Search

Yang Fu,1 Yuan Tang,2 Yue Zheng,1 Yue-Yun Chen,1 Ye Hong,1 Pei-Pei Wang,1 Qing Li,1 Ting Liu,1 Zhen-Yu Ding1 1Department of Biotherapy, Cancer Center, West China Hospital, West China Medical School, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, People’s Republic of China; 2Department of Pathology, West China Hospital, West China Medical School, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Zhen-Yu DingDepartment of Biotherapy, Cancer Center, West China Hospital, West China Medical School, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People’s Republic of ChinaTel +86 028 8542 2562Fax +86 028 8516 4059Email dingzhenyu@scu.edu.cnBackground: Epidermal growth factor receptor (EGFR) mutations are more frequently seen in miliary intrapulmonary metastases than EGFR wild-type non-small cell lung cancer (NSCLC). Also, small-scale retrospective studies showed that patients harboring EGFR mutation with miliary pulmonary metastases had a worse prognosis. This study aimed to explore the impact of imaging patterns on the outcomes of EGFR tyrosine kinase inhibitor (TKI) treatment.Methods: A cohort of treatment-naive NSCLC patients harboring EGFR mutation with intrapulmonary metastases who were prescribed with TKI were enrolled. The demographic feature, clinical outcome, and CT imaging of each patient were reviewed and analyzed.Results: A cohort of 174 patients were enrolled. Five intrapulmonary patterns of imaging were recognized: solid nodular, ground-glass nodular, miliary, multiple uniform nodular, and not otherwise specified. Among them, miliary and multiple uniform nodular patterns had similar poor prognosis, and, therefore, were combined as diffuse group. A worse PFS (9.0 mon, 95% CI: 8.0– 10.0 mon) was observed compared with the rest (non-diffuse group, 13.3 mon, 95% CI: 10.2– 16.4 mon, p< 0.001, HR=0.49). The objective response rates (ORR) between the two groups were 76.8% and 84.1%, respectively, with no significant difference (p = 0.474). The OS of the diffuse and the non-diffuse group were 25.6 mon (95% CI 21.9– 29.3 mon) and 35.0 mon (95% CI: 27.5– 42.5, p = 0.01, HR= 0.59). Organs like bone (p=0.167), liver (p=0.513), and adrenal gland (p=0.375) were involved in similar frequencies in both groups. However, brain (p=0.070) and leptomeningeal (p=0.078) metastases were less common in the non-diffuse group with marginally statistical significance. The 2 groups contained similar missense mutations, and gene amplification was more common in the non-diffuse group.Conclusion: Patients with diffuse intrapulmonary metastases had inferior outcomes after TKI treatment. More aggressive treatments might be warranted for these patients.Keywords: epidermal growth factor receptor, EGFR, tyrosine kinase inhibitor, TKI, CT imaging, outcome, genetic aberration

Jianfen Shen,1 Youzhi Zhang,2 Hui Shen,1 Hua Pan,1 Longsheng Xu,1 Linna Yuan,1 Zhiying Ding1 1Department of Central Laboratory, The First Affiliated Hospital of Jiaxing University, Jiaxing 314000, China; 2School of Pharmacy, Hubei University of Science and Technology, Xianning 437100, China Objective: Breast cancer has been reported to be a serious disease and a threat to women’s health. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG) is a bioactive natural compound originating from Polygonum multiflorum Thunb., which has been shown to possess anti-inflammatory and antitumor properties. Adriamycin (ADM) is a chemotherapy agent used in tumor therapy that is limited by its side effects. However, little is known about the synergistic effect of THSG combined with ADM on breast cancer. This study seeks to investigate the effects of the combination of THSG plus ADM on MCF-7 breast cancer cells and to test the mechanisms involved.Materials and methods: MTT assay was detected to determine cell viability. Furthermore, cell apoptosis was tested by flow cytometry and TUNEL assay. In addition, protein expression was measured by Western blot analysis.Results: The individual treatment of THSG and ADM induced cell injury. Moreover, cotreatment further increased it, which the effect may be associated with the elevation of the apoptotic-related protein expression such as Bax/Bcl-2 and cleaved caspase-3/caspase-3. Lastly, our results also show the reduction of vascular endothelial growth factor/phosphatidylinositol 3-kinase/Akt protein expression in the individual or synergistic treatment.Conclusion: Taken together, cotreatment of THSG and ADM may exert a synergistic reduction of cell injury via the inhibition of vascular endothelial growth factor/phosphatidylinositol 3-kinase/Akt pathway. Thus, THSG might possess potent anti-breast cancer effect with ADM. Keywords: THSG, ADM, synergistic effect, apoptosis, VEGF/PI3K/Akt, breast cancer

Background: Neoadjuvant immunotherapy is under intensive investigation for esophageal squamous cell carcinoma (ESCC). This study assesses the efficacy and immune response of neoadjuvant immunochemotherapy (nICT) in ESCC., Methods: In this phase II trial (ChiCTR2100045722), locally advanced ESCC patients receiving nICT were enrolled. The primary endpoint was the pathological complete response (pCR) rate. Multiplexed immunofluorescence, RNA-seq and TCR-seq were conducted to explore the immune response underlying nICT., Results: Totally 42 patients were enrolled, achieving a 27.0% pCR rate. The 1-year, 2-year DFS and OS rates were 89.2%, 64.4% and 97.3%, 89.2%, respectively. RNA-seq analysis highlighted T-cell activation as the most significantly enriched pathway. The tumour immune microenvironment (TIME) was characterised by high CD4, CD8, Foxp3, and PD-L1 levels, associating with better pathological regression (TRS0/1). TIME was categorised into immune-infiltrating, immune-tolerant, and immune-desert types. Notably, the immune-infiltrating type and tertiary lymphoid structures correlated with improved outcomes. In the context of nICT, TIM-3 negatively influenced treatment efficacy, while elevated TIGIT/PD-1 expression post-nICT correlated positively with CD8+ T cell levels. TCR-seq identified three TCR rearrangements, underscoring the specificity of T-cell responses., Conclusions: Neoadjuvant camrelizumab plus chemotherapy is effective for locally advanced, resectable ESCC, eliciting profound immune response that closely associated with clinical outcomes., (© 2024. The Author(s).)

