhi , Ji Li , Luo Zhong
Published: November 2022

Forest succession is a central ecological topic, due to the importance of the associated dynamic processes for terrestrial ecosystems. However, very little is currently known about the community assembly and interaction of soil microbial communities along forest successional trajectories, particularly regarding the microbial community dynamics in contrasting seasons. To bridge these knowledge gaps, we studied soil bacterial and fungal community compositions, assemblages, and co-occurrence networks in a well-established successional gradient of Phoebe bournei-dominated forest, spanning about 65 years of forest development in a subtropical region. Illumina MiSeq sequencing of 16S and ITS genes was employed for the assessment of soil bacterial and fungal community composition and diversity, respectively. The relative abundance and α–diversity of soil bacteria and fungi showed a differential trend over forest succession. The dominant fungal phyla (Basidiomycota and Ascomycota) changed more frequently than the dominant bacterial phyla (Proteobacteria, Acidobacteriota, and Actinobacteriota), indicating that soil fungi have a more sensitive relationship with forest succession compared with bacteria. The soil microbial community variation induced by forest succession was significantly affected by soil total phosphorus, dissolved organic carbon content and pH. Compared to deterministic processes, stochastic processes mainly dominated the community assembly of soil microbial communities. Meanwhile, the relative importance of stochasticity in soil fungal communities increased in the later stages. In Particular, dispersal limitation and drift accounted for a large proportion of bacterial and fungal community assembly, respectively. In addition, the co-occurrence networks of soil microbial communities became more complex as succession proceeds. Soil bacteria and fungi exhibited more competition and cooperation along the forest successional gradient. Collectively, our findings suggest that forest succession improves the complexity of soil microbial interactions and the ecological stochasticity of community assembly in Phoebe bournei-dominated forests, providing key insights into the relationship between microbial communities and forest succession.
Transcription factor ZNF22 regulates blood-tumor barrier permeability by interacting with HDAC3 protein
Authors: Zhu Baicheng , Zhang Lu , Zhou Xinxin , Ning Hao , Ma Teng
Published: November 2022

Objective

The primary goals of this study were to investigate the potential roles of ZNF22 and HDAC3 as a histone deacetylase in regulating an increases in blood-tumor barrier (BTB) permeability and some of the possible molecular mechanisms associated with this effect.

Methods

The expression of ZNF22 and HDAC3 in glioma-exposed endothelial cells (GECs) of BTB were detected transcription real-time PCR or western blot. The interaction of ZNF22 and HDAC3 in GECs associated with transcript effect was analyzed by means of Co-Immunoprecipitation and luciferase reporter assay.

Results

In the present investigation, GECs expressed higher levels of ZNF22 as a zinc finger transcription factor and HDAC3 than endothelial cells. We then affirmed that silencing HDAC3 or ZNF22 led to a reduction in BTB permeability. By bioinformatics analysis, chromatin immunoprecipitation (ChIP) assays and luciferase assay, we found that ZNF22 had a target binding relationship with the promoter regions of ZO-1, Occludin, and Claudin-5 and negatively regulated the expression of ZO-1, Occludin, and Claudin-5. Furthermore, we revealed that HDAC3, as a co-transcript repressor with histone deacetylase activity, could interact with ZNF22 to hinder the expression of TJ-associated proteins, thereby further facilitating the permeability of BTB.

Conclusion

ZNF22 acted as a transcription factor in conjunction with HDAC3 to modulate the expression of TJ-associated proteins, which was correlated with an increase in BTB permeability. These results may provide new strategies and targets for the chemotherapy of gliomas as well as intracranial infections.
Extracorporeal membrane oxygenation support in oncological thoracic surgery
Authors: Mangiameli Giuseppe , Testori Alberto , Cioffi Ugo , Alloisio Marco , Cariboni Umberto
Published: November 2022

The use of extracorporeal lung support (ECLS) during thoracic surgery is a recent concept that has been gaining increasing approval. Firstly introduced for lung transplantation, this technique is now increasingly adopted also in oncological thoracic surgical procedures. In this review, we focus on the cutting-edge application of extracorporeal membrane oxygenation (ECMO) during oncological thoracic surgery. Therefore, we report the most common surgical procedures in oncological thoracic surgery that can benefit from the use of ECMO. They will be classified and discussed according to the aim of ECMO application. In particular, the use of ECMO is usually limited to certain lung surgery procedures that can be resumed such as in procedures in which an adequate ventilation is not possible such as in single lung patients, procedures where conventional ventilation can cause conflict with the surgical field such as tracheal or carinal surgery, and conventional procedures requiring both ventilators and hemodynamic support. So far, all available evidence comes from centers with large experience in ECMO and major thoracic surgery procedures.
Mapping of lymph node dissection determined by the epicenter location and tumor extension for esophagogastric junction carcinoma
Authors: Liang Rong , Bi Xiaogang , Fan Daguang , Du Qiao , Wang Rong , Zhao Baoyu
Published: November 2022

Backgrounds

Previous studies identified the extent of lymph node dissection for esophagogastric junction (EGJ) carcinoma based on the metastatic incidence. The study aimed to determine the optimal extent and priority of lymphadenectomy based on the therapeutic efficacy from each station.

