Serine/threonine-protein kinase D2-mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression.

Desmoglein-2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell-cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine-protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2-T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2-mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

eccDB: a comprehensive repository for eccDNA-mediated chromatin contacts in multi-species.

SUMMARY: We developed the eccDB database to integrate available resources for extrachromosomal circular DNA (eccDNA) data. eccDB is a comprehensive repository for storing, browsing, searching, and analyzing eccDNAs from multispecies. The database provides regulatory and epigenetic information on eccDNAs, with a focus on analyzing intrachromosomal and interchromosomal interactions to predict their transcriptional regulatory functions. Moreover, eccDB identifies eccDNAs from unknown DNA sequences and analyzes the functional and evolutionary relationships of eccDNAs among different species. Overall, eccDB offers web-based analytical tools and a comprehensive resource for biologists and clinicians to decipher the molecular regulatory mechanisms of eccDNAs. AVAILABILITY AND IMPLEMENTATION: eccDB is freely available at http://www.xiejjlab.bio/eccDB.

Clinical characteristics and outcome analysis of pulmonary nocardiosis in southern China: a two-center retrospective study.

BACKGROUND: Pulmonary nocardiosis (PN) is a rare and opportunistic infection. This study aimed to analyze clinical, radiological, and microbiological features, treatment and outcome of PN in southern china. METHODS: Clinical, laboratory, imaging, treatment and outcome data of PN patients at two tertiary hospitals from January 1, 2018, to January 1, 2024 were collected. Factors associated with clinical outcomes were determined by multivariate logistic regression analysis. RESULTS: 67 PN patients including 53 with clinical improvement and 14 with treatment failure were enrolled. Bronchiectasis was the most common respiratory disease in patients with PN (31.3%). The major symptoms of PN were cough (89.6%) and sputum (79.1%). Lung nodules, bronchiectasis, consolidation, pleural involvement, mass, cavity, and lymph node enlargement were the frequent computed tomography findings of PN. Among the Nocardia species detected, N. farcinica was the most common pathogen. Neutrophil-to-lymphocyte ratio (OR = 1.052, p = 0.010), concurrent bacterial infection (OR = 7.706, p = 0.016), and the use of carbapenems (OR = 9.345, p = 0.023) were independently associated with poor prognosis in patients with PN. CONCLUSIONS: This study provides important insights into the clinical features of PN in southern china. neutrophil-to-lymphocyte ratio, concurrent bacterial infection, and the use of carbapenems were independently associated with poor prognosis in patients with PN.

Molecular characterization and expression of twenty interleukin-17 transcripts in the common Chinese cuttlefish (Sepiella japonica) in response to Vibrio harveyi infection.

The common Chinese cuttlefish (Sepiella japonica) is an essential species for stock enhancement by releasing juveniles in the East China Sea now. S. japonica is susceptible to bacterial diseases during parental breeding. In vertebrates, Interleukin-17 (IL-17) cytokine family plays critical roles in both acute and chronic inflammatory responses. In Cephalopoda, few studies have been reported on IL-17 genes so far. In this study, twenty IL-17 transcripts obtained from S. japonica were divided into eight groups (designated as Sj_IL-17-1 to Sj_IL-17-8). Multiple alignment analysis showed that IL-17s in S. japonica and human both contained four ß-folds (ß1-ß4), except for Sj_IL-17-6 with two ß-folds (ß1 and ß2), and the third and fourth ß-folds of Sj_IL-17-5 and Sj_IL-17-8 were longer than those of other Sj_IL-17. Protein structure and conserved motifs analysis demonstrated that Sj_IL-17-5 and Sj_IL-17-6 displayed different protein structure with respect to other six Sj_IL-17 proteins. The homology and phylogenetic analysis of amino acids showed that Sj_IL-17-5, Sj_IL-17-6 and Sj_IL-17-8 had low homology with the other five Sj_IL-17s. Eight Sj_IL-17 mRNAs were ubiquitously expressed in ten examined tissues, with dominant expression in the hemolymph. qRT-PCR data showed that the mRNA expression levels of Sj_IL-17-2, Sj_IL-17-3, Sj_IL-17-6, and Sj_IL-17-8 were significantly up-regulated in infected cuttlefishes, and Sj_IL-17-2, Sj_IL-17-6, Sj_IL-17-7, and Sj_IL-17-8 mRNAs Awere significantly up-regulated after bath infection of Vibrio harveyi, suggesting that certain Sj_IL-17s were involved in the immune response of S. japonica against V. harveyi infection. These results implied that Sj_IL-17s were likely to have distinct functional diversification. This study aims to understand the involvement of Sj_IL-17 genes in immune responses of cuttlefish against bacterial infections.

