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Abstract Background Ethanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways. Methods Male Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays. Results MESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS. Conclusions These results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.

Abstract Purpose To explore the influence of circulating lymphocyte subsets, serum markers, clinical factors, and their impact on overall survival (OS) in locally advanced nasopharyngeal carcinoma (LA-NPC). Additionally, to construct a nomogram predicting OS for LA-NPC patients using independent prognostic factors. Methods A total of 530 patients with LA-NPC were included in this study. In the training cohort, Cox regression analysis was utilized to identify independent prognostic factors, which were then integrated into the nomogram. The concordance index (C-index) was calculated for both training and validation cohorts. Schoenfeld residual analysis, calibration curves, and decision curve analysis (DCA) were employed to evaluate the nomogram. Kaplan-Meier methods was performed based on risk stratification using the nomogram. Results A total of 530 LA-NPC patients were included. Multivariate Cox regression analysis revealed that the circulating CD8+T cell, platelet-to-lymphocyte ratio (PLR), lactate dehydrogenase (LDH), albumin (ALB), gender, and clinical stage were independent prognostic factors for LA-NPC (p

Background Cellular senescence, macrophages infiltration, and vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation participate in the pathophysiology of vascular calcification in chronic kidney disease (CKD). Senescent macrophages are involved in the regulation of inflammation in pathological diseases. In addition, senescent cells spread senescence to neighboring cells via Interferon-induced transmembrane protein3 (IFITM3). However, the role of senescent macrophages and IFITM3 in VSMCs calcification remains unexplored.Aims To explore the hypothesis that senescent macrophages contribute to the calcification and senescence of VSMCs via IFITM3.Methods Here, the macrophage senescence model was established using Lipopolysaccharides (LPS). The VSMCs were subjected to supernatants from macrophages (MCFS) or LPS-induced macrophages (LPS-MCFS) in the presence or absence of calcifying media (CM). Senescence-associated β-galactosidase (SA-β-gal), Alizarin red (AR), immunofluorescent staining, and western blot were used to identify cell senescence and calcification.Results The expression of IFITM3 was significantly increased in LPS-induced macrophages and the supernatants. The VSMCs transdifferentiated into osteogenic phenotype, expressing higher osteogenic differentiation markers (RUNX2) and lower VSMCs constructive makers (SM22α) when cultured with senescent macrophages supernatants. Also, senescence markers (p16 and p21) in VSMCs were significantly increased by senescent macrophages supernatants treated. However, IFITM3 knockdown inhibited this process.Conclusions Our study showed that LPS-induced senescence of macrophages accelerated the calcification of VSMCs via IFITM3. These data provide a new perspective linking VC and aging, which may provide clues for diagnosing and treating accelerated vascular aging in patients with CKD.

Introduction: Surgical resection following systemic therapy is feasible in patients with initially unresectable hepatocellular carcinoma (HCC). However, postoperative tumor recurrence is common after surgery, and the factors affecting this recurrence remain unclear. This study aimed to assess factors influencing postoperative outcomes in patients with initially unresectable HCC undergoing hepatectomy after systemic therapy. Methods: This study retrospectively enrolled patients with initially unresectable HCC who underwent hepatectomy after targeted therapy plus immunotherapy (with or without locoregional therapy). Multivariate Cox regression analyses were used to identify the independent prognostic factors for recurrence-free survival (RFS) and overall survival (OS). Machine learning was used to determine the RFS rates at different intervals for different radiographic responses. Results: Eighty-one patients who underwent R0 hepatectomy after systemic therapy were included. With a median follow-up of 17.4 (interquartile range: 7.2–22.3) months, median RFS and OS were not reached. Preoperative tumor downstaging and achieving pathological complete response were associated with improved RFS and OS. Multivariate Cox analyses identified radiographic response as an independent prognostic factor for RFS and OS. Furthermore, a radiographic response >40% (assessed using the Response Evaluation Criteria in Solid Tumors, version 1.1) or >50% (assessed using the modified Response Evaluation Criteria in Solid Tumors) was associated with a longer RFS (P = 0.006 and 0.003, respectively). Conclusion: Radiographic response depth was an independent prognostic factor in patients with initially unresectable HCC who underwent hepatectomy following targeted therapy plus immunotherapy, and the response to systemic therapy may be the determining factor for patient prognosis after surgery.

BackgroundFor decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors.MethodsThis is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study’s main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL.ResultsThe study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy.ConclusionIn this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

Interfacial adhesion between surface coating and cement paste under aggressive environment is the most key properties that responsible the effectiveness of coating on cement paste. The present work is dedicated to an in-depth investigation concerning the temperature influence on the interfacial adhesion degradation between rubber nano-coating and Calcium-Silicate-Hydrate (CSH) paste under harsh environments. Results indicate that a well-distributed fully rubber nano-coating on CSH maintains its impermeability within temperature range of 260–373K for pure water molecules and up to 420K for salty water solution. However, the nano-coated structure loses its impermeability at 380K and 440K in pure water and salty water solution, respectively. The interfacial adhesion between rubber and CSH surface decreases with increasing temperature under both conditions. In addition, the effectiveness of the rubber nano-coating surface weakens due to temperature rising inducing the breaking of the hardest interfacial interatomic cao-c = bonds in both conditions.

