bluuebunny/crossref_metadata_2025_split huggingface dataset:
The risk of all-cause and cause-specific mortality in people prescribed mirtazapine: an active comparator cohort study using electronic health records
Authors: Joseph Rebecca M. , Jack Ruth H. , Morriss Richard , Knaggs Roger David , Butler Debbie , Hollis Chris , Hippisley-Cox Julia , Coupland Carol 
Published: February 2022

Abstract
Background
Studies have reported an increased risk of mortality among people prescribed mirtazapine compared to other antidepressants. The study aimed to compare all-cause and cause-specific mortality between adults prescribed mirtazapine or other second-line antidepressants.

Methods
This cohort study used English primary care electronic medical records, hospital admission records, and mortality data from the Clinical Practice Research Datalink (CPRD), for the period 01 January 2005 to 30 November 2018. It included people aged 18–99 years with depression first prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine (5081), a different SSRI (15,032), amitriptyline (3905), or venlafaxine (1580). Follow-up was from starting to stopping the second antidepressant, with a 6-month wash-out window, censoring at the end of CPRD follow-up or 30 November 2018. Age-sex standardised rates of all-cause mortality and death due to circulatory system disease, cancer, or respiratory system disease were calculated. Survival analyses were performed, accounting for baseline characteristics using inverse probability of treatment weighting.

Results
The cohort contained 25,598 people (median age 41 years). The mirtazapine group had the highest standardised mortality rate, with an additional 7.8 (95% confidence interval (CI) 5.9–9.7) deaths/1000 person-years compared to the SSRI group. Within 2 years of follow-up, the risk of all-cause mortality was statistically significantly higher in the mirtazapine group than in the SSRI group (weighted hazard ratio (HR) 1.62, 95% CI 1.28–2.06). No significant difference was found between the mirtazapine group and the amitriptyline (HR 1.18, 95% CI 0.85–1.63) or venlafaxine (HR 1.11, 95% CI 0.60–2.05) groups. After 2 years, the risk was significantly higher in the mirtazapine group compared to the SSRI (HR 1.51, 95% CI 1.04–2.19), amitriptyline (HR 2.59, 95% CI 1.38–4.86), and venlafaxine (HR 2.35, 95% CI 1.02–5.44) groups. The risks of death due to cancer (HR 1.74, 95% CI 1.06–2.85) and respiratory system disease (HR 1.72, 95% CI 1.07–2.77) were significantly higher in the mirtazapine than in the SSRI group.

Conclusions
Mortality was higher in people prescribed mirtazapine than people prescribed a second SSRI, possibly reflecting residual differences in other risk factors between the groups. Identifying these potential health risks when prescribing mirtazapine may help reduce the risk of mortality.
Spatial maps of hepatocellular carcinoma transcriptomes highlight an unexplored landscape of heterogeneity and a novel gene signature for survival
Authors: Zhao Nan , Zhang Yanhui , Cheng Runfen , Zhang Danfang , Li Fan , Guo Yuhong , Qiu Zhiqiang , Dong Xueyi , Ban Xinchao , Sun Baocun , Zhao Xiulan 
Published: February 2022

Abstract
Background
Hepatocellular carcinoma (HCC) often presents with satellite nodules, rendering current curative treatments ineffective in many patients. The heterogeneity of HCC is a major challenge in personalized medicine. The emergence of spatial transcriptomics (ST) provides a powerful strategy for delineating the complex molecular landscapes of tumours.

Methods
In this study, the heterogeneity of tissue-wide gene expression in tumour and adjacent nonneoplastic tissues using ST technology were investigated. The transcriptomes of nearly 10,820 tissue regions and identified the main gene expression clusters and their specific marker genes (differentially expressed genes, DEGs) in patients were analysed. The DEGs were analysed from two perspectives. First, two distinct gene profiles were identified to be associated with satellite nodules and conducted a more comprehensive analysis of both gene profiles. Their clinical relevance in human HCC was validated with Kaplan–Meier (KM) Plotter. Second, DEGs were screened with The Cancer Genome Atlas (TCGA) database to divide the HCC cohort into high- and low-risk groups according to Cox analysis. HCC patients from the International Cancer Genome Consortium (ICGC) cohort were used for validation. KM analysis was used to compare the overall survival (OS) between the high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors for OS.

