ZMAT2 condensates regulate the alternative splicing of TRIM28 to reduce cellular ROS accumulation, thereby promoting the proliferation of HCC cells.

Dysregulation of splicing factor expression plays a crucial role in the progression of hepatocellular carcinoma (HCC). Our research found that the expression level of splicing factor ZMAT2 was increased in HCC, promoting the proliferation of HCC cells. RNAseq data indicated that the absence of ZMAT2 induced skipping exon of mRNA, while RIPseq data further revealed the mRNA binding motifs of ZMAT2. A comprehensive analysis of RNAseq and RIPseq data indicateed that ZMAT2 played a crucial role in the maturation process of TRIM28 mRNA. Knocking down of ZMAT2 led to the deletion of 25 bases in exon 11 of TRIM28, ultimately resulting in nonsense-mediated decay (NMD). Our data revealed that ZMAT2 could regulate TRIM28 to reduce the accumulation of ROS in HCC cells, thereby promoting their proliferation. Our research also discovered that ZMAT2 was capable of undergoing phase separation, resulting in the formation of liquid droplet condensates within HCC cells. Additionally, it was found that ZMAT2 was able to form protein-nucleic acid condensates with TRIM28 mRNA. In summary, this study is the first to reveal that ZMAT2 and TRIM28 mRNA form protein-nucleic acid condensates, thereby regulating the splicing of TRIM28 mRNA. The increased expression of ZMAT2 in HCC leads to upregulated TRIM28 expression and reduced ROS accumulation, ultimately accelerating the proliferation of HCC cells.

Cost-effectiveness of sotorasib as a second-line treatment for non-small cell lung cancer with KRASG12C mutation in China and the United States.

Purpose: To evaluate the cost-effectiveness of sotorasib versus docetaxel in non-small cell lung cancer (NSCLC) patients with KRASG12C mutation from the China and United States'social perspective. Materials and Methods: A Markov model that included three states (progression-free survival, post-progression survival, and death) was developed. Incremental cost-effectiveness ratio (ICER), quality-adjusted life-year (QALY), and incremental QALY were calculated for the two treatment strategies. One-way sensitivity analysis was used to investigate the factors that had a greater impact on the model results, and tornado diagrams were used to present the results. Probabilistic sensitivity analysis was performed with 1,000 Monte Carlo simulations. Assume distributions based on parameter types and randomly sample all parameter distributions each time., The results were presented as cost-effectiveness acceptable curves. Results: This economic evaluation of data from the CodeBreak 200 randomized clinical trial. In China, sotorasib generated 0.44 QAYL with a total cost of $84372.59. Compared with docetaxel, the ICER value of sotorasib was $102701.84/QALY, which was higher than willingness to pay (WTP), so sotorasib had no economic advantage. In the US, sotorasib obtained 0.35 QALY more than docetaxel, ICER was $15,976.50/QALY, which was more than 1 WTP but less than 3 WTP, indicating that the increased cost of sotorasib was acceptable. One-way sensitivity analysis showed that the probability of sotorasib having economic benefits gradually increased when the cost of follow-up examination was reduced in China. And there was no influence on the conclusions within the range of changes in China. When the willingness to pay (WTP) exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%. Conclusion: Sotorasib had a cost effect from the perspective in the United States. However, sotorasib had no cost effect from the perspective in China, and only when the WTP exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.

Imaging manifestations of ductal adenoma of the breast: A case report.

Tubular adenomas of the breast are rare benign epithelium-derived tumours, and so few cases have been reported. Most often, the tumours are palpable, well-circumscribed masses in women of childbearing age and are commonly diagnosed as fibroadenomas both clinically and radiographically. We describe the case of a premenopausal patient with tubular adenoma of the breast who presented with small nipple discharge and a palpable breast mass. On imaging, tubular adenomas are practically indistinguishable from fibroadenomas and most commonly present as oval, circumscribed masses that are hypoechoic on ultrasound. On magnetic resonance imaging (MRI), tubular adenomas may present as lobulated or oval masses with a hyperintense signal on T2-weighted imaging and inhomogeneous internal enhancement on dynamic contrast-enhanced MRI. Pathologic findings after resection of the mass confirmed the diagnosis of tubular adenoma.

