bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative spatial evaluation of tumor-immune interactions in the immunotherapy setting of metastatic melanoma lymph nodes
Authors: Maus Rachel L. G. , Leontovich Alexey A. , Moore Raymond M. , Fogarty Zachary , Guo Ruifeng , Davidson Tara M. , Tekin Burak , Atherton Chathu , Schimke Jill M. , Dicke Betty A. , Chen Benjamin J. , Markovic Svetomir N. 
Published: December 2022

IntroductionImmune cell infiltration into the tumor microenvironment is generally associated with favorable clinical outcomes in solid tumors. However, the dynamic interplay among distinct immune cell subsets within the tumor-immune microenvironment as it relates to clinical responses to immunotherapy remains unresolved. In this study, we applied multiplex immunofluorescence (MxIF) to spatially characterize tumor-immune interactions within the metastatic melanoma lymph node.MethodsPretreatment, whole lymph node biopsies were evaluated from 25 patients with regionally metastatic melanoma who underwent subsequent anti-PD1 therapy. Cyclic MxIF was applied to quantitatively and spatially assess expression of 45 pathologist-validated antibodies on a single tissue section. Pixel-based single cell segmentation and a supervised classifier approach resolved 10 distinct tumor, stromal and immune cell phenotypes and functional expression of PD1.ResultsSingle cell analysis across 416 pathologist-annotated tumor core regions of interest yielded 5.5 million cells for spatial evaluation. Cellular composition of tumor and immune cell subsets did not differ in the tumor core with regards to recurrence outcomes (p&gt;0.05) however spatial patterns significantly differed in regional and paracrine neighborhood evaluations. Specifically, a regional community cluster comprised of primarily tumor and dendritic cells was enriched in patients that did not experience recurrence (p=0.009). By an independent spatial approach, cell-centric neighborhood analyses identified an enrichment for dendritic cells in cytotoxic T cell (CTL) and tumor cell-centric neighborhoods in the no recurrence patient response group (p&lt;0.0001). Further evaluation of these neighborhoods identified an enrichment for CTL-dendritic cell interactions in patients that did not experience recurrence (p&lt;0.0001) whereas CTL-macrophage interactions were more prevalent in CTL-centric neighborhoods of patients who experienced recurrence (p&lt;0.0001).DiscussionOverall, this study offers a more comprehensive evaluation of immune infiltrates and spatial-immune signatures in the metastatic tumor-immune microenvironment as it informs recurrence risk following immunotherapy.
Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia
Authors: Yang You , Yang Yan , Liu Jing , Zeng Yan , Guo Qulian , Guo Jing , Guo Ling , Lu Haiquan , Liu Wenjun 
Published: December 2022

IntroductionThe heterogeneity of treatment response in acute myeloid leukemia (AML) patients poses great challenges for risk scoring and treatment stratification. Carbohydrate metabolism plays a crucial role in response to therapy in AML. In this multicohort study, we investigated whether carbohydrate metabolism related genes (CRGs) could improve prognostic classification and predict response of immunity and treatment in AML patients.MethodsUsing univariate regression and LASSO-Cox stepwise regression analysis, we developed a CRG prognostic signature that consists of 10 genes. Stratified by the median risk score, patients were divided into high-risk group and low-risk group. Using TCGA and GEO public data cohorts and our cohort (1031 non-M3 patients in total), we demonstrated the consistency and accuracy of the CRG score on the predictive performance of AML survival.ResultsThe overall survival (OS) was significantly shorter in high-risk group. Differentially expressed genes (DEGs) were identified in the high-risk group compared to the low-risk group. GO and GSEA analysis showed that the DEGs were mainly involved in immune response signaling pathways. Analysis of tumor-infiltrating immune cells confirmed that the immune microenvironment was strongly suppressed in high-risk group. The results of potential drugs for risk groups showed that inhibitors of carbohydrate metabolism were effective.DiscussionThe CRG signature was involved in immune response in AML. A novel risk model based on CRGs proposed in our study is promising prognostic classifications in AML, which may provide novel insights for developing accurate targeted cancer therapies.
Evaluating IL-6 and IL-10 as rapid diagnostic tools for Gram-negative bacteria and as disease severity predictors in pediatric sepsis patients in the intensive care unit
Authors: Zhang Yunyu , Li Biru , Ning Botao 
Published: December 2022