Background: To construct an effective prognostic index to predict overall survival (OS) and triplet regimen efficacy for advanced gastric cancer (AGC) patients treated with platinum-based and fluorouracil-based chemotherapy. Objectives: Between 2011 and 2021, 679 patients from two randomized phase III trials and one phase II trial were enrolled. Designs: We collected 11 baseline clinicopathological and 14 hematological parameters to establish a prognostic index. Methods: Univariate and multivariate Cox analyses were used to screen prognostic factors, and a prognostic index nomogram was conducted. Results: Seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic nomogram named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in the low-risk group (median OS, 15.5 versus 8.0 months, p < 0.001). The areas under the curve of the FARS index for 1-, 2-, and 3-year OS were 0.70, 0.72, and 0.77, respectively. A validation and external cohort verified the prognostic value of the FARS index. Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen ( p = 0.018). Conclusion: The constructed FARS index to predict the OS of AGC patients and the TRIS index to screen out the dominant population for triplet regimens can be used to aid clinical decision-making and individual risk stratification.

Abstract Electrocatalytic oxygen reduction reaction (ORR) to prepare H2O2 in acidic medium has the advantages of green, safety, and portability, which shows broad development prospects. However, it still suffers from low catalyst activity, insufficient selectivity, and high cost. Herein, Pt1/CoSe2 with ultralow 0.01 wt.% Pt atomic distribution was synthesized by a simple hydrothermal method. The Pt1/CoSe2 with ultralow Pt content exhibits high activity, high selectivity, and long‐term stability for ORR to H2O2 in O2‐saturated 0.1 M HClO4. The onset potential is as low as 0.75 V versus reversible hydrogen electrode (RHE), H2O2 selectivity is as high as 84% (0.4 V vs. RHE), and the electron transfer number is 2.3 (0.4 V vs. RHE). Moreover, the hydrogen peroxide yield using the flow cell testing is 110.02 mmol gcat.−1 h−1 with high Faradaic efficiency of 78% (0 V vs. RHE) at 0.1 M HClO4, and the catalyst did not deactivate significantly after 60 h stability testing. Mechanistic studies and in situ X‐ray photoelectron spectroscopy characterization confirm that the ultralow Pt content on CoSe2 can effectively regulate the electronic structure of Co as the real active site around the Pt site, which gives a suitable ∆dp value (the difference between the d‐band center of the active metal site and the p‐band center of the terminal oxygen in *OOH), provides an ideal *OOH binding energy, and inhibits the O–O bond breakage. This work successfully improves the intrinsic activity of the Co active sites around Pt in Pt1/CoSe2 for acidic ORR to H2O2 by constructing ultralow‐content Pt single atom.

Abstract Background Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. Methods We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti–programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. Results We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558–0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785–0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. Conclusions In patients with unresectable HCC receiving combined TKI/anti–PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.

Abstract Objective Lenvatinib plus anti‐programmed death‐1 (anti‐PD‐1) antibody combinations have shown potent anti‐tumor effect in phase I/II trials in advanced or unresectable hepatocellular carcinoma (HCC), but real‐world data are limited. Methods To investigate the effectiveness and safety of lenvatinib plus anti‐PD‐1 antibodies in a real‐world cohort, we retrospectively evaluated 210 patients with unresectable or advanced HCC treated with these regimens between October 2018 and February 2022. Results The objective response rate and disease control rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were 28.1% and 75.2%. Median overall survival (OS) and progression‐free survival (PFS) in the overall cohort were 17.2 and 8.4 months, respectively. Median OS and PFS of patients receiving first‐line treatment reached 18.9 and 9.6 months. Median OS was significantly longer in patients with Child‐Pugh class A versus B (18.8 vs. 5.9 months, respectively), as was median PFS (9.1 vs. 4.4 months). Patients with albumin–bilirubin (ALBI) grade 1 versus grade 2/3 also had significantly greater median OS (23.5 vs. 13.4 months). Treatment‐related adverse events (AEs) occurred in 79.5% of patients. Patients with ALBI grade 2/3 had a higher rate of grade 3/4 AEs than patients with ALBI grade 1 (57.5% vs. 38.5%). Conclusion Lenvatinib combined with anti‐PD‐1 antibody therapy was effective in patients with sufficient liver function reserve. Further study is needed to improve therapeutic efficacy and AE management in patients with Child‐Pugh class B or ALBI grade 2/3.

Highlights The super-elastic and robust MXene aerogels are created herein by assembling the 1D fibrous MXenes with sufficiently large aspect ratios and superior flexibility. The underlying regulatory mechanism and a complete diagram for the pore structure evolution of MXene aerogels are revealed for the first time, which are particularly instructive for future structure-specific designs. Fibrous MXene aerogels exhibit 8.3% plastic deformation at the 1000th compressions and achieve high evaporation rate (1.48 kg m−2 h−1) and light to thermal conversion efficiency (92.08%) on oil-contaminated seawater.

Abstract Background The optimal number of cycles of induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) is unclear. We aimed to combine the tumor response during IC and tumor stage to individualize the number of IC cycles. Methods Totally, 498 LANPC patients who received IC plus CCRT between 2014 and 2018 were reviewed. Tumor response during IC was used to stratify patients with different risks. All patients were classified into those who received two cycles of IC and those who were treated with three cycles. Propensity score matching methods were performed to compare the treatment efficiency. Results After two cycles of IC, 340/498 (68.3%) cases showed complete tumor response (CR)/partial response (PR) and 158 (31.7%) achieved stable disease (SD)/disease progression (PD). Unfavorable responders (SD/PD) exhibited poor survival outcomes. The three‐cycle IC regimen was correlated with better OS and PFS than the two‐cycle regimen for N2‐3 patients in the CR/PR group. However, the use of different IC cycle strategies achieved similar survival outcomes for SD/PD or N0‐1 patients. The incidences of acute toxicities were higher in the IC = 3 group. Conclusions Tumor response during IC could be a powerful predictor of LANPC and could be used to guide the individualized number of IC cycles. A three‐cycle IC regimen seemed to be preferable for N2‐3 patients who received CR/PR during IC. However, an additional cycle of IC could not benefit N0‐1 or SD/PD patients, and the optimal treatment strategies for these patients require further consideration.