Smad2/3/4 complex could undergo liquid liquid phase separation and induce apoptosis through TAT in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most significant causes of mortality due to cancer-related deaths. It has been previously reported that the TGF-ß signaling pathway may be associated with tumor progression. However, the relationship between TGF-ß signaling pathway and HCC remains to be further elucidated. The objective of our research was to investigate the impact of TGF-ß signaling pathway on HCC progression as well as the potential regulatory mechanism involved. METHODS: We conducted a series of bioinformatics analyses to screen and filter the most relevant hub genes associated with HCC. E. coli was utilized to express recombinant protein, and the Ni-NTA column was employed for purification of the target protein. Liquid liquid phase separation (LLPS) of protein in vitro, and fluorescent recovery after photobleaching (FRAP) were utilized to verify whether the target proteins had the ability to drive force LLPS. Western blot and quantitative real-time polymerase chain reaction (qPCR) were utilized to assess gene expression levels. Transcription factor binding sites of DNA were identified by chromatin immunoprecipitation (CHIP) qPCR. Flow cytometry was employed to examine cell apoptosis. Knockdown of target genes was achieved through shRNA. Cell Counting Kit-8 (CCK-8), colony formation assays, and nude mice tumor transplantation were utilized to test cell proliferation ability in vitro and in vivo. RESULTS: We found that Smad2/3/4 complex could regulate tyrosine aminotransferase (TAT) expression, and this regulation could relate to LLPS. CHIP qPCR results showed that the key targeted DNA binding site of Smad2/3/4 complex in TAT promoter region is -1032 to -1182. In addition. CCK-8, colony formation, and nude mice tumor transplantation assays showed that Smad2/3/4 complex could repress cell proliferation through TAT. Flow cytometry assay results showed that Smad2/3/4 complex could increase the apoptosis of hepatoma cells. Western blot results showed that Smad2/3/4 complex would active caspase-9 through TAT, which uncovered the mechanism of Smad2/3/4 complex inducing hepatoma cell apoptosis. CONCLUSION: This study proved that Smad2/3/4 complex could undergo LLPS to active TAT transcription, then active caspase-9 to induce hepatoma cell apoptosis in inhibiting HCC progress. The research further elucidate the relationship between TGF-ß signaling pathway and HCC, which contributes to discover the mechanism of HCC development.

Advances in Metabolism and Metabolic Toxicology of Quinoxaline 1,4-Di-N-oxides.

Quinoxaline 1,4-di-N-Oxides (QdNOs) have been used as synthetic antimicrobial agents in animal husbandry and aquaculture. The metabolism and potential toxicity have been also concerns in recently years. The metabolism investigations showed that there were 8 metabolites of Carbadox (CBX), 34 metabolites of Cyadox (CYA), 33 metabolites of Mequindox (MEQ), 35 metabolites of Olaquindox (OLA), and 56 metabolites of Quinocetone (QCT) in different animals. Among them, Cb3 and Cb8, M6, and O9 are metabolic residual markers of CBX, MEQ and OLA, which are associated with N → O reduction. Toxicity studies revealed that QdNOs exhibited severe tumorigenicity, cytotoxicity, and adrenal toxicity. Metabolic toxicology showed that toxicity of QdNOs metabolites might be related to the N → O group reduction, and some metabolites exhibited higher toxic effects than the precursor, which could provide guidance for further research on the metabolic toxicology of QdNOs and provide a wealth of information for food safety evaluation.

Risk prediction models of mortality after hip fracture surgery in older individuals: a systematic review.

