bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune features of the peritumoral stroma in pancreatic ductal adenocarcinoma
Authors: Ahmed Azaz , Klotz Rosa , Köhler Sophia , Giese Nathalia , Hackert Thilo , Springfeld Christoph , Jäger Dirk , Halama Niels 
Published: September 2022

BackgroundThe peritumoral stroma is a hallmark of pancreatic ductal adenocarcinoma (PDA) with implications for disease development, progression and therapy resistance. We systematically investigated immune features of the stroma in PDA patients to identify markers of clinical importance and potential therapeutic targets.MethodsTissue and blood samples of 51 PDA patients with clinical and follow-up information were included. Laser Capture Microdissection allowed us to analyze the stromal compartment in particular. Systematic immunohistochemistry, followed by software-based image analysis were conducted. Also, multiplex cytokine analyses (including 50 immune-related molecules) were performed. Functional analyses were performed using patient-derived 3D bioprints. Clinical information was used for survival analyses. Intercompartmental IL9 and IL18 gradients were assessed in matched samples of tumor epithelium, stroma, and serum of patients. Serum levels were compared to an age-matched healthy control group.ResultsStromal IL9 and IL18 are significantly associated with patient survival. While IL9 is a prognostic favorable marker (p=0.041), IL18 associates with poor patient outcomes (p=0.030). IL9 correlates with an anti-tumoral cytokine network which connects regulation of T helper (Th) 9, Th1 and Th17 cells (all: p&lt;0.05 and r&gt;0.5). IL18 correlates with a Th1-type cytokine phenotype and stromal CXCL12 expression (all: p&lt;0.05 and r&gt;0.5). Further, IL18 associates with a higher level of exhausted T cells. Inhibition of IL18 results in diminished Th1- and Th2-type cytokines. Patients with high stromal IL9 expression have a tumor-to-stroma IL9 gradient directed towards the stroma (p=0.019). Low IL18 expression associates with a tumor-to-stroma IL18 gradient away from the stroma (p=0.007). PDA patients showed higher serum levels of IL9 than healthy controls while serum IL18 levels were significantly lower than in healthy individuals. The stromal immune cell composition is distinct from the tumor epithelium. Stromal density of FoxP3+ regulatory T cells showed a tendency towards improved patient survival (p=0.071).ConclusionAn unexpected high expression of the cytokines IL9 and IL18 at different ends is of significance in the stroma of PDA and relates to opposing patient outcomes. Sub-compartmental cytokine analyses highlight the importance of a differentiated gradient assessment. The findings suggest stromal IL9 and/or IL18 as markers for patient stratification and as potential therapeutic targets. Future steps include investigating e. g. the role of local microbiota as both cytokines are also regulated by microbial compositions.
Severe aplastic anemia patients with infection who received an allogeneic hematopoietic stem cell transplantation had a better chance: Long-term outcomes of a multicenter study
Authors: Liu Limin , Miao Miao , He Hailong , Wang Shunqing , Zhang Yanming , Guo Ailian , Jiao Wenjing , Lei Meiqing , Cai Yifeng , Shangguan Xiaohui , Liu Zefa , Xu Jinge , Li Xiaoli , Zhang Liansheng , Wu Depei 
Published: September 2022