Abstract Background Infection is a major cause of death in children, and it is particularly important to identify biological indicators of early infection. Previous studies showed that the neutrophil CD64 (nCD64) index may be a useful biomarker for infection. The purpose of this study was to investigate use of the nCD64 index to identify infection in children from a pediatric ICU (PICU) in China. Methods This prospective observational study enrolled 201 children who were admitted to our PICU and were divided into an infection group and a non-infection group. In each patient, C-reactive protein (CRP), nCD64 index, procalcitonin (PCT), and white blood cell count were measured during the first 24 h after admission. Receiver operating characteristic (ROC) analyses were used to determine the sensitivity, specificity, and diagnostic value of the nCD64 index for infection. Results Among all 201 children, the infection group had greater levels of CRP, nCD64 index, and PCT (all p

PurposeThis study explored the relationship between the prognostic nutritional index (PNI) and overall survival rate (OS) in patients with nasopharyngeal carcinoma (NPC), and established and validated an effective nomogram to predict clinical outcomes.MethodsThis study included 618 patients newly diagnosed with locoregionally advanced NPC. They were divided into training and validation cohorts at a ratio of 2:1 based on random numbers. The primary endpoint of this study was OS, progression-free survival (PFS) was the second endpoint. A nomogram was drawn from the results of multivariate analyses. Harrell’s concordance index (C-index), area under the receiver operator characteristic curve (AUC), and decision curve analysis (DCA) were used to evaluate the clinical usefulness and predictive ability of the nomogram and were compared to the current 8th edition of the International Union Against Cancer/American Joint Committee (UICC/AJCC) staging system.ResultsThe PNI cutoff value was 48.1. Univariate analysis revealed that age (p

Abstract As a new generation of high‐efficiency energy storage devices, lithium–sulfur (Li–S) battery attract increasing attention. However, slow conversion kinetics of lithium polysulfides (LiPSs) and severe shuttle effect are bottlenecks. Developing efficient sulfur host materials to suppress the shuttling of LiPSs and accelerate their conversion kinetics is a general strategy to enhance the performance of Li–S batteries. Herein, MoS2 quantum dots (QDs)@MgB2 nanosheet was synthesized using a simple liquid‐phase mixing method. The MoS2 QDs not only inhibit the stacking of MgB2 nanosheets but also expose more unsaturated metal active sites, which can effectively improve the adsorption of LiPSs, accelerate its catalytic conversion and suppress its shuttle effect. Moreover, MgB2 nanosheets can be used as polypropylene (PP) separator modifier. The battery using MoS2 QDs@MgB2 as the sulfur host material and MgB2@PP as the separator has high rate capability and excellent stability. In addition, the discharge‐specific capacity shows a good application prospect.

Abstract Background There is no consensus on whether triplet regimen is better than doublet regimen in the first‐line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. Methods This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non‐inferiority in progression‐free survival (PFS) for XELOX as compared with EOX on an intention‐to‐treat basis. Results Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5‐6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0‐6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812‐1.203; Pnon‐inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health‐related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. Conclusions This non‐inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first‐line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

Abstract Background Physical activity is known to have anti-cancer effects, including immunomodulatory actions. This study investigated the hypothesis that physical activity synergizes with combined lenvatinib plus anti-PD-1 therapy to enhance efficacy in patients with unresectable HCC. Methods The physical activity levels of patients with unresectable HCC receiving combined lenvatinib plus anti-PD-1 therapy were recorded by questionnaire. Patients were categorized according to physical activity levels (active vs. sedentary). The primary outcome was overall survival (OS). Secondary outcomes included objective response rate (ORR) and progression-free survival (PFS). A subcutaneous syngeneic HCC model was generated in C57BL/6 mice. Mice were randomized to receive placebo, combined lenvatinib plus anti-PD-1 antibodies or combination therapy plus physical activity. Tumors were measured every 3 days and harvested for immunohistochemistry analysis at 20 mm maximum diameter. Results Fifty-nine patients with unresectable HCC were categorized to active (n = 28) or sedentary (n = 31) groups. The active group had higher albumin and des-γ-carboxy prothrombin levels and lower hepatitis B virus load at baseline; other clinical and oncologic characteristics were comparable between the two groups. Patients in the active group had significantly longer OS (HR = 0.220, 95% CI 0.060–0.799) and PFS (HR = 0.158, 95% CI 0.044–0.562) and higher ORR (OR = 4.571, 95% CI 1.482–14.102) than patients in the sedentary group. Regular physical activity was independently associated with OS, PFS and ORR. The mouse model showed that physical activity significantly suppressed tumor growth and prolonged survival of tumor-bearing mice. Furthermore, physical activity inhibited Treg cell infiltration and immune checkpoint expression (including CTLA4, TIGIT and TIM3) induced by long-term combined lenvatinib plus anti-PD-1 therapy, improving efficacy. Conclusions Regular physical activity was associated with improved outcomes in unresectable HCC receiving combined lenvatinib plus anti-PD-1 therapy. Physical activity may improve therapeutic efficacy by reprograming the tumor microenvironment from an immunosuppressive to immunostimulatory phenotype.

