bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning and bioinformatics-based insights into the potential targets of saponins in Paris polyphylla smith against non-small cell lung cancer
Authors: Wang Yue , Huang Xulong , Xian Bin , Jiang Huajuan , Zhou Tao , Chen Siyu , Wen Feiyan , Pei Jin
Published: October 2022

Background: Lung cancer has the highest mortality rate among cancers worldwide, and non-small cell lung cancer (NSCLC) is the major lethal factor. Saponins in Paris polyphylla smith exhibit antitumor activity against non-small cell lung cancer, but their targets are not fully understood.

Methods: In this study, we used differential gene analysis, lasso regression analysis and support vector machine recursive feature elimination (SVM-RFE) to screen potential key genes for NSCLC by using relevant datasets from the GEO database. The accuracy of the signature genes was verified by using ROC curves and gene expression values. Screening of potential active ingredients for the treatment of NSCLC by molecular docking of the reported active ingredients of saponins in Paris polyphylla Smith with the screened signature genes. The activity of the screened components and their effects on key genes expression were further validated by CCK-8, flow cytometry (apoptosis and cycling) and qPCR.

Results: 204 differential genes and two key genes (RHEBL1, RNPC3) stood out in the bioinformatics analysis. Overall survival (OS), First-progression survival (FP) and post-progression survival (PPS) analysis revealed that low expression of RHEBL1 and high expression of RNPC3 indicated good prognosis. In addition, Polyphyllin VI(PPVI) and Protodioscin (Prot) effectively inhibited the proliferation of non-small cell lung cancer cell line with IC50 of 4.46 μM ± 0.69 μM and 8.09 μM ± 0.67μM, respectively. The number of apoptotic cells increased significantly with increasing concentrations of PPVI and Prot. Prot induces G1/G0 phase cell cycle arrest and PPVI induces G2/M phase cell cycle arrest. After PPVI and Prot acted on this cell line for 48 h, the expression of RHEBL1 and RNPC3 was found to be consistent with the results of bioinformatics analysis.

Conclusion: This study identified two potential key genes (RHEBL1 and RNPC3) in NSCLC. Additionally, PPVI and Prot may act on RHEBL1 and RNPC3 to affect NSCLC. Our findings provide a reference for clinical treatment of NSCLC.
Identification of molecular subtypes and a six-gene risk model related to cuproptosis for triple negative breast cancer
Authors: Zhu Baoxi , Wang Songping , Wang Rui , Wang Xiaoliang
Published: October 2022

Background: Breast cancer is the mostly diagnosed cancer worldwide, and triple negative breast cancer (TNBC) has the worst prognosis. Cuproptosis is a newly identified form of cell death, whose mechanism has not been fully explored in TNBC. This study thought to unveil the potential association between cuproptosis and TNBC.

Materials and Methods: Gene expression files with clinical data of TNBC downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were included in this study. Consensus clustering was utilized to perform molecular subtyping based on cuproptosis-associated genes. Limma package was applied to distinguish differentially expressed genes. Univariate Cox regression was used to identify prognostic genes. Least absolute shrinkage and selection operator and stepwise Akaike information criterion optimized and established a risk model.

Results: We constructed three molecular subtypes based on cuproptosis-associated genes, and the cuproptosis-based subtyping showed a robustness in different datasets. Clust2 showed the worst prognosis and immune-related pathways such as chemokine signaling pathway were significantly activated in clust2. Clust2 also exhibited a high possibility of immune escape to immune checkpoint blockade. In addition, a six-gene risk model was established manifesting a high AUC score over 0.85 in TCGA dataset. High- and low-risk groups had distinct prognosis and immune infiltration. Finally, a nomogram was constructed with strong performance in predicting TNBC prognosis than the staging system.

Conclusion: The molecular subtyping system related to cuproptosis had a potential in guiding immunotherapy for TNBC patients. Importantly, the six-gene risk model was effective and reliable to predict TNBC prognosis.
Organelle bottlenecks facilitate evolvability by traversing heteroplasmic fitness valleys
Authors: Radzvilavicius Arunas L. , Johnston Iain G.
Published: October 2022