Results
Novel markers for the prediction of satellite nodules were identified and a tumour clusters-specific marker gene signature model (6 genes) for HCC prognosis was constructed.

Conclusion
The establishment of marker gene profiles may be an important step towards an unbiased view of HCC, and the 6-gene signature can be used for prognostic prediction in HCC. This analysis will help us to clarify one of the possible sources of HCC heterogeneity and uncover pathogenic mechanisms and novel antitumour drug targets.
Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs
Authors: Zhao Jian , Ye Hao , Lu Qi , Wang Kaiyuan , Chen Xiaofeng , Song Jiaxuan , Wang Helin , Lu Yutong , Cheng Maosheng , He Zhonggui , Zhai Yinglei , Zhang Haotian , Sun Jin 
Published: February 2022

AbstractBackgroundMelanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis.MethodsSmall EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo.ResultsHerein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment.ConclusionOur findings indicated that the immunotherapeutic fibrin gel could “awaken” the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.Graphical Abstract
Multiscale imaging of therapeutic anti-PD-L1 antibody localization using molecularly defined imaging agents
Authors: Hagemans Iris M. , Wierstra Peter J. , Steuten Kas , Molkenboer-Kuenen Janneke D. M. , van Dalen Duco , ter Beest Martin , van der Schoot Johan M. S. , Ilina Olga , Gotthardt Martin , Figdor Carl G. , Scheeren Ferenc A. , Heskamp Sandra , Verdoes Martijn 
Published: February 2022

AbstractBackgroundWhile immune checkpoint inhibitors such as anti-PD-L1 antibodies have revolutionized cancer treatment, only subgroups of patients show durable responses. Insight in the relation between clinical response, PD-L1 expression and intratumoral localization of PD-L1 therapeutics could improve patient stratification. Therefore, we present the modular synthesis of multimodal antibody-based imaging tools for multiscale imaging of PD-L1 to study intratumoral distribution of PD-L1 therapeutics.ResultsTo introduce imaging modalities, a peptide containing a near-infrared dye (sulfo-Cy5), a chelator (DTPA), an azide, and a sortase-recognition motif was synthesized. This peptide and a non-fluorescent intermediate were used for site-specific functionalization of c-terminally sortaggable mouse IgG1 (mIgG1) and Fab anti-PD-L1. To increase the half-life of the Fab fragment, a 20 kDa PEG chain was attached via strain-promoted azide-alkyne cycloaddition (SPAAC). Biodistribution and imaging studies were performed with111In-labeled constructs in 4T1 tumor-bearing mice. Comparing our site-specific antibody-conjugates with randomly conjugated antibodies, we found that antibody clone, isotype and method of DTPA conjugation did not change tumor uptake. Furthermore, addition of sulfo-Cy5 did not affect the biodistribution. PEGylated Fab fragment displayed a significantly longer half-life compared to unPEGylated Fab and demonstrated the highest overall tumor uptake of all constructs. PD-L1 in tumors was clearly visualized by SPECT/CT, as well as whole body fluorescence imaging. Immunohistochemistry staining of tumor sections demonstrated that PD-L1 co-localized with the fluorescent and autoradiographic signal. Intratumoral localization of the imaging agent could be determined with cellular resolution using fluorescent microscopy.ConclusionsA set of molecularly defined multimodal antibody-based PD-L1 imaging agents were synthesized and validated for multiscale monitoring of PD-L1 expression and localization. Our modular approach for site-specific functionalization could easily be adapted to other targets.Graphical Abstract
Identification and validation of serum autoantibodies in children with B-cell acute lymphoblastic leukemia by serological proteome analysis
Authors: Yu Runhong , Yang Shiwei , Liu Yufeng , Zhu Zunmin 
Published: February 2022

Abstract
Background
B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. Even though significant progresses have been made in the treatment of B-ALL, some pediatric B-ALL have still poor prognosis. The identification of tumor autoantibodies may have utility in early cancer diagnosis and immunotherapy. In this study, we used serological proteome analysis (SERPA) to screen serum autoantibodies of pediatric B-ALL, aiming to contribute to the early detection of B-ALL in children.