[Distribution of surface components in spray-dried powder of binary system of berberine hydrochloride and dextran based on hydrodynamic size].

The present study explored the correlation between the hydrodynamic size(i.e., hydrated particle size) and the surface component distribution of spray-dried powder based on the binary system model of berberine hydrochloride and dextran. A variety of mixture solutions containing substances of different proportions were prepared, and the hydrated particle sizes of the solutions were measured by laser light scattering technique. Then the effects of molecular weight and mixing proportion on the particle size were analyzed. After the solutions were spray-dried, the surface components of spray-dried powder were determined by X-ray photoelectron spectroscopy. The changes of hydrated particle size of the two substances in different solutions were measured with the altered solution environments, and the distribution of surface components after spray-drying was observed. The results of particle size measurement showed that different solution environments would change the hydrodynamic size of substances. Specifically, the particle size of berberine hydrochloride increased with the increase in ionic strength and solution pH, while the particle size of dextran decreased with the increase in ionic strength and increased with the increase in solution pH. The results of surface components of the spray-dried powder indicated that berberine hydrochloride was prone to accumulate on the surface of particles during spray-drying because of its large hydrodynamic size. Therefore, hydrodynamic size is considered an important factor affecting the surface component distribution of spray-dried powder. As revealed by scanning electron microscopy of the particle morphology of spray-dried powder, the particles of berberine hydrochloride spray-dried powder were irregularly elliptic, and the particles of dextran and mixture spray-dried powders were irregularly spherical with the shrunken surface. Finally, the FT4 powder rheometer and DVS instrument were used to determine the stability, adhesion, and hygroscopicity of the powder. The results showed that when berberine hydrochloride was enriched on the surface, the adhesion of the mixture increased and the fluidity became worse, but the hygroscopicity was improved to a certain extent. In addition, as found by hygroscopic kinetic curve fitting of spray-dried powder, the hygroscopic behaviors of all spray-dried powder conformed to the double exponential function.

TP63, SOX2, and KLF5 Establish a Core Regulatory Circuitry That Controls Epigenetic and Transcription Patterns in Esophageal Squamous Cell Carcinoma Cell Lines.