Background and aimsHow to select the treatment is a challenge for the management of acquired patients with infections. This study aimed at comparing the outcomes of SAA with infections who had an allogeneic hematopoietic stem cell transplantation (allo-HSCT)with that of patients who had an infection and received non-HSCT therapy.MethodsWe retrospectively compared the outcomes of patients with acquired SAA and infections who had an allo-HSCT (n = 141) with that of patients who had an infection and received non-HSCT therapy (n = 186) between July 2004 and January 2020.ResultsThe treatment-related mortality (TRM) of grade 1-2 infections in the HSCT and non-HSCT groups was 24.99% and 13.68%, respectively (P = 0.206), while the TRM of grade 3-4 infections was lower in the HSCT group than that observed in the non-HSCT group (18.54% vs. 33.33%, P = 0.036). At 6 months post-treatment, 91.30% patients in the HSCT group and 8.78% patients in the non-HSCT group had achieved a normal blood profile (P &lt; 0.0001). The time required to discontinue transfusions of red blood cells and platelets in the non-HSCT group was longer than in the HSCT group (P &lt; 0.0001). Estimated overall survival (OS) at 6 years was similar in the two groups (75.5% ± 3.9% vs. 76.3% ± 3.1%, P = 0.996), while the estimated failure-free survival (FFS) at 6 years was 75.2% ± 3.8% in the HSCT group and 48.9% ± 3.7% in the non-HSCT group (P &lt; 0.0001). Multivariate analysis showed that younger age, lower grade of infection (grade 1-2), and SAA (vs. very SAA) were favorable factors for OS (P &lt; 0.05), and that the choice of HSCT and younger age were favorable factors for FFS (P &lt; 0.0001).ConclusionThese results suggest that allo-HSCT has a better chance of a successful outcome than non-HSCT in SAA patients with an infection.
Large-scale effects of turbidity on coral bleaching in the Hawaiian islands
Authors: Carlson Rachel R. , Li Jiwei , Crowder Larry B. , Asner Gregory P. 
Published: September 2022

Turbidity from land-based runoff has been identified as a possible driver of coral bleaching refugia, as particulate matter in turbid habitats may block excessive irradiance and alter the food supply to corals during ocean heatwaves. However, negative effects of turbidity have also been documented worldwide, and high-resolution data across reef regions are required to identify habitats where turbidity is harmful or helpful during heatwaves. We monitored turbidity across five Main Hawaiian Islands during a 2019 ocean heatwave using Planet Dove satellites (3.7 m spatial resolution, extracted at 100 m resolution) to examine relationships between turbidity and coral bleaching occurrence and severity. We also attributed turbidity to urban and non-urban land uses to determine how turbidity associated with different human activities affects coral bleaching. We found that, while turbidity had a negative relationship with coral bleaching severity, this effect weakened at higher temperatures, especially in rural areas. However, turbidity maintained a slightly negative effect on bleaching severity in urban settings. In addition, while thermal stress was the predominant driver of bleaching occurrence, interactions between temperature and local variables like turbidity and wave energy were the most significant drivers of bleaching severity. This study represents one of the first high-resolution analyses of turbid refugia at large spatial scales. We show how new data sources from remote sensing can provide scalable yet context-specific information to coastal managers addressing land-sea runoff.
A novel pyroptosis-regulated gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma
Authors: Zhang Baozhu , Wang Zhan 
Published: September 2022

Background: Pyroptosis, a newly discovered type of programmed cell death, has both anti-tumor and tumor-promoting effects on carcinogenesis. In hepatocellular carcinoma (HCC), however, the associations between pyroptosis-regulated genes and prognosis, immune microenvironment, and immunotherapy response remain unclear.Samples and methods: Sequencing data were collected from The Cancer Genome Atlas database, The International Cancer Genome Consortium (ICGC), and The Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB). First, we investigated the expression levels and copy number variations (CNVs) of 56 pyroptosis genes in HCC and pan-cancer. Next, we identified 614 genes related to 56 pyroptosis-associated genes at the expression, mutation, and CNVs levels. Pathway enrichment analysis of 614 genes in the Hallmark, KEGG, and Reactome databases yielded a total of 253 significant signaling pathways. The pyroptosis-regulated genes (PRGs) comprised 108 genes that were derived from the top 20 signaling pathways, of which 57 genes had prognostic value in HCC. The least absolute shrinkage and selection operator (LASSO) analysis was performed to screen for PRGs with prognostic values. Ultimately, we constructed a risk score model with seven PRGs to predict HCC prognosis and validated its predictive value in three independent HCC cohorts. Risk scores were used to illustrate receiver operating characteristic (ROC) curves predicting 1, 3, and 5-years overall survival (OS). Single-sample gene set enrichment analysis (ssGSEA), was performed to study 28 types of immune cells infiltrated in HCC. The relationship between the risk signature and six immune checkpoint genes and immunotherapy was analyzed.Results: A total of seven PRGs were obtained following multiple screening steps. The risk score model containing seven PRGs was found to correlate significantly with the HCC prognosis of the training group. In addition, we validated the risk score model in two additional HCC cohorts. The risk score significantly correlated with infiltrating immune cells (i. e. CD4+ T cells, etc.), ICB key molecules (i. e. HAVCR2, etc.), and ICB response.Conclusions: This study demonstrated a vital role of PRGs in predicting the prognosis and immunotherapy response of HCC patients. The risk model could pave the way for drugs targeting pyroptosis and immune checkpoints in HCC.
A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia
Authors: Rodden Layne N. , Rummey Christian , Dong Yi Na , Lagedrost Sarah , Regner Sean , Brocht Alicia , Bushara Khalaf , Delatycki Martin B. , Gomez Christopher M. , Mathews Katherine , Murray Sarah , Perlman Susan , Ravina Bernard , Subramony S. H. , Wilmot George , Zesiewicz Theresa , Bolotta Alessandra , Domissy Alain , Jespersen Christine , Ji Baohu , Soragni Elisabetta , Gottesfeld Joel M. , Lynch David R. 
Published: September 2022

