A radiomics model of contrast-enhanced computed tomography for predicting post-acute pancreatitis diabetes mellitus.

Background: Diabetes mellitus can occur after acute pancreatitis (AP), but the accurate quantitative methods to predict post-acute pancreatitis diabetes mellitus (PPDM-A) are lacking. This retrospective study aimed to establish a radiomics model based on contrast-enhanced computed tomography (CECT) for predicting PPDM-A. Methods: A total of 374 patients with first-episode AP were retrospectively enrolled from two tertiary referral centers. There were 224 patients in the training cohort, 56 in the internal validation cohort, and 94 in the external validation cohort, and there were 86, 22, and 27 patients with PPDM-A in these cohorts, respectively. The clinical characteristics were collected from the hospital information system. A total of 2,398 radiomics features, including shape-based features, first-order histogram features, high order textural features, and transformed features, were extracted from the arterial- and venous-phase CECT images. Intraclass correlation coefficients were used to assess the intraobserver reliability and interobserver agreement. Random forest-based recursive feature elimination, collinearity analysis, and least absolute shrinkage and selection operator (LASSO) were used for selecting the final features. Three classification methods [eXtreme Gradient Boosting (XGBoost), Adaptive Boosting, and Decision Tree] were used to build three models and performances of the three models were compared. Each of the three classification methods were used to establish the clinical model, radiomics model, and combined model for predicting PPDM-A, resulting in a total of nine classifiers. The predictive performances of the models were evaluated by the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F1-score. Results: Eleven radiomics features were selected after a reproducibility test and dimensionality reduction. Among the three classification methods, the XGBoost classifier showed better and more consistent performances. The AUC of the XGBoost's radiomics model to predict PPDM-A in the training, internal, and external cohorts was good (0.964, 0.901, and 0.857, respectively). The AUC of the XGBoost's combined model to predict PPDM-A in the training, internal, and external cohorts was good (0.980, 0.901, and 0.882, respectively). The AUC of the XGBoost's clinical model to predict PPDM-A in the training, internal, and external cohorts did not perform well (0.685, 0.733, and 0.619, respectively). In the external validation cohort, the AUC of the XGBoost's radiomics model was significantly higher than that of the clinical model (0.857 vs. 0.619, P<0.001), but there was no significant difference between the combined and radiomics models (0.882 vs. 0.857, P=0.317). Conclusions: The radiomics model based on CECT performs well and can be used as an early quantitative method to predict the occurrence of PPDM-A.

TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via ß1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9.

BACKGROUND: Breast cancer stem cell (CSC) expansion results in tumor progression and chemoresistance; however, the modulation of CSC pluripotency remains unexplored. Transmembrane protein 120B (TMEM120B) is a newly discovered protein expressed in human tissues, especially in malignant tissues; however, its role in CSC expansion has not been studied. This study aimed to determine the role of TMEM120B in transcriptional coactivator with PDZ-binding motif (TAZ)-mediated CSC expansion and chemotherapy resistance. METHODS: Both bioinformatics analysis and immunohistochemistry assays were performed to examine expression patterns of TMEM120B in lung, breast, gastric, colon, and ovarian cancers. Clinicopathological factors and overall survival were also evaluated. Next, colony formation assay, MTT assay, EdU assay, transwell assay, wound healing assay, flow cytometric analysis, sphere formation assay, western blotting analysis, mouse xenograft model analysis, RNA-sequencing assay, immunofluorescence assay, and reverse transcriptase-polymerase chain reaction were performed to investigate the effect of TMEM120B interaction on proliferation, invasion, stemness, chemotherapy sensitivity, and integrin/FAK/TAZ/mTOR activation. Further, liquid chromatography-tandem mass spectrometry analysis, GST pull-down assay, and immunoprecipitation assays were performed to evaluate the interactions between TMEM120B, myosin heavy chain 9 (MYH9), and CUL9. RESULTS: TMEM120B expression was elevated in lung, breast, gastric, colon, and ovarian cancers. TMEM120B expression positively correlated with advanced TNM stage, lymph node metastasis, and poor prognosis. Overexpression of TMEM120B promoted breast cancer cell proliferation, invasion, and stemness by activating TAZ-mTOR signaling. TMEM120B directly bound to the coil-coil domain of MYH9, which accelerated the assembly of focal adhesions (FAs) and facilitated the translocation of TAZ. Furthermore, TMEM120B stabilized MYH9 by preventing its degradation by CUL9 in a ubiquitin-dependent manner. Overexpression of TMEM120B enhanced resistance to docetaxel and doxorubicin. Conversely, overexpression of TMEM120B-∆CCD delayed the formation of FAs, suppressed TAZ-mTOR signaling, and abrogated chemotherapy resistance. TMEM120B expression was elevated in breast cancer patients with poor treatment outcomes (Miller/Payne grades 1-2) than in those with better outcomes (Miller/Payne grades 3-5). CONCLUSIONS: Our study reveals that TMEM120B bound to and stabilized MYH9 by preventing its degradation. This interaction activated the ß1-integrin/FAK-TAZ-mTOR signaling axis, maintaining stemness and accelerating chemotherapy resistance.