Methods
The total proteins from three pooled B-ALL cell lines (NALM-6, REH and BALL-1 cells) were separated using two-dimensional gel electrophoresis (2-DE), which was followed by Western blot by mixed serum samples from children with B-ALL (n=20) or healthy controls (n=20). We analyzed the images of 2-D gel and Western blot by PDQuest software, and then identified the spots of immune responses in B-ALL samples compared with those in control samples. The proteins from spots were identified using mass spectrometry (MS). The autoantibodies against alpha-enolase (α-enolase) and voltage-dependent anion-selective channel protein 1 (VDAC1) were further validated in sera from another 30 children with B-ALL and 25 normal individuals by the use of enzyme-linked immunosorbent assay (ELISA). The protein expression levels of the candidate antigens α-enolase and VDAC1 in B-ALL were thoroughly studied by immunohistochemical analysis.

Results
Utilizing the SERPA approach, α-enolase and VDAC1 were identified as candidate autoantigens in children with B-ALL. The frequencies of autoantibodies against α-enolase and VDAC1 in children with B-ALL were 27% and 23% by using ELISA analysis, respectively, which were significantly higher than those in normal controls (4% and 0, p<0.05). Immunohistochemical analysis showed the expression of α-enolase and VDAC1 was positive in 95% and 85% of B-ALL patients, respectively, but negative expression levels were showed in the control group.

Conclusions
This study incidated that α-enolase and VDAC1 may be the autoantigens associated with B-ALL. Therefore, α-enolase and VDAC1 autoantibodies may be the potential serological markers for children with B-ALL.
Efficacy and safety of endovascular brachytherapy combined with transarterial chemoembolization for the treatment of hepatocellular carcinoma patients with type III or IV portal vein tumor thrombosis
Authors: Li Ling , Cheng Niangmei , Huang Xinhui , Weng Xiadi , Jiao Yubin , Liu Jingfeng , Guo Wuhua 
Published: February 2022

Abstract
Background
The purpose of this study was to evaluate the efficacy and safety of endovascular brachytherapy (EVBT) combined with transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) complicated with type III OR IV portal vein tumor thrombosis (PVTT) and to further analyze the prognostic predictors for the patients with HCC and PVTT.

Methods
We retrospectively analyzed the medical records of 54 patients who were diagnosed with HCC complicated with type III or IV PVTT and received EVBT combined with modified TACE treatment from January 2017 to June 2019. Adverse events, treatment response, overall survival (OS), progression-free survival (PFS), and stent patency were analysed to evaluate the efficacy and safety of this treatment. The independent prognostic predictors of OS were also statistically analyzed by the cox regression model.

Results
No adverse events occurred in the enrolled patients receiving EVBT combined with TACE treatment. The objective response and disease control rates were 42.6% and 96.3% respectively within 4 weeks after the treatment. The median OS and PFS were 209 days and 138 days, respectively. Cumulative stent patency rate was 70.4% at the last follow-up. AFP ≥ 400 ng/ml, ECOG PS > 1, Child Pugh grade B, and non-hemihepatic HCC were independent risk predictors to evaluate the OS of HCC patient with type III or IV PVTT.

Conclusions
EVBT combined with TACE was a relatively effective and safe strategy to treat HCC patients with type III or IV PVTT.
Combining serum inflammation indexes at baseline and post treatment could predict pathological efficacy to anti‑PD‑1 combined with neoadjuvant chemotherapy in esophageal squamous cell carcinoma
Authors: Zhang Xinke , Gari A. , Li Mei , Chen Jierong , Qu Chunhua , Zhang Lihong , Chen Jiewei 
Published: February 2022

Abstract
Background
The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) have been used to predict therapeutic response in different tumors. However, no assessments of their usefulness have been performed in esophageal squamous cell carcinoma (ESCC) patients receiving anti‑PD‑1 combined with neoadjuvant chemotherapy.