Purpose: The characteristic of RENT3B in cancer remains ambiguous. We aimed to study the relationship between RENT3B and immune infiltration in liver hepatocellular carcinoma (LIHC) and lung squamous cell carcinoma (LUSC)., Patients and Methods: We investigated the expression levels of RENT3B using ONCOMINE and TIMER databases, and assessed the interrelationship between RENT3B expression and survival using PrognoScan, GEPIA, and Kaplan-Meier plotter. Additionally, we examined the association between RENT3B and immune cells in the tumor microenvironment (TME), as well as markers of immune cells, using TIMER. Subsequently, we performed prognostic analysis based on the expression level of RENT3B within specific immune cell subgroups. Furthermore, we evaluated the promoter methylation profile of RENT3B between tumor and normal tissues in LIHC and LUSC using the DNMIVD database., Results: RENT3B exhibited increased levels in both in LIHC and LUSC. High RENT3B expression was associated with unfavorable prognosis in LIHC, whereas it indicated a beneficial prognosis in LUSC. In LIHC, the expression of RENT3B positively correlated with immune infiltration levels of B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. However, in LUSC, the expression of RENT3B showed a negative correlation with immune infiltration levels of B cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. RENT3B exhibited positive correlations with 42 immune markers in LIHC, while it displayed negative associations with 10 immune markers in LUSC. Despite variations in immune cell enrichment and reduction subgroups, high RENT3B expression consistently indicated poor prognosis in LIHC, whereas it remained favorable in LUSC. Additionally, there were no significant differences observed in RENT3B promoter methylation between tumor and normal tissues in both LIHC and LUSC., Conclusion: RENT3B can affect the overall tumor prognosis and is associated with immune infiltration, especially in LIHC and LUSC. Consequently, RENT3B can become a prognostic biomarker for LIHC and LUSC., (© 2024. The Author(s).)

The microbial terroir is an indispensable part of the terroir panorama, and can improve wine quality with special characteristics. In this study, eight autochthonous yeasts ( Saccharomyces cerevisiae ), selected in Huailai country, China, were trailed in small-scale and pilot fermentations for both white (Riesling and Sémillon) and red (Cabernet Sauvignon and Syrah) wines and evaluated by GC-MS analysis and the rate-all-that-apply (RATA) method. Compared to commercial yeast strains, the indigenous yeasts were able to produce higher concentrations of ethyl esters and fatty acid ethyl esters, and higher alcohol, resulting in higher odor activity values of fruity, floral attributes. Marked varietal effects were observed in the pilot fermentation, but yeast strains exerted a noticeable impact in modulating wine aroma and sensory profile. Overall, indigenous yeast could produce more preferred aroma compounds and sensory characteristics for both white and red wines, demonstrating the potential for improving wine quality and regional characteristics.

Background: Liver progenitor cells (LPCs) are a subpopulation of cells that contribute to liver regeneration, fibrosis and liver cancer initiation under different circumstances., Results: By performing adenoviral-mediated transfection, CCK-8 analyses, F-actin staining, transwell analyses, luciferase reporter analyses and Western blotting, we observed that TGF-β promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-β activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFβ-Smad signaling induced growth inhibition and partial EMT, whereas TGFβ-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-β was mutually restricted in LPCs. Mechanistically, we found that TGF-β activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFβ-MAPK signaling inhibited the phosphorylation of Smad3 but not Smad2 at the C-terminus, and it reinforced the linker phosphorylation of Smad3 at T179 and S213. We then found that overexpression of mutated Smad3 at linker phosphorylation sites intensifies TGF-β-induced cytostasis and EMT, mimicking the effects of MAPK inhibition in LPCs, whereas mutation of Smad3 at the C-terminus caused LPCs to blunt TGF-β-induced cytostasis and partial EMT., Conclusion: These results suggested that TGF-β downstream of Smad3 and MAPK signaling were mutually antagonistic in regulating the viability and partial EMT of LPCs. This antagonism may help LPCs overcome the cytostatic effect of TGF-β under fibrotic conditions and maintain partial EMT and progenitor phenotypes.

Background: Esophageal neuroendocrine carcinoma (ENEC) is a rare subtype of esophageal cancer (EC). It presents distinctive clinical and pathological features in comparison to esophageal squamous cell carcinoma (ESCC). To better elucidate the disparities between the two and establish a prognostic prediction model for ENEC, we conducted this study., Methods: Data of ENEC and ESCC patients (1975 to 2016) were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Patients with a confirmed pathological diagnosis of ENEC and ESCC were enrolled in the study. The Chi-square test was employed to compare categorical variables, and the median survival time was analyzed using the Kaplan-Meier curve. Training and validation groups were randomly assigned at a ratio of 7:3. Factors with a significance level of <0.05 in the multifactor regression model as well as age were integrated into the nomogram model. Concordance index (C-index), calibration curves, and decision curve analyses (DCA) were generated for model validation., Results: This study encompassed a total of 737 ENEC patients and 29,420 ESCC. Compared to ESCC, ENEC patients had higher probability of liver metastasis (13.8% vs. 1.9%, P<0.001), poor differentiation (68.0% vs. 37.1%, P<0.001), and late SEER stage (52.8% vs. 26.9%, P<0.001). Patients who received either surgery, radiotherapy (RT), or chemotherapy had a significantly longer disease-specific survival (DSS) and overall survival (OS) (all P<0.001). After propensity score matching (PSM), ENEC patients were associated with shorter DSS (7.0 months vs. not reached, P<0.0001) and OS (7.0 vs. 12.0 months, P<0.0001) compared to ESCC. Race, SEER stage, surgery, RT, and chemotherapy were identified as predictors of DSS and were incorporated into the nomogram model together with age. The validation of the model using C-index (0.751 and 0.706, respectively) and calibration curves reflected the better discrimination power of the model. In addition, DCA supported the favorable potential clinical effect of the predictive model. Lastly, a risk classification based on the nomogram also verified the reliability of the model., Conclusions: ENEC and ESCC exhibit distinct clinicopathological features. Patients with ENEC experience significantly poorer survival outcomes compared to those with ESCC. Surgical intervention, radiation therapy, and chemotherapy significantly improve OS and DSS for ENEC patients. The nomogram prediction model, constructed based on age, race, stage, and treatment regimen, demonstrates accurate and effective predictive capabilities for prognostic factors in ENEC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-905/coif). R.A.R. has been a paid consultant and accepted speaker bureau fees from Astra Zeneca. The other authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