BACKGROUND & AIMS: We investigated the transcriptome of esophageal squamous cell carcinoma (ESCC) cells, activity of gene regulatory (enhancer and promoter regions), and the effects of blocking epigenetic regulatory proteins. METHODS: We performed chromatin immunoprecipitation sequencing with antibodies against H3K4me1, H3K4me3, and H3K27ac and an assay for transposase-accessible chromatin to map the enhancer regions and accessible chromatin in 8 ESCC cell lines. We used the CRC_Mapper algorithm to identify core regulatory circuitry transcription factors in ESCC cell lines, and determined genome occupancy profiles for 3 of these factors. In ESCC cell lines, expression of transcription factors was knocked down with small hairpin RNAs, promoter and enhancer regions were disrupted by CRISPR/Cas9 genome editing, or bromodomains and extraterminal (BET) family proteins and histone deacetylases (HDACs) were inhibited with ARV-771 and romidepsin, respectively. ESCC cell lines were then analyzed by whole-transcriptome sequencing, immunoprecipitation, immunoblots, immunohistochemistry, and viability assays. Interactions between distal enhancers and promoters were identified and verified with circular chromosome conformation capture sequencing. NOD-SCID mice were given injections of modified ESCC cells, some mice where given injections of HDAC or BET inhibitors, and growth of xenograft tumors was measured. RESULTS: We identified super-enhancer-regulated circuits and transcription factors TP63, SOX2, and KLF5 as core regulatory factors in ESCC cells. Super-enhancer regulation of ALDH3A1 mediated by core regulatory factors was required for ESCC viability. We observed direct interactions between the promoter region of TP63 and functional enhancers, mediated by the core regulatory circuitry transcription factors. Deletion of enhancer regions from ESCC cells decreased expression of the core regulatory circuitry transcription factors and reduced cell viability; these same results were observed with knockdown of each core regulatory circuitry transcription factor. Incubation of ESCC cells with BET and HDAC disrupted the core regulatory circuitry program and the epigenetic modifications observed in these cells; mice given injections of HDAC or BET inhibitors developed smaller xenograft tumors from the ESCC cell lines. Xenograft tumors grew more slowly in mice given the combination of ARV-771 and romidepsin than mice given either agent alone. CONCLUSIONS: In epigenetic and transcriptional analyses of ESCC cell lines, we found the transcription factors TP63, SOX2, and KLF5 to be part of a core regulatory network that determines chromatin accessibility, epigenetic modifications, and gene expression patterns in these cells. A combination of epigenetic inhibitors slowed growth of xenograft tumors derived from ESCC cells in mice.

Super-Enhancer-Driven Long Non-Coding RNA LINC01503, Regulated by TP63, Is Over-Expressed and Oncogenic in Squamous Cell Carcinoma.

BACKGROUND & AIMS: Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigate mechanisms that control their expression and function. METHODS: We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription polymerase chain reaction assays to measure expression levels of LINC01503. We collected clinical data from patients and compared expression levels with survival times. LINC01503 was knocked down using small interfering RNAs and oligonucleotides in TE7, TE5, and KYSE510 cell lines and overexpressed in KYSE30 cells. Cells were analyzed by chromatin immunoprecipitation sequencing, luciferase reporter assays, colony formation, migration and invasion, and mass spectrometry analyses. Cells were injected into nude mice and growth of xenograft tumors was measured. LINC01503 interaction with proteins was studied using fluorescence in situ hybridization, RNA pulldown, and RNA immunoprecipitation analyses. RESULTS: We identified a lncRNA, LINC01503, which is regulated by a super enhancer and is expressed at significantly higher levels in esophageal and head and neck SCCs than in non-tumor tissues. High levels in SCCs correlated with shorter survival times of patients. The transcription factor TP63 bound to the super enhancer at the LINC01503 locus and activated its transcription. Expression of LINC01503 in ESCC cell lines increased their proliferation, colony formation, migration, and invasion. Knockdown of LINC01503 in SCC cells reduced their proliferation, colony formation, migration, and invasion, and the growth of xenograft tumors in nude mice. Expression of LINC01503 in ESCC cell lines reduced ERK2 dephosphorylation by DUSP6, leading to activation of ERK signaling via MAPK. LINC01503 disrupted the interaction between EBP1 and the p85 subunit of PI3K, increasing AKT signaling. CONCLUSIONS: We identified an lncRNA, LINC01503, which is increased in SCC cells compared with non-tumor cells. Increased expression of LINC01503 promotes ESCC cell proliferation, migration, invasion, and growth of xenograft tumors. It might be developed as a biomarker of aggressive SCCs in patients.

[Pelvic MRI combined with TRUS-guided transperineal template mapping biopsy for the diagnosis of prostate cancer].