Bioenergetic organelles—mitochondria and plastids—retain their own genomes (mtDNA and ptDNA), and these organelle DNA (oDNA) molecules are vital for eukaryotic life. Like all genomes, oDNA must be able to evolve to suit new environmental challenges. However, mixed oDNA populations in cells can challenge cellular bioenergetics, providing a penalty to the appearance and adaptation of new mutations. Here we show that organelle “bottlenecks,” mechanisms increasing cell-to-cell oDNA variability during development, can overcome this mixture penalty and facilitate the adaptation of beneficial mutations. We show that oDNA heteroplasmy and bottlenecks naturally emerge in evolutionary simulations subjected to fluctuating environments, demonstrating that this evolvability is itself evolvable. Usually thought of as a mechanism to clear damaging mutations, organelle bottlenecks therefore also resolve the tension between intracellular selection for pure cellular oDNA populations and the “bet-hedging” need for evolvability and adaptation to new environments. This general theory suggests a reason for the maintenance of organelle heteroplasmy in cells, and may explain some of the observed diversity in organelle maintenance and inheritance across taxa.
SARS-CoV-2 RNAs are processed into 22-nt vsRNAs in Vero cells
Authors: Liu Yang , Rao Jian , Mi Yingjie , Chen Lan , Feng Lijuan , Li Qi , Geng Jianing , Yang Xianguang , Zhan Xiangjiang , Ren Lili , Chen Jinfeng , Zhang Xiaoming
Published: October 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic, resulting in great fatalities around the world. Although the antiviral roles of RNA interference (RNAi) have been well studied in plants, nematodes and insects, the antiviral roles of RNAi in mammalians are still debating as RNAi effect is suspected to be suppressed by interferon (IFN) signaling pathways in most cell types. To determine the role of RNAi in mammalian resistance to SARS-CoV-2, we studied the profiling of host small RNAs and SARS-CoV-2 virus-derived small RNAs (vsRNAs) in the early infection stages of Vero cells, an IFN-deficient cell line. We found that host microRNAs (miRNAs) were dysregulated upon SARS-CoV-2 infection, resulting in downregulation of microRNAs playing antiviral functions and upregulation of microRNAs facilitating viral proliferations. Moreover, vsRNA peaked at 22 nt at negative strand but not the positive strand of SARS-CoV-2 and formed successive Dicer-spliced pattern at both strands. Similar characteristics of vsRNAs were observed in IFN-deficient cell lines infected with Sindbis and Zika viruses. Together, these findings indicate that host cell may deploy RNAi pathway to combat SARS-CoV-2 infection in IFN-deficient cells, informing the alternative antiviral strategies to be developed for patients or tissues with IFN deficiency.
Transcriptome analysis reveals immune and metabolic regulation effects of Poria cocos polysaccharides on Bombyx mori larvae
Authors: Liu Jiajie , Hong Wanyu , Li Mei , Xiao Yang , Yi Yunhong , Liu Yi , Wu Gongqing
Published: October 2022

Poria cocos polysaccharides (PS) have been used as Chinese traditional medicine with various pharmacological effects, including antiviral, anti-oxidative, and immunomodulatory activities. Herein Bombyx mori silkworm was used as a model animal to evaluate the immunomodulatory effects of PS via detecting the changes of innate immune parameters and explore the underlying molecular mechanism of the immunoregulatory effect of PS using Illumina HiSeq Xten platform. The results presented here demonstrated that a hemocoel injection of PS significantly enhanced the cellular immunity of silkworm, including hemocyte phagocytosis, microaggregation, and spreading ability. A total of 335 differentially expressed genes (DEGs) were screened, including 214 upregulated genes and 121 downregulated genes by differential expression analysis. Gene annotation and enrichment analyses showed that many DEGs related to immune signal recognition, detoxification, proPO activation, carbohydrate metabolism, and lipid metabolism were significantly upregulated in the treatment group. The Kyoto Encyclopedia of Genes and Genomes-based Gene Set Enrichment Analysis also revealed that the more highly expressed gene sets in the PS treatment silkworm were mainly related to immune signal transduction pathways and energy metabolism. In addition, the activity of four enzymes related to immunity and energy metabolism—including phenoloxidase, glucose-6-phosphate dehydrogenase, hexokinase, and fatty acid synthetase—were all significantly increased in the larvae injected with PS. We performed qRT-PCR to examine the expression profile of immune and metabolic-related genes, which further verified the reliability of our transcriptome data and suggested that PS can regulate the immunity of silkworm by enhancing the cellular immunity and modulating the expression levels of genes related to immune responses and physiological metabolism. These findings will lay a scientific foundation for the use of PS as an immunomodulator in disease prevention in human beings or animals.
The magnitude of the germinal center B cell and T follicular helper cell response predicts long-lasting antibody titers to plague vaccination
Authors: Galloway Darrell R. , Nguyen Nguyen X. , Li Jiahui , Houston Nicholas , Gregersen Gage , Williamson E. Diane , Falkenberg Frank W. , Herron James N. , Hale J. Scott
Published: October 2022