Leukoaraiosis (LA) results from ischemic injury in small cerebral vessels, which may be attributable to decreased vascular density, reduced cerebrovascular angiogenesis, decreased cerebral blood flow, or microcirculatory dysfunction in the brain. In this study, we enrolled 357 patients with mild intracerebral hemorrhage (ICH) from five hospitals in China and analyzed the relationships between LA and clinical symptom severity at admission, neurological function prognosis at 3 months, and 1-year stroke recurrence. Patients were divided into groups based on Fazekas scale scores: no LA (n = 83), mild LA (n = 64), moderate LA (n = 98) and severe LA (n = 112). More severe LA, larger hematoma volume, and higher blood glucose level at admission were associated with more severe neurological deficit. More severe LA, older age and larger hematoma volume were associated with worse neurological function prognosis at 3 months. In addition, moderate-to-severe LA, admission glucose and symptom-free cerebral infarction were associated with 1-year stroke recurrence. These findings suggest that LA severity may be a potential marker of individual ICH vulnerability, which can be characterized by poor tolerance to intracerebral attack or poor recovery ability after ICH. Evaluating LA severity in patients with mild ICH may help neurologists to optimize treatment protocols. This study was approved by the Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiao Tong University (approval No. 12) on March 10, 2011.

Introduction: Lenvatinib plus an anti–PD-1 antibody has shown promising anti-tumor effects in patients with advanced hepatocellular carcinoma (HCC), but with clinical benefit limited to a subset of patients. We developed and validated a radiomic-based model to predict objective response to this combination therapy in advanced HCC patients. Methods: Patients (N = 170) who received first-line combination therapy with lenvatinib plus an anti–PD-1 antibody were retrospectively enrolled from 9 Chinese centers; 124 and 46 into the training and validation cohorts, respectively. Radiomic features were extracted from pretreatment contrast-enhanced MRI. After feature selection, clinicopathologic, radiomic, and clinicopathologic-radiomic models were built using a neural network. The performance of models, incremental predictive value of radiomic features compared with clinicopathologic features and relationship between radiomic features and survivals were assessed. Results: The clinicopathologic model modestly predicted objective response with an AUC of 0.748 (95% CI: 0.656–0.840) and 0.702 (95% CI: 0.547–0.884) in the training and validation cohorts, respectively. The radiomic model predicted response with an AUC of 0.886 (95% CI: 0.815–0.957) and 0.820 (95% CI: 0.648–0.984), respectively, with good calibration and clinical utility. The incremental predictive value of radiomic features to clinicopathologic features was confirmed with a net reclassification index of 47.9% (P < 0.001) and 41.5% (P = 0.025) in the training and validation cohorts, respectively. Furthermore, radiomic features were associated with overall survival and progression-free survival both in the training and validation cohorts, but modified albumin-bilirubin grade and neutrophil-to-lymphocyte ratio were not. Conclusion: Radiomic features extracted from pretreatment MRI can predict individualized objective response to combination therapy with lenvatinib plus an anti–PD-1 antibody in patients with unresectable or advanced HCC, and provide incremental predictive value over clinicopathologic features, and are associated with overall survival and progression-free survival after initiation of this combination regimen.

BackgroundConversion therapy is feasible in patients with oncologically unresectable hepatocellular carcinoma (HCC). However, it is challenging to prospectively identify patients who are more likely to achieve successful conversion before initiating systemic therapy, either alone or combined with locoregional therapy.MethodsCriteria for identifying potentially resectable patients with initially oncologically unresectable HCC before treatment with lenvatinib plus an anti-PD-1 antibody were proposed based on real-world evidence. Multivariate Firth logistic regression was used to validate the proposed criteria in a retrospective cohort of consecutive patients with advanced HCC, who received combination therapy with lenvatinib plus an anti-PD-1 antibody between September 2018 and September 2021.ResultsThe proposed criteria were as follows: (1) Eastern Cooperative Oncology Group performance status of 0 or 1; (2) Child-Pugh class A; (3) intrahepatic tumors confined to one lobe (left, right, or middle lobe), or present in one lobe alongside a single tumor with diameter ≤5 cm or up to three tumors each with diameter ≤3 cm in the remaining lobes, with R0 resection achievable by hemihepatectomy, alone or combined with locoregional therapy to the remaining lobes during surgery; and (4) no portal vein tumor thrombus involving the contralateral liver lobe or reaching the superior mesenteric vein, no hepatic vein tumor thrombus involving more than two major hepatic vein branches on the tumor side, and no tumor thrombus of the inferior vena cava reaching the atrium. Firth logistic regression confirmed the criteria were an independent predictor of surgery following conversion therapy with lenvatinib plus an anti-PD-1 antibody.ConclusionsThis study proposed and validated criteria for identifying patients with initially oncologically unresectable HCC who are potentially resectable when treated with combination therapy with lenvatinib plus an anti-PD-1 antibody. The proposed criteria could help standardize conversion therapy studies in advanced HCC.