OBJECTIVE: This study aimed to critically assess existing risk prediction models for postoperative mortality in older individuals with hip fractures, with the objective of offering substantive insights for their clinical application. DESIGN: A comprehensive search was conducted across prominent databases, including PubMed, Embase, Cochrane Library, SinoMed, CNKI, VIP, and Wanfang, spanning original articles in both Chinese and English up until 1 December 2023. Two researchers independently extracted pertinent research characteristics, such as predictors, model performance metrics, and modeling methodologies. Additionally, the bias risk and applicability of the incorporated risk prediction models were systematically evaluated using the Prediction Model Risk of Bias Assessment Tool (PROBAST). RESULTS: Within the purview of this investigation, a total of 21 studies were identified, constituting 21 original risk prediction models. The discriminatory capacity of the included risk prediction models, as denoted by the minimum and maximum areas under the subject operating characteristic curve, ranged from 0.710 to 0.964. Noteworthy predictors, recurrent across various models, included age, sex, comorbidities, and nutritional status. However, among the models assessed through the PROBAST framework, only one was deemed to exhibit a low risk of bias. Beyond this assessment, the principal limitations observed in risk prediction models pertain to deficiencies in data analysis, encompassing insufficient sample size and suboptimal handling of missing data. CONCLUSION: Subsequent research endeavors should adopt more stringent experimental designs and employ advanced statistical methodologies in the construction of risk prediction models. Moreover, large-scale external validation studies are warranted to rigorously assess the generalizability and clinical utility of existing models, thereby enhancing their relevance as valuable clinical references.

CTSL, a prognostic marker of breast cancer, that promotes proliferation, migration, and invasion in cells in triple-negative breast cancer.

Introduction: In the world, the incidence of breast cancer has surpassed that of lung cancer, and it has become the first malignant tumor among women. Triple-negative breast cancer (TNBC) shows an extremely heterogeneous malignancy toward high recurrence, metastasis, and mortality, but there is a lack of effective targeted therapy. It is urgent to develop novel molecular targets in the occurrence and therapeutics for TNBC, and novel therapeutic strategies to block the recurrence and metastasis of TNBC. Methods: In this study, CTSL (cathepsin L) expression in tissues and adjacent tissues of TNBC patients was monitored by immunohistochemistry and western blots. The correlations between CTSL expressions and clinicopathological characteristics in the patient tissues for TNBC were analyzed. Cell proliferation, migration, and invasion assay were also performed when over-expressed or knocked-down CTSL. Results: We found that the level of CTSL in TNBC is significantly higher than that in the matched adjacent tissues, and associated with differentiated degree, TNM Stage, tumor size, and lymph node metastatic status in TNBC patients. The high level of CTSL was correlated with a short RFS (p<0.001), OS (p<0.001), DMFS (p<0.001), PPS (p= 0.0025) in breast cancer from online databases; while in breast cancer with lymph node-positive, high level of CTSL was correlated with a short DMFS (p<0.001) and RFS (p<0.001). Moreover, in vitro experiments showed that CTSL overexpression promotes the abilities for proliferation, migration, and invasion in MCF-7 and MDA-MB-231 cell lines, while knocking-down CTSL decreases its characteristics in MDA-MB-231 cell lines. Conclusion: CTSL might involve into the regulation of the proliferation, invasion, and metastasis of TNBC. Thus, CTSL would be a novel, potential therapeutic, and prognostic target of TNBC.

Hyaluronic acid-based M1 macrophage targeting and environmental responsive drug releasing nanoparticle for enhanced treatment of rheumatoid arthritis.

Herein, hyaluronic acid (HA) and ß-cyclodextrin (ß-CD) is used to form targeted drug delivery platform HCPC/DEX NPs with previously prepared carbon dots (CDs) as cross-linker, dexamethasone (DEX) is loaded for rheumatoid arthritis (RA) treatment. The drug loading capacity of ß-CD and M1 macrophage targeting of HA were utilized for efficient delivery of DEX to the inflammatory joints. Because of the environmental responsive degradation of HA, DEX can be released in 24 h and inhibit the inflammatory response in M1 macrophages. The drug loading of NPs is 4.79 %. Cellular uptake evaluation confirmed that NPs can specifically target to M1 macrophages via HA ligands, the uptake of M1 macrophages is 3.7 times that of normal macrophages. In vivo experiments revealed that NPs can accumulate in RA joints to alleviate inflammation and accelerate cartilage healing, the accumulation can be observed in 24 h. The cartilage thickness increased to 0.45 mm after HCPC/DEX NPs treatment, indicating its good RA therapeutic effect. Importantly, this study was the first to utilize the potential acid and reactive oxygen species responsiveness of HA to release drug and prepare M1 macrophage targeting nanodrug for RA treatment, which provides a safe and effective RA therapeutic strategy.