The development of a safe and effective vaccine againstYersinia pestis, the causative organism for plague disease, remains an important global health priority. Studies have demonstrated effective immune-based protection against plague challenge that is induced by plague antigen subunit vaccination in an aqueous alhydrogel formulation; however, whether these candidate vaccines in this formulation and presentation, induce long-lasting immunological memory in the form of durable cellular and antibody recall responses has not been fully demonstrated. In this study, we analyzed germinal center T follicular helper and germinal center B cell responses following F1V and F1 + V plague subunit immunization of mice with vaccines formulated in various adjuvants. Our data demonstrate that recombinant plague protein immunization formulated with IL-2/GM-CSF cytokines bound to alhydrogel adjuvant drive an increase in the magnitude of the germinal center T follicular helper and germinal center B cell responses following primary immunization, compared to vaccines formulated with Alhydrogel adjuvant alone. In contrast, plague protein subunit immunization combined with CpG ODN bound to alhydrogel increased the magnitude and duration of the germinal center Tfh and B cell responses following booster immunization. Importantly, enhanced germinal center Tfh and B cell responses correlated with long-lasting and high F1V-specific antibody titers and more robust antibody recall responses to F1V re-exposure. These findings indicate that vaccine formulations that drive enhancement of the germinal center Tfh and B cell responses are critical for inducing durable plague-specific humoral immunity.
Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation
Authors: Saas Philippe , Vetter Mathieu , Maraux Melissa , Bonnefoy Francis , Perruche Sylvain
Published: October 2022

Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (i.e., “eat-me” signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft-versus-host disease) inflammatory diseases.
Immunotherapy for the treatment of multiple myeloma
Authors: Boussi Leora S. , Avigan Zachary M. , Rosenblatt Jacalyn
Published: October 2022

Despite advances in treatment for multiple myeloma, the majority of patients ultimately develop relapsed disease marked by immune evasion and resistance to standard therapy. Immunotherapy has emerged as a powerful tool for tumor-directed cytotoxicity with the unique potential to induce immune memory to reduce the risk of relapse. Understanding the specific mechanisms of immune dysregulation and dysfunction in advanced myeloma is critical to the development of further therapies that produce a durable response. Adoptive cellular therapy, most strikingly CAR T cell therapy, has demonstrated dramatic responses in the setting of refractory disease. Understanding the factors that contribute to immune evasion and the mechanisms of response and resistance to therapy will be critical to developing the next generation of adoptive cellular therapies, informing novel combination therapy, and determining the optimal time to incorporate immune therapy in the treatment of myeloma.
Current clinical spectrum of common variable immunodeficiency in Spain: The multicentric nationwide GTEM-SEMI-CVID registry
Authors: Cabañero-Navalon Marta Dafne , Garcia-Bustos Victor , Nuñez-Beltran Maria , Císcar Fernández Pascual , Mateu Lourdes , Solanich Xavier , Carrillo-Linares Juan Luis , Robles-Marhuenda Ángel , Puchades-Gimeno Francesc , Pelaez Ballesta Ana , López-Osle Nuria , Torralba-Cabeza Miguel Ángel , Bielsa Masdeu Ana María , Diego Gil Jorge , Tornador Gaya Nuria , Pascual Castellanos Guillem , Sánchez-Martínez Rosario , Barragán-Casas José Manuel , González-García Andrés , Patier de la Peña José Luís , López-Wolf Daniel , Mora Rufete Antonia , Canovas Mora Alba , Forner Giner Maria José , Moral Moral Pedro
Published: October 2022

Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans’ syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients.
CD4+-mediated colitis in mice is independent of the GPR183 and GPR18 pathways
Authors: Dicker Martina , Li Yingcong , Giles Daniel A. , Verstichel Greet , Castelan Viankail Cedillo , Ascui-Gac Gabriel , Chou Ting-Fang , Perez-Jeldres Tamara , Cheroutre Hilde , Kronenberg Mitchell
Published: October 2022

Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patients that also are near loci identified by genome wide association studies (GWAS) associated with IBD risk. One such SNP, rs9557195 was of particular interest because it is within an intron of G-protein-coupled receptor (GPR) 183, known to be important for lymphocyte migration. Furthermore, this SNP is in close proximity to the gene encoding another G-protein coupled receptor, GPR18. Analyzing publicly available datasets, we found transcripts of GPR183 and GPR18 to be increased in colon biopsies from ulcerative colitis and Crohn’s disease patients, and GPR183 was even more increased in patients resistant to TNF treatment. Expression of both genes also was increased in mouse models of colitis. Therefore, our aim was to understand if increased expression of these GPRs in the intestine is related to disease severity in colitis models. Here we investigated the role of these receptors in the T cell transfer model and the dextran sulfate sodium model. In the T cell transfer model, GPR183 expression on donor T cells, as well as on other cell types in the Rag-/- recipients, was not essential for severe colitis induction. Furthermore, deficiency in Rag-/- mice for the enzyme that synthesizes a cholesterol metabolite that is a major ligand for GPR183 also did not affect disease. Similarly, lack of GPR18 expression in T cells or other cell types did not affect colitis pathogenesis in the T cell transfer or in the dextran sulfate sodium model. Therefore, despite increased expression of transcripts for these genes in the intestine during inflammation in humans and mice, they are not required for disease severity in mouse models of colitis induced by chemical injury or T cell cytokines, perhaps due to redundancy in mechanisms important for homing and survival of lymphocytes to the inflamed intestine.
Microglia shield the murine brain from damage mediated by the cytokines IL-6 and IFN-α
Authors: West Phillip K. , Viengkhou Barney , Campbell Iain L. , Hofer Markus J.
Published: October 2022

Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production.
Regulation of epigenetic modifications in the head and neck tumour microenvironment
Authors: Liu Huimin , Wang Dongxu , Yang Zhijing , Li Shuangji , Wu Han , Xiang Jingcheng , Kan Shaoning , Hao Ming , Liu Weiwei
Published: October 2022

Head and neck tumours are common malignancies that are associated with high mortality. The low rate of early diagnosis and the high rates of local recurrence and distant metastasis are the main reasons for treatment failure. Recent studies have established that the tumour microenvironment (TME) can affect the proliferation and metastasis of head and neck tumours via several mechanisms, including altered expressions of certain genes and cytokines. Increasing evidence has shown that epigenetic modifications, such as DNA methylation, histone modification, RNA modification, and non-coding RNAs, can regulate the head and neck TME and thereby influence tumour development. Epigenetic modifications can regulate the expression of different genes and subsequently alter the TME to affect the progression of head and neck tumours. In addition, the cell components in the TME are regulated by epigenetic modifications, which, in turn, affect the behaviour of head and neck tumour cells. In this review, we have discussed the functions of epigenetic modifications in the head and neck TME. We have further examined the roles of such modifications in the malignancy and metastasis of head and neck tumours.
Long pentraxin 3 (PTX3) levels predict death, intubation and thrombotic events among hospitalized patients with COVID-19
Authors: Lapadula Giuseppe , Leone Roberto , Bernasconi Davide Paolo , Biondi Andrea , Rossi Emanuela , D’Angiò Mariella , Bottazzi Barbara , Bettini Laura Rachele , Beretta Ilaria , Garlanda Cecilia , Valsecchi Maria Grazia , Mantovani Alberto , Bonfanti Paolo
Published: October 2022

Background

PTX3 is an important mediator of inflammation and innate immunity. We aimed at assessing its prognostic value in a large cohort of patients hospitalized with COVID-19.

Methods

Levels of PTX3 were measured in 152 patients hospitalized with COVID-19 at San Gerardo Hospital (Monza, Italy) since March 2020. Cox regression was used to identify predictors of time from admission to in-hospital death or mechanical ventilation. Crude incidences of death were compared between patients with PTX3 levels higher or lower than the best cut-off estimated with the Maximally Selected Rank Statistics Method.

Results

Upon admission, 22% of the patients required no oxygen, 46% low-flow oxygen, 30% high-flow nasal cannula or CPAP-helmet and 3% MV. Median level of PTX3 was 21.7 (IQR: 13.5-58.23) ng/ml. In-hospital mortality was 25% (38 deaths); 13 patients (8.6%) underwent MV. PTX3 was associated with risk of death (per 10 ng/ml, HR 1.08; 95%CI 1.04-1.11; P<0.001) and death/MV (HR 1.04; 95%CI 1.01-1.07; P=0.011), independently of other predictors of in-hospital mortality, including age, Charlson Comorbidity Index, D-dimer and C-reactive protein (CRP). Patients with PTX3 levels above the optimal cut-off of 39.32 ng/ml had significantly higher mortality than the others (55% vs 8%, P<0.001). Higher PTX3 plasma levels were found in 14 patients with subsequent thrombotic complications (median [IQR]: 51.4 [24.6-94.4] versus 21 [13.4-55.2]; P=0.049).