BackgroundTo explore the diagnostic performance of interleukin (IL)-6 and IL-10 in discriminating Gram bacteria types and predicting disease severity in intensive care unit (ICU)-hospitalized pediatric sepsis patients.MethodWe retrospectively collected Th1/Th2 cytokine profiles of 146 microbiologically documented sepsis patients. Patients were categorized into Gram-positive (G+) or Gram-negative (G-) sepsis groups, and cytokine levels were compared. Subgroup analysis was designed to eliminate the influence of other inflammatory responses on cytokine levels.ResultsAfter propensity score matching, 78 patients were matched and categorized according to Gram bacteria types. Compared with G+ sepsis, IL-6 and IL-10 were significantly elevated in G- sepsis (p &lt; 0.05). Spearman test proved the linear correlation between IL-6 and IL-10 (r = 0.654, p &lt; 0.001), and their combination indicators (ratio and differences) were effective in identifying G- sepsis. In the subgroup analysis, such cytokine elevation was significant regardless of primary infection site. However, for patients with progressively deteriorating organ function [new or progressive multiple organ dysfunction syndrome (NPMODS)], differences in IL-6 and IL-10 levels were less significant between G+ and G- sepsis. In the receiver operating characteristic (ROC) curves of the G- sepsis group, the area under the curve (AUC) value for IL-6 and IL-10 was 0.679 (95% CI 0.561–0.798) and 0.637 (95% CI 0.512–0.762), respectively. The optimal cutoff value for diagnosing G- sepsis was 76.77 pg/ml and 18.90 pg/ml, respectively. While for the NPMODS group, the AUC for IL-6 and IL-10 was 0.834 (95% CI 0.766–0.902) and 0.781 (95% CI 0.701–0.860), respectively.ConclusionIL-6 and IL-10 are comparably effective in discriminating G+/G- sepsis in pediatric intensive care unit (PICU) patients. The deteriorated organ function observed in ICU patients reveals that complex inflammatory responses might have contributed to the cytokine pattern observed in severe sepsis patients, therefore confounding the discriminating efficacy of Th1/Th2 cytokines in predicting Gram bacteria types.
Correlation of the TIGIT-PVR immune checkpoint axis with clinicopathological features in triple-negative breast cancer
Authors: Boissière-Michot Florence , Chateau Marie-Christine , Thézenas Simon , Guiu Séverine , Bobrie Angélique , Jacot William 
Published: December 2022