Association between preoperative diagnosis of sarcopenia and postoperative pneumonia in resectable esophageal squamous cell carcinoma patients: a retrospective cohort study.

Background: Postoperative outcomes for patients suffering from resectable esophageal squamous cell carcinoma (ESCC) are related to sarcopenia. In patients with resectable ESCC, this study investigated the link between sarcopenia and postoperative pneumonia. Methods: The McKewon procedure was the only one used to treat resectable ESCC patients from January 2018 to December 2021 in this retrospective analysis. Sarcopenia was assessed using skeletal muscles at L3 and planning CT scans. It was defined when PMI was below 6.36 cm2/m2 and 3.92 cm2/m2 for men and women, separately. Analyses of multivariate and univariate logistic regression were applied for identifying the risk factors for postoperative pneumonia. Results: The study included 773 patients with resectable ESCC in total. Sarcopenia was an independent risk factor for postoperative pneumonia in individuals with resectable ESCC based on univariate and multivariate analysis (P < 0.05). The stratified analysis indicated that neither of the clinical outcomes in the logistic regression model were affected by gender, age, BMI, smoking, or pre-albumin (P for interaction > 0.006). Conclusion: Following the McKewon procedure, patients with resectable ESCC who were sarcopenic had a higher postoperative pneumonia rate. To prevent the development of postoperative pneumonia during the perioperative period, it may be important to control the incidence of sarcopenia.

Deficiency of interleukin-6 receptor ameliorates PM2.5 exposure-induced pulmonary dysfunction and inflammation but not abnormalities in glucose homeostasis.

BACKGROUND: Ambient fine particulate matter (PM2.5) exposure increases local and systemic interleukin-6 (IL-6). However, the pathogenic role of IL-6 signalling following PM2.5 exposure, particularly in the development of pulmonary dysfunction and abnormal glucose homeostasis, has hardly been investigated. RESULTS: In the study, IL-6 receptor (IL-6R)-deficient (IL-6R-/-) and wildtype littermate (IL-6R+/+) mice were exposed to concentrated ambient PM2.5 (CAP) or filtered air (FA), and their pulmonary and metabolic responses to these exposures were analyzed. Our results demonstrated that IL-6R deficiency markedly alleviated PM2.5 exposure-induced increases in lung inflammatory markers including the inflammation score of histological analysis, the number of macrophages in bronchoalveolar lavage fluid (BALF), and mRNA expressions of TNFα, IL-1ß and IL-6 and abnormalities in lung function test. However, IL-6R deficiency did not reduce the hepatic insulin resistance nor systemic glucose intolerance and insulin resistance induced by PM2.5 exposure. CONCLUSION: Our findings support the crucial role of IL-6 signalling in the development of pulmonary inflammation and dysfunction due to PM2.5 exposure but question the putative central role of pulmonary inflammation for the extra-pulmonary dysfunctions following PM2.5 exposure, providing a deep mechanistic insight into the pathogenesis caused by PM2.5 exposure.

Regulation of survivin and caspase/Bcl-2/Cyto-C signaling by TDB-6 induces apoptosis of colorectal carcinoma LoVo cells.