Conclusions

High PTX3 levels in patients hospitalized with COVID-19 are associated with a worse outcome. The evaluation of this marker could be useful in prognostic stratification and identification of patients who could benefit from immunomodulant therapy.
Development of a novel glycolysis-related genes signature for isocitrate dehydrogenase 1-associated glioblastoma multiforme
Authors: Cai Xiaomin , Chen Zheng , Huang Caiquan , Shen Jie , Zeng Wenxian , Feng Shuang , Liu Yu , Li Shiting , Chen Ming
Published: October 2022

Background

The significant difference in prognosis between IDH1 wild-type and IDH1 mutant glioblastoma multiforme (GBM) may be attributed to their metabolic discrepancies. Hence, we try to construct a prognostic signature based on glycolysis-related genes (GRGs) for IDH1-associated GBM and further investigate its relationships with immunity.

Methods

Differentially expressed GRGs between IDH1 wild-type and IDH1 mutant GBM were screened based on the TCGA database and the Molecular Signature Database (MSigDB). Consensus Cluster Plus analysis and KEGG pathway analyses were used to establish a new GRGs set. WGCNA, univariate Cox, and LASSO regression analyses were then performed to construct the prognostic signature. Then, we evaluated association of the prognostic signature with patients’ survival, clinical characteristics, tumor immunogenicity, immune infiltration, and validated one hub gene.

Results

956 differentially expressed genes (DEGs) between IDH1 wild-type and mutant GBM were screened out and six key prognostically related GRGs were rigorously selected to construct a prognostic signature. Further evaluation and validation showed that the signature independently predicted GBM patients’ prognosis with moderate accuracy. In addition, the prognostic signature was also significantly correlated with clinical traits (sex and MGMT promoter status), tumor immunogenicity (mRNAsi, EREG-mRNAsi and HRD-TAI), and immune infiltration (stemness index, immune cells infiltration, immune score, and gene mutation). Among six key prognostically related GRGs, CLEC5A was selected and validated to potentially play oncogenic roles in GBM.

Conclusion

Construction of GRGs prognostic signature and identification of close correlation between the signature and immune landscape would suggest its potential applicability in immunotherapy of GBM in the future.
Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment
Authors: Zheng Xiaoyong , Ma Yajie , Bai Yan , Huang Tao , Lv Xuefeng , Deng Jinhai , Wang Zhongquan , Lian Wenping , Tong Yalin , Zhang Xinyu , Yue Miaomiao , Zhang Yan , Li Lifeng , Peng Mengle
Published: October 2022

The incidence and mortality of colorectal cancer (CRC) are increasing year by year. The accurate classification of CRC can realize the purpose of personalized and precise treatment for patients. The tumor microenvironment (TME) plays an important role in the malignant progression and immunotherapy of CRC. An in-depth understanding of the clusters based on the TME is of great significance for the discovery of new therapeutic targets for CRC. We extracted data on CRC, including gene expression profile, DNA methylation array, somatic mutations, clinicopathological information, and copy number variation (CNV), from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) (four datasets—GSE14333, GSE17538, GSE38832, and GSE39582), cBioPortal, and FireBrowse. The MCPcounter was utilized to quantify the abundance of 10 TME cells for CRC samples. Cluster repetitive analysis was based on the Hcluster function of the Pheatmap package in R. The ESTIMATE package was applied to compute immune and stromal scores for CRC patients. PCA analysis was used to remove batch effects among different datasets and transform genome-wide DNA methylation profiling into methylation of tumor-infiltrating lymphocyte (MeTIL). We evaluated the mutation differences of the clusters using MOVICS, DeconstructSigs, and GISTIC packages. As for therapy, TIDE and SubMap analyses were carried out to forecast the immunotherapy response of the clusters, and chemotherapeutic sensibility was estimated based on the pRRophetic package. All results were verified in the TCGA and GEO data. Four immune clusters (ImmClust-CS1, ImmClust-CS2, ImmClust-CS3, and ImmClust-CS4) were identified for CRC. The four ImmClusts exhibited distinct TME compositions, cancer-associated fibroblasts (CAFs), functional orientation, and immune checkpoints. The highest immune, stromal, and MeTIL scores were observed in CS2, in contrast to the lowest scores in CS4. CS1 may respond to immunotherapy, while CS2 may respond to immunotherapy after anti-CAFs. Among the four ImmClusts, the top 15 markers with the highest mutation frequency were acquired, and CS1 had significantly lower CNA on the focal level than other subtypes. In addition, CS1 and CS2 patients had more stable chromosomes than CS3 and CS4. The most sensitive chemotherapeutic agents in these four ImmClusts were also found. IHC results revealed that CD29 stained significantly darker in the cancer samples, indicating that their CD29 was highly expressed in colon cancer. This work revealed the novel clusters based on TME for CRC, which would guide in predicting the prognosis, biological features, and appropriate treatment for patients with CRC.
Uncertainty in Atlantic Multidecadal Oscillation derived from different observed datasets and their possible causes
Authors: Zhao Bowen , Lin Pengfei , Hu Aixue , Liu Hailong , Ding Mengrong , Yu Zipeng , Yu Yongqiang
Published: October 2022