Ectoine Globally Hypomethylates DNA in Skin Cells and Suppresses Cancer Proliferation.

Epigenetic modifications, mainly aberrant DNA methylation, have been shown to silence the expression of genes involved in epigenetic diseases, including cancer suppression genes. Almost all conventional cancer therapeutic agents, such as the DNA hypomethylation drug 5-aza-2-deoxycytidine, have insurmountable side effects. To investigate the role of the well-known DNA protectant (ectoine) in skin cell DNA methylation and cancer cell proliferation, comprehensive methylome sequence analysis, 5-methyl cytosine (5mC) analysis, proliferation and tumorigenicity assays, and DNA epigenetic modifications-related gene analysis were performed. The results showed that extended ectoine treatment globally hypomethylated DNA in skin cells, especially in the CpG island (CGIs) element, and 5mC percentage was significantly reduced. Moreover, ectoine mildly inhibited skin cell proliferation and did not induce tumorigenicity in HaCaT cells injected into athymic nude mice. HaCaT cells treated with ectoine for 24 weeks modulated the mRNA expression levels of Dnmt1, Dnmt3a, Dnmt3b, Dnmt3l, Hdac1, Hdac2, Kdm3a, Mettl3, Mettl14, Snrpn, and Mest. Overall, ectoine mildly demethylates DNA in skin cells, modulates the expression of epigenetic modification-related genes, and reduces cell proliferation. This evidence suggests that ectoine is a potential anti-aging agent that prevents DNA hypermethylation and subsequently activates cancer-suppressing genes.

ZNF500 abolishes breast cancer proliferation and sensitizes chemotherapy by stabilizing P53 via competing with MDM2.

Zinc finger protein 500 (ZNF500) has an unknown expression pattern and biological function in human tissues. Our study revealed that the ZNF500 mRNA and protein levels were higher in breast cancer tissues than those in their normal counterparts. However, ZNF500 expression was negatively correlated with advanced TNM stage (p = 0.018), positive lymph node metastasis (p = 0.014), and a poor prognosis (p < 0.001). ZNF500 overexpression abolished in vivo and in vitro breast cancer cell proliferation by activating the p53-p21-E2F4 signaling axis and directly interacting with p53 via its C2H2 domain. This may prevent ubiquitination of p53 in a manner that is competitive to MDM2, thus stabilizing p53. When ZNF500-∆C2H2 was overexpressed, the suppressed proliferation of breast cancer cells was neutralized in vitro and in vivo. In human breast cancer tissues, ZNF500 expression was positively correlated with p53 (p = 0.022) and E2F4 (p = 0.004) expression. ZNF500 expression was significantly lower in patients with Miller/Payne Grade 1-2 than in those with Miller/Payne Grade 3-5 (p = 0.012). ZNF500 suppresses breast cancer cell proliferation and sensitizes cells to chemotherapy.

cfSNV: a software tool for the sensitive detection of somatic mutations from cell-free DNA.