The genus Gongronella is important in agriculture and industry by secreting various natural bioactive metabolites such as chitosanases and organic acids. During the most recent 8 years, a total of 14 new species have been described, remarkably enriching the diversity of this genus. In this study, we added three more new species to this valuable genus, based on a combination of morphological traits and phylogenetic information. Six strains of the genus Gongronella were isolated from soil collected in Hainan Province, China. Phylogenetic analyses of ITS and LSU rDNA sequences grouped these strains into three independent clades. According to their unique morphological characteristics, they were classified as G. multiramosa sp. nov., G. qichaensis sp. nov. and G. oleae sp. nov. The G. multiramosa was characterized by multiple branched sporangiophores and was closely related to G. pedratalhadensis . The G. qichaensis was characterized by obscure collars and closely related to G. butleri , G. hydei and G. banzhaoae . The G. oleae was characterized by the presence of oil droplets in the sporangiospores and was closely related to G. chlamydospora and G. multispora . Their descriptions and illustrations were provided, and their differences from morphological allies and phylogenetic-related species are discussed.

The steerability of a quantum state can be detected by steering inequalities. The linear steering inequalities show that more steerable states can be discovered with the increase of measurements. In order to detect more steerable states in two-photon systems, we first theoretically derive an optimized steering criterion based on infinity measurements for an arbitrary two-qubit state. The steering criterion is only determined by the spin correlation matrix of the state, and do not require infinity measurements. Then, we prepared the Werner-like states in two-photon systems, and measure their spin correlation matrices. Finally, we apply three steering criteria, which include our steering criterion, the three-measurement steering criterion and the geometric Bell-like inequality, to distinguish the steerability of these states. The results show that our steering criterion can detect the most steerable states under the same experimental conditions. Thus, our work provides a valuable reference for detecting the steerability of quantum states.

Agricultural non-point source pollution is threatening water environmental health of the Three Gorges reservoir. However, current studies for precision management of the agricultural non-point source pollution within this area are still limited. The objective of this study was identifying the critical areas and primary sources of agricultural non-point source pollution for precision management. Firstly, the inventory analysis approach was used to estimate the discharge amount of total nitrogen (TN), total phosphorus (TP), and chemical oxygen demand (COD) from farmland fertilizer, crop residues, livestock breeding, and daily activities. Afterwards, the deviation standardization method was applied to evaluate the emission intensity of TN, TP, and COD, as well as calculating the comprehensive pollution index (CPI) of each village, based on which the critical areas for agricultural non-point source pollution management could be distinguished. Moreover, the equivalence pollution load method was conducted to identify the primary pollution sources within each critical zone. The above methods were implemented to an emigrant town within the Three Gorges reservoir area named Gufu. Results showed that agricultural non-point source pollution in Gufu town has been alleviated to a certain extent since 2016. Nevertheless, in four areas of the town (i.e., Longzhu, Fuzi, Shendu, and Maicang), the agricultural non-point source pollution still deserved attention and improvement. For the mentioned critical areas, farmland fertilizer and livestock breeding were the primary sources causing agricultural non-point source pollution. The emission amount of TN and TP from farmland fertilizer accounted for 60% and 48% of the total, respectively. And those from livestock breeding were 29% and 46%. Our research could provide definite targets to relieve agricultural non-point source pollution, which had great significance to protect water environment while coordinating regional economic growth after emigrant resettlement., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC 50 values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo, both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: he authors (Z.L., X.Y., and Q.W.) have applied for patents related to this study., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The tripartite motif (TRIM) protein family is a highly conserved group of E3 ligases with 77 members known in the human, most of which consist of a RING-finger domain, one or two B-box domains, and a coiled-coil domain. Generally, TRIM proteins function as E3 ligases to facilitate specific proteasomal degradation of target proteins. In addition, E3 ligase independent functions of TRIM protein were also reported. In hepatocellular carcinoma, expressions of TRIM proteins are both regulated by genetic and epigenetic mechanisms. TRIM proteins regulate multiple biological activities and signaling cascades. And TRIM proteins influence hallmarks of HCC. This review systematically demonstrates the versatile roles of TRIM proteins in HCC and helps us better understand the molecular mechanism of the development and progression of HCC., (© 2022. The Author(s).)

In this study, Eu 3+ /Gd 3+ co-doped fluoroapatitååe (Eu/Gd:FAP) nanocrystals were synthesized by the hydrothermal method as a fluorescent bioimaging agent. The phase composition, morphology, fluorescence, and biosafety of the resulting samples were characterized. Moreover, the in vivo fluorescent bioimaging application of Eu/Gd:FAP nanocrystals was evaluated in mice with subcutaneously transplanted tumors. The results showed that the Eu/Gd:FAP nanocrystals were short rod-like particles with a size of 59.27 ± 13.34 nm × 18.69 ± 3.32 nm. With an increasing F substitution content, the Eu/Gd:FAP nanocrystals displayed a decreased size and enhanced fluorescence emission. Eu/Gd:FAP nanocrystals did not show hemolysis and cytotoxicity, indicating good biocompatibility. In vivo fluorescent bioimaging study demonstrated that Eu/Gd:FAP nanocrystals could be used as a bioimaging agent and displayed stable fluorescence emitting in tumors, indicating an accumulation in tumor tissue due to the passive targeting ability. In addition, any adverse effects of Eu/Gd:FAP nanocrystals on major organs were not observed. This study shows that biocompatible rare earth co-doped FAP nanocrystals have the potential to be used as a bioimaging agent in vivo.