OBJECTIVE: To assess the clinical value and safety of pelvic MRI combined with transurethral ultrasound (TRUS)-guided transperineal template mapping biopsy (TTMB) in the diagnosis of prostate cancer. METHODS: A total of 164 men underwent MRI plus TRUS-guided TTMB for the diagnosis of prostate cancer from December 2015 to May 2018. The patients averaged 71.2 years of age and, based on the PSA level, were divided into four groups: PSA <10 µg/L (n = 28), PSA 10－20 µg/L (n = 56), PSA 20.01－100 µg/L (n = 53) and PSA >100 µg/L (n = 27). All the patients received digital rectal examination, pelvic MRI and TRUS-guided X+12-core TTMB. RESULTS: The procedures of TRUS-guided TTMB were successfully completed in all the patients, with an average number of 14.2 (14－16) cores and mean operation time of 18 (15－28) minutes. Post-biopsy complications included transient hematuria in 4 cases, perineal hematoma in 12 and fever in 1, but no acute urinary retention. Pathological results revealed 95 cases of prostate cancer, 2 cases of ductal epithelial carcinoma, 63 cases of prostatic hyperplasia with benign interstitial inflammation, and 4 cases of atypical prostatic hyperplasia. The positive biopsy rates in the PSA <10 µg/L, 10－20 µg/L, 20.01－100 µg/L and >100 µg/L groups were 25.00%, 42.86%, 73.58% and 100.00% respectively, with statistically significant difference between the PSA <10 µg/L group and the PSA 20.01－100 µg/L and >100 µg/L groups (P < 0.01), but not between the PSA <10 µg/L and PSA 10－20 µg/L groups (P = 0.086). CONCLUSIONS: Pelvic MRI combined with TRUS-guided X+12-core TTMB, with the advantages of high accuracy and low rate of complications, is an ideal approach to the diagnosis of prostate cancer.

Identification of distinct mutational patterns and new driver genes in oesophageal squamous cell carcinomas and adenocarcinomas.

OBJECTIVES: Oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC) are distinct cancers in terms of a number of clinical and epidemiological characteristics, complicating the design of clinical trials and biomarker developments. We analysed 1048 oesophageal tumour-germline pairs from both subtypes, to characterise their genomic features, and biological and clinical significance. DESIGN: Previously exome-sequenced samples were re-analysed to identify significantly mutated genes (SMGs) and mutational signatures. The biological functions of novel SMGs were investigated using cell line and xenograft models. We further performed whole-genome bisulfite sequencing and chromatin immunoprecipitation (ChIP)-seq to characterise epigenetic alterations. RESULTS: OSCC and OAC displayed nearly mutually exclusive sets of driver genes, indicating that they follow independent developmental paths. The combined sample size allowed the statistical identification of a number of novel subtype-specific SMGs, mutational signatures and prognostic biomarkers. Particularly, we identified a novel mutational signature similar to Catalogue Of Somatic Mutations In Cancer (COSMIC)signature 16, which has prognostic value in OSCC. Two newly discovered SMGs, CUL3 and ZFP36L2, were validated as important tumour-suppressors specific to the OSCC subtype. We further identified their additional loss-of-function mechanisms. CUL3 was homozygously deleted specifically in OSCC and other squamous cell cancers (SCCs). Notably, ZFP36L2 is associated with super-enhancer in healthy oesophageal mucosa; DNA hypermethylation in its super-enhancer reduced active histone markers in squamous cancer cells, suggesting an epigenetic inactivation of a super-enhancer-associated SCC suppressor. CONCLUSIONS: These data comprehensively contrast differences between OSCC and OAC at both genomic and epigenomic levels, and reveal novel molecular features for further delineating the pathophysiological mechanisms and treatment strategies for these cancers.