BackgroundT cell immunoreceptor with Ig and ITIM domains (TIGIT) interacts with poliovirus receptor (PVR) to contribute to cancer immune escape. Recently, TIGIT and PVR have been identified as promising immunotherapy targets. Their gene expression is upregulated in many solid tumors, but their protein expression level is not well documented, particularly in triple negative breast cancer (TNBC), the breast cancer subtype that most benefit from immunotherapy.MethodsTIGIT and PVR expression levels were assessed by immunohistochemistry in 243 surgically resected localized TNBC and then their relationship with clinical-pathological features and clinical outcome was analyzed.ResultsTIGIT expression was observed in immune cells from the tumor microenvironment, whereas PVR was mainly expressed by tumor cells. High TIGIT expression was significantly associated with age (p=0.010), histological grade (p=0.014), non-lobular histology (p=0.024), adjuvant chemotherapy (p=0.006), and various immune cell populations (tumor infiltrating lymphocytes (TILs), CD3+, CD8+, PD-1+ cells; all p&lt;0.0001), PD-L1+ tumor cells (p&lt;0.0001), and PD-L1+ stromal cells (p=0.003). Infiltration by TIGIT+ cells tended to be higher in non-molecular apocrine tumors (p=0.088). PVR was significantly associated with histological grade (p&lt;0.0001), the basal-like (p=0.003) and non-molecular apocrine phenotypes (p=0.039), high TILs infiltration (p=0.011), CD3+ (p=0.002), CD8+ (p=0.024) T cells, and PD-L1 expression in tumor (p=0.003) and stromal cells (p=0.001). In univariate analysis, only known prognostic factors (age, tumor size, lymph node status, adjuvant chemotherapy, TILs and CD3+ T-cell infiltrate) were significantly associated with relapse-free survival (RFS) and overall survival. High TIGIT and PVR expression levels tended to be associated with longer RFS (p=0.079 and 0.045, respectively). The analysis that included only non-molecular apocrine TNBC revealed longer RFS for tumors that strongly expressed TIGIT or PVR (p=0.025 for TIGIT and 0.032 for PVR).ConclusionsThese results indicated that in TNBC, TIGIT+ cells can easily interact with PVR to exert their inhibitory effects. Their wide expression in TNBC and their association with other immune checkpoint components suggest the therapeutic interest of the TIGIT-PVR axis.
Transcriptomic FHITlow/pHER2high signature as a predictive factor of outcome and immunotherapy response in non-small cell lung cancer
Authors: Brisebarre Audrey , Ancel Julien , Ponchel Théophile , Loeffler Emma , Germain Adeline , Dalstein Véronique , Dormoy Valérian , Durlach Anne , Delepine Gonzague , Deslée Gaëtan , Polette Myriam , Nawrocki-Raby Béatrice 
Published: December 2022

IntroductionIn recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance.Materials and methodsWe performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITlow/pHER2high signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI).ResultsWe showed that up-regulated genes in FHITlow/pHER2high tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHITlow/pHER2high signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHITlow/pHER2high tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts.ConclusionThese data suggest that ICI might not be a relevant option for NSCLC patients with FHITlow/pHER2high tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis.
Combining PD-1 or PD-L1 inhibitors with chemotherapy is a good strategy for the treatment of extensive small cell lung cancer: A retrospective analysis of clinical studies
Authors: Luo Hao , Song Guangbin , Wang Dong , Li Mengxia , Dai Nan 
Published: December 2022

ObjectivesTo provide an updated systematic review and meta-analysis of published randomized controlled trials (RCTs) of the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of extensive-stage small-cell lung cancer (ES-SCLC).MethodsPubMed, Web of Science, Embase, Clinicaltrials and the Cochrane Library were systematically searched to extract RCTs concerning the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of ES-SCLC from the time of database inception to October 31, 2022. The literature was independently selected, information was extracted and the risk of bias of the RCTs was evaluated according to the inclusion and exclusion criteria. Stata14.0 was used for the meta-analysis.ResultsSix studies involving 2,600 patients were included in the analysis. The results of the meta-analysis showed that the combination of PD-1/PD-L1 inhibitors significantly improved the OS (HR: 0.73, 95% CI: 0.66-0.80; P&lt;0.0001), prolonged PFS (HR: 0.66,95% CI: 0.55-0.79; P&lt;0.0001) and did not increase overall incidence of treatment-related adverse events (TRAEs) (RR: 1.03, 95% CI: 0.97-1.09; P=0.330) in ES-SCLC patients compared with chemotherapy alone. The subgroup analysis found that patients with negative PD-L1 expression (&lt; 1%) benefited in OS, whereas patients with positive PD-L1 expression (≥1%) had no statistically significant difference in OS. There was a statistically significant difference in PFS between PD-L1-negative (&lt; 1%) and PD-L1-positive (≥1%) patients. The addition of a PD-1 inhibitor or PD-L1 inhibitor to the chemotherapy regimen can improve OS and prolong PFS in patients with ES-SCLC.ConclusionsPD-1/PD-L1 inhibitors combination chemotherapy significantly improves PFS and OS in ES-SCLC patients without increasing the overall incidence of TRAEs.
Deciphering a mitochondria-related signature to supervise prognosis and immunotherapy in hepatocellular carcinoma
Authors: Shi Yanlong , Huang Guo , Jiang Fei , Zhu Jun , Xu Qiyang , Fang Hanlu , Lan Sheng , Pan Ziyuan , Jian Haokun , Li Li , Zhang Yewei 
Published: December 2022