Introduction: Friedreich ataxia (FRDA) is a recessive neurodegenerative disease characterized by progressive ataxia, dyscoordination, and loss of vision. The variable length of the pathogenic GAA triplet repeat expansion in the FXN gene in part explains the interindividual variability in the severity of disease. The GAA repeat expansion leads to epigenetic silencing of FXN; therefore, variability in properties of epigenetic effector proteins could also regulate the severity of FRDA.Methods: In an exploratory analysis, DNA from 88 individuals with FRDA was analyzed to determine if any of five non-synonymous SNPs in HDACs/SIRTs predicted FRDA disease severity. Results suggested the need for a full analysis at the rs352493 locus in SIRT6 (p.Asn46Ser). In a cohort of 569 subjects with FRDA, disease features were compared between subjects homozygous for the common thymine SIRT6 variant (TT) and those with the less common cytosine variant on one allele and thymine on the other (CT). The biochemical properties of both variants of SIRT6 were analyzed and compared.Results: Linear regression in the exploratory cohort suggested that an SNP (rs352493) in SIRT6 correlated with neurological severity in FRDA. The follow-up analysis in a larger cohort agreed with the initial result that the genotype of SIRT6 at the locus rs352493 predicted the severity of disease features of FRDA. Those in the CT SIRT6 group performed better on measures of neurological and visual function over time than those in the more common TT SIRT6 group. The Asn to Ser amino acid change resulting from the SNP in SIRT6 did not alter the expression or enzymatic activity of SIRT6 or frataxin, but iPSC-derived neurons from people with FRDA in the CT SIRT6 group showed whole transcriptome differences compared to those in the TT SIRT6 group.Conclusion: People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.
Cost-effectiveness analysis of adjuvant therapy with atezolizumab in Chinese patients with stage IB-IIIA resectable NSCLC after adjuvant chemotherapy
Authors: Chen Ping , Yang Qing , Li Yinfeng , Jing Xiaomei , Chen Jing 
Published: September 2022

BackgroundAtezolizumab was first shown to significantly improve progression-free survival (PFS) after platinum-based chemotherapy in early-stage non-small cell lung cancer (NSCLC) in the IMpower010 Phase 3 trial. However, the cost-effectiveness and potential economic impact of atezolizumab treatment in Chinese patients are unknown.MethodsMarkov models were constructed based on follow-up data from the IMpower010 trial and assessed separately in the programmed cell death receptor ligand-1 (PD-L1) tumor cells (TC) ≥ 1% stage II – IIIA group, all stage II – IIIA groups, and the intention-to-treat (ITT) group (stage IB–IIIA). Efficacy and safety data were obtained from the IMpower010 trial, and costs and utility values were derived from the literature and local surveys to estimate their incremental cost-effectiveness ratios (ICERs) compared with willingness-to-pay (WTP) thresholds in scenarios implementing patient assistance programs (PAP) or drug price negotiations. Univariate sensitivity analysis and probabilistic sensitivity analysis (PSA) were performed to investigate the stability of the model results.ResultsCompared with best supportive care (BSC), atezolizumab produced an additional 0.45 quality-adjusted life-years (QALYs), 0.04 QALYs, and -0.0028 QALYs in the PD-L1 TC ≥ 1% stage II – IIIA group, all stage II – IIIA groups, and the ITT group, and the ICERs were 108,825.37/QALY, 1,028,538.22/QALY, and -14,381,171.55/QALY, respectively. The ICERs all exceeded the WTP threshold of $27,354 per QALY (three times the per capita gross domestic product of China in 2022), and univariate sensitivity analysis showed that the price of atezolizumab played a crucial role in the model results. PSA showed that the probability of cost-effectiveness of atezolizumab in the PD-L1 TC ≥ 1% stage II – IIIA group, all stage II – IIIA groups, and the ITT group increased with the increasing WTP threshold.ConclusionFrom the perspective of China’s health care system, in the PD-L1 TC ≥ 1% stage II – IIIA group, all stage II – IIIA groups, and the ITT group, the use of atezolizumab in the adjuvant treatment of patients with early-stage NSCLC after platinum-based chemotherapy is unlikely to be cost-effective. The implementation of PAP or price reduction negotiations for atezolizumab might be among the most effective measures to improve its cost-effectiveness.
Efficacy and safety of neoadjuvant immunotherapy combined with chemotherapy in locally advanced esophageal cancer: A meta-analysis
Authors: Wang Jincheng , Zhang Kun , Liu Tianzhou , Song Ying , Hua Peiyan , Chen Shu , Li Jindong , Liu Yang , Zhao Yinghao 
Published: September 2022