The aims of this study were to explore the need for psychological counseling in breast cancer patients before radiotherapy during the COVID-19 pandemic, to distinguish which type of psychological guidance they demanded and to investigate the related factors that could be associated with the need for psychological counseling. A total of 112 eligible patients diagnosed with stage I–IV breast cancer who had received surgery were included. The self-rating depression scale (SDS), self-rating anxiety scale (SAS), Pittsburgh sleep quality index (PSQI), cancer fatigue scale (CFS), and survey for the need for psychological counseling were completed for all subjects prior to radiotherapy. A total of 8.9% and 3.6% of patients suffered from depression and anxiety during the COVID-19 pandemic, respectively. The prevalence of sleep disturbance was 62.5%. Only 12.5% of the patients needed psychological counseling, especially for the type of tumor diagnosis and treatment rather than COVID-19-related protection. The higher the total CFS score was, the lower the need for psychological counseling in breast cancer patients during this pandemic (OR = 0.91, 95% CI = 0.84–0.98). Patients who received 7–8 chemotherapeutic cycles had 6.7 times the risk of needing psychological counseling when compared with those who received 1–6 chemotherapeutic cycles. Fewer breast cancer patients suffered from depression and anxiety before radiotherapy during the COVID-19 pandemic. However, a large number of patients complained of sleep disturbance and fatigue. The majority of patients did not need psychological counseling. More chemotherapeutic cycles or less fatigue could increase their risk of needing psychological counseling, especially for tumor diagnosis and treatment, but not COVID-19-related protection.

Abstract Background We evaluated organ-specific response rates (OSRRs) to first-line lenvatinib plus anti-PD-1 antibodies in patients with advanced hepatocellular carcinoma (HCC). Methods This retrospective analysis included Chinese patients with unresectable/advanced HCC who received first-line lenvatinib (8 mg/day) plus ≥3 infusions of anti-PD-1 antibodies between October 2018 and May 2020. Tumor and macrovascular tumor thrombi (MVTT) treatment responses were evaluated every 2 months using RECIST v1.1. The overall response rate (ORR)/OSRR was defined as the percentage of patients with a best overall response of complete or partial response (CR or PR). Results In total, 60 patients were included in the analysis; 96.7% had measurable intrahepatic lesions, 55% had MVTT and 26.7% had extrahepatic disease. In all 60 patients, the ORR was 33.3%, median progression-free survival was 7.0 months (95% CI, 1.7–12.3) and median overall survival was not reached. The OSRR for MVTT (54.5%) was higher versus intrahepatic tumors (32.8%), extrahepatic lung metastases (37.5%) and lymph node metastases (33.3%). Among 33 patients with intrahepatic tumors and MVTT, 18 had differential responses in each site, including 13 with a better response in MVTT versus intrahepatic lesions. Among 18 patients whose MVTT achieved a radiographic CR or PR, six underwent surgical resection: 4/6 achieved a pathological CR in MVTT and 2/6 in the intrahepatic tumor. Conclusions First-line lenvatinib plus anti-PD-1 antibodies resulted in better tumor responses in MVTT versus intrahepatic lesions. Complete MVTT necrosis may allow downstaging and subsequent eligibility for surgical resection in a proportion of patients with advanced HCC.

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key enzymes in the process of lipid transport, is involved in the disease progression of various types of tumors. This article is to study the role of PCSK9 in the progression of hepatocellular carcinoma (HCC). Methods Immunohistochemistry was used to assess the expression of PCSK9 in tumor specimens from 105 HCC patients who underwent curative resection. Western blotting and quantitative real-time PCR were used to test the protein and mRNA expression levels in HCC cell lines. Cell Counting Kit-8 (CCK-8) and clone formation assays were performed to evaluate the proliferation ability of different kinds of cells in vitro. Flow cytometry was used to analyze cell cycle distribution and apoptosis rate. A xenograft model was established to study the effect of PCSK9 on HCC growth in vivo. TUNEL and immunofluorescence assays were used to detect cell apoptosis. Results High expression of PCSK9 in tumor tissues was related to microvascular invasion (p = 0.036) and large tumor size (p = 0.001) in HCC patients. Overall survival and disease-free survival after surgery were poor in patients with high expression of PCSK9 (p = 0.035 and p = 0.007, respectively). In vivo and in vitro experiments showed that PCSK9 promoted the growth of HCC by inhibiting cell apoptosis. A mechanistic study revealed that PCSK9 increases FASN expression, thereby inhibiting apoptosis of HCC cells via the Bax/Bcl-2/Caspase9/Caspase3 pathway. Conclusions PCSK9 expression level in HCC is an indicator of poor prognosis for patients with HCC. FASN-mediated anti-apoptosis plays an important role in PCSK9-induced HCC progression.

Background: Combined therapy with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies has shown high tumor response rates for patients with unresectable hepatocellular carcinoma (HCC). However, using this treatment strategy to convert initially unresectable HCC to resectable HCC was not reported. Methods: Consecutive patients with unresectable HCC who received first-line therapy with combined TKI/anti-PD-1 antibodies were analyzed. Tumor response and resectability were evaluated via imaging every 2 months (±2 weeks) using RECIST v1.1. Resectability criteria were (1) R0 resection could be achieved with sufficient remnant liver volume and function; (2) intrahepatic lesions were evaluated as partial responses or stable disease for at least 2 months; (3) no severe or persistent adverse effects occurred; and (4) hepatectomy was not contraindicated. Results: Sixty-three consecutive patients were enrolled. Of them, 10 (15.9%) underwent R0 resection in 3.2 months (range: 2.4–8.3 months) after the initiation of combination therapy. At baseline, these 10 patients had a median largest tumor diameter of 9.3 cm, 7 had Barcelona Clinic Liver Cancer stage C (vascular invasion) disease, 2 had stage B, and 1 had stage A. Before surgery, 6 patients were evaluated as a partial response, 3 stable disease, and 1 partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland. Six patients (60%) achieved a pathological complete response. One patient died from immune-related adverse effects 2.4 months after hepatectomy. After a median follow-up of 11.2 months (range: 7.8–15.9 months) for other 9 patients, 8 survived without disease recurrence, and 1 experienced tumor recurrence. Conclusions: Combination of TKI/anti-PD-1 antibodies is a feasible conversion therapy for patients with unresectable HCC to become resectable. This study represents the largest patient cohort on downstaging role of combinational systemic therapy on TKI and PD-1 antibody for HCC.