Introduction: Acute kidney injury (AKI) is a major public health problem worldwide. However, there is no definitive therapies to treat established AKI. In this study, we used FG-4592 to induce hypoxia inducible factor (HIF) expression in cells and then explored whether the extracellular vesicles (EVs) secreted by HIF-upregulated cells could alleviate ischemia/reperfusion injury (IRI)-induced AKI., Methods: FG-4592/HK2-EVs and FG-4592/HEK293-EVs were prepared by treating HK2 or HEK293 cells with FG-4592 for 24 h, respectively. HK2 cells under hypoxia were treated with FG-4592/HK2-EVs or FG-4592/HEK293-EVs to observe the therapeutic effect of EVs on H/R-induced apoptosis and inflammation. Mice were treated with FG-4592/HEK293-EVs after IRI to observe whether FG-4592/HEK293-EVs treatment could alleviate ischemic AKI., Results: The expression of HIF was induced by FG-4592 in a dose-dependent manner in HK2 and HEK293 cells under normoxia. In vitro, FG-4592/HK2-EVs and FG-4592/HEK293-EVs inhibited apoptosis and inflammation induced by H/R. In vivo, treatment with FG-4592/HEK293-EVs significantly ameliorated renal tubular injury and inflammation caused by IRI. In addition, the expression of HIF-1α in cells and kidneys was significantly downregulated by FG-4592/HK2-EVs and FG-4592/HEK293-EVs treatment., Conclusion: This study demonstrated that EVs derived from HK2 or HEK293 cells after FG-4592 treatment could alleviate renal tubular injury and inflammation, suggesting a novel therapeutic role of FG-4592/EVs in the treatment of AKI., Competing Interests: Bi-Cheng Liu is one of Editorial Board Member of Kidney Diseases. Other authors have no conflicts of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)

At present, there are various treatment strategies for colorectal cancer, including surgery, chemotherapy, radiotherapy, and targeted therapy. In recent years, with the continuous development of immunotherapy, immune checkpoint inhibitors (ICIs) can significantly improve the treatment of advanced colorectal cancer patients with high levels of microsatellite instability. In addition to ICIs, neoantigens, as a class of tumor-specific antigens (TSA), are regarded as new immunotherapy targets for many cancer species and are being explored for antitumor therapy. Immunotherapy strategies based on neoantigens include tumor vaccines and adoptive cell therapy (ACT). These methods aim to eliminate tumor cells by enhancing the immune response of host T-cells to neoantigens. In addition, for MSS colorectal cancer, such "cold tumors" with low mutation rates and stable microsatellites are not sensitive to ICIs, whereas neoantigens could provide a promising immunotherapeutic avenue. In this review, we summarized the current status of colorectal cancer neoantigen prediction and current clinical trials of neoantigens and discussed the difficulties and limitations of neoantigens-based therapies for the treatment of CRC., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Yue Zheng et al.)

The development of high-performance ultraelastic metals with superb strength, a large elastic strain limit and temperature-insensitive elastic modulus (Elinvar effect) are important for various industrial applications, from actuators and medical devices to high-precision instruments 1,2 . The elastic strain limit of bulk crystalline metals is usually less than 1 per cent, owing to dislocation easy gliding. Shape memory alloys 3 -including gum metals 4,5 and strain glass alloys 6,7 -may attain an elastic strain limit up to several per cent, although this is the result of pseudo-elasticity and is accompanied by large energy dissipation 3 . Recently, chemically complex alloys, such as 'high-entropy' alloys 8 , have attracted tremendous research interest owing to their promising properties 9-15 . In this work we report on a chemically complex alloy with a large atomic size misfit usually unaffordable in conventional alloys. The alloy exhibits a high elastic strain limit (approximately 2 per cent) and a very low internal friction (less than 2 × 10 -4 ) at room temperature. More interestingly, this alloy exhibits an extraordinary Elinvar effect, maintaining near-constant elastic modulus between room temperature and 627 degrees Celsius (900 kelvin), which is, to our knowledge, unmatched by the existing alloys hitherto reported., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The overuse of chemical fertilizers has resulted in the degradation of the physicochemical properties and negative changes in the microbial profiles of agricultural soil. These changes have disequilibrated the balance in agricultural ecology, which has resulted in overloaded land with low fertility and planting obstacles. To protect the agricultural soil from the effects of unsustainable fertilization strategies, experiments of the reduction of nitrogen fertilization at 10, 20, and 30% were implemented. In this study, the bacterial responses to the reduction of nitrogen fertilizer were investigated. The bacterial communities of the fertilizer-reducing treatments (D10F, D20F, and D30F) were different from those of the control group (CK). The alpha diversity was significantly increased in D20F compared to that of the CK. The analysis of beta diversity revealed variation of the bacterial communities between fertilizer-reducing treatments and CK, when the clusters of D10F, D20F, and D30F were separated. Chemical fertilizers played dominant roles in changing the bacterial community of D20F. Meanwhile, pH, soil organic matter, and six enzymes (soil sucrase, catalase, polyphenol oxidase, urease, acid phosphatase, and nitrite reductase) were responsible for the variation of the bacterial communities in fertilizer-reducing treatments. Moreover, four of the top 20 genera (unidentified JG30-KF-AS9, JG30-KF-CM45, Streptomyces , and Elsterales ) were considered as key bacteria, which contributed to the variation of bacterial communities between fertilizer-reducing treatments and CK. These findings provide a theoretical basis for a fertilizer-reducing strategy in sustainable agriculture, and potentially contribute to the utilization of agricultural resources through screening plant beneficial bacteria from native low-fertility soil., Competing Interests: Authors BY, PW, Z-YD were employed by Shandong Qingdao Tobacco Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen, Zhang, Bo, Yang, Wang, Ding, Wang, Yang, Zhang and Yuan.)