ObjectiveThe progress of neoadjuvant therapy for resectable locally advanced esophageal cancer has been stagnant. There has been much progress in immunotherapy for advanced esophageal cancer, but the efficacy and safety of neoadjuvant immunotherapy for resectable locally advanced esophageal cancer have not yet been definitively demonstrated.MethodsOriginal articles describing the safety and efficacy of neoadjuvant immunotherapy in resectable locally advanced esophagus published until July 2022 were retrieved from PubMed, Embase, and the Cochrane Library. The ratio (OR) and 95% confidence interval (CI) were calculated to conduct heterogeneity and subgroup analysis.ResultsIn total, 759 patients from 21 studies were enrolled. The effectiveness of neoadjuvant immunotherapy in combination with chemotherapy was evaluated using the major pathologic response (MPR) and pathologic complete response (PCR). In the enrolled patients, 677 were treated surgically and 664 achieved R0 resection. Major pathological remission was achieved in 52.0% (95% CI: 0.44–0.57) of patients on neoadjuvant immunotherapy combined with chemotherapy and complete pathological remission in 29.5% (95% CI: 0.25–0.32) of patients. The safety was primarily assessed by the incidence of treatment-related adverse events (TRAEs) and surgical resection rates. The incidence of TRAEs and the surgical resection rate combined ORs were 0.15 (95% CI: 0.09–0.22) and 0.86 (95% CI: 0.83–0.89), respectively.ConclusionNeoadjuvant immunotherapy combined with chemotherapy in locally advanced resectable esophageal cancer is effective and safe.
Molecular characteristics, clinical significance, and cancer immune interactions of cuproptosis and ferroptosis-associated genes in colorectal cancer
Authors: Li Yang , Wang Ru-yao , Deng Yu-jiao , Wu Shao-hua , Sun Xinti , Mu Hong 
Published: September 2022

ObjectiveTo systematically analyze the expression of cuproptosis and ferroptosis genes and their impact on the development, prognosis, tumor microenvironment (TME), and treatment response in colorectal cancer (CRC) patientsMethodsWe systematically evaluated 33 cuproptosis and ferroptosis-related genes and comprehensively identified the correlations between cuproptosis and ferroptosis-related genes and transcriptional patterns, prognosis, and clinical features. Three distinct subgroups were identified in CRC using the TCGA database and the GEO database. We next assessed the relationship between the molecular features, prognostic significance, and clinical indicators of the prognostic genes in the cuproptosis and ferroptosis-related gene clusters. In addition, a PAC_score, which accurately predicted the prognosis of CRC patients and the efficacy of immunomodulatory mAbs, was obtained.ResultsPatients in the low expression group (low expression of cuproptosis and ferroptosis-related genes) had a longer survival compared to the high expression group. We identified two distinct prognosis-associated molecular subtypes and observed an association between clinical information and prognosis. The enrichment analysis of differential genes associated with prognosis showed that the main enrichment was related to biological processes such as metastasis and metabolism. Next, the PCA_score for predicting overall survival (OS) was established and its reliable predictive value in CRC patients was confirmed. Furthermore, highly reliable nomogram was created to facilitate the clinical feasibility of the PCA_score. It was found that the immunomodulatory mAbs, PD-L1 and CTLA4 were highly expressed in the low PCA_score score group with statistically significance.ConclusionOverall, the PCA scores of prognostic differential genes in the cuproptosis and ferroptosis-related gene clusters were strongly associated with clinical characteristics, prognosis, and immunotherapy in CRC patients. This data may promote further exploration of more effective immunotherapy strategies for CRC.
OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis via regulating the arachidonic acid metabolism
Authors: Wen Jie , Aili Abudureyimujiang , Yan Yao Xue , Lai YuLin , Niu Shaoqing , He Shasha , Zhang Xiaokai , Zhang Guixiong , Li Jiaping 
Published: September 2022