Liver cancer, mostly hepatocellular carcinoma (HCC), is the second leading cause of cancer mortality globally. Most patients were diagnosed at an advanced stage, and systemic therapy is the standard of care. All the approved systemic therapies for HCC are molecular targeted therapies with anti-angiogenic effects targeting the vascular endothelial growth factor signaling pathway. Sorafenib and lenvatinib are the first-line treatment, and regorafenib, ramucirumab, and cabozantinib are second-line treatment options. Although anti-PD-1 antibodies, including nivolumab and pembrolizumab, demonstrated promising anti-tumor effects as monotherapy for advanced HCC in phase II clinical trials, both failed in phase III studies. Anti-angiogenic treatment remains the backbone of systemic therapy for HCC. In this review, we summarized the approved anti-angiogenic medicines and discussed the potential strategies to improve the efficacy of anti-angiogenic therapy, including combination therapy with other treatments, and discussed the approaches to overcome the drawbacks of anti-angiogenic therapies.

Abstract Background To clarify the role of apolipoprotein D (Apod) in alleviating glucocorticoid-induced osteogenesis suppression in bone marrow mesenchymal stem cells (MSCs) via the PI3K/Akt pathway, thus influencing the progression of osteoporosis (OP). Methods Osteogenesis in MSCs was induced by dexamethasone (DEX) stimulation. Dynamic expressions of Apod in MSCs undergoing osteogenesis for different time points were determined by qRT-PCR. Relative levels of osteogenesis-associated genes, including ALP, RUNX2, and Osterix, in DEX-induced MSCs overexpressing Apod or not were examined. Moreover, the protein level of RUNX2, ALP, and Osterix; ALP activity; and mineralization ability influenced by Apod in osteogenic MSCs were assessed. At last, the potential influences of Apod on the PI3K/Akt pathway were identified through detecting the expression levels of PI3K and Akt in MSCs by Western blot. Results Apod was time-dependently upregulated in MSCs undergoing osteogenesis. DEX induction downregulated ALP, RUNX2, and Osterix and attenuated ALP activity and mineralization ability in MSCs undergoing osteogenesis, which were partially reversed by overexpression of Apod. In addition, Apod overexpression upregulated the reduced levels of PI3K and Akt in DEX-induced MSCs. Conclusion Apod alleviates glucocorticoid-induced osteogenesis suppression in MSCs via the PI3K/Akt pathway, thus protecting the progression of OP.

Abstract Background Malignant behavior and radioresistance, which severely limits the efficacy of radiation therapy (RT) in nasopharyngeal carcinoma (NPC), are associated with tumor progression and poor prognosis. Mesenchymal stem cells (MSCs) are used as a therapeutic tool in a variety of tumors. The aim of this study was to reveal the effect of tumor suppressor microRNA-34c-5p (miR-34c) on NPC development and radioresistance, as well as to confirm that exosomes derived from MSCs overexpressing miR-34c restore the sensitivity to radiotherapy in NPCs. Methods Potentially active microRNAs were screened by cell sequencing, Gene Expression Omnibus (GEO) database analysis, and analysis of clinical serum samples from 70 patients. The expression of genes and proteins was detected by Western blotting, quantitative reverse transcription PCR (qRT-PCR), and immunohistochemistry (IHC). Proliferation, apoptosis, invasion, migration and radioresistance of NPC were detected. Luciferase reporter assays were used to verify the interactions of microRNAs with their downstream targets. MSCs exosomes were isolated by ultrafiltration and verified by electron microscopy and nanoparticle tracking technology. Results The expression of miR-34c was associated with the occurrence and radiation resistance of NPC. In vitro and in vivo experiments indicated that overexpression of miR-34c inhibit malignant behavior such as invasion, migration, proliferation and epithelial-mesenchymal transition (EMT) in NPCs by targeting β-Catenin. In addition, we found alleviated radioresistance upon miR-34c overexpression or β-catenin knockdown in NPCs. Exosomes derived from miR-34c-transfected MSCs attenuated NPC invasion, migration, proliferation and EMT. Moreover, miR-34c-overexpressing exosomes drastically increased radiation-induced apoptosis in NPC cells. Conclusion miR-34c is a tumor suppressor miR in NPC, which inhibits malignant behavior as well as radioresistance of tumor. Therefore, exogenous delivery of miR-34c to NPCs via MSC exosomes inhibits tumor progression and increases the efficiency of RT. Combination IR with miR-34c-overexpressing exosomes may be effective treatment for radioresistant NPCs.