The histone deacetylase inhibitor panobinostat exerts anticancer effects on esophageal squamous cell carcinoma cells by inducing cell cycle arrest.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Histone deacetylase inhibitors (HDACIs) have been demonstrated as an emerging class of anticancer drugs for a range of haematological and solid tumours. However, the effect of HDACIs has not yet been investigated on ESCC cells. In this study, HDACIs were initially considered to have anticancer activity for ESCC, due to the high expression of HDAC genes in ESCC cell lines by analysing expression data of 27 ESCC cell lines from the Broad-Novartis Cancer Cell Line Encyclopedia. Next, we used five ESCC cell lines and one normal immortalized esophageal epithelial cell line to screen three HDACIs, panobinostat (LBH589), vorinostat (SAHA), and trichostatin A (TSA), for the ability to inhibit growth. Here, we report that LBH589 more effectively suppressed cell proliferation of ESCC cell lines, in a dose-dependent manner, than TSA and SAHA, as well as had lower toxicity against the SHEE normal immortalized esophageal epithelial cell line. Further experiments indicated that LBH589 treatment significantly inhibited TP53 (mutated TP53) expression, both at the mRNA and protein level, and simultaneously increased p21 and decreased cyclin D1 expression. Taken together, we propose that LBH589 inhibits ESCC cell proliferation mainly through inducing cell cycle arrest by increasing p21 and decreasing cyclin D1 in a p53-independent manner. SIGNIFICANCE OF THE STUDY: In this study, the antitumor activity of HDACIs LBH589, SAHA, and TSA on ESCC was characterized, with LBH589 displaying the most potent anti-proliferative activity while not harming normal immortalized esophageal epithelial cells. Furthermore, we propose that LBH589 exerts its anti-proliferative effect by inducing cell cycle arrest. The ability to specifically target cancer cells indicates therapeutic potential for use of LBH589 in the treatment of ESCC.

Fascin phosphorylation sites combine to regulate esophageal squamous cancer cell behavior.

Filopodia are dynamic membrane extensions generated by F-actin bundling and are involved in cancer cell migration, invasion and metastasis. Fascin is the crucial actin-bundling protein in filopodia, with phosphorylation at fascin serine 39 being well characterized to regulate fascin-mediated actin bundling in filopodia. However, increasing evidence indicates that fascin is phosphorylated at a number of sites. Whether phosphorylation at other sites also regulates fascin function is unknown. In this study, we show that four potential phosphorylation sites in fascin, specifically tyrosine 23, serine 38, serine 39 and serine 274, regulate cell behavior and filopodia formation in esophageal squamous cancer cells. Expression of non-phosphorylatable mutations at each of the four sites promoted anchorage-independent growth, cell motility and filopodia formation, whereas phosphomimetic mutations at each of these sites inhibited these cell behaviors, implying that fascin function in esophageal squamous cancer is regulated by fascin phosphorylation at multiple sites. Furthermore, phosphorylation at S38 and S39 cooperatively regulated cell behavior and filopodia formation, with dual dephosphorylation at both S38 and S39 residues maximally enhancing cell proliferation, migration and filopodia formation, and phosphorylation at any of the two phosphorylatable sites resulting in reduced enhancement. Taken together, our results reveal that phosphorylation at fascin amino acids Y23, S38, S39 and S274, in combination, downregulates the extent of anchorage-independent growth, cell migration and filopodia formation in esophageal squamous cancer cells.

Lipocalin 2 promotes the migration and invasion of esophageal squamous cell carcinoma cells through a novel positive feedback loop.

Lipocalin 2 (LCN2) is a poor prognostic factor in esophageal squamous cell carcinoma (ESCC), however its functional roles and molecular mechanisms of action remain to be clarified. Here, we described the functions and signaling pathways for LCN2 in ESCC. Overexpression of LCN2 in ESCC cells accelerated cell migration and invasion in vitro, and promoted lung metastasis in vivo. Blocking LCN2 expression inhibited its pro-oncogenic effect. Either overexpression of LCN2 or treatment with recombinant human LCN2 protein enhanced the activation of MEK/ERK pathway, which in turn increases endogenous LCN2 to increase MMP-9 activity. The decreased p-cofilin and increased p-ERM induced by pERK1/2 cause the cytoskeleton F-actin rearrangement and alter the behavior of ESCC cells mediated by LCN2. As a consequence, activation of MMP-9 and the rearrangement of F-actin throw light on the mechanisms for LCN2 in ESCC. These results imply that LCN2 promotes the migration and invasion of ESCC cells through a novel positive feedback loop.

Association between the CYP1B1 polymorphisms and risk of cancer: a meta-analysis.