Cell-free DNA (cfDNA) in blood, viewed as a surrogate for tumor biopsy, has many clinical applications, including diagnosing cancer, guiding cancer treatment and monitoring treatment response. All these applications depend on an indispensable, yet underdeveloped task: detecting somatic mutations from cfDNA. The task is challenging because of the low tumor fraction in cfDNA. Recently, we developed the computational method cfSNV, the first method that comprehensively considers the properties of cfDNA for the sensitive detection of mutations from cfDNA. cfSNV vastly outperformed the conventional methods that were developed primarily for calling mutations from solid tumor tissues. cfSNV can accurately detect mutations in cfDNA even with medium-coverage (e.g., ≥200×) sequencing, which makes whole-exome sequencing (WES) of cfDNA a viable option for various clinical utilities. Here, we present a user-friendly cfSNV package that exhibits fast computation and convenient user options. We also built a Docker image of it, which is designed to enable researchers and clinicians with a limited computational background to easily carry out analyses on both high-performance computing platforms and local computers. Mutation calling from a standard preprocessed WES dataset (~250× and ~70 million base pair target size) can be carried out in 3 h on a server with eight virtual CPUs and 32 GB of random access memory.

Computational Analysis of High-Dimensional DNA Methylation Data for Cancer Prognosis.

Developing cancer prognostic models using multiomics data is a major goal of precision oncology. DNA methylation provides promising prognostic biomarkers, which have been used to predict survival and treatment response in solid tumor or plasma samples. This review article presents an overview of recently published computational analyses on DNA methylation for cancer prognosis. To address the challenges of survival analysis with high-dimensional methylation data, various feature selection methods have been applied to screen a subset of informative markers. Using candidate markers associated with survival, prognostic models either predict risk scores or stratify patients into subtypes. The model's discriminatory power can be assessed by multiple evaluation metrics. Finally, we discuss the limitations of existing studies and present the prospects of applying machine learning algorithms to fully exploit the prognostic value of DNA methylation.

Efficacy and Safety of PD-1 Immune Checkpoint Inhibitors in Locally Advanced and Advanced Non-Small-Cell Lung Cancer Patients with Chronic Infection.

BACKGROUND: Immune checkpoint inhibitors have become new research hot spots in the treatment of non-small-cell lung cancer (NSCLC), but the efficacy and safety of immunotherapy for patients with chronic infection are still unclear because existing clinical trials often exclude those patients. MATERIALS AND METHODS: We identified 78 locally advanced or advanced NSCLC patients with chronic infection treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: Objective responses were observed in 19 out of 78 (24.36%) patients, and the disease control rate was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI: 3.71-9.27). PFS was 1.44 months (95% CI: 0.00-4.34) for monotherapy versus 7.34 months (95% CI: 4.50-10.18) for combination therapy (p = 0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, p = 0.001; PFS: 7.67 vs. 5.57 months, p = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs. 4.62, p = 0.027). The incidence of AEs of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 AEs. The incidence of leukopenia in any grade of AEs was the highest (57.69%), followed by anemia (25.64%), elevated alanine aminotransferase or aspartate aminotransferase (24.36%), and fatigue (21.79%). Hepatic transaminase increased in 26.7% (16/60) of HBV-infected patients and remained unchanged in 65.0% (39/60) patients. CONCLUSIONS: The PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on NSCLC patients with chronic infection, but still has the potential to increase the incidence of hepatitis.

Genome-Wide Identification of the TIFY Gene Family in Brassiceae and Its Potential Association with Heavy Metal Stress in Rapeseed.

The TIFY gene family plays important roles in various plant biological processes and responses to stress and hormones. The chromosome-level genome of the Brassiceae species has been released, but knowledge concerning the TIFY family is lacking in the Brassiceae species. The current study performed a bioinformatics analysis on the TIFY family comparing three diploid (B. rapa, B. nigra, and B. oleracea) and two derived allotetraploid species (B. juncea, and B. napus). A total of 237 putative TIFY proteins were identified from five Brassiceae species, and classified into ten subfamilies (six JAZ types, one PPD type, two TIFY types, and one ZML type) based on their phylogenetic relationships with TIFY proteins in A. thaliana and Brassiceae species. Duplication and synteny analysis revealed that segmental and tandem duplications led to the expansion of the TIFY family genes during the process of polyploidization, and most of these TIFY family genes (TIFYs) were subjected to purifying selection after duplication based on Ka/Ks values. The spatial and temporal expression patterns indicated that different groups of BnaTIFYs have distinct spatiotemporal expression patterns under normal conditions and heavy metal stresses. Most of the JAZIII subfamily members were highest in all tissues, but JAZ subfamily members were strongly induced by heavy metal stresses. BnaTIFY34, BnaTIFY59, BnaTIFY21 and BnaTIFY68 were significantly upregulated mostly under As3+ and Cd2+ treatment, indicating that they could be actively induced by heavy metal stress. Our results may contribute to further exploration of TIFYs, and provided valuable information for further studies of TIFYs in plant tolerance to heavy metal stress.

Genetic characterisation of sarcomatoid carcinomas reveals multiple novel actionable mutations and identifies KRAS mutation as a biomarker of poor prognosis.

BACKGROUND: Sarcomatoid component occurs in various epithelial malignancies and is associated with an aggressive disease course and poor clinical outcome. As it is largely rare, the molecular events underlying sarcomatoid carcinomas (SCs) remain poorly characterised. Here, we performed targeted next-generation sequencing (NGS) on patients with surgically resected SCs comprising distinct tissues of origin. METHODS: A total of 71 patients with pathological diagnosis of sarcomatoid carcinomas and underwent surgery were retrospectively enrolled in this study. Overall survival (OS) was defined as the time from surgery to death from any cause. Patients alive or lost to follow-up were censored. Genomic DNA from formalin-fixed paraffin-embedded samples was extracted for NGS and tumour mutation burden (TMB) analysis. RESULTS: In general, SCs occurred more commonly in males, except those of the gallbladder. SCs of the lung and the larynx were associated with a higher proportion of smokers (p=0.0015). Alterations in TP53, RB1, TERT and KRAS were highly frequent, with KRAS mutations being a biomarker of poor prognosis (median OS=8 vs 16 months, p=0.03). Multiple alterations in potentially actionable genes, including ROS1 and NTRK1 fusions and ERBB2 amplification, were detected in the extra-pulmonary cohort. A relatively high proportion (30%) of patients with extra-pulmonary SC had high TMB, with a median of 5.39 mutations per Mb. Lastly, copy number variations were common in SCs, and were non-overlapping between the primary and metastatic tumours. CONCLUSION: Taken together, our results suggest that comprehensive genetic testing may be necessary to inform treatment options and identify prognostic biomarkers.

Isolation of the Novel Phage PHB09 and Its Potential Use against the Plant Pathogen Pseudomonas syringae pv. actinidiae.

Bacteriophages are viruses that specifically infect target bacteria. Recently, bacteriophages have been considered potential biological control agents for bacterial pathogens due to their host specificity. Pseudomonas syringae pv. actinidiae (Psa) is a reemerging pathogen that causes bacterial canker of kiwifruit (Actinidia sp.). The economic impact of this pest and the development of resistance to antibiotics and copper sprays in Psa and other pathovars have led to investigation of alternative management strategies. Phage therapy may be a useful alternative to conventional treatments for controlling Psa infections. Although the efficacy of bacteriophage φ6 was evaluated for the control of Psa, the characteristics of other DNA bacteriophages infecting Psa remain unclear. In this study, the PHB09 lytic bacteriophage specific to Psa was isolated from kiwifruit orchard soil. Extensive host range testing using Psa isolated from kiwifruit orchards and other Pseudomonas strains showed PHB09 has a narrow host range. It remained stable over a wide range of temperatures (4-50 °C) and pH values (pH 3-11) and maintained stability for 50 min under ultraviolet irradiation. Complete genome sequence analysis indicated PHB09 might belong to a new myovirus genus in Caudoviricetes. Its genome contains a total of 94,844 bp and 186 predicted genes associated with phage structure, packaging, host lysis, DNA manipulation, transcription, and additional functions. The isolation and identification of PHB09 enrich the research on Pseudomonas phages and provide a promising biocontrol agent against kiwifruit bacterial canker.

Effects of MXene on Nonisothermal Crystallization Kinetics of Isotactic Polypropylene.

MXenes, a family of two-dimensional transition-metal carbides/nitrides, have attracted great attention and shown promising application in polymer composites. In this study, a typical MXene Ti3C2T x was prepared by selective etching. The structure and morphology of Ti3C2T x were studied by X-ray diffraction (XRD), scanning electron microscopy, and transmission electron microscopy, and the results proved that Ti3C2T x was successively fabricated. Then, Ti3C2T x /isotactic polypropylene composites with different Ti3C2T x dosages were fabricated, and the nonisothermal crystallization kinetics and melting behavior of the composites were investigated. The results indicated that when a small amount of Ti3C2T x was added, the crystallization parameters including the crystallization peak temperature and the crystallization rate increased, suggesting that crystallization was promoted. When the weight percentage of Ti3C2T x exceeded 1%, the crystallization parameters showed a reverse trend, suggesting that crystallization was hindered. The activation energy of composites with 0, 0.25, 0.5, and 1 wt % Ti3C2T x were calculated to be -164.5, -196.5, -193.8, and -147.95 kJ/mol, respectively, revealing that the crystallization of composites is concentration-dependent. The impact of Ti3C2T x dosage on the crystalline structure of the composites was studied using XRD. The related mechanism was proposed.

Metabolite Profiling and Transcriptome Analysis Provide Insight into Seed Coat Color in Brassica juncea.

The allotetraploid species Brassica juncea (mustard) is grown worldwide as oilseed and vegetable crops; the yellow seed-color trait is particularly important for oilseed crops. Here, to examine the factors affecting seed coat color, we performed a metabolic and transcriptomic analysis of yellow- and dark-seeded B. juncea seeds. In this study, we identified 236 compounds, including 31 phenolic acids, 47 flavonoids, 17 glucosinolates, 38 lipids, 69 other hydroxycinnamic acid compounds, and 34 novel unknown compounds. Of these, 36 compounds (especially epicatechin and its derivatives) accumulated significantly different levels during the development of yellow- and dark-seeded B. juncea. In addition, the transcript levels of BjuDFR, BjuANS,BjuBAN, BjuTT8, and BjuTT19 were closely associated with changes to epicatechin and its derivatives during seed development, implicating this pathway in the seed coat color determinant in B. juncea. Furthermore, we found numerous variations of sequences in the TT8A genes that may be associated with the stability of seed coat color in B. rapa, B. napus, and B. juncea, which might have undergone functional differentiation during polyploidization in the Brassica species. The results provide valuable information for understanding the accumulation of metabolites in the seed coat color of B. juncea and lay a foundation for exploring the underlying mechanism.

Immune checkpoint inhibitors combined with chemotherapy/bevacizumab therapy for patients with advanced lung cancer and heavily treated with EGFR mutation: a retrospective analysis.

BACKGROUND: EGFR-mutated lung cancer poorly responded to anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy. Whether patients with EGFR-mutated lung cancer can benefit from anti-PD-1/PD-L1 therapy combined with other drugs remains controversial. We retrospectively evaluated the safety and efficacy of the PD-1 inhibitor combined with other drugs (chemotherapy and/or bevacizumab) in patients with EGFR-mutated lung cancer, who have progressed on EGFR-TKI treatment to determine the activity of the anti-PD-1/PD-L1 therapy combined with chemotherapy or/and bevacizumab therapy in heavily treated patients with EGFR-mutated lung cancer. METHODS: We identified 56 patients with EGFR-mutated lung cancer treated with PD-1/PD-L1 inhibitors alone or combined with the chemotherapy/bevacizumab therapy. The objective response rates were assessed using RECIST v1.1. Adverse events (AEs) were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Academic Ethics Committee of Jiangsu Cancer Hospital. (NO. 2019 160), and individual consent for this retrospective analysis was waived. RESULTS: Objective responses were observed in 6 of 56 (10.7%) patients, and the disease control rate was 53.6% (30/56). The median progression-free survival (PFS) was 3.33 months with 95% CI of 1.58-5.08 months. No patient achieved a complete response. All six patients that achieved PR were treated with the PD-1 inhibitor combined with chemotherapy or bevacizumab therapy. Three of the six patients who achieved PR were treated with radiotherapy combined with PD-1 inhibitor-based therapy. Patients treated with the PD-1 inhibitor-based therapy as second-line therapy showed relatively longer PFS and higher objective response rates than those treated with PD-1 inhibitor-based therapy as third- or late-line therapy (PFS: 5.50 vs. 3.27 months, P=0.301; objective response rates: 25.0% vs. 6.82%, P=0.071). No additional AE profile was observed. CONCLUSIONS: The PD-1 inhibitor combined with the chemotherapy/bevacizumab therapy showed acceptable toxicity profile and moderate efficacy on heavily treated advanced EGFR-mutated lung cancer after the exhaustion of target therapy.

Film entrainment and microplastic particles retention during gas invasion in suspension-filled microchannels.

Understanding of microplastics transport mechanism is highly important for soil contamination and remediation. The transport behaviors of microplastics in soils are complex and influenced by various factors including soil and particle properties, hydrodynamic conditions, and biota activities. Via a microfluidic experiments we study liquid film entrainment and microplastics transport and retention during two-phase displacement in microchannels with one end connected to the air and the other connected to the liquid with suspended particles. We discover three transport patterns of microplastic particles, ranging from no deposition to particle entrapment and to particle layering within liquid films, depending on the suspension withdrawal rates and the particle volume fraction in the suspension. The general behavior of particle motion is effectively captured by the film thickness evolution which is shown to be dependent on a modified capillary number Ca0 taking into account the effects of flow velocity, particle volume fraction, and channel shape. We also provide a theoretical prediction of the critical capillary number Ca0* for particle entrapment, consistent with the experimental results. In addition, the probability of microplastics being dragged into the trailing liquid film near the gas invading front is found to be proportional to both particle volume fraction and the capillary number. This work elucidates the microplastics transport mechanism during unsaturated flow, and therefore is of theoretical and practical importance to understand the contaminant migration in many natural and engineered systems spanning from groundwater sources to water treatment facilities.

B7-H4 and HHLA2, members of B7 family, are aberrantly expressed in EGFR mutated lung adenocarcinoma.

BACKGROUND: In order to find new immune targets for lung cancer with different EGFR mutant status, we describe differential expression profiles of checkpoint molecules of the new discovery B7 family member to find new immune targets for lung cancer with different EGFR statuses. METHODS: We performed immunohistochemistry with antibodies of B7-H3, B7-H4, VISTA, B7-H6, HHLA2, IDO-1, PD-L1 and CD8 in lung adenocarcinoma tissues constructed from 372 cases in the discovery cohort and 231 cases in the validation set. The differential expression profiles of these indices in EGFR mutant and wild-type lung adenocarcinoma was described and compared. RESULTS: In the discovery cohort, the median IHC scores of B7-H4 and HHLA2 for the EGFR mutant group were significantly higher than those in the wild-type group (median score [interquartile range], mutant vs. wild type: 3.250 [0-7.000] vs. 5.000 [1.000-7.000], P = 0.045 for B7-H4; 8.000 [6.000-10.500] vs. 7.000 [5.000-8.630] P = 0.003 for HHLA2). Meanwhile, the median IHC scores of IDO-1 and PD-L1 in the wild-type group were significantly higher than those in the mutant group (median score [interquartile range], mutant vs. wild type: 1.000 [0-5.000] vs. 3.000 [0-8.500], P = 0.000 for IDO-1; 0 [0-3.500] vs. 3.000 [0-6.000], P = 0.000 for PD-L1). Results above was confirmed in the discovery cohort. The increased CD8 and decreased HHLA2 expression levels were associated with long disease-free survival in lung adenocarcinoma (P = 0.000 for CD8 expression and P = 0.004 for HHLA2 expression). CONCLUSIONS: B7-H4 and HHLA2 are promising immune targets for lung adenocarcinoma, especially for patients with EGFR mutation.

Adjuvant chemoradiotherapy versus adjuvant chemotherapy for patients with N3 gastric cancer after D2/R0 resection: a retrospective study based on propensity score analyses.

Purpose: N3 gastric cancer (GC) is characterized by a heavy burden of lymph node metastasis and a high postoperative recurrence rate. The role of radiotherapy in this group of patients remains undetermined. The purpose of this study was to compare the effectiveness of adjuvant chemoradiotherapy (CRT) and adjuvant chemotherapy (ChT) for N3 GC after D2/R0 resection. Patients and methods: From January 2004 to December 2015, patients with N3 GC in the database of Fudan University Shanghai Cancer Center were retrospectively reviewed. The eligible patients were enrolled in an adjuvant CRT group and an adjuvant ChT group. Four different methods based on a propensity score model were used to balance the baseline characteristics. Then, survival analyses between the two groups were performed in addition to patterns of recurrence and subgroup analyses. Results: In total, 175 and 365 eligible patients were enrolled into the CRT and ChT groups, respectively. After balancing, the disease-free survival (DFS) of patients in the CRT group was significantly better than that of patients in the ChT group (p=0.021). Subgroup analyses showed that patients with N3a GC benefitted from adjuvant CRT. Conclusion: Compared with adjuvant ChT, adjuvant CRT can further improve the DFS of patients with N3 GC after D2/R0 resection. Patients with lymph node metastases should be further stratified when selecting patients for adjuvant CRT.

Stanniocalcin­1 promotes cell proliferation, chemoresistance and metastasis in hypoxic gastric cancer cells via Bcl­2.

Gastric cancer (GC) is one of the most lethal diseases worldwide, but the mechanism of GC development remains elusive. In the present study, the roles of stanniocalcin­1 (STC1) in GC were investigated. It was demonstrated that overexpression of STC1 mRNA and protein were associated with poor survival of patients with GC. The expression of STC1 was enhanced in hypoxic GC cells and overexpression of STC1 facilitated cell proliferation in hypoxia but not in normoxia. Furthermore, STC1 promoted chemoresistance, migration and invasion in hypoxia. Upregulating the expression of STC1 enhanced the expression of B cell lymphoma (Bcl)­2, neural­cadherin and matrix metalloproteinase­2, whereas it reduced the levels of cytochrome c, cleaved­caspase­9, cleaved­caspase­3 and epithelial­cadherin. However, downregulation of STC1 altered the expression of these proteins in the opposite direction. Furthermore, disturbing the expression of Bcl­2 partly reversed the changes to these proteins and also the pro­proliferation, anti­apoptosis and pro­invasion potential of STC1. In vivo experiments indicated that enhanced expression of STC1 promoted tumor growth and metastasis in mice. Collectively, the results indicated that STC1 may serve an oncogenic role in hypoxic GC via dysregulating Bcl­2, indicating that STC1 may be a potential therapeutic target in the treatment of GC.

Protein kinase p38α signaling in dendritic cells regulates colon inflammation and tumorigenesis.

Dendritic cells (DCs) play pivotal roles in maintaining intestinal homeostasis, but how the DCs regulate diverse immune networks on homeostasis breakdown remains largely unknown. Here, we report that, in response to epithelial barrier disruption, colonic DCs regulate the differentiation of type 1 regulatory T (Tr1) cells through p38α-dependent IL-27 production to initiate an effective immune response. Deletion of p38α in DCs, but not in T cells, led to increased Tr1 and protected mice from dextran sodium sulfate-induced acute colitis and chronic colitis-associated colorectal cancer. We show that higher levels of IL-27 in p38α-deficient colonic cDC1s, but not cDC2s, were responsible for the increase of Tr1 cells. Moreover, p38α-dependent IL-27 enhanced IL-22 secretion from intestinal group 3 innate lymphoid cells and protected epithelial barrier function. In p38α-deficient DCs, the TAK1-MKK4/7-JNK-c-Jun axis was hyperactivated, leading to high IL-27 levels, and inhibition of the JNK-c-Jun axis suppressed IL-27 expression. ChIP assay revealed direct binding of c-Jun to the promoter of Il27p28, which was further enhanced in p38α-deficient DCs. In summary, here we identify a key role for p38α signaling in DCs in regulating intestinal inflammatory response and tumorigenesis, and our finding may provide targets for the treatment of inflammatory intestinal diseases.