BackgroundOncoprotein-Induced Transcript 3 Protein (OIT3) was identified as a liver-specific gene with abnormal expression in hepatocellular carcinoma (HCC). Herein, we aimed to examine the function and specific mechanism of OIT3 in HCC.MethodsBioinformatic analyses and tissue microarray via immunohistochemistry were used to validate the expression of OIT3 in HCC. The biofunctions of OIT3 in HCC were determined in vitro and in vivo. The mechanism was confirmed by RNA-Sequence and Western blotting. The uni- and multivariate analyses were used to identify the independent predictors for HCC.ResultsLow expression of OIT3 was observed in HCC and predicted a poor clinical outcome. Ectopic expression of OIT3 could inhibit the proliferation, migration, and invasion abilities of HCC cells. Mechanistically, OIT3 upregulated the expression of ALOX15 and CYP4F3, thus inducing arachidonic acid increase, ROS accumulation, and lipid peroxidation, and eventually causing ferroptosis. OIT3 was validated as a prognostic predictor for HCC patients.ConclusionsOur findings revealed a novel role of OIT3 in the process of tumorigenesis of HCC. OIT3 inhibited reproliferation, migration, and invasion of HCC cells by triggering ferroptosis, which indicates that OIT3 could serve as a potential biomarker in HCC.
Clinical course and role of embolization in patients with spontaneous rupture of hepatocellular carcinoma
Authors: Park Juil , Jeong Yun Soo , Suh Yun Seok , Kim Hyo-Cheol , Chung Jin Wook , Choi Jin Woo 
Published: September 2022

BackgroundA diverse clinical course after the spontaneous rupture of hepatocellular carcinoma (HCC) renders nonstandardized treatment protocols.PurposeTo evaluate clinical course and role of transcatheter arterial embolization (TAE) in patients with rupture of HCC.Materials and methodsThis retrospective study included 127 patients who were treated for ruptured HCC at single institution between 2005 and 2014. After multidisciplinary discussion, patients underwent medical management, TAE, emergency surgery or staged surgery. Patients were retrospectively divided into two groups based on the intent of treatment: curative and palliative. The rebleeding rate and 1-month and overall survival (OS) were compared between two groups. The incidence and survival of patients with intraperitoneal drop metastasis (IPDM) were also analyzed.ResultsThe overall rebleeding rate in patients who underwent TAE was 3.1% (3/96). One-month mortality rate was 6.3% (8/127). The rebleeding and 1-month mortality rates were not significantly different between two groups. OS was significantly higher in the curative treatment group (median: 12.0 vs 2.2 months,p&lt;0.001). Among 96 patients who initially received TAE, ten patients underwent staged operation (10.4%). The median OS for medical management, TAE, emergency surgery and staged surgery was 2.8, 8.7, 19.1 and 71.1 months, respectively. Of all patients, 15.2% developed IPDM mostly within 1 year and their survival was poorer than that of patients without IPDM (median: 6.3 vs. 15.1 months,p&lt;0.001).ConclusionTAE provided effective immediate hemostasis with a low rebleeding rate and may serve as a bridge to elective surgery. IPDM frequently occurred within 1 year and manifested poor survival; thus, close surveillance should be considered for patients with spontaneous rupture of HCC.