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Over the past thirty years, the importance of chemokines and their seven-transmembrane G protein-coupled receptors (GPCRs) has been increasingly recognized. Chemokine interactions with receptors trigger signaling pathway activity to form a network fundamental to diverse immune processes, including host homeostasis and responses to disease. Genetic and nongenetic regulation of both the expression and structure of chemokines and receptors conveys chemokine functional heterogeneity. Imbalances and defects in the system contribute to the pathogenesis of a variety of diseases, including cancer, immune and inflammatory diseases, and metabolic and neurological disorders, which render the system a focus of studies aiming to discover therapies and important biomarkers. The integrated view of chemokine biology underpinning divergence and plasticity has provided insights into immune dysfunction in disease states, including, among others, coronavirus disease 2019 (COVID-19). In this review, by reporting the latest advances in chemokine biology and results from analyses of a plethora of sequencing-based datasets, we outline recent advances in the understanding of the genetic variations and nongenetic heterogeneity of chemokines and receptors and provide an updated view of their contribution to the pathophysiological network, focusing on chemokine-mediated inflammation and cancer. Clarification of the molecular basis of dynamic chemokine-receptor interactions will help advance the understanding of chemokine biology to achieve precision medicine application in the clinic.

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Purpose:Metallothionein 2A (MT2A) suppresses the progression of human gastric cancer potentially through an “MT2A–NF-κB pathway” with unclear mechanisms. This study explored the role of a transcription factor, myeloid zinc-finger 1 (MZF1), in MT2A-NF-κB pathway and its clinical significance in gastric cancer.Experimental Design:MZF1 expression and function in gastric cancer were investigated in vitro and in vivo. The relationship between MZF1 and MT2A was determined by gain-of-function and loss-of-function assays in gastric cancer cells and an immortalized gastric cell line GES-1. The prognostic value of MZF1 expression in association with MT2A was evaluated using IHC in two cohorts.Results:MZF1 was epigenetically silenced in human gastric cancer cell lines and primary tumors. Overexpression of MZF1 in gastric cancer cells suppressed cell proliferation and migration, as well as the growth of xenograft tumors in nude mice. Knocking-down of MZF1 transformed GES-1 cells into a malignant phenotype characterized by increased cell growth and migration. Mechanistically, MZF1 was upregulated in both GC and GES-1 cells by MT2A ectopically expressed or induced upon treatment with a garlic-derived compound, diallyl trisulfide (DATS). MZF1 associated with MT2A was colocalized in the nuclei of GES-1 cells to target the promoter of NF-κB inhibitor alpha (NFKBIA). Clinically, MT2A and MZF1 were progressively downregulated in clinical specimens undergoing gastric malignant transformation. Downregulation of MT2A and MZF1 was significantly correlated with poorer patient prognosis.Conclusions:MT2A exerts its anti-gastric cancer effects by complexing with MZF1 to target NFKBIA. MT2A/MZF1 may serve as a valuable prognostic marker and a novel therapeutic target for human gastric cancer.

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The physiological homeostasis of gut mucosal barrier is maintained by both genetic and environmental factors and its impairment leads to pathogenesis such as inflammatory bowel disease. A cytokine like molecule, FAM3D (mouse Fam3D), is highly expressed in mouse gastrointestinal tract. Here, we demonstrate that deficiency in Fam3D is associated with impaired integrity of colonic mucosa, increased epithelial hyper-proliferation, reduced anti-microbial peptide production and increased sensitivity to chemically induced colitis associated with high incidence of cancer. Pretreatment of Fam3D−/− mice with antibiotics significantly reduces the severity of chemically induced colitis and wild type (WT) mice co-housed with Fam3D−/− mice phenocopy Fam3D-deficiency showing increased sensitivity to colitis and skewed composition of fecal microbiota. An initial equilibrium of microbiota in cohoused WT and Fam3D−/− mice is followed by an increasing divergence of the bacterial composition after separation. These results demonstrate the essential role of Fam3D in colon homeostasis, protection against inflammation associated cancer and normal microbiota composition., The cytokine like protein FAM3D (Fam3D in mice) is highly expressed in the digestive tract with unknown role in colon pathophysiology. Here, by using gene deficient mice, the authors show that Fam3D is critically involved in colon homeostasis, host defense against colitis-associated carcinogenesis, and the balance of microbiota.

