The relationship between brain metastasis and HER2 expression status in gastric cancer

Background Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. Methods HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan–Meier method. Result There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) Conclusion The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients (AU)

Silicon and iron nanoparticles protect rice against lead (Pb) stress by improving oxidative tolerance and minimizing Pb uptake.

Lead (Pb) is toxic to the development and growth of rice plants. Nanoparticles (NPs) have been considered one of the efficient remediation techniques to mitigate Pb stress in plants. Therefore, a study was carried out to examine the underlying mechanism of iron (Fe) and silicon (Si) nanoparticle-induced Pb toxicity alleviation in rice seedlings. Si-NPs (2.5 mM) and Fe-NPs (25 mg L-1) were applied alone and in combination to rice plants grown without (control; no Pb stress) and with (100 µM) Pb concentration. Our results revealed that Pb toxicity severely affected all rice growth-related traits, such as inhibited root fresh weight (42%), shoot length (24%), and chlorophyll b contents (26%). Moreover, a substantial amount of Pb was translocated to the above-ground parts of plants, which caused a disturbance in the antioxidative enzyme activities. However, the synergetic use of Fe- and Si-NPs reduced the Pb contents in the upper part of plants by 27%. It reduced the lethal impact of Pb on roots and shoots growth parameters by increasing shoot length (40%), shoot fresh weight (48%), and roots fresh weight (31%). Both Si and Fe-NPs synergistic application significantly elevated superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and glutathione (GSH) concentrations by 114%, 186%, 135%, and 151%, respectively, compared to plants subjected to Pb stress alone. The toxicity of Pb resulted in several cellular abnormalities and altered the expression levels of metal transporters and antioxidant genes. We conclude that the synergistic application of Si and Fe-NPs can be deemed favorable, environmentally promising, and cost-effective for reducing Pb deadliness in rice crops and reclaiming Pb-polluted soils.

The relationship between brain metastasis and HER2 expression status in gastric cancer.

BACKGROUND: Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. METHODS: HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method. RESULT: There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients.

Modulation of metal transporters, oxidative stress and cell abnormalities by synergistic application of silicon and titanium oxide nanoparticles: A strategy for cadmium tolerance in rice.

Heavy metals, especially cadmium (Cd), cause severe toxicity symptoms in crop plants. Applying nanoparticles (NPs) as nano-fertilizers is a novel approach to mitigating plants' Cd stress. However, knowledge about the combinational use of silicon (Si) and titanium dioxide (TiO2) NPs to mitigate Cd stress, especially in rice, must be highlighted. TiO2-NPs (15 mg L-1) and Si-NPs (2.5 mM) were applied alone and in combination to rice plants grown without (control; no Cd stress) and with (100 µM) Cd concentration. Results revealed that compared to the control plants, root length, shoot length, shoot fresh weight, and root dry weight of rice seedlings were significantly decreased by 25.43%, 26.64%, 34.13%, and 29.87% under Cd exposure. However, the synergistic effect of TiO2- and Si-NPs increased rice plants' shoot length, root length, root dry weight, and shoot fresh weight by 24.62%, 29.81%, 36.16%, and 33.07%, respectively, under the Cd-toxicity. The concentration of malondialdehyde (MDA) and H2O2 were amplified due to Cd stress, which leads to damage to the subcellular structures. Si and TiO2-NPs co-application improved the anti-oxidative enzymatic activities (catalase, peroxidase, superoxide dismutase) and an elevated concentration of non-enzymatic glutathione in Cd-exposed rice. The Cd accumulation was condensed by 21.37% and 19.7% in the shoot, while 48.31% and 45.65% in root tissues under Si-NPs + Cd and TiO2-NPs + Cd treatments compared to Cd-alone treated seedlings, respectively. The expression patterns of metal transporters, such as OsNramp1 and OsHMA3, were the highest when rice plants were cultivated under Cd stress and significantly reduced when treated with sole and combined Si- and TiO2-NPs treatments. In conclusion, combining Si- and TiO2-NPs significantly improved the antioxidant enzymatic activities, chlorophyll contents, biomass production, and reduced cellular damage. Despite limitations, our findings guide future research, addressing risks, optimizing concentrations, and assessing long-term effects that can balance agricultural progress with environmental sustainability.

Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins.

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.

Polyploidy and zinc oxide nanoparticles alleviated Cd toxicity in rice by modulating oxidative stress and expression levels of sucrose and metal-transporter genes.

The Cd toxicity causes severe perturbations to the plant's growth and development. Here, polyploid and diploid rice lines were treated with zinc-oxide nanoparticles (ZnO-NPs) and Cd, and physiological, cytological and molecular changes were observed. The Cd toxicity significantly reduced plant's growth attributes (such as shoot length, biological yield, dry matter, and chlorophyll contents, which decreased by 19%, 18%, 16%, 19% in polyploid and 35%, 43%, 45% and 43% in diploid rice, respectively), and disturbed the sugar level through the production of electrolytes, hydrogen peroxide, and malondialdehyde. The application of ZnO-NPs significantly alleviated the Cd toxicity in both lines by improving the antioxidant enzymes activities and physiochemical attributes. Semi-thin sections and transmission electron microscope revealed more and different types of abnormalities in diploid rice compared to polyploid rice under Cd stress. Moreover, RNA-seq analysis identified several differentially expressed genes between polyploid and diploid rice, especially metal and sucrose transporter genes. The GO, COG, and KEGG analyses revealed ploidy-specific pathways associated with plant growth and development. In conclusion, ZnO-NPs application to both rice lines significantly improved plant growth and decreased Cd accumulation in plants. We inferred that polyploid rice is more resistant to Cd stress than diploid rice.

Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer.

Importance: The E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown. Objective: To assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC. Design, Setting, and Participants: This cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020. Main Outcomes and Measures: Incidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC. Results: Among 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC. Conclusions and Relevance: This study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer.

BACKGROUND: Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. We analyzed the consistency of TRG and RECIST 1.1 for gastric cancer (GC) patients and compared their prognostic values