Background: Colorectal carcinoma (CRC) treatment remains severe. Survivin is aberrantly overexpressed in CRC tissues and might be a potential target for CRC treatment. TDB-6 is a new taspine derivative. The purpose of this study is to investigate the inhibitory effect of TDB-6 on CRC and its underlying mechanism. Methods: The MTT assay and xenograft model were utilized to investigate the inhibitory effect of TDB-6 on LoVo cells in vitro and in vivo. Hoechst staining and Annexin-V FITC/PI analysis were conducted to study the effect of TDB-6 on LoVo cell apoptosis. Mitochondrial membrane potential (Δψm) assay was conducted to demonstrated whether TDB-6 could induce mitochondrial-mediated apoptosis of LoVo cells. Western blotting was conducted to investigate the effect of TDB-6 on survivin protein and caspase/Bcl-2/Cyto-C signaling. Results: The results indicated that TDB-6 induced mitochondria-mediated apoptosis and inhibited the proliferation and growth of LoVo cells in vitro and in vivo. Mechanistic investigation utilizing western blotting indicated that TDB-6 inhibited survivin protein expression, and the inhibitory effect was augmented by TDB-6 and YM-155 co-administration, which revealed that TDB-6 might induce apoptosis of LoVo cells by targeted regulation of survivin. TDB-6 also regulated survivin downstream signaling. It significantly increased the protein level of cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, cleaved-PARP, and Cyto-C, and decreased the protein level of Bcl-2. Conclusions: TDB-6 might be a promising survivin inhibitor with great potential for CRC treatment.

Identification and verification of a glycolysis-related gene signature for gastric cancer.

Background: Glycolysis is a central metabolic pathway for tumor cells. However, the relationship between glycolysis and the prognosis of gastric cancer (GC) patients is not well established. In this study, we sought to construct a glycolysis-related gene signature for GC. Methods: The messenger ribonucleic acid (mRNA) expression profiles were analyzed using data from The Cancer Genome Atlas (TCGA) database. Glycolysis-related gene sets and pathways were obtained from the Molecular Signatures Database (MSigDB). Subsequently, a prognosis prediction model of the glycolysis-related genes was constructed using Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. An external validation was conducted using data from the Gene Expression Omnibus (GEO) database. Risk scores were also calculated based on the signature. Finally, the correlations between the risk score and overall survival (OS), mutation, immune cell infiltration, immune score, and stromal score were examined in 22 types of infiltrating immune cells. Results: Fifty-five glycolysis-related genes were identified from TCGA database and MSigDB. Using the LASSO and Cox models, 4 novel genes (i.e., VCAN, EFNA3, ADH4, and CLDN9) were identified to construct a gene signature for GC prognosis prediction. The GC patients with low-risk scores had significantly better OS than those with high-risk scores in the training set. Similar results were also found in the independent GEO GSE84437 testing set. Additionally, the degree of cell infiltration in the low-risk group was significantly higher than that in the high-risk group in terms of naive B cells, plasma cells, and T follicular helper cells. In monocytes, M2 macrophages, resting dendritic cells, and resting Mast cells, the degree of infiltration in the high-risk group was significantly higher than that in the low-risk group. The immune score and stromal score of the high-risk group were also significantly higher than those of the low-risk group. Finally, the univariate and multivariate Cox regression analyses showed that 4 glycolysis-related genes were independent prognostic factors for GC. Conclusions: The established 4 glycolysis-related gene signature may serve as a reliable tool for the prognosis of GC patients and provide a potential glycolysis therapeutic target for GC.

Severe stomatitis caused by osimertinib combined with gefitinib: A case report.

The 2017 NCCN Guidelines for NSCLC recommend epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as the first-line treatment for patients with gene-sensitive mutations of pulmonary adenocarcinoma. The TKI combination can effectively inhibit the gene mutations caused by the drug resistance and enhance the antitumor effect. However, more clinical investigations are required of the efficacy and the adverse drug reactions (ADRs) of this combination. A 62-year-old female patient diagnosed as lung adenocarcinoma with brain metastasis, meningeal metastasis, multiple bone metastasis, and liver metastasis was treated with the combination of gefitinib and osimertinib. Evident improvement was observed after 10 days of combined treatment with these tyrosine kinase inhibitors (TKIs), including in the CT features and symptoms. The level of tumor marker CEA decreased significantly after 40 days. However, severe stomatitis occurred after 49 days. By analyzing the relationship between stomatitis and TKI combined treatment based on the temporal correlation, instructions and literature reports, mechanisms, and reaction, we discovered that the combination of the two TKI drugs can increase the incidence and severity of severe stomatitis. Following targeted treatment and drug withdrawal, the patient fully recovered. TKI combination may increase the incidence and severity of stomatitis, suggesting that closely care and timely withdrawal are necessary measures.