BackgroundHepatocellular carcinoma (HCC) is a major public health problem in humans. The imbalance of mitochondrial function has been discovered to be closely related to the development of cancer recently. However, the role of mitochondrial-related genes in HCC remains unclear.MethodsThe RNA-sequencing profiles and patient information of 365 samples were derived from the Cancer Genome Atlas (TCGA) dataset. The mitochondria-related prognostic model was established by univariate Cox regression analysis and LASSO Cox regression analysis. We further determined the differences in immunity and drug sensitivity between low- and high-risk groups. Validation data were obtained from the International Cancer Genome Consortium (ICGC) dataset of patients with HCC. The protein and mRNA expression of six mitochondria-related genes in tissues and cell lines was verified by immunohistochemistry and qRT-PCR.ResultsThe six mitochondria-related gene signature was constructed for better prognosis forecasting and immunity, based on which patients were divided into high-risk and low-risk groups. The ROC curve, nomogram, and calibration curve exhibited admirable clinical predictive performance of the model. The risk score was associated with clinicopathological characteristics and proved to be an independent prognostic factor in patients with HCC. The above results were verified in the ICGC validation cohort. Compared with normal tissues and cell lines, the protein and mRNA expression of six mitochondria-related genes was upregulated in HCC tissues and cell lines.ConclusionThe signature could be an independent factor that supervises the immunotherapy response of HCC patients and possess vital guidance value for clinical diagnosis and treatment.
Identification of necroptosis-related subtypes, development of a novel signature, and characterization of immune infiltration in colorectal cancer
Authors: Sun Mengyu , Ji Xiaoyu , Xie Meng , Chen Xiaoping , Zhang Bixiang , Luo Xiangyuan , Feng Yangyang , Liu Danfei , Wang Yijun , Li Yiwei , Liu Bifeng , Xia Limin , Huang Wenjie 
Published: December 2022

IntroductionNecroptosis, a type of programmed cell death, has recently been extensively studied as an important pathway regulating tumor development, metastasis, and immunity. However, the expression patterns of necroptosis-related genes (NRGs) in colorectal cancer (CRC) and their potential roles in the tumor microenvironment (TME) have not been elucidated.MethodsWe explored the expression patterns of NRGs in 1247 colorectal cancer samples from genetics and transcriptional perspective. Based on a consensus clustering algorithm, we identified NRG molecular subtypes and gene subtypes, respectively. Furthermore, we constructed a necroptosis-related signature for predicting overall survival time and verified the predictive ability of the model. Using the ESTIMATE, CIBERSORT, and ssGSEA algorithms, we assessed the association between the above subtypes, scores and immune infiltration. ResultsMost NRGs were differentially expressed between CRC tissues and normal tissues. We found that distinct subtypes exhibited different NRGs expression, patients’ prognosis, immune checkpoint gene expression, and immune infiltration characteristics. The scores calculated from the necroptosis-related signature can be used to classify patients into high-risk and low-risk groups, with the high-risk group corresponding to reduced immune cell infiltration and immune function, and a greater risk of immune dysfunction and immune escape. DiscussionOur comprehensive analysis of NRGs in CRC demonstrated their potential role in clinicopathological features, prognosis, and immune infiltration in the TME. These findings help us deepen our understanding of NRGs and the tumor microenvironment landscape, and lay a foundation for effectively assessing patient outcomes and promoting more effective immunotherapy.
A triton X-100 assisted PMAxx-qPCR assay for rapid assessment of infectious African swine fever virus
Authors: Liu Huan , Meng Fei , Nyaruaba Raphael , He Ping , Hong Wei , Jiang Mengwei , Liu Dongqing , Zhou Wenhao , Bai Dan , Yu Junping , Wei Hongping 
Published: December 2022