As a leading mode of sea surface temperature (SST) variability over the North Atlantic in both observations and model simulations, the Atlantic Multidecadal Oscillation (AMO) can have a substantial influence on regional and global climate. By using Low-Frequency Component Analysis, we explore the uncertainties of the resulting AMO indices and the corresponding spatial patterns derived from three observational SST datasets. We found that the known coherent spatial pattern of the AMO at the basin scale over the North Atlantic appears in two out of the three datasets. Further analysis indicates that both the warming trend and the different techniques used to construct these observed gridded SSTs contribute to the AMO’s spatial coherence over the North Atlantic, especially during periods of sparse data sampling. The SST in the Extended Reconstructed SST dataset version 5 (ERSSTv5), changes from being systematically below the other datasets during the dense sampling periods on either side of the Second World War (WWII), to systematically above the other datasets during WWII, thereby introducing an artificial 10–20-year variability that affects the AMO’s spatial coherence. This coherence in the AMO’s spatial pattern is also affected by bias adjustment in ERSSTv5 at relative cool (i.e., non-summer) seasons, and by the heterogeneous North Atlantic warming pattern. The different AMO patterns can induce the different effects of wind, surface heat fluxes, and then drive ocean circulation and its heat transport convergence, especially for some seasons. For AMO indices, both the different detrending methods and different observational data result in uncertainty for the period 1935–1950. Such SST uncertainty is important to detect the relative role of the atmosphere and ocean in shaping the AMO.
Multi-scale permutation Lempel-Ziv complexity and its application in feature extraction for Ship-radiated noise
Authors: Yi Yingmin , Li Yuxing , Wu Junxian
Published: October 2022

Permutation Lempel-Ziv complexity (PLZC) is a recently proposed method for analyzing signal complexity. However, PLZC only characterizes the signal complexity from single scale and has certain limitations. In order to overcome these shortcomings and improve the performance of feature extraction for underwater acoustic signal, this paper introduced coarse graining operation, proposed the multi-scale permutation Lempel-Ziv complexity (MPLZC), and proposed an automatic hybrid multi-feature extraction method for ship-radiated noise signal (S-S) based on multi-scale Lempel-Ziv complexity (MLZC), multi-scale permutation entropy (MPE) and MPLZC. The results of simulation and realistic experiments show that MPLZC can better reflect the change of signal complexity in detecting the dynamic change of signals, and more effectively distinguish white noise, pink noise and blue noise than MPE and MLZC; compared with the three feature extraction methods based on MLZC, MPE and MPLZC respectively, the proposed method has the highest recognition rates of six S-Ss under the same number of features, and the recognition rate reaches 100% when the number of features is 5; the introduction of MPLZC significantly improves the performance for ship-radiated noise signal of the automatic hybrid multi-feature extraction method. It is indicated that the proposed method, as a new underwater acoustic technology, is valid in other underwater acoustic signals.
Steel rebar corrosion and corrosion-induced cracking in reinforced foamed concrete
Authors: Luo Yongheng , Zhu Qilin , Chen Depeng , Liu Chunlin , Pan Suiwei
Published: October 2022

This study investigated the corrosion behavior of steel rebar in foamed concrete and the effects of water-cement ratio, fly ash, and fiber on reinforced foamed concrete’s corrosion rate and crack width. It was found that the corrosion rate of steel rebar and crack width of foamed concrete increased slowly with time and then developed rapidly, finally growing slowly. The higher the density of foamed concrete, the stronger the corrosion resistance of steel rebar. The best corrosion resistance of steel rebar in foamed concrete is achieved when the water-cement ratio is 0.5, fly ash and fiber are 20% and 0.6%, respectively.
Modeling precipitation kinetics in multicomponent alloys during deformation
Authors: Bonvalet Rolland Manon , Borgenstam Annika
Published: October 2022