Isatidis Radix and Isatidis Folium: A systematic review on ethnopharmacology, phytochemistry and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Isatidis Radix (called Banlangen, BLG in Chinese) and Isatidis Folium (called Daqingye, DQY in Chinese) are common traditional edible-medicinal herbs in detoxifying for thousands of years, have been traditionally applied in traditional Chinese medicine for centuries. Both of them are bitter in taste, coolness in nature, acting on the heart and stomach channels. They are often used to treat influenza and other viral infectious diseases in clinic, as well as could treat fever, dizziness, and cough and sore throat caused by lung heat. AIMS OF THE REVIEW: This review aimed at summarizing the latest and comprehensive information of BLG and DQY on the ethnopharmacology, phytochemistry, pharmacology, toxicity and clinical application to explore the therapeutic potential of them. In addition, outlooks and perspective for possible future researches that related are also discussed. MATERIALS AND METHODS: Related information concerning BLG and DQY were gathered from the internet database of Google Scholar, PubMed, Baidu Scholar, GeenMedical, CNKI and Web of Science, as well as other relevant textbooks, reviews, and documents (e.g., Chinese Pharmacopoeia, 2020 edition, Chinese herbal classic books and PhD and MSc thesis, etc.). Among of them with the keywords including "Isatis indigotica" "Isatidis Radix", "Isatidis Folium", "phytochemistry", "pharmacology", "toxicology", "clinical application" etc. and their combinations. RESULTS: To date, 39 Chinese patent medicines containing BLG and/or DQY have been developed on basis of the data of NMPA. Besides, 304 and 142 compounds have been found in BLG and DQY, respectively. The main chemical differences between BLG and DQY were concentrated on alkaloids and lignans, such as indican, indirubin, (R, S)-epigoitrin, 4(3H)-quinazolinone, clemastanin B and isatindigotindolines A-D. In 2020 Edition ChP, (R, S)-goitrin and indirubin are now used as the official marker to monitor the quality of BLG and DQY, respectively. Modern pharmacology has mainly studied some monomer components such as 4(3H)-quinazolinone, clemastanin B, erucic acid and adenosine, etc., all of which have shown good effects. These active compounds can resist various viruses, such as influenza virus, respiratory syncytial virus, herpes simplex virus, etc.. By regulating the level of immunity and a variety of inflammatory factors, inhibit the growth and reproduction of the virus. At the same time, it is worth noting that different components of BLG and DQY lead to BLG is more powerful in antiviral and immunomodulatory activity than DQY, while DQY possesses a higher intensity than BLG in anti-oxidant activity. CONCLUSION: By collecting and collating a large number of literature and various data websites, we concluded that the common compounds are mainly alkaloids. Recent findings regarding the phytochemical and pharmacological properties of BLG and DQY have confirmed their traditional uses in antiviral, antibacterial and treatment immune diseases. Without doubt, their significant differences on ethnopharmacology, phytochemistry and pharmacology can be used as evidence of separate list of BLG and DQY. For shortcomings, some comprehensive studies should be well designed for further utilization of BLG and DQY.

PTIP Inhibits Cell Invasion in Esophageal Squamous Cell Carcinoma via Modulation of EphA2 Expression.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy and treatment failure is largely due to metastasis and invasion. Aberrant tumor cell adhesion is often associated with tumor progression and metastasis. However, the exact details of cell adhesion in ESCC progression have yet to be determined. In our study, the clinical relevance of Pax2 transactivation domain-interacting protein (PTIP/PAXIP1) was analyzed by immunohistochemistry of ESCC tissues. We found that low expression of PTIP was associated with lymph node metastasis in ESCC, and loss-of-function approaches showed that depletion of PTIP promoted ESCC cell migration and invasion both in vitro and in vivo. Analysis integrating RNA-seq and ChIP-seq data revealed that PTIP directly regulated ephrin type-A receptor 2 (EphA2) expression in ESCC cells. Moreover, PTIP inhibited EphA2 expression by competing with Fosl2, which attenuated the invasion ability of ESCC cells. These results collectively suggest that PTIP regulates ESCC invasion through modulation of EphA2 expression and hence presents a potential therapeutic target for its treatment.