Background: Bile duct ligation (BDL) in animals is a classical method for mimicking cholestatic fibrosis. Although different surgical techniques have been described in rats and rabbits, mouse models can be more cost-effective and reproducible for investigating cholestatic fibrosis. Magnetic resonance imaging (MRI) has made great advances for noninvasive assessment of liver fibrosis. More comprehensive liver fibrotic features of BDL on MRI are important. However, the utility of multiparameter MRI to detect liver fibrosis in a BDL mouse model has not been assessed., Aim: To evaluate the correlation between the pathological changes and multiparameter MRI characteristics of liver fibrosis in a BDL mouse model., Methods: Twenty-eight healthy adult male balb/c mice were randomly divided into four groups: sham, week 2 BDL, week 4 BDL, and week 6 BDL. Multiparameter MRI sequences, included magnetic resonance cholangiopancreatography, T1-weighted, T2-weighted, T2 mapping, and pre- and post-enhanced T1 mapping, were performed after sham and BDL surgery. Peripheral blood and liver tissue were collected after MRI. For statistical analysis, Student's t -test and Pearson's correlation coefficient were used., Results: Four mice died after BDL surgery; seven, six, five and six mice were included separately from the four groups. Signal intensities of liver parenchyma showed no difference on TI- and T2-weighted images. Bile duct volume, ΔT1 value, T2 value, and the rate of liver fibrosis increased steadily in week 2 BDL, week 4 BDL and week 6 BDL groups compared with those in the sham group ( P < 0.01). Alanine aminotransferase and aspartate transaminase levels initially surged after surgery, followed by a gradual decline over time. Strong correlations were found between bile duct volume ( r = 0.84), T2 value ( r = 0.78), ΔT1 value ( r = 0.62), and hepatic fibrosis rate (all P < 0.01) in the BDL groups., Conclusion: The BDL mouse model induces changes that can be observed on MRI. The MRI parameters correlate with the hepatic fibrosis rate and allow for detection of cholestatic fibrosis., Competing Interests: Conflict-of-interest statement: None of the authors have identified a conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Coherence and steerability are two essential characteristics of quantum systems. For a two-qubit state, the first-order coherence and the maximal violation of linear steering inequality are used to operationally measure the degree of coherence and steerability, respectively. Recently, a complementary relation between first-order coherence and linear steerability has been proposed. In this paper, we report an experimental verification of the complementary relation by preparing biphoton polarization entangled states in an all-optical setup. We propose an operable method for experimental measurement of the first-order coherence and linear steerability and calculate the purity of the initial states by reconstructing the density matrices of them. The experimental results coincide with the theoretical predictions very well, which provides a valuable reference for the application of optical quantum technology.

Background: Aberrant TAK1 (transforming growth factor β-activated kinase 1) activity is known to be involved in a variety of malignancies, but the regulatory mechanisms of TAK1 remain poorly understood. GRAMD4 (glucosyltransferase Rab-like GTPase activator and myotubularin domain containing 4) is a newly discovered p53-independent proapoptotic protein with an unclear role in HCC (hepatocellular carcinoma)., Results: In this research, we found that GRAMD4 expression was lower in HCC samples, and its downregulation predicted worse prognosis for patients after surgical resection. Functionally, GRAMD4 inhibited HCC migration, invasion and metastasis. Mechanistically, GRAMD4 interacted with TAK1 to promote its protein degradation, thus, resulting in the inactivation of MAPK (Mitogen-activated protein kinase) and NF-κB pathways. Furthermore, GRAMD4 was proved to recruit ITCH (itchy E3 ubiquitin protein ligase) to promote the ubiquitination of TAK1. Moreover, high expression of TAK1 was correlated with low expression of GRAMD4 in HCC patients., Conclusions: GRAMD4 inhibits the migration and metastasis of HCC, mainly by recruiting ITCH to promote the degradation of TAK1, which leads to the inactivation of MAPK and NF-κB signalling pathways., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue., Methods: We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets., Results: REVs targeted with Kim-1-binding LTH peptide (REV LTH ) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REV LTH , siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD., Conclusions: A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1 , alleviating inflammation and fibrosis in the tubules., (Copyright © 2021 by the American Society of Nephrology.)

Quantum entanglement, quantum steering and Bell nonlocality, as significant quantum resources in the field of quantum information science, can achieve variously valuable quantum information tasks. Among of them, quantum entanglement and Bell nonlocality are the weakest and strongest nonlocal correlations, respectively. One can capture the quantum steering and Bell nonlocality via violating steering inequality and Bell inequality, respectively. In general, the detections of quantum steering and Bell nonlocality are strictly harder than entanglement detection. Here, based on steering inequality test and quantum state tomography, we attain various nonlocal correlations and experimentally demonstrate that the estimations of quantum steering and Bell nonlocality can be realized according to the quantum entanglement of the prepared two-photon test states. The estimated efficiency of quantum steering is stronger than the one of Bell nonlocality in this scenario, i.e., more steerable two-photon test states can be verified through quantum entanglement. In addition, quantum steering and Bell nonlocality are bounded by the corresponding upper and lower bounds, and these bounds cannot be punctured by all prepared two-photon states in experiment. These results are conducive to understand the relations among these nonlocal correlations.

Aberrant mechanical properties and immunosuppression are the two key factors that limit the antitumor efficacy of T cell immune checkpoint blockade inhibitors, e.g., programmed cell death-1 antibody (PD-1 Ab), against solid tumors in the clinic. This study leverages hyperbaric oxygen (HBO) for the first time to address these two issues and reports the PD-1-Ab-mediated immune responses against various stroma-rich solid malignancies. The results demonstrate that HBO promoted PD-1 Ab delivery and T cells infiltration into tumor parenchyma by depleting the extracellular matrix's main components, such as collagen and fibronectin. Furthermore, HBO disrupts hypoxia-mediated immunosuppression and helps PD-1 Ab trigger robust cytotoxic T lymphocytes and long-lasting immunological memory to inhibit tumor relapses. Such enhanced immune responses are effective in solid tumors from rodents and the cancer cells from hepatocellular carcinoma patients. The results illustrate that HBO bolsters antitumor efficacy of PD-1 Ab, and the HBO-PD-1 Ab combination is a promising stroma-rich solid tumors' treatment in the clinic., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Small cell lung cancer (SCLC), composing 15-20% of lung cancer, is a fatal disease with extremely poor prognosis. In the past two decades, etoposide platinum doublet chemotherapy remained the only choice of therapy, with disappointing overall survival ≤1 year for the metastatic disease. Novel treatments including immunotherapy are urgently needed and extensively explored. Recently, in two phase III trials, atezolizumab and durvalumab were shown to bring survival benefit to patients. While immunotherapy brings better outcome, it is accompanied by adverse events different from traditional treatments. Although these immune-related adverse events (irAEs) are generally mild and can be managed, some irAEs (myocarditis, pneumonitis) may be severe and even life-threatening. Accompanying with the increasing application of immunotherapy in clinical practice, the irAEs should not be overlooked. In this review, the irAEs profile in clinical trials of immunotherapy for SCLC will be summarized, also its unique features compared with irAEs in other malignancies will be explored. This review may be helpful for the appropriate clinical use of immunotherapy for SCLC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fu, Zheng, Wang and Ding.)