A new mean-field modeling tool is developed to correctly tackle the problem of precipitation during deformation. The model is an extension of a previously developed Langer–Schwartz–Kampmann–Wagner precipitation modeling approach for multicomponent alloys. The latter is now integrated together with Thermo-Calc software and with physically based equations describing the evolution of the dislocation density during hot-working. New equations for the nucleation barrier and the critical size have also been added to correctly simulate the early stages of precipitation. The model is applied to hot compression tests, for which experimental information was available. The model shows the importance of accounting for the overall precipitation kinetics, and not only for constant values of the precipitate volume fraction or size, to investigate the mechanical property evolution. This is due to a complex interplay between the defects and the precipitates’ evolution driven by a competition between thermodynamics and kinetics. Finally, it is highlighted how the strain rate used affects the final microstructure of the material.
Metal foams: A review for mechanical properties under tensile and shear stress
Authors: Kalpakoglou Thomas , Yiatros Stylianos
Published: October 2022

Due to their mechanical properties, metal foams are used in various fields. The aim of the present research is to collect different studies about the important mechanical properties of metal foams, such as Young’s modulus, tensile and shear strength, relative density, etc. under tensile and shear loading. Gaps were identified in the methodological embodiments of the experiments due to the use of different standards, as well as in the calculation of mechanical properties through mathematical relations in tensile and shear, which led to deviations between the experimental results and these. Furthermore, this work records sequences and connections between experimental results of different tasks as well as solutions to the aforementioned issues.
Vasculitis and familial Mediterranean fever: Description of 22 French adults from the juvenile inflammatory rheumatism cohort
Authors: Abbara Salam , Monfort Jean-Benoit , Savey Léa , Moguelet Philippe , Saadoun David , Bachmeyer Claude , Fain Olivier , Terrier Benjamin , Amoura Zahir , Mathian Alexis , Gilardin Laurent , Buob David , Job-Deslandre Chantal , Dufour Jean-François , Sberro-Soussan Rebecca , Grateau Gilles , Georgin-Lavialle Sophie
Published: October 2022

Objective

The frequency of vasculitis may be increased in patients with Familial Mediterranean Fever (FMF), according to several studies. Our aim was to assess the characteristics of French adult patients with both diseases.

Methods

Patients with vasculitis were selected from patients followed for FMF in the French JIR-cohort.

Results

Twenty-two patients were included [polyarteritis nodosa (PAN) n = 10, IgA vasculitis n = 8, unclassified vasculitis n = 2, granulomatosis with polyangiitis n = 1, and microscopic polyangiitis n = 1]. Pathogenic mutations in exon 10 were found in all 21 patients (96%) for which MEFV testing results were available, and 18 (82%) had two pathogenic mutations. Histology showed vasculitis in 59% of patients. Most patients with FMF-associated PAN were HBV-negative and had an inactive FMF before PAN onset, and 40% had a peri-renal or central nervous system bleeding. Most patients with FMF-associated IgA vasculitis had an active FMF before vasculitis onset, and 25% had digestive bleeding. Both patients with unclassified vasculitis had ischemic and/or hemorrhagic complications.

Conclusion

This study confirms the predominance of PAN and IgA vasculitis in patients with FMF and the high frequency of bleeding in FMF-associated PAN. FMF should be considered in case of persistent symptoms and/or inflammatory syndrome despite vasculitis treatment in Mediterranean patients.
Establishment and validation of the survival prediction risk model for appendiceal cancer
Authors: Liu Tao , Mi Junli , Wang Yafeng , Qiao Wenjie , Wang Chenxiang , Ma Zhijun , Wang Cheng
Published: October 2022

Objective

Establishing a risk model of the survival situation of appendix cancer for accurately identifying high-risk patients and developing individualized treatment plans.

Methods

A total of 4,691 patients who were diagnosed with primary appendix cancer from 2010 to 2016 were extracted using Surveillance, Epidemiology, and End Results (SEER) * Stat software. The total sample size was divided into 3,283 cases in the modeling set and 1,408 cases in the validation set at a ratio of 7:3. A nomogram model based on independent risk factors that affect the prognosis of appendix cancer was established. Single-factor Cox risk regression, Lasso regression, and multifactor Cox risk regression were used for analyzing the risk factors that affect overall survival (OS) in appendectomy patients. A nomogram model was established based on the independent risk factors that affect appendix cancer prognosis, and the receiver operating characteristic curve (ROC) curve and calibration curve were used for evaluating the model. Survival differences between the high- and low-risk groups were analyzed through Kaplan–Meier survival analysis and the log-rank test. Single-factor Cox risk regression analysis found age, ethnicity, pathological type, pathological stage, surgery, radiotherapy, chemotherapy, number of lymph nodes removed, T stage, N stage, M stage, tumor size, and CEA all to be risk factors for appendiceal OS. At the same time, multifactor Cox risk regression analysis found age, tumor stage, surgery, lymph node removal, T stage, N stage, M stage, and CEA to be independent risk factors for appendiceal OS. A nomogram model was established for the multifactor statistically significant indicators. Further stratified with corresponding probability values based on multifactorial Cox risk regression, Kaplan–Meier survival analysis found the low-risk group of the modeling and validation sets to have a significantly better prognosis than the high-risk group (p < 0.001).