The previous, published data on the association between CYP1B1 polymorphisms and cancer risk remained controversial. To derive a more precise estimation of the association between the CYP1B1 polymorphisms and cancer risk, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP1B1 Leu432Val, Asn453Ser, Arg48Gly, and Ala119Ser polymorphisms. For Asn453Ser and Arg48Gly polymorphisms, significantly decreased endometrial cancer was observed among Caucasians. For Ala119Ser polymorphism, we found that individuals with the minor variant genotypes had a high risk of prostate cancer. For Leu432Val polymorphism, we found that individuals with the minor variant genotypes had a higher risk of endometrial cancer and lung cancer and had a lower risk of ovarian cancer. In summary, this meta-analysis suggests that Leu432Val polymorphism is associated with ovarian cancer, lung cancer, and endometrial cancer risk; Asn453Ser and Arg48Gly polymorphisms are associated with endometrial cancer risk among Caucasians, Ala119Ser polymorphism is associated with prostate cancer risk, and Ala119Ser polymorphism is associated with breast cancer risk in Caucasians. In addition, our work also points out the importance of new studies for Ala119Ser polymorphism in endometrial cancer, because high heterogeneity was observed (I (2) > 75 %).

Association between the STK15 polymorphisms and risk of cancer: a meta-analysis.

The previous published data on the association between STK15 F31I and V57I polymorphisms and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and STK15 F31I (42,315 cases and 50,542 controls from 62 studies) and V57I polymorphisms (12,891 cases and 17,391 controls from 18 studies) in different inheritance models. Overall, significant association was observed between F31I and cancer risk when all the eligible studies were pooled into the meta-analysis (recessive model: OR = 1.14, 95 % CI = 1.06-1.24; AA vs. TT: OR = 1.12, 95 % CI = 1.02-1.24; A vs. T: OR = 1.05, 95 % CI = 1.01-1.09). In the further stratified and sensitivity analyses, for STK15 F31I, significantly increased breast cancer (recessive model: OR = 1.16, 95 % CI = 1.02-1.33; AA vs. TT: OR = 1.16, 95 % CI = 1.01-1.33) and ovarian cancer (dominant model: OR = 1.20, 95 % CI = 1.07-1.34; TA vs. TT: OR = 1.19, 95 % CI = 1.06-1.34; A vs. T: OR = 1.15, 95 % CI = 1.05-1.26) risk was found among Caucasians, and significantly decreased lung cancer risk was found among Caucasians (recessive model: OR = 0.65, 95 % CI = 0.49-0.87; AA vs. TT: OR = 0.65, 95 % CI = 0.49-0.88). For V57I polymorphism, significant decreased breast cancer risk was found among Caucasians (recessive model: OR = 0.76, 95 % CI = 0.61-0.95; AA vs. GG: OR = 0.75, 95 % CI = 0.60-0.94; A vs. G: OR = 0.92, 95 % CI = 0.86-0.98). In summary, this meta-analysis suggests that STK15 F31I polymorphism is associated with increased breast cancer and ovarian cancer risk among Caucasians, F31I polymorphism is associated with decreased lung cancer risk among Caucasians, and V57I polymorphism is associated with decreased breast cancer risk among Caucasians.

Association between the CYP1A2 polymorphisms and risk of cancer: a meta-analysis.

The previously published data on the association between CYP1A2*1C (rs2069514) and CYP1A2*1F (rs762551) polymorphisms and cancer risk have remained controversial. Hence, we performed a meta-analysis to investigate the association between CYP1A2*1F and CYP1A2*1C polymorphisms and cancer risk under different inheritance models. Overall, significant association was observed between CYP1A2*1F and cancer risk when all the eligible studies were pooled into the meta-analysis (dominant model: OR 1.08, 95 % CI 1.02-1.15; heterozygous model: OR 1.06, 95 % CI 1.01-1.12; additive model: OR 1.07, 95 % CI 1.02-1.13). In the further stratified and sensitivity analyses, for CYP1A2*1F polymorphism, significantly increased lung cancer risk and significantly decreased bladder cancer risk were observed in Caucasians. For CYP1A2*1C polymorphism, no significant association was found in overall and all subgroup analyses. In summary, this meta-analysis suggests that CYP1A2*1F polymorphism is associated with lung cancer and bladder cancer risk in Caucasians.