PurposeTo characterize clinical features and identify baseline prognostic factors for survival in young adults with advanced gastric cancer (YAAGC).Materials and MethodsA total of 220 young inpatients (age less than or equal to 40 years) with an initial diagnosis of advanced gastric cancer were retrospectively enrolled in this study.ResultsOf a consecutive cohort of 220 patients with YAAGC, the median overall survival (OS) time was 16.3 months. One-year survival rate was 43.6% (95% CI: 36.5 to 50.7). In this cohort, a female (71.4%, n = 157) predominance and a number of patients with poorly differentiated tumors (95.9%, n = 211) were observed. In the univariate analysis, OS was significantly associated with neutrophil–lymphocyte ratio (NLR) (≥3.12), hypoproteinemia (

ObjectivesTo establish and validate an effective nomogram to predict clinical outcomes for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC).Materials and MethodsThe clinicopathological parameters and follow-up information of 402 locoregionally advanced NPC patients (training cohort, n = 302; validation cohort, n = 100) were retrospectively enrolled. The nomogram was built with the important prognostic variables identified by Cox regression analysis. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively. The predictive power and clinical utility of the nomogram were assessed using the Harrell concordance index (C-index), calibration curve, and decision curve analysis. We compared the eighth staging system model with the nomogram to analyze whether the model could improve the accuracy of prognosisResultsEpstein–Barr virus (EBV) DNA load, the gross tumor volume (GTVnx), and cervical lymph node tumor volume (GTVnd) after induction chemotherapy were the independent predictors of OS and PFS. The calibration curves indicated superb agreement between the nomogram-predicted probabilities and observed actual probabilities of survival. The C-index and area under the receiver operator characteristic curve (AUC) of the nomogram integrating these significant factors and N stage, and TNM stage were higher than those of the eighth TNM system alone. In addition, the decision curve analyses demonstrated the clinical value and higher overall net benefit of the nomogram. High-risk groups identified by the nomogram had significantly poorer OS and PFS than the low-risk group (p < 0.05).ConclusionsThe multidimensional nomogram incorporating TNM stage, EBV DNA load, and tumor volume after induction chemotherapy led to a more precise prognostic prediction and could be helpful for stratifying risk and guiding treatment decisions in locoregionally advanced NPC patients who have undergone induction chemotherapy and concurrent chemoradiation.

Portal vein tumor thrombus (PVTT) is one of the most serious forms of hepatocellular carcinoma (HCC) vessel metastasis and has a poor survival rate. However, the molecular mechanism of PVTT has not yet been elucidated. In this study, the molecular mechanism of AXL expressed in tumor-derived endothelial cells (TECs) in vessel metastasis was investigated. High AXL expression was observed in TECs, but not in the tumor cells of HCC patients with PVTT and this was associated with poor overall survival (OS) and disease-free survival (DFS). AXL overexpression was positively associated with CD 31 expression both in vitro and in vivo. AXL promoted the cell proliferation, tube formation, and migration of both TECs and normal endothelial cells (NECs). High expression of AXL in TECs promoted the cell migration, but not the proliferation of HCC cells. Further studies demonstrated that AXL promoted cell migration and tube formation through activation of the PI3K/AKT/SOX2/DKK-1 axis. AXL overexpression in HUVECs promoted tumor growth and liver or vessel metastasis of HCC in xenograft nude mice, which could be counteracted by treatment with R428, an AXL inhibitor. R428 reduced tumor growth and CD 31 expression in HCC in PDX xenograft nude mice. Therefore, AXL over-expression in TECs promotes vessel metastasis of HCC, which indicates that AXL in TECs could be a potential therapeutic target in HCC patients with PVTT.

Fly-ash, a kind of large solid waste in energy industry, has brought about serious environmental problems and safety consequences. No efficient way has been found yet to deal with it worldwide. The focus of contemporary research are mainly placed on the reuse of aluminum and iron, but with a low utilization rate less than 30%. Having destroyed the ecological balance, fly-ash has become a challenge drawing the attention of people in the solid waste industry. In this paper, a smoke-suppressant and flame-retardant layered double hydroxide (LDH) featuring Mg-Al-Fe ternary was successfully synthesized by fly-ash after coprecipitation. XRD results presented LDHs successful synthesis. Then, exploration on the flame retarding properties of LDHs in composites composed by ethylene vinyl acetate (hereinafter referred to as EVA)/LDHs was carried out by UL-94, limiting oxygen index (LOI), cone calorimeter (CCT), smoke density (SDT), and thermogravimetry-Fourier transform infrared spectrometry (TG-IR) tests. UL testing results showed that most of the samples had a vertical combustion rating of V-0. LOI results showed the highest LOI value of ELDH-1, amounting to as high as 28.5 ± 0.1 while CCT results showed that the rate of heat releasing, mass loss, and smoke production of composite materials were decreased significantly compared with corresponding data of pure EVA. The ELDH-1 sample displayed the lowest peaks of heat release rate (pHRR) value of 178.4 ± 12.8 Kw·m−2 and the lowest total heat release (THR) value of 114.5 ± 0.35 KJ·m−2. Then, SDT indicated that under respective ignition and non-ignition conditions, all composite materials present a good smoke suppression performance. Additionally, digital photographs after CCT demonstrated that EVA/LDHs composites could enhance the formation of compact charred layers, and prevent their splitting, which effectively prevent the underlying materials from burning. Finally, TG-IR findings showed that compared with pure EVA, EVA/LDHs composites also achieved a higher-level thermal stability.