Methods

The studies on the lymph node metastasis (LNM) and therapeutic efficacy index (EI) for EGJ carcinomas were identified until April 2022. The obligatory stations with the LNM rates over 5% and therapeutic EI exceeding 2% should be routinely resected for D2 dissection, whereas the optional stations with EI between 0.5% and 2% should be resected for D3 dissection in selective cases.

Results

The survey yielded 16 eligible articles including 6,350 patients with EGJ carcinoma. The metastatic rates exceeded 5% at no. 1, 2, 3, 7, 9, 11p, and 110 stations and were less than 5% in abdominal no. 4sa~6, 8a, 10, 11d, 12a, and 16a2/b1 and mediastinal no. 105~112 stations. Consequently, obligatory stations with EI over 2% were largely determined by the epicenter location and located at the upper perigastric, lower mediastinal, and suprapancreatic zones, corresponding to those with rates of LNM over 5%. Consistent with the LNM rates less than 5%, the optional stations with EI between 0.5% and 2% were largely dependent on the degree of tumor extension toward the lower perigastric, splenic hilar (grecurvature), para-aortic (less curvature of the cardia), and middle or upper mediastinal zones.

Conclusions

The obligatory stations can be resected as an “envelope-like” wrap by transhiatal proximal gastrectomy with lower esophagectomy, whereas the optional stations for dissection are indicated by the tumor extension. The extended gastrectomy is required for the lower perigastric in the stomach-predominant tumor with gastric involvement exceeding 5.0 cm, para-aortic dissection in the less curvature-predominant tumor and splenic hilar dissection in the grecurvature-predominant tumor whereas transthoracic subtotal esophagectomy is required for complete mediastinal dissection and adequate negative margin in the esophagus-predominant tumor with esophageal invasion exceeding 3.0 cm.
New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022
Authors: Jiang JingSi , Wang Yan , Deng Min
Published: November 2022

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord. In the recent past, there have been just two drugs approved for treatment, riluzole and edaravone, which only prolong survival by a few months. However, there are many novel experimental drugs in development. In this review, we summarize 53 new drugs that have been evaluated in clinical trials from 2020 to 2022, which we have classified into eight mechanistic groups (anti-apoptotic, anti-inflammatory, anti-excitotoxicity, regulated integrated stress response, neurotrophic factors and neuroprotection, anti-aggregation, gene therapy and other). Six were tested in phase 1 studies, 31 were in phase 2 studies, three failed in phase 3 studies and stopped further development, and the remaining 13 drugs were being tested in phase 3 studies, including methylcobalamin, masitinib, MN-166, verdiperstat, memantine, AMX0035, trazodone, CNM-Au8, pridopidine, SLS-005, IONN363, tofersen, and reldesemtiv. Among them, five drugs, including methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, have shown potent therapeutic effects in clinical trials. Recently, AMX0035 has been the third medicine approved by the FDA for the treatment of ALS after riluzole and edaravone.
Cost-Effectiveness Analysis of Sintilimab Combined with Chemotherapy Versus Chemotherapy Alone as the First-Line Treatment for Advanced Esophageal Cancer
Authors: Ye Zhuo-Miao , Xu Zhe , Zeng Fan-Yuan , Tang Zi-Qing , Zhou Qin
Published: November 2022

Background: Esophageal cancer has a poor prognosis and currently ranks sixth in global cancer mortality rates. The ORIENT-15 trial showed sintilimab plus chemotherapy significantly improved survival when compared to chemotherapy alone. This study aimed to evaluate the cost-effectiveness of sintilimab, a programmed death-ligand 1 (PD-L1) inhibitor, plus chemotherapy in treating patients with esophageal cancer compared with chemotherapy alone.

Methods: A Markov model with a 10-year horizon was developed based on the perspective of the Chinese healthcare payers. We conducted a cost-effectiveness analysis for sintilimab combined with chemotherapy based on a questionnaire. Patients were grouped into the sintilimab group based on a positive score of 10 or more (combined positive score (CPS) ≥ 10 groups), and those with any other PD-L1 expression were randomized into patient groups. We estimated the cost and the effectiveness of sintilimab on the quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) was computed. One-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness results.

Results: In the base-case analysis, compared with chemotherapy alone, the ICER of sintilimab plus chemotherapy for all patients was $21024.05 per QALY, and in the CPS≥10 group, it was $20974.23 per QALY. This was lower than $37653 per QALY. One-way sensitivity analysis demonstrated that ICERs were most sensitive to the price of sintilimab.