Identification of a novel lysyl oxidase-like 2 alternative splicing isoform, LOXL2 Δe13, in esophageal squamous cell carcinoma.

Lysyl oxidase-like 2 (LOXL2) participates in every stage of cancer progression and promotes invasion and metastasis. In this study, we identified a novel alternative splicing isoform of LOXL2, namely LOXL2 Δe13, which lacked exon 13. Deletion of exon 13 caused an open reading frame shift and produced a truncated protein. LOXL2 Δe13 was expressed ubiquitously in cell lines and tissues and was mainly localized to the cytoplasm. Although it showed impaired deamination enzymatic activity compared with full-length LOXL2, LOXL2 Δe13 promoted the cell mobility and invasion of esophageal squamous cell carcinoma (ESCC) cells to greater degrees. In further research on the mechanisms, gene expression profiling and signaling pathway analysis revealed that LOXL2 Δe13 induced the expression of MAPK8 without affecting the FAK, AKT, and ERK signaling pathways. RNAi-mediated knockdown of MAPK8 could block the cell migration promoted by LOXL2De13, but it had little effect on that of full-length LOXL2. Our data suggest that LOXL2 Δe13 modulates the effects of cancer cell migration and invasion through a different mechanism from that of full-length LOXL2 and that it may play a very important role in tumor carcinogenesis and progression.

Association between the CYP3A4 and CYP3A5 polymorphisms and cancer risk: a meta-analysis and meta-regression.

Previously published data on the association between CYP3A4 A392G and CYP3A5 Met235Thr polymorphisms and the risk of cancer remained controversial. Thus, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP3A4 A392G (18,629 cases and 22,323 controls from 49 studies) and CYP3A5 Met235Thr polymorphisms (14,334 cases and 18,183 from 39 studies) in different inheritance models. We used odds ratios with 95 % confidence intervals to assess the strength of the association. Overall, significant association was found between CYP3A4 A392G polymorphism and cancer susceptibility (dominant model, odds ratio (OR) = 1.19; 95 % confidence interval (CI) = 1.03-1.38). In the further stratified and sensitivity analyses, significant increased prostate cancer risk was found among Caucasians (dominant model, OR = 1.88; 95 % CI = 1.20-2.95; recessive model, OR = 2.10; 95 % CI = 1.23-3.60; additive model, OR = 1.80, 95 % CI = 1.24-2.63; homozygous model, OR = 2.34, 95 % CI = 1.36-4.03; heterozygote model, OR = 1.79, 95 % CI = 1.11-2.89) for CYP3A4 A392G. For CYP3A5 Met235Thr polymorphism, no significant association was found among overall analysis and any subgroup analysis. In summary, this meta-analysis suggests that CYP3A4 A392G polymorphism is associated with increased prostate cancer risk among Caucasians and CYP3A5 Met235Thr polymorphism is not associated with the risk of cancer.

Effects of three polycyclic aromatic hydrocarbons on sediment bacterial community.

Mangrove sediment is susceptible to anthropogenic pollutants, including polycyclic aromatic hydrocarbons (PAHs). However, the effects of PAHs on the bacterial diversity in mangrove sediment have been rarely studied. In the present study, the effects of three types of PAHs (Naphthalene, Fluorene, and Pyrene) at three doses on sediment microbial populations were investigated by using denaturing gradient gel electrophoresis (DGGE). After 7 and 24 days of incubation of the three types of PAHs, markedly different patterns were observed in the bacterial communities. Overall, the diversity of bacterial community was suppressed before 7 days but was promoted after 24 days. Multidimensional scaling analysis suggested that the composition of bacterial communities after 7 days was distinctly distant from that after 24 days. Also despite a slight shift of bacterial abundance, the bacterial communities were relatively steady in these sediments after exposure to PAHs. In addition, DGGE suggested that the applications of three PAHs (especially PYR) had considerable effects on bacterial communities. For phylogenetic analysis, bacteria species belonging to Proteobacteria (α-, ß-, and γ-), Actinobacteria, Chloroflexi, Bacteroidetes, and Planctomycetes were changed dramatically after treatment with PAHs. These results suggest that PAHs play key roles in the change of bacterial community, which may be important for understanding the relationship between PAHs and sediment microbial ecology.

