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BackgroundEarly identification of patients who will benefit from immune checkpoint inhibitors (ICIs) has recently become a hot issue in cancer immunotherapy. Peripheral cytokines are key regulators in the immune system that can induce the expression of immune checkpoint molecules; however, the association between peripheral cytokines and the efficiency of ICIs remains unclear.MethodsA systematic review was conducted in several public databases from inception through 3 February 2022 to identify studies investigating the association between peripheral cytokines (i.e., IL-1β, IL-2, IL-2RA, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, TNF-α, IFN-γ, and TGF-β) and ICI treatment. Survival data, including overall survival (OS) and/or progression-free survival (PFS), were extracted, and meta-analyses were performed.ResultsTwenty-four studies were included in this analysis. The pooled results demonstrated that the pretreatment peripheral levels of IL-6 (univariate analysis: HR = 2.53, 95% CI = 2.21–2.89, p < 0.00001; multivariate analysis: HR = 2.21, 95% CI = 1.67–2.93, p < 0.00001) and IL-8 (univariate analysis: HR = 2.17, 95% CI = 1.98–2.38, p < 0.00001; multivariate analysis: HR = 1.88, 95% CI= 1.70–2.07, p < 0.00001) were significantly associated with worse OS of cancer patients receiving ICI treatment in both univariate and multivariate analysis. However, high heterogeneity was found for IL-6, which might be attributed to region, cancer type, treatment method, sample source, and detection method.ConclusionThe peripheral level of IL-8 may be used as a prognostic marker to identify patients with inferior response to ICIs. More high-quality prospective studies are warranted to assess the predictive value of peripheral cytokines for ICI treatment.

Background Most of hepatocellular carcinoma (HCC) arises on the background of chronic inflammation. The presence of infiltrating inflammatory cells is associated with tumour initiation, progression and clinical response to treatment. The influence of white blood cell (WBC) subtype counts on HCC progression remains unclear. Methods In this study, we performed a Mendelian randomization (MR) study with the validation of two datasets. The summary data for WBC counts were extracted from a recent large GWAS of individuals of European ancestry. The GWAS data related to HCC were obtained from the UK Biobank (UKB). Univariable and multivariable MR analyses were used to identify risk factors genetically associated with HCC risks. Results In the discovery dataset, multivariable MR analysis revealed that sum basophil neutrophil counts had an independent causal effect on the occurrence of HCC, with the sum basophil neutrophil counts as follows: (OR = 0.437, P  = 0.003, CI 0.252–0.757). Similarly, in the validation dataset, total basophil neutrophil counts were also been identified as an independent risk factor for HCC. The sum basophil neutrophil counts were as follows: (OR = 0.574, P  = 0.021, CI 0.358–0.920). Conclusion In the European population, genetically predicted lower total basophil neutrophil counts might be an independent risk factor for HCC.

Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive. Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells’ pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes’ expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation. Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines. Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.

As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies.

PurposeTo evaluate the effectiveness and safety of prophylactic intraoperative uterine artery embolization (UAE) performed immediately after fetal delivery during planned cesarean section or cesarean hysterectomy in patients with placenta accreta spectrum disorder or placenta previa.MethodsA systematic search was conducted on Ovid MEDLINE and Embase, PubMed, Web of Science, and Cochrane databases. Studies were selected using the Population/Intervention/Comparison/Outcomes (PICO) strategy. The intraoperative blood loss and the rate of emergent peripartum hysterectomy (EPH) were the primary outcomes, whereas the length of hospital stay and volume of blood transfused were the secondary outcomes. A random-effects model was employed to pool each effect size. The cumulative values of the primary outcomes were calculated using the generic inverse variance method.ResultsEleven retrospective cohort studies and five case series were included, recruiting 421 women who underwent prophylactic intraoperative UAE (UAE group) and 374 women who did not (control group). Compared with the control group, the UAE group had significantly reduced intraoperative blood loss (p = 0.020) during cesarean section or cesarean hysterectomy. Furthermore, the EPH rate was also significantly decreased (p = 0.020; cumulative rate: 19.65%), but not the length of hospital stay (p = 0.850) and volume of pRBC transfused (p = 0.140), after cesarean section in the UAE group. The incidence of major complications was low (3.33%), despite two patients with uterine necrosis.ConclusionThe currently available data provides encouraging evidence that prophylactic intraoperative UAE may contribute to hemorrhage control and fertility preservation in women with abnormal placentation.RegistrationPROSPERO registration code: CRD42021230581. https://clinicaltrials.gov/ct2/show/CRD42021230581Level of EvidenceLevel 2a, systematic review of retrospective cohort studies.

Background Multiple studies have shown that tumor-associated macrophages (TAMs) promote cancer initiation and progression. However, the reprogramming of macrophages in the tumor microenvironment (TME) and the cross-talk between TAMs and malignant subclones in intrahepatic cholangiocarcinoma (iCCA) has not been fully characterized, especially in a spatially resolved manner. Deciphering the spatial architecture of variable tissue cellular components in iCCA could contribute to the positional context of gene expression containing information pathological changes and cellular variability. Methods Here, we applied spatial transcriptomics (ST) and digital spatial profiler (DSP) technologies with tumor sections from patients with iCCA. Results The results reveal that spatial inter- and intra-tumor heterogeneities feature iCCA malignancy, and tumor subclones are mainly driven by physical proximity. Tumor cells with TME components shaped the intra-sectional heterogenetic spatial architecture. Macrophages are the most infiltrated TME component in iCCA. The protein trefoil factor 3 (TFF3) secreted by the malignant subclone can induce macrophages to reprogram to a tumor-promoting state, which in turn contributes to an immune-suppressive environment and boosts tumor progression. Conclusions In conclusion, our description of the iCCA ecosystem in a spatially resolved manner provides novel insights into the spatial features and the immune suppressive landscapes of TME for iCCA.