Methods
The respective data of 64 ESCC patients receiving anti‑PD‑1 combined with neoadjuvant chemotherapy were analyzed. Whether NLR, LMR, PLR, and SII at baseline and post-treatment might predict pathological response to anti‑PD‑1 plus neoadjuvant chemotherapy, and cutoff values of these parameters were all determined by ROC curve analysis.

Results
NLR (cutoff = 3.173, AUC = 0.644, 95% CI 0.500–0.788, P = 0.124, sensitivity = 1.000, specificity = 0.373), LMR (cutoff = 1.622, AUC = 0.631, 95% CI 0.477–0.784, P = 0.161, sensitivity = 0.917, specificity = 0.137), PLR (cutoff = 71.108, AUC = 0.712, 95% CI 0.575–0.849, P = 0.023, sensitivity = 1.000, specificity = 0.059), and SII at baseline (cutoff = 559.266, AUC = 0.681, 95% CI 0.533–0.830, P = 0.052, sensitivity = 0.373, specificity = 1.000) seemed to be a useful predictor for distinguishing responders from non-responders. Combining NLR with SII at baseline (AUC = 0.729, 95% CI 0.600–0.858, P = 0.014, sensitivity = 0.917, specificity = 0.510), LMR and SII at baseline (AUC = 0.735, 95% CI 0.609–0.861, P = 0.012, sensitivity = 1.000 specificity = 0.471), PLR and SII at baseline (AUC = 0.716, 95% CI 0.584–0.847, P = 0.021, sensitivity = 1.000 specificity = 0.431), and LMR and PLR at post-treatment in the third period (AUC = 0.761, 95% CI 0.605–0.917, P = 0.010, sensitivity = 0.800, specificity = 0.696) might slightly increase the prediction ability to determine patients who have response or no response. Finally, combining LMR at baseline, SII at post-treatment in the second period with PLR at post-treatment in the third period could be considered a better predictor for discriminating responders and non-responders than single or dual biomarkers (AUC = 0.879, 95% CI 0.788–0.969, P = 0.0001, sensitivity = 0.909, specificity = 0.800).

Conclusions
The models we constructed allowed for the accurate and efficient stratification of ESCC patients receiving anti-PD-1 plus chemotherapy and are easily applicable for clinical practice at no additional cost.
Tumor angiogenesis at baseline identified by 18F-Alfatide II PET/CT may predict survival among patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy
Authors: Wei Yuchun , Qin Xueting , Liu Xiaoli , Zheng Jinsong , Luan Xiaohui , Zhou Yue , Yu Jinming , Yuan Shuanghu 
Published: February 2022

Abstract
Background
The study investigated the predictive value of tumor angiogenesis observed by 18F-ALF-NOTA-PRGD2 II (denoted as 18F-Alfatide II) positron emission tomography (PET)/computed tomography (CT) before concurrent chemoradiotherapy (CCRT) for treatment response and survival among patients with locally advanced non-small cell lung cancer (LA-NSCLC).

Methods
Patients with unresectable stage IIIA or IIIB NSCLC (AJCC Cancer Staging 7th Edition) who received CCRT were included in this prospective study. All patients had undergone 18F-Alfatide PET/CT scanning before CCRT, and analyzed parameters included maximum uptake values (SUVmax) of primary tumor (SUVP) and metastatic lymph nodes (SUVLN) and mean uptake value of blood pool (SUVblood). Tumor-to-background ratios (TBRs) and changes in tumor diameter before and after CCRT (ΔD) were calculated. The ratios of SUVP to SUVblood, SUVLN to SUVblood, and SUVP to SUVLN were denoted as TBRP, TBRLN, and T/LN. Short-term treatment response, progression-free survival (PFS), and overall survival (OS) were evaluated.