Hepatocellular carcinoma (HCC) is one of the most lethal human tumors with extensive intratumor heterogeneity (ITH). Serine protease 3 (PRSS3) is an indispensable member of the trypsin family and has been implicated in the pathogenesis of several malignancies, including HCC. However, the paradoxical effects ofThe expression and DNA methylation ofThese results provide the first evidence for the transcriptional and functional characterization of

In clinical practice, some patients undergoing surgery for thymoma require post-surgical ventilator support, although, factors associated with administration of ventilator support are unclear. This study aimed to explore factors associated with incidence of post-surgical severe respiratory failure requiring ventilator support after thymoma resection.Clinical data of patients who underwent thymoma re-section in our thoracic surgery department between January 2001 and February 2020 was retrospectively analyzed. Multiple logistic regression analysis was used to identify factors associated with patient need for post-surgical ventilator support after thymoma resection.Among 157 patients who underwent thymoma resection, 17.8% (28/157) required post-surgical ventilator support. Results of univariate analysis revealed that gender, myasthenia gravis (MG) grade, anti-MG medication use (neostigmine or prednisone), Masaoka thymoma stage, pulmonary function test index values, surgical approach, and intraoperative blood loss were associated with increased incidence of severe respiratory failure requiring post-operative ventilator support (P 0.05). Results of multivariable logistic regression analysis revealed that median sternotomy, MG grade three status, and patient use of anti-MG drug treatments before thymoma resection surgery were associated with greater need for post-surgical ventilator support.Our data suggest that median sternotomy, MG grade three status, and preoperative use of anti-MG drugs are associated with greater incidence of severe respiratory failure requiring respiratory support after thymoma surgery. Therefore, patients with these risk factors should be closely monitored to reduce the incidence of severe postoperative respiratory failure.

Disruption in mucins (MUCs) is involved in cancer development and metastasis and is thus used as a biomarker. Non-small cell lung carcinoma (NSCLC) is characterized by heterogeneous genetic and epigenetic alterations. Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the two primary subtypes of NSCLC that require different therapeutic interventions. Here, we report distinct expression and epigenetic alterations in mucin 22 (MUC22), a new MUC family member, in LUSC vs. LUAD. In lung cancer cell lines and tissues, MUC22 was downregulated in LUSC (MUC22Low) but upregulated in LUAD (MUC22High) with co-expression of MUC21. The aberrant expression of MUC22 was inversely correlated with its promoter hypermethylation in LUSC and hypomethylation in LUAD cells and tissues, respectively. Decreased MUC22 expression in NSCLC cell lines was restored upon treatment with epigenetic modifiers 5-aza-2′-deoxycytidine (5-Aza) or trichostatin A (TSA), accompanied by reduction in global protein level of histone deacetylase 1 (HDAC1) but increased enrichment of histone H3 lysine 9 acetylation (H3K9ac) specifically in the MUC22 promoter in the SK-MES-1 cell line. MUC22 knockdown increased the growth and motility of lung cancer cells and an immortalized human bronchial epithelial BEAS-2B cell line via NF-κB activation. Clinically, MUC22Low in LUSC and MUC22High in LUAD were shown to be indicators of unfavorable overall survival for patients with early cancer stages. Our study reveals that changes in MUC22 expression due to epigenetic alterations in NSCLC may have important biological significance and prognostic potential in LUSC when compared to LUAD. Thus, MUC22 expression and epigenetic alterations may be used for molecular subtyping of NSCLC in precision medicine.