PurposeTo investigate dosimetry of submandibular glands on xerostomia after intensity-modulated radiotherapy for nasopharyngeal carcinoma (NPC).MethodsFrom September 2015 to March 2016, 195 NPC patients were investigated. Xerostomia was evaluated at 12 months after treatment via the RTOG/EORTC system. The least absolute shrinkage and selection operator regression model was used to optimize feature selection for grades 2–3 xerostomia. Multivariable logistic regression analysis was applied to build a predicting model incorporating the feature selected in the least absolute shrinkage and selection operator regression model. Discrimination, calibration, and clinical usefulness of the predicting model were assessed using the C-index, calibration plot, and decision curve analysis.ResultsThe V30 of the parotid glands was selected based on the least absolute shrinkage and selection operator regression. The nomogram displayed good discrimination with a C-index of 0.698 (95% confidence interval [CI]: 0.626–0.771) and good calibration (model 1). Addition of the dosimetric parameters including the mean dose to the submandibular glands, V50 of the submandibular glands, and volume of the submandibular glands to the model 1 failed to show incremental prognostic value (model 2). The model 2 showed a C-index of 0.704 (95% CI: 0.632–0.776). Decision curve analysis demonstrated that the model 1 was clinically useful when intervention was decided at the possibility threshold of > 20%. Within this range, net benefit was comparable between the model 1 and model 2.ConclusionPGv30 was a major predictive factor of grades 2–3 xerostomia for NPC. In contrast, the mean dose to the submandibular glands, V50 of the submandibular glands, and volume of the submandibular glands were not independent predictive factors.

Commercial diesel consists of hundreds of hydrocarbons such as alkanes, cycloalkanes, and aromatics. The components of the fuel’s composition are what determine its physical and ignition properties, and their variations affect engine performance. In this study, n-heptane, n-dodecane, tetralin, and decalin were chosen as typical additives to blend with commercial diesel according to the China VI standard (Heavy Duty Diesel Vehicle Pollutant Emission Limits and Measurement Methods) in 20% and 50% volume fractions, respectively. The physical properties of the fuel blends, such as viscosity, density, cetane number (CN), and distillation range, were measured first. Then, the commercial diesel’s lower heat value was measured, and blended fuels were calculated accordingly. The CN of the blended fuel is tested by an Ignition Quality Tester (IQT), which is known as the derived cetane number (DCN). The results show that adding n-dodecane increases the value of DCN, while tetralin reduces the DCN, and n-heptane and decalin have negative effects. This study uses a type of WP12 diesel engine made by Weichai that meets China’s emission regulation 6. During the tests, the fuel injection strategy was kept as a pure diesel operation without any modifications. Compared with pure diesel operation, the bench test results show the following characteristics: the maximum torque output increased with increased decalin, followed by tetralin and n-dodecane, while n-heptane has a side effect compared to pure diesel operation. The addition of n-dodecane and n-heptane can reduce fuel consumption, while tetralin will increase it, and decalin has no obvious effect on fuel consumption. It was found that n-heptane increases HC and NOx emissions significantly. Furthermore, n-dodecane slightly increases CO, HC and NOx emissions. Decalin increases CO and HC emissions when mixed in a large proportion. In addition, tetralin causes a substantial increase in HC, CO and NOx emissions at medium and high loads.

Abstract Background This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression. Methods Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with β-galactosidase assays. Kaplan-Meier analyses and Cox regression models were used for prognostic evaluation. Results NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26–2.76, overall survival [OS] 2.26, 95% CI 1.44–3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner. Conclusions NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment.

Background: For Chinese patients with hepatocellular carcinoma (HCC), surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis after surgery is diverse. We aimed to construct a scoring system (Shanghai Score) for individualized prognosis estimation and adjuvant treatment evaluation. Methods: A multivariate Cox proportional hazards model was constructed based on 4166 HCC patients undergoing resection during 2001–2008 at Zhongshan Hospital. Age, hepatitis B surface antigen, hepatitis B e antigen, partial thromboplastin time, total bilirubin, alkaline phosphatase, γ-glutamyltransferase, α-fetoprotein, tumor size, cirrhosis, vascular invasion, differentiation, encapsulation, and tumor number were finally retained by a backward step-down selection process with the Akaike information criterion. The Harrell's concordance index (C-index) was used to measure model performance. Shanghai Score is calculated by summing the products of the 14 variable values times each variable's corresponding regression coefficient. Totally 1978 patients from Zhongshan Hospital undergoing resection during 2009–2012, 808 patients from Eastern Hepatobiliary Surgery Hospital during 2008–2010, and 244 patients from Tianjin Medical University Cancer Hospital during 2010–2011 were enrolled as external validation cohorts. Shanghai Score was also implied in evaluating adjuvant treatment choices based on propensity score matching analysis. Results: Shanghai Score showed good calibration and discrimination in postsurgical HCC patients. The bootstrap-corrected C-index (confidence interval [CI]) was 0.74 for overall survival (OS) and 0.68 for recurrence-free survival (RFS) in derivation cohort (4166 patients), and in the three independent validation cohorts, the CI s for OS ranged 0.70–0.72 and that for RFS ranged 0.63–0.68. Furthermore, Shanghai Score provided evaluation for adjuvant treatment choices (transcatheter arterial chemoembolization or interferon-α). The identified subset of patients at low risk could be ideal candidates for curative surgery, and subsets of patients at moderate or high risk could be recommended with possible adjuvant therapies after surgery. Finally, a web server with individualized outcome prediction and treatment recommendation was constructed. Conclusions: Based on the largest cohort up to date, we established Shanghai Score – an individualized outcome prediction system specifically designed for Chinese HCC patients after surgery. The Shanghai Score web server provides an easily accessible tool to stratify the prognosis of patients undergoing liver resection for HCC.