Exposure to different fractions of diesel exhaust PM2.5 induces different levels of pulmonary inflammation and acute phase response.

AIM: Ambient fine particulate matter (PM2.5) consists of various components, and their respective contributions to the toxicity of PM2.5 remains to be determined. To provide specific recommendations for preventing adverse effects due to PM2.5 pollution, we determined whether the induction of pulmonary inflammation, the putative pathogenesis for the morbidity and mortality due to PM2.5 exposure, was fractioned through solubility-dependent fractioning. METHODS: In the present study, the water and heptane solubilities-dependent serial fractioning of diesel exhaust particulate matter (DEP), a prominent source of urban PM2.5 pollution, was performed. The pro-inflammatory actions of these resultant fractions were then determined using both an intratracheal instillation mouse model and cultured BEAS-2B cells, a human bronchial epithelial cell line. RESULTS: Instillation of the water-insoluble, but not -soluble fraction elicited significant pulmonary inflammatory and acute phase responses, comparable to those induced by instillation of DEP. The water-insoluble fraction was further fractioned using heptane, a polar organic solvent, and instillation of heptane-insoluble, but not -soluble fraction elicited significant pulmonary inflammation and acute phase responses. Furthermore, we showed that DEP and water-insoluble DEP, but not water-soluble DEP, activated pro-inflammatory signaling in cultured BEAS-2B cells, ruling out the possibility that the solubility impacts the in vivo distribution and thus the pulmonary inflammatory response.

ASPM Predicts Poor Clinical Outcome and Promotes Tumorigenesis for Diffuse Large B-cell Lymphoma.

BACKGROUND: Abnormal spindle-like microcephaly-associated protein (ASPM) has been implicated in the aggressive behavior of several malignant tumors. However, its potential effects on diffuse large B-cell lymphoma (DLBCL) still remain unknown. METHODS: ASPM levels were determined by immunohistochemically in DLBCL tissues from 54 patients and 15 reactive lymphoid hyperplasia (RLH) tissues as control, and its association with clinical features and overall survival were evaluated. The effects of ASPM on cell growth, cell apoptosis and cell cycle of DLBCL cells were assessed. Bioinformatics, quantitative RT-PCR and western blotting were conducted for mechanic investigation. RESULTS: ASPM expression was upregulated in DLBCL tissues compared with RLH tissues. Its high expression was correlated with inferior clinicopathological characteristics and poor outcomes of DLBCL patients. Multivariate analysis revealed that high ASPM expression emerged as an independent factor for poor prognosis. In DLBCL cell lines, silencing of ASPM suppressed cell growth, induced cell apoptosis and arrested the cell cycle. Mechanically, effects of ASPM knockdown on DLBCL cells were partially dependent on its block of the Wnt/ß-catenin pathway. CONCLUSION: Collectively, our results suggested that ASPM potentially served as a predictive biomarker of DLCBL tumorigenesis and prognosis, representing a potential therapeutic target for DLCBL.