Background: Targeted therapy has been established as the standard-of-care for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Among patients with advanced lung cancer, 30-40% have bone metastases (BoM) at first diagnosis. However, little is known on the clinical characteristics and prognostic factors of BoM in patients with NSCLC harboring EGFR mutations., Methods: Treatment-naive patients with advanced NSCLC harboring EGFR mutations who were prescribed tyrosine kinase inhibitors (TKIs) were screened and enrolled between June 2009 and April 2019 from West China Hospital. Patients were dichotomized according to whether they had BoM. The demographic characteristics, gene mutation status and therapeutic efficacy, including objective response rate (ORR), progression-free survival (PFS) and overall survival (OS), were collected., Results: A cohort of 604 patients were enrolled. The BoM group had worse PFS (11.7 vs. 14.0 months, HR = 0.73, p  = 0.00013) and OS (32.8 vs. 46.1 months, HR = 0.54, p  < 0.0001) compared with the non-BoM group. No significant differences were observed in disease control rate ( p  = 0.407) or ORR ( p  = 0.537) between the two groups. The metastatic sites in the two groups exhibited obvious differences. In multivariate analysis, BoM was found to be an independent factor of worse prognosis., Conclusion: BoM was identified as an independent inferior prognostic factor for EGFR-TKI treatment, and may have complex biological implications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Coronavirus Disease 2019 (COVID-19) emerges as a global pandemic and there is a lack of evidence about the clinical course and outcome of patients on maintenance hemodialysis (MHD). Here we conducted a retrospective longitudinal study aimed to analyze the clinical features and outcome of MHD patients hospitalized with COVID-19. Of 3126 inpatients with COVID-19 at 3 Branches of Wuhan Tongji Hospital from Jan 18th to Mar 9th, 2020, 19 patients were undergoing maintenance hemodialysis. Among the 19 MHD patients with COVID-19, 6 patients (31.6%) died, and 13 patients (68.4%) were able to be discharged. Baseline characteristics, clinical courses, laboratory findings, and dynamic trajectories of major laboratory markers were compared between survivors and nonsurvivors. According to our findings, MHD patients with COVID-19 who experienced non-surviving outcome had more elevated CRP, IL6 and procalcitonin as well as fibrinogen levels at various points compared to survivors. Thus the dysregulation of immune response as well as coagulation abnormalities might be highly involved in the pathological process of COVID-19, contributing to the poor prognosis in MHD patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Esophageal spindle cell carcinoma (ESpCC) is a rare subtype of esophageal carcinoma, accounting for 1% of all esophageal malignancies. The clinical outcome is unknown due to the lack of treatment options. Here, we present the case of a 60-year-old male with initially unresectable ESpCC, in which platinum-based concurrent chemoradiotherapy was unsuccessful. He was subsequently treated with neoadjuvant immunotherapy and after surgery achieved a complete pathological response; therefore, neoadjuvant immunotherapy might be a novel option for ESpCC patients., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Numerous studies have explored the suitability of biocompatible materials in regenerative medicine. Platelet concentrates are derived from centrifuged blood and are named according to their biological characteristics, such as platelet-rich plasma, platelet-rich fibrin and concentrated growth factor. Platelet concentrates have gained considerable attention in soft and hard tissue engineering. Indeed, multiple components of autologous platelet concentrates, such as growth factors, fibrin matrix and platelets, serve essential roles in wound healing. Current studies are focused on cutting-edge strategies to meet the requirements for tissue restoration by improving the properties of autologous platelet concentrates. In the present review, applications of platelet concentrates for tissue engineering are discussed, presenting a selection of recent advances and novel protocols. In addition, several aspects of these strategies, such as the advantages of lyophilized platelet concentrates and the combination of platelet concentrates with biomaterials, stem cells or drugs are discussed. The present review aims to summarize novel strategies using platelet concentrates to improve the outcomes of wound healing., (Copyright: © Ding et al.)

During the past decades, drugs targeting transforming growth factor-β (TGFβ) signaling have received tremendous attention for late-stage cancer treatment since TGFβ signaling has been recognized as a prime driver for tumor progression and metastasis. Nonetheless, in healthy and pre-malignant tissues, TGFβ functions as a potent tumor suppressor. Furthermore, TGFβ signaling plays a key role in normal development and homeostasis by regulating cell proliferation, differentiation, migration, apoptosis, and immune evasion, and by suppressing tumor-associated inflammation. Therefore, targeting TGFβ signaling for cancer therapy is challenging. Recently, we and others showed that blocking TGFβ signaling increased chemotherapy efficacy, particularly for nanomedicines. In this review, we briefly introduce the TGFβ signaling pathway, and the multifaceted functions of TGFβ signaling in cancer, including regulating the tumor microenvironment (TME) and the behavior of cancer cells. We also summarize TGFβ targeting agents. Then, we highlight TGFβ inhibition strategies to restore the extracellular matrix (ECM), regulate the tumor vasculature, reverse epithelial-mesenchymal transition (EMT), and impair the stemness of cancer stem-like cells (CSCs) to enhance cancer chemotherapy efficacy. Finally, the current challenges and future opportunities in targeting TGFβ signaling for cancer therapy are discussed., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Dendritic morphology is inextricably linked to neuronal function. Systematic large-scale screens combined with genetic mapping have uncovered several mechanisms underlying dendrite morphogenesis. However, a comprehensive overview of participating molecular mechanisms is still lacking. Here, we conducted an efficient clonal screen using a collection of mapped P-element insertions that were previously shown to cause lethality and eye defects in Drosophila melanogaster . Of 280 mutants, 52 exhibited dendritic defects. Further database analyses, complementation tests, and RNA interference validations verified 40 P-element insertion genes as being responsible for the dendritic defects. Twenty-eight mutants presented severe arbor reduction, and the remainder displayed other abnormalities. The intrinsic regulators encoded by the identified genes participate in multiple conserved mechanisms and pathways, including the protein folding machinery and the chaperonin-containing TCP-1 (CCT) complex that facilitates tubulin folding. Mutant neurons in which expression of CCT4 or CCT5 was depleted exhibited severely retarded dendrite growth. We show that CCT localizes in dendrites and is required for dendritic microtubule organization and tubulin stability, suggesting that CCT-mediated tubulin folding occurs locally within dendrites. Our study also reveals novel mechanisms underlying dendrite morphogenesis. For example, we show that Drosophila Nogo signaling is required for dendrite development and that Mummy and Wech also regulate dendrite morphogenesis, potentially via Dpp- and integrin-independent pathways. Our methodology represents an efficient strategy for identifying intrinsic dendrite regulators, and provides insights into the plethora of molecular mechanisms underlying dendrite morphogenesis., (Copyright © 2020 Wang, Ding, Cheng, Chien and Huang.)