Antifibrotic therapy has changed the treatment paradigm for idiopathic pulmonary fibrosis (IPF); however, a subset of patients still experienced rapid disease progression despite treatment. This study aimed to determine whether CT-based radiomic features can predict therapeutic response to antifibrotic agents. In this retrospective study, 35 patients with IPF on antifibrotic treatment enrolled from two centers were divided into training (n = 26) and external validation (n = 9) sets. Clinical and pulmonary function data were collected. The patients were categorized into stable disease (SD) and progressive disease (PD) groups based on functional or radiologic criteria. From pretreatment non-enhanced high-resolution CT (HRCT) images, twenty-six radiomic features were extracted through whole-lung texture analysis, and six parenchymal patterns were quantified using dedicated imaging platforms. The predictive factors for PD were determined via univariate and multivariate logistic regression analyses. In the training set (SD/PD: 12/14), univariate analysis identified eight radiomic features and ground-glass opacity percentage (GGO%) as potential predicators of PD. However, multivariate analysis found that the single independent predictor was the sum entropy (accuracy, 80.77%; AUC, 0.75). The combined sum entropy-GGO% model improved the predictive performance in the training set (accuracy, 88.46%; AUC, 0.77). The overall accuracy of the combined model in the validation set (SD/PD: 7/2) was 66.67%. Our preliminary results demonstrated that radiomic features based on pretreatment HRCT could predict the response of patients with IPF to antifibrotic treatment.

A portion of individuals diagnosed with primary central nervous system lymphomas (PCNSL) may experience early relapse or refractory (R/R) disease following treatment. This research explored the potential of MRI-based radiomics in forecasting R/R cases in PCNSL. Forty-six patients with pathologically confirmed PCNSL diagnosed between January 2008 and December 2020 were included in this study. Only patients who underwent pretreatment brain MRIs and complete postoperative follow-up MRIs were included. Pretreatment contrast-enhanced T1WI, T2WI, and T2 FLAIR imaging were analyzed. A total of 107 radiomic features, including 14 shape-based, 18 first-order statistical, and 75 texture features, were extracted from each sequence. Predictive models were then built using five different machine learning algorithms to predict R/R in PCNSL. Of the included 46 PCNSL patients, 20 (20/46, 43.5%) patients were found to have R/R. In the R/R group, the median scores in predictive models such as support vector machine, k-nearest neighbors, linear discriminant analysis, naïve Bayes, and decision trees were significantly higher, while the apparent diffusion coefficient values were notably lower compared to those without R/R (p < 0.05). The support vector machine model exhibited the highest performance, achieving an overall prediction accuracy of 83%, a precision rate of 80%, and an AUC of 0.78. Additionally, when analyzing tumor progression, patients with elevated support vector machine and naïve Bayes scores demonstrated a significantly reduced progression-free survival (p < 0.05). These findings suggest that preoperative MRI-based radiomics may provide critical insights for treatment strategies in PCNSL.

The Sabatier principle is widely explored in heterogeneous catalysis, graphically depicted in volcano plots. The most desirable activity is located at the peak of the volcano, and further advances in activity past this optimum are possible by designing a catalyst that circumvents the limitation entailed by the Sabatier principle. Herein, by density functional theory calculations, we discovered an unusual Sabatier principle on high entropy alloy (HEA) surface, distinguishing the “just right” (Δ G H*  = 0 eV) in the Sabatier principle of hydrogen evolution reaction (HER). A new descriptor was proposed to design HEA catalysts for HER. As a proof-of-concept, the synthesized PtFeCoNiCu HEA catalyst endows a high catalytic performance for HER with an overpotential of 10.8 mV at −10 mA cm −2 and 4.6 times higher intrinsic activity over the state-of-the-art Pt/C. Moreover, the unusual Sabatier principle on HEA catalysts can be extended to other catalytic reactions. The advancement of high entropy alloy development is both rapid and challenging. Here, the authors discover an unusual Sabatier principle operating on the high entropy alloy surface, which leads to a notable enhancement in catalytic activity for hydrogen evolution reactions.

Background Primary lymphoma of the cavernous sinus is a rare form of extranodal non-Hodgkin lymphoma, of which very few cases have been reported in the published literature. This report presents the MRI findings with apparent diffusion coefficient (ADC) value in an exceedingly rare primary marginal zone B-cell lymphoma (MZBCL) of the cavernous sinus. Case presentation The case in this study is a 59-year-old immunocompetent male patient with a 2-month history of right ptosis and blurred vision. Right third cranial nerve palsy and binocular diplopia were observed upon neurological examination. Preoperative brain CT showed an extra-axial enhancing mass lesion in the right cavernous sinus. On MRI, ipsilateral internal carotid arterial encasement was noted without causing stenosis of the vessel. Isointense signal on T1-weighted and T2-weighted images, homogeneous contrast enhancement, and diffusion restriction were also observed. The mean ADC value of the tumor is 0.64 × 10 –3  mm 2 /s (b value = 1000 s/mm 2 ). Subtotal resection of the tumor was performed, and improvement of clinical symptoms were observed. The pathologic diagnosis of MZBCL was established by immunohistochemical examinations. Conclusions Primary MZBCL of the cavernous sinus is exceedingly rare, and preoperative confirmation poses a major challenge with CT and conventional MRI only. In this case, preoperative quantitative ADC value is shown to offer valuable additional information in the diagnostic process.