C1222C Deletion in Exon 8 of ABL1 Is Involved in Carcinogenesis and Cell Cycle Control of Colorectal Cancer Through IRS1/PI3K/Akt Pathway.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. ABL1 (c-Abl) is a non-receptor tyrosine kinase, whose role, and molecular mechanism in CRC remain largely unclear. The aim of this study was to elucidate the role of ABL1 to obtain information on colon cancer gene mutation. We analyzed the tissue samples obtained from patients with CRC, CRC cell lines, and the immunodeficient mice. The proliferation, cell cycle, and apoptosis of CRC cells were examined. IPA software was used to analyze the molecules involved in CRC after ABL1 RNA interference. We found ABL1 was highly expressed in CRC tissues and cells. This high expression was associated with the TNM stage of CRC patients. In exon 8 of the ABL1 gene, we identified a novel mutation of C1222C deletion, which was related to the CRC stage. Depletion of ABL1 resulted in the inhibition of proliferation and escalation of apoptosis in two CRC cell lines, SW480, and HCT-116. Our in vivo study also demonstrated that depletion of ABL1 reduced CRC tumor progression. The results of the ingenuity pathway analysis indicated that the expression of 732 genes was upregulated and that of 691 genes was downregulated in mice transplanted with ABL1-downregulated CRC cells, among which we confirmed that depletion of ABL1 inhibited TGF-ß1 via IRS1/PI3K/AKT pathway in CRC progression. These findings demonstrated that ABL1 plays an important role and that it can be a potential molecular target for CRC therapy.

Correlation between the dynamic contrast-enhanced MRI features and prognostic factors in breast cancer: A retrospective case-control study.

This study analyzed the correlation between the dynamic contrast-enhanced MRI (DCE-MRI) features with prognostic factors of breast cancer. Eighty-five breast cancer patients verified by pathology and immunohistochemistry underwent DCE-MRI examination. Spearman correlation analysis was used to analyze the DCE-MRI features [the strengthening types, shape, distribution, edge, internal reinforcement and the time-signal intensity curve (TIC) types] and the 4 immunohistochemical markers (ER, PR, Her-2, and Ki-67) by GraphPad InStat version 6.0 software. The enhanced morphology types, shapes, edge had significant correlation with the expression of ER (P = .001, P = .000, P = .001, respectively), PR (P = .045, P = .015, P = .000, respectively) and Ki-67 (P = .039, P = .000, P = .024, respectively), and no significant correlation with Her-2 expression (P = .906, P = .074, P = .679, respectively) was observed. There was significant correlation between internal enhancement patterns and Ki-67 expression (P = .004), and no significant correlation between internal enhancement patterns and the expression of ER, PR, and Her-2 (P = .208, P = .682, P = .437, respectively) was observed. TIC had significant correlation with ER, Ki-67 expressions (P = .022, P = .001, respectively), and no correlation with expressions of PR and Her-2 (P = .128, P = .391, respectively) was observed. The DCE-MRI features of breast cancer were well correlated with the expression of immunohistochemistry, and might also be helpful to evaluate the biological progress and prognosis.

High YBX1 expression indicates poor prognosis and promotes cell migration and invasion in nasopharyngeal carcinoma.

Y-box binding protein-1 (YBX1) is a multifunctional protein and often acts as an indicator of poor prognosis in cancers. Increasing evidence has shown that the levels of YBX1 protein were closely associated with multidrug resistance, relapse, metastasis and poor prognosis in cancers. However, its role in nasopharyngeal carcinoma (NPC) metastasis remains unknown. In our study, we discovered that the expression of YBX1 was increased in nasopharyngeal carcinoma tissues. YBX1 protein levels positively correlated with T stage and metastasis of NPC patients. Moreover, expression of YBX1 was negatively correlated with membrane E-cadherin levels and positively correlated with Vimentin expression. In vitro, the expression of YBX1 was closely related to the invasive and migratory ability of nasopharyngeal carcinoma cells. Knockdown of YBX1 inhibited migration and invasion in 5-8F cells, and over-expression of YBX1 promoted CNE1 cells migration and invasion. Transforming growth factor-ß1 (TGF-ß1) treatment led to epithelial-to-mesenchymal transition (EMT) in CNE1 cells accompanied by elevated YBX1 expression. On the contrary, knockdown of YBX1 partially inhibited the TGF-ß1-induced CNE1 cell migration, together with changes of EMT-associated markers. Our study revealed that TGF-ß1/YBX1 signaling might be one of novel mechanisms mediating EMT in NPC, providing a new target for the treatment of nasopharyngeal carcinoma.