[Determination of three methylimidazole compounds in cosmetics by high performance liquid chromatography-tandem mass spectrometry].

Methylimidazole compounds are byproducts formed during the caramel-coloring process and are used in various cosmetics. In addition metronidazole is an antibacterial and anti-inflammatory drug commonly used in modern medicine and is used in cosmetics to treat acne in the short-term. The illegal addition of metronidazole during cosmetics production can result in residual 2-methylimidazole (2-MEI), which, along with 4-methylimidazole (4-MEI), is a class 2B carcinogen. Therefore, establishing efficient, accurate, and sensitive analytical techniques for analyzing methylimidazole compounds in cosmetics is an urgent objective. In this study, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneously determining 1-methylimidazole (1-MEI), 2-MEI, and 4-MEI in cosmetics was developed. Cosmetics samples were extracted via ultrasonication in acetonitrile and purified using a mixed cation-exchange (MCX) solid-phase extraction (SPE) column, with subsequent drying under a stream of nitrogen and redissolution in acetonitrile. The resulting solution was then filtered through a 0.22 µm organic filter membrane for further testing. The analytes were separated using an XBridge® shield RP18 chromatographic column (150 mm×4.6 mm, 3.5 µm) and isocratically eluted with 20 mmol/L ammonium formate solution (containing 0.1% formic acid)-acetonitrile (98∶2, v/v). The target compounds were ionized by electrospray ionization (ESI) source, analyzed in multi-reaction monitoring (MRM) mode, and quantified using the external standard method, with the peak area of the quantitative ion and the mass concentration of the compound taken as the longitudinal and transverse coordinates, respectively. Matrix-matching working curves were also constructed. 1-MEI exhibited good linear relationships in the range of 5-200 µg/L, with correlation coefficients (r2)≥0.9994, while 2-MEI and 4-MEI showed good linearities in the range of 2-100 µg/L with r2≥0.9984. The three methylimidazole compounds exhibited limits of detection (LODs) and quantification (LOQs) of 10-30 µg/kg and 25-100 µg/kg, respectively. Under three spiked levels (LOQ, 2LOQ, 10LOQ), the recoveries of three methylimidazole compounds were 80.9%-107.9%, with relative standard deviations (RSDs, n=6) of 1.2%-12.8%. The practicability of the method was examined using 48 cosmetic samples; 4-MEI was detected in nine samples at contents of 26-1000 µg/kg, while two samples contained 240 and 267 µg/kg of 2-MEI, respectively. 1-MEI was not detected in any of the 48 samples tested. The developed method is simple, fast, and highly sensitive, and provides methodological support for assessing risks and monitoring the three methylimidazole compounds in cosmetics through screening.

Combined detection of serum EFNA1 and MMP13 as diagnostic biomarker for gastric cancer.

We previously identified that serum EFNA1 and MMP13 were potential biomarker for early detection of esophageal squamous cell carcinoma. In this study, our aim is to explore the diagnostic value of serum EFNA1 and MMP13 for gastric cancer. We used enzyme-linked immunosorbent assay (ELISA) to detect the expression levels of serum EFNA1 and MMP13 in 210 GCs and 223 normal controls. The diagnostic value of EFNA1 and MMP13 was evaluated in an independent cohorts of GC patients and normal controls (n = 238 and 195, respectively). Receiver operating characteristics were used to calculate diagnostic accuracy. In training and validation cohorts, serum EFNA1 and MMP13 levels in the GC groups were significantly higher than those in the normal controls (P < 0.001). The area under the curve (AUC) of the combined detection of serum EFNA1 and MMP13 for GC was improved (0.794), compared with single biomarker used. Similar results were observed in the validation cohort. Importantly, the combined measurement of serum EFNA1 and MMP13 to detect early-stage GC also had acceptable diagnostic accuracy in training and validation cohort. Combined detection of serum EFNA1 and MMP13 could help identify early-stage GC, suggesting that it may be a promising tool for the early detection of GC.