Immunotherapy has revolutionized the standard of care for a range of malignancies. Accumulating evidence suggests that the success of immunotherapy is likely attributable to neoantigen-specific T cells. Thus, adoptive cell therapy with these neoantigen-specific T cells is highly promising. This strategy has proven to successfully elicit tumor regression or even complete remission in metastatic cancer patients. However, a fundamental challenge is to effectively identify and isolate neoantigen-specific T cells or their T cell receptors (TCRs), from either tumor-infiltrating lymphocytes (TILs) or peripheral blood lymphocytes (PBLs), and many methods have been developed to this end. In this review, we focus on the current proposed strategies for identifying and isolating neoantigen-specific T cells., (Copyright © 2020 Li and Ding.)

Styrene monooxygenases (SMOs) are two-component enzymes known to catalyze the epoxidation of styrene to (S)-styrene oxide. In this work, we identified a new oxygenase component, named StStyA, from the genome of Streptomyces sp. NRRL S-31. StStyA displayed complementary stereoselectivity to all of the known SMOs when coupled with a known reductase component (PsStyB), which made it the first natural SMO that produces (R)-styrene oxide. Accordingly, a plasmid co-expressing StStyA and PsStyB was constructed, which led to an artificial two-component SMO, named StStyA/B. When applied in the bio-epoxidation of nine aromatic alkenes, the enzyme showed activity toward five alkenes, and consistently displayed (R)-selectivity. Excellent stereoselectivity was achieved for all five substrates with enantiomeric excesses ranging from 91% to >99%ee., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: For women of the same age and body mass index, increased mammographic density is one of the strongest predictors of breast cancer risk. There are multiple methods of measuring mammographic density and other features in a mammogram that could potentially be used in a screening setting to identify and target women at high risk of developing breast cancer. However, it is unclear which measurement method provides the strongest predictor of breast cancer risk., Methods and Analysis: The measurement challenge has been established as an international resource to offer a common set of anonymised mammogram images for measurement and analysis. To date, full field digital mammogram images and core data from 1650 cases and 1929 controls from five countries have been collated. The measurement challenge is an ongoing collaboration and we are continuing to expand the resource to include additional image sets across different populations (from contributors) and to compare additional measurement methods (by challengers). The intended use of the measurement challenge resource is for refinement and validation of new and existing mammographic measurement methods. The measurement challenge resource provides a standardised dataset of mammographic images and core data that enables investigators to directly compare methods of measuring mammographic density or other mammographic features in case/control sets of both raw and processed images, for the purposes of the comparing their predictions of breast cancer risk., Ethics and Dissemination: Challengers and contributors are required to enter a Research Collaboration Agreement with the University of Melbourne prior to participation in the measurement challenge. The Challenge database of collated data and images are stored in a secure data repository at the University of Melbourne. Ethics approval for the measurement challenge is held at University of Melbourne (HREC ID 0931343.3)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Esophageal cancer (EC) is a lethal disease, and ranks 7th in incidence and 6th in mortality worldwide. Patients are treated with surgery and/or chemoradiotherapy for a curative intent, but for those with advanced diseases systemic chemotherapy and targeted therapy are the mainstay treatment with poor prognosis. For the patients with squamous cell carcinoma and those progressed after chemotherapy, treatment option is even fewer, and effective treatment modalities are urgently needed. Preclinical and clinical studies have found the PD-1/PD-L1 inhibitors activate T lymphocytes, inhibit cancer growth, and improve survival in cancer patients. Multiple PD-1/PD-L1 inhibitors have been approved for the management of a variety of cancers. Interestingly, a large of proportion of EC patients have tumors with PD-L1 expression and high tumor mutation burden. Trials have been performed to evaluate the efficacy and safety of the PD-1/PD-L1 inhibitors in EC patients. This review will summarize the current progress in this field, especially the toxicities associated with these agents., (Copyright © 2019 Hong and Ding.)

Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte antigen 4, programmed cell death-1, and PD-ligand 1 have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. ICIs are increasingly being used in early cancer settings and in combination with various other types of therapies, including targeted therapy, radiotherapy, and chemotherapy. However, despite the excellent therapeutic effect of ICIs, these medications typically result in a broad spectrum of toxicity reactions, termed immune-related adverse events (irAEs). Of all irAEs, cardiotoxicity, uncommon but with high mortality, has not been well recognized. Herein, based on previous published reports and current evidence, we summarize the incidence, diagnosis, clinical manifestations, underlying mechanisms, treatments, and outcomes of ICI-associated cardiotoxicity and discuss possible management strategies. A better understanding of these characteristics is critical to managing patients with ICI-associated cardiotoxicity., (Copyright © 2019 Zhou, Zhu, Wang, Xie, Chen, Zhang, Xia, Ding and Liu.)

Introduction: The prognosis for recurrent intrahepatic cholangiocarcinoma with bone metastasis remains dismal and its treatment poses a challenge for oncologists. To date, only 2 cases were reported in which pembrolizumab, an agent against programmed cell death protein-1 (PD-1), combined with chemotherapy led to a complete response. The safety and efficacy of nivolumab-based immunotherapy combined with lenvatinibin intrahepatic cholangiocarcinoma is unknown., Patient Concerns: A 40-year-old female was identified as having a lesion of 7.0 cm in diameter in the right lobe of the liver. In addition, calculi in the main and left hepatic bile ducts as well as the gallbladder were found., Diagnosis: Based on the results of imaging studies and tumor biomarker level, the patient was initially diagnosed as having intrahepatic cholangiocellular carcinoma and cholelithiasis, after which surgery was performed. The pathological examination confirmed that the tumor was cholangiocarcinoma. Adjuvant chemotherapy was administered after surgery. However, the patient developed recurrent lesions at the 5th month after surgery, and the cholangiocarcinoma expanded to the right thoracic vertebral pedicle (T7-8) at the 6th month., Interventions: The patient underwent percutaneous microwave ablation after recurrence in the liver was identified. After that, the patient received nivolumab plus lenvatinib., Outcomes: The lesions in the liver decreased in size and disappeared after treatment with nivolumab plus lenvatinib. Additionally, the metastases in the right thoracic vertebral pedicle were stable after 9 months of therapy., Lessons: Immunotherapy has revolutionized the treatment of non-small-cell lung cancer, melanoma, and advanced renal cell carcinoma. In this case, the patient achieved an excellent radiological and symptomatic response after receiving nivolumab plus lenvatinib combination therapy. Patients suffering from cholangiocarcinoma with dMMR status and a high tumor mutation burden (TMB) may have a consistent eutherapeutic effect with anti-PD-1-directed treatment.