Results
Of 38 enrolled patients, 28 completed CCRT. SUVP, SUVLN, TBRP, TBRLN and T/LN showed significant correlation with PFS (all P < 0.05). SUVP was negatively correlated with OS (P = 0.005). SUVP and TBRP were higher in non-responders than in responders (6.55 ± 2.74 vs. 4.61 ± 1.94, P = 0.039; 10.49 ± 7.58 vs. 7.73 ± 6.09, P = 0.023). ΔD was significantly greater in responders (2.78 ± 1.37) than in non-responders (-0.16 ± 1.33, P < 0.001). Exploratory receiver operating characteristic curve analysis identified TBRP (area under the curve [AUC] = 0.764, P = 0.018), with a cutoff value of 6.52, as the only parameter significantly predictive of the response to CCRT, with sensitivity, specificity, and accuracy values of 71.43%, 78.57%, and 75.00%, respectively. ROC curve analysis also identified SUVP (AUC = 0.942, P < 0.001, cutoff value 4.64) and TBRP (AUC = 0.895, P = 0.001, cutoff value 4.95) as predictive of OS with high sensitivity (84.21%, 93.75%), specificity (100.00%, 66.67%), and accuracy (89.29%, 82.14%).

Conclusions
Evaluation of tumor angiogenesis by 18F-Alfatide II at baseline may be useful in predicting the short-term response to CCRT as well as PFS and OS in patients with LA-NSCLC.
High frequency of PDGFRA and MUC family gene mutations in diffuse hemispheric glioma, H3 G34-mutant: a glimmer of hope?
Authors: Hu Wanming , Duan Hao , Zhong Sheng , Zeng Jing , Mou Yonggao 
Published: February 2022

Abstract
Background
Diffuse hemispheric glioma H3 G34-mutant (G34-DHG) is a new type of pediatric-type diffuse high-grade glioma in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The current treatment for G34-DHG involves a combination of surgery and conventional radiotherapy or chemotherapy; however, the therapeutic efficacy of this approach is not satisfactory. In recent years, molecular targeted therapy and immunotherapy have achieved significant benefits in a variety of tumors. In-depth understanding of molecular changes and immune infiltration in G34-DHGs will help to establish personalized tumor treatment strategies. Here, we report the clinicopathological, molecular and immune infiltration characteristics of G34-DHG cases from our center along with cases from the HERBY Trial and the Chinese Glioma Genome Atlas database (CGGA).

Methods
Hematoxylin–eosin (HE) and immunohistochemistry (IHC) staining were used to present the clinicopathological characteristics of 10 Chinese G34-DHG patients treated at our institution. To address the molecular characteristics of G34-DHG, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analyses of 5 patients from our center and 3 Chinese patients from the Chinese Glioma Genome Atlas (CGGA) database. Additionally, 7 European G34-DHG patients from the HERBY Trail were also subjected to analyses, with 7 cases of WES data and 2 cases of RNA-seq data. Six G34-DHG patients from another organization were used as external validation.

Results
WES showed a high frequency of PDGFRA mutation in G34-DHGs (12/15). We further identified frequent mutations in MUC family genes in G34-DHGs, including MUC16 (8/15) and MUC17 (8/15). Although no statistical difference was found, PDGFRA mutation tended to be an indicator for worse prognosis whereas MUC16/MUC17 mutation indicated a favorable prognosis in G34-DHGs. RNA sequencing results revealed that most G34-DHG are considered to be immune cold tumors. However, one patient in our cohort with MUC16 mutation showed significant immune infiltration, and the total overall survival of this patient reached 75 months.

Conclusions
Our results demonstrate that G34-DHG is a new high-grade glioma with high frequency of PDGFRA and MUC gene family mutations. PDGFRA may serve as an indicator of poor prognosis and an effective therapeutic target. Moreover, MUC16 tends to be a favorable prognostic factor and indicates high immune infiltration in certain patients, and these findings may provide a new direction for targeted therapy and immunotherapy of patients with G34-DHGs.