Conclusion

The established appendix cancer survival model can be used for the prediction of 1-, 3-, and 5-year OS and for the development of personalized treatment options through the identification of high-risk patients.
Trends in research related to menopausal hormone therapy from 2000 to 2021: A bibliometric analysis
Authors: Li Jing , Wei Zhipeng , Wu Jingxi , Min Kaili , Li Xiao , Yao Yuan , Li Yao , Zhang Ningning , Shi Anya , Han Jiani , Qiao Chengdong , Yang Kehu
Published: October 2022

We conducted the present bibliometric analysis to explore menopausal hormone therapy (MHT)-related research trends between 2000 and 2021. The Web of Science database was systematically searched from 2000 to 2021 to retrieve MHT-related publications. Visualization mapping and keyword cluster graphs were utilized to illustrate the research topics and hotpots. We included 11,616 MHT-related publications for this bibliometric analysis. The results showed that (1) MHT-related research had a very slow increase in the past 22 years, and the trend fluctuated. Sum of times cited and average citations per item had the same trend: a sharp decline from 2002 to 2003, and a rapid increase from 2003 to 2006, reaching the peak in 2006, then following a downward trend. The average H-index was 57, peaking in 2001; (2) the USA, the League of European Research Universities, and Dr. JoAann Manson from Harvard University contributed the most; (3) Menopause: The Journal of The North American Menopause Society had the most significant number of MHT-related publications; (4) the research hotpots primarily focused on MHT for treating menopausal symptoms and the impact of MHT on women’s health. According to previous studies, MHT was the most effective treatment for managing vasomotor symptoms of menopause, but results from the clinical trials and observational studies regarding MHT adverse events remain inconsistent. Mechanisms are fundamental when clinical studies give conflicting results. Therefore, future studies should focus on adverse events and their mechanisms.
Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies
Authors: Ruiz-Romero Cristina , Fernández-Puente Patricia , González Lucía , Illiano Anna , Lourido Lucía , Paz Rocío , Quaranta Patricia , Perez-Pampín Eva , González Antonio , Blanco Francisco J. , Calamia Valentina
Published: October 2022

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and presence of systemic autoantibodies, with a great clinical and molecular heterogeneity. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are routinely used for the diagnosis of RA. However, additional serological markers are needed to improve the clinical management of this disease, allowing for better patient stratification and the desirable application of precision medicine strategies. In the present study, we investigated those systemic molecular changes that are associated with the RF and ACPA status of RA patients. To achieve this objective, we followed a proteomic biomarker pipeline from the discovery phase to validation. First, we performed an iTRAQ-based quantitative proteomic experiment on serum samples from the RA cohort of the Hospital of Santiago de Compostela (CHUS). In this discovery phase, serum samples from the CHUS cohort were pooled according to their RF/ACPA status. Shotgun analysis revealed that, in comparison with the double negative group (RF–/ACPA–), the abundance of 12 proteins was altered in the RF+/ACPA+ pool, 16 in the RF+/ACPA– pool and 10 in the RF-/ACPA+ pool. Vitamin D binding protein and haptoglobin were the unique proteins increased in all the comparisons. For the verification phase, 80 samples from the same cohort were analyzed individually. To this end, we developed a Multiple Reaction Monitoring (MRM) method that was employed in a comprehensive targeted analysis with the aim of verifying the results obtained in the discovery phase. Thirty-one peptides belonging to 12 proteins associated with RF and/or ACPA status were quantified by MRM. In a final validation phase, the serum levels of alpha-1-acid glycoprotein 1 (A1AG1), haptoglobin (HPT) and retinol-binding protein 4 (RET4) were measured by immunoassays in the RA cohort of the Hospital of A Coruña (HUAC). The increase of two of these putative biomarkers in the double seropositive group was validated in 260 patients from this cohort (p = 0.009 A1AG1; p = 0.003 HPT). The increased level of A1AG1 showed association with RF rather than ACPA (p = 0.023), whereas HPT showed association with ACPA rather than RF (p = 0.013). Altogether, this study has allowed a further classification of the RA seropositive patients into two novel clusters: RF+A1AG+ and ACPA+HPT+. The determination of A1AG1 and HPT in serum would provide novel information useful for RA patient stratification, which could facilitate the effective implementation of personalized medicine in routine clinical practice.