Conclusion: The study demonstrated that sintilimab plus chemotherapy for advanced esophageal cancer as its first-line treatment would be more cost-effective than chemotherapy alone in Chinese patients.
Yi-Shen-Hua-Shi granules inhibit diabetic nephropathy by ameliorating podocyte injury induced by macrophage-derived exosomes
Authors: Liang Mingzhu , Zhu Xiaodong , Zhang Di , He Wenfang , Zhang Jinshi , Yuan Shizhu , He Qiang , Jin Juan
Published: November 2022

Objective: To observe the therapeutic effect of Yi-Shen-Hua-Shi (YSHS) granule in podocyte damage and diabetic nephropathy (DN) proteinuria and to explore the corresponding mechanism.

Methods: The db/db mice were used to establish the DN model. Serum creatinine (SCr), blood urea nitrogen (BUN), and 24 h urinary proteinuria were detected with specific kits. Glomerular structural lesions and podocyte apoptosis were detected through HE staining, TUNEL assay, and immunofluorescence. The medicated serum of YSHS granule (YSHS-serum) or control serum was prepared. Macrophage-derived exosomes were extracted using an exosome extraction kit. Morphology and the protein concentration of exosomes were evaluated by a transmission electron microscope (TEM) and BCA kit. The activity and apoptosis of podocyte MPC5 cells, the M1 macrophage polarization, and the protein expression of an exosome marker and cleaved caspase were detected by the CCK8 experiment, flow cytometry, and Western blot, respectively. The miR-21a-5p expression in podocytes and the exosomes from macrophages were measured by qRT-PCR. The effect of YSHS granule on the infiltration of M1 macrophages in the kidney tissue in db/db mice was measured by immunofluorescence.

Results: The YSHS granule could improve renal function, reduce proteinuria, and inhibit glomerular structural lesions and podocyte apoptosis in db/db mice. High-glucose (HG) stimulation and YSHS granule treatment did not affect the protein concentration in macrophage-derived exosomes. Macrophage-derived exosomes could inhibit the cell viability and increase apoptosis of podocytes, especially the exosomes from macrophages treated with HG and control serum. Compared with the exosomes secreted by macrophages after an HG treatment, the exosome from macrophages treated with HG and YSHS granule showed lower inhibitory effects on podocyte activity, accompanied by the decreased upregulating effects of macrophage-derived exosomes on the miR-21a-5p in podocytes. miR-21a-5p mimics could reduce podocyte activity and promote caspase-3 shearing. M1 polarization of macrophages could change the content of miR-21a-5p in macrophage-derived exosomes. In addition, YSHS granule could inhibit HG-induced M1 polarization of macrophages and M1 macrophage infiltration in renal tissues.

Conclusion: The YSHS granule could improve the podocyte injury induced by macrophage-derived exosomes and alleviate the progression of DN. This regulation might be related to the inhibition of M1 macrophage polarization by YSHS granule and the reduction of the miR-21a-5p content in macrophage-derived exosomes.
Effects of stocking density on the growth performance, mitophagy, endocytosis and metabolism of Cherax quadricarinatus in integrated rice–crayfish farming systems
Authors: Dong Yin , Jia Rui , Hou Yiran , Diao Weixu , Li Bing , Zhu Jian
Published: November 2022

Red claw crayfish (Cherax quadricarinatus) is an economic freshwater shrimp with great commercial potential. However, the suitable stocking density of C. quadricarinatus is still unclear in integrated rice–crayfish farming system. Thus, this study aimed to investigate the effects of stocking density on growth performance, mitophagy, endocytosis and metabolism of C. quadricarinatus. The C. quadricarinatus was reared at low density (LD, 35.73 g/m2), middle density (MD, 71.46 g/m2) and high density (HD, 107.19 g/m2) in an integrated rice–crayfish farming system. After 90 days of farming, the growth performance of C. quadricarinatus significantly decreased in the MD and HD groups relative to that in the LD group. The HD treatment caused oxidative stress and lipid peroxidation at the end of the experiment in hepatopancreas. Transcriptome analysis showed that there were 1,531 DEGs (differently expressed genes) between the LD group and HD group, including 1,028 upregulated genes and 503 downregulated genes. KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis indicated that the DEGs were significantly enriched in endocytosis and mitophagy pathways. Meanwhile, four lipid metabolism pathways, including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis, glycerolipid metabolism and glycerophospholipid metabolism, exhibited an upregulated tendency in the HD group. In conclusion, our data showed that when the stocking density reached up to 207.15 g/m2 in HD group, the growth performance of C. quadricarinatus was significantly inhibited in this system. Meanwhile, the data indicated that C. quadricarinatus may respond to the stressful condition via activating antioxidant defense system, endocytosis, mitophagy and metabolism-related pathways in hepatopancreas.