Therapeutic cancer vaccines have proven to seldom induce dramatic clinical response when used alone, and therefore, they are being studied in combination with additional treatment modalities to achieve optimal treatment activities. Growing preclinical data show that combining vaccines and immune checkpoint inhibitors (ICIs) can prime intensified immunogenicity and modulate immunosuppressive tumor microenvironment. Herein, we focus on the safety and efficacy of approved and promising cancer vaccines alone or combined with ICIs in the treatment of several malignancies. Generally, the majority of clinical trials support the concept of synergy that combination therapy of vaccines and ICIs holds maximized potential to improve clinical outcomes. Importantly, the combination has acceptable safety and minimal additional toxicity compared with single-agent vaccines or ICIs. Additionally, the potential strategies of combining personalized tumor vaccines with ICIs will become priority option and future direction of vaccine development and application and the urgent need to develop effective biomarkers to screen appropriate patient populations and predict response to combination therapy., (Copyright © 2019 Zhao, Chen, Ding and Liu.)

Acute lung injury (ALI) is a disease with high incidence and no effective therapeutic treatments. miR- 145-5p has been reported to be aberrantly expressed in lung injury tissues, suggesting a potential role in the progression and development of ALI. To validate this hypothesis and explore the underlying mechanism, a mouse model of ALI was established using lipopolysaccharide (LPS). Hematoxylin and eosin (Hand E) staining verified the successful establishment of mouse model with ALI. Levels of interleukin (IL)-1β, IL- 6, tumor necrosis factor α (TNF-α) and myeloperoxidase (MPO) were detected by both enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Mouse type II alveolar epithelial cells (AT II) were isolated and treated with LPS. miR-145-5p was significantly down-regulated both in mice with acute lung injury and LPS-induced AT II cells. Dual luciferase assays confirmed miR-145-5p could target and regulate Toll Like Receptor 4 (TLR4). Further analysis showed that miR-145-5p overexpression decreased the expression levels of IL-1β, IL-6 and TNF-α in LPS-induced AT II cells. miR-145-5p overexpression also blocked the LPS-induced activation of nuclear factor kappa B (NF-κB) pathway and reactive oxygen species (ROS) accumulation in AT II cells. Finally, in ALI mouse model, miR-145-5p overexpression alleviated lung tissue injury, decreased the expression levels of IL-1β, IL-6 and TNF-α and reduced MPO activity. In conclusion, miR-145-5p participated in the progression and development of ALI by decreasing the production of pro-inflammatory cytokines, inhibiting NF-κB pathway and suppressing ROS accumulation, shedding light on miR-145-5p as a potential therapeutic target for the treatment of ALI., (Copyright 2019 Biolife Sas. www.biolifesas.org.)

Cyclin D2/D3 (CCND2/3) are core components of the machinery that drives cell cycle progression and therefore, are associated with tumorigenesis. Currently, there are contradictory evidences on the function of CCND2/3 in tumorigenesis. Thus, we conducted a comprehensive meta-analysis to derive a precise predictive value of CCND2/3 in various tumors. We searched PubMed, EMBASE, Web of Science for eligible studies up to October 8, 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of OS or DFS/PFS/RFS were calculated using Forest plot analysis to demonstrate their associations. A total of 14 studies were ultimately included in this meta-analysis. Our results indicated CCND2/3 played an oncogenic role in all of the cancer patients (CCND2: pooled HR = 2.21, 95% CI: 1.67-2.93; CCND3: pooled HR = 2.29, 95% CI: 1.05-5.03). In tumor subgroup, CCND2 was associated with shorter OS in patients with gastric cancer (HR = 2.20, 95% CI: 1.66-2.92), whereas it might be a tumor suppressor in NSCLC (HR = 0.28, 95% CI: 0.12-0.64). In addition, CCND3 was correlated to reduced OS in breast cancer patients (HR = 1.64, 95% CI: 1.07-2.52) and shorter DFS/PFS/RFS in bladder cancer patients (HR = 4.60, 95% CI: 1.89-12.57). Taken together, CCND2/3 could be the promising biomarkers for predicting the prognosis of patients with malignant neoplasms., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Epithelial growth factor receptor tyrosine kinase inhibitor (EGFR TKI) revolutionize the standard of care for advanced non-small cell lung cancer (NSCLC) harboring sensitive EGFR mutation. Liver toxicity is the dose-limiting factor for TKI but its importance is largely overlooked. Here the relationship between the elevation of transaminase and progression-free survival (PFS) was explored. Methods: This was a retrospective study where patients with advanced NSCLC were screened. And those treatment-naïve and with sensitive EGFR mutation who were prescribed with EGFR TKI were enrolled. The highest level of transaminase (alanine aminotransferase, ALT, and aspartate transaminase, AST) during the treatment course was recorded. Results: Totally 208 patients were recruited, and most of them (48.6%) took gefitinib. The whole cohort achieved a median PFS of 11.2 months (95%CI: 10.0-12.3 m). 73 (35.1%) patients had elevated transaminase and most was attributed to gefitinib (n=43, 42.5%). Specifically, ALT was elevated in 65 patients (31.3%) while AST in 24 patients (11.5%). Again, gefitinib was associated with more cases of ALT (40.6%) and AST (17.8%) elevation. The elevation of AST was not related to PFS (P=0.259, HR=0.751, 95%CI: 0.464-1.214). Interestingly, those with normal ALT level had a longer PFS (12.6m, 95%CI: 10.6-14.5 m) than those with elevated ALT (9.5m 95%CI: 7.9-11.0 m, P=0.025, HR=0.682, 95%CI: 0.488-0.953). The inverse relationship was confirmed in the COX regression analysis (P=0.047). Conclusion: This study revealed the side effects of elevated ALT was inversely related to the PFS of EGFR TKI treatment. The liver impairment by TKI should not be overlooked., (Creative Commons Attribution License)