IntroductionAfrican Swine Fever (ASF) is a highly infectious disease of pigs, caused by African swine fever virus (ASFV). The lack of vaccines and drugs makes strict disinfection practices to be one of the main measurements to curb the transmission of ASF. Therefore, it is important to assess if all viruses are inactivated after disinfection or after long time exposure in their natural conditions. Currently, the infectivity of ASFV is determined by virus isolation and culture in a biosafety level 3 (BSL-3) laboratory. However, BSL-3 laboratories are not readily available, need skilled expertise and may be time consuming.MethodsIn this study, a Triton X-100 assisted PMAxx-qPCR method was developed for rapid assessment of infectious ASFV in samples. PMAxx, an improved version of propidium monoazide (PMA), can covalently cross-link with naked ASFV-DNA or DNA inside inactivated ASFV virions under assistance of 0.1% (v/v) TritonX-100, but not with ASFV-DNA inside live virions. Formation of PMAxx-DNA conjugates prevents PCR amplification, leaving only infectious virions to be detected. Under optimum conditions, the limit of detection of the PMAxx-qPCR assay was 2.32log10HAD50/mL of infectious ASFV. Testing different samples showed that the PMAxx-qPCR assay was effective to evaluate intact ASFV virions after treatment by heat or chemical disinfectants and in simulated samples such as swine tissue homogenate, swine saliva swabs, and environmental swabs. However, whole-blood and saliva need to be diluted before testing because they may inhibit the PCR reaction or the cross-linking of PMAxx with DNA.ConclusionThe Triton X-100 assisted PMAxx-qPCR assay took less than 3 h from sample to result, offering an easier and faster way for assessing infectious ASFV in samples from places like pig farms and pork markets.
Effect of lactobacilli inoculation on protein and carbohydrate fractions, ensiling characteristics and bacterial community of alfalfa silage
Authors: Huo Wenjie , Zhang Yujuan , Zhang Luyao , Shen Chen , Chen Lei , Liu Qiang , Zhang Shuanlin , Wang Cong , Guo Gang 
Published: December 2022

IntroductionAlfalfa (Medicago sativa L.) silage is one of the major forages with high protein for ruminants.MethodsThe objective of this study was to investigate the effects of lactobacilli inoculants on protein and carbohydrate fractions, ensiling characteristics and bacterial community of alfalfa silage. Wilted alfalfa (35% dry matter) was inoculated without (control) or with Lactobacillus coryniformis, Lactobacillus casei, Lactobacillus plantarum, and Lactobacillus pentosus and ensiled for 7, 15, and 60 days.Results and discussionSilage inoculated with L. pentosus was superior to L. coryniformis, L. casei, L. plantarum in improving the fermentation quality of alfalfa silage, as indicated by the lowest ammonia nitrogen content and silage pH during ensiling. There was minor difference in water soluble carbohydrates content among all silages, but L. pentosus inoculants was more efficient at using xylose to produce lactic acid, with lower xylose content and higher lactic acid content than the other inoculants. Compared with the control, L. pentosus inoculants did not affect true protein content of silage, but increased the proportions of buffer soluble protein and acid detergent soluble protein. The L. pentosus inoculants reduced the bacterial diversity In alfalfa silage with lower Shannon, Chao1, and Ace indices, and promoted relative abundance of lactobacillus and decreased the relative abundance of Pediococcus compared with the control. As well as L. pentosus inoculants up-regulated amino acid, carbohydrate, energy, terpenoids, and polypeptides metabolism, and promoted lactic acid fermentation process. In summary, the fermentation quality and nutrient preservation of alfalfa silage were efficiently improved by inoculated with L. pentosus.