Hydrogen/potassium ATPase β (ATP4B) is a proton pump acting an essential role in gastric acid secretion. This study aimed to investigate the diagnostic performance of ATP4B and its biological role in tumor progression in gastric cancer.The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in gastric cancer were verified by gain- and loss-of-function cell models and tumor xenograft models. The possible downstream effects of ATP4B were analyzed by iTRAQ-based quantitative proteomics analysis.A dramatic decrease in ATP4B was associated with malignant transformation in gastric mucosa lesions and correlated with poor differentiation. Restoration of ATP4B expression in gastric cancer cells significantly suppressed cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a quality control on mitochondrial metabolism and functions in ATP4B-overexpression GC cells.Our data suggest that decreasing ATP4B is an indicator for gastric mucosa malignant transformation and GC aggressive phenotype and it plays an inhibitory role in gastric cancer as a tumor suppressor via regulating mitochondrial metabolism and apoptosis pathway.

Recurrence is a primary cause of gastric cancer (GC)-related deaths. We reported previously that low expression of miR-142-5p could predict recurrence in GC. The present study aimed to investigate the function and mechanism of miR-142-5p in metastasis of GC. MiR-142-5p expression was detected in 101 GC samples by qRT-PCR. Its clinical significance was statistically analyzed. The roles of miR-142-5p and its candidate target gene CYR61 in metastasis were determined both in vivo and in vitro. MiR-142-5p downregulation was significantly associated with the recurrence (P = 0.031) and poor prognosis of GC (P = 0.043). MiR-142-5p inhibited cancer cell migration and invasion both in vitro and in vivo. CYR61 was identified as a novel direct target of miR-142-5p by bioinformatics analysis of target prediction and luciferase reporter assay. The re-expression and knockdown of CYR61 could, respectively, rescue the effects induced by miR-142-5p overexpression and knockdown. MiR-142-5p attenuated GC cell migration and invasion, at least partially, by inactivation of the canonical Wnt/β-catenin signaling pathway through CYR61. The newly identified miR-142-5p-CYR61-Wnt/β-catenin axis partially illustrates the molecular mechanism of GC recurrence and represents a novel prognosis biomarker for GC.

Background: Hydrogen/Potassium ATPase β (ATP4B) is a key protein in gastric mucosa barrier acting an essential role in gastric acid secretion. However, the exact role and precise mechanism of ATP4B in gastric cancer (GC) remain obscure. This study aimed to investigate the clinical significance of ATP4B in GC and its biological role in tumor progression.Methods: We evaluated ATP4B expression in GC cell lines and patient specimens via qPCR and Immunofluorescence. The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in GC were verified by gain- and loss-of-function cell models and xenograft tumor model. The possible downstream effects of ATP4B were analyzed by iTRAQ‑based quantitative proteomics analysis.Results: A dramatic decrease of ATP4B expression in GC cells and tissues compared with the adjacent normal tissues was observed; Downexpression of ATP4B was associated with the malignant transformation in gastric mucosa lesions and correlated with poor prognosis, high grade of TNM stage, and vessel carcinoma embolus in GC patients. Restoration of ATP4B expression in GC cells significantly inhibited cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a constitutive activation of p53 and inactivation of NF-κB signaling correlated with the mitochondrial pathway in ATP4B-overexpressing GC cells.Conclusion: Our data suggest that ATP4B perform the promising tumor suppressor gene by regulating p53/NF-κB/mitochondrial pathway in GC.

Fault prediction models are typically built using software metrics collected throughout the software lifecycle process. Given without a previous release version of the software product, the earlier software metrics collected, the earlier the prediction models can be built to guide software verification and validation activities. In this experiment, we investigate the problem in software fault prediction modeling: would it be possible to replace later code metrics by earlier design metrics? We find that 11 code metrics can be replaced by 6 design metrics using Canonical Correlation Analysis (CCA), a multivariate statistical analysis method. After removing these 11 replaceable code metrics from building fault prediction models, the built models typically have the same performance statistically as using all code metrics. This study shows that earlier available design metrics can be used to replace late lifecycle code metrics. This would make it possible to identify faults earlier before code implementation in software lifecycle. Furthermore, due to the expensiveness of metric collection, using less metrics to maintain the same predictive power models has potential high cost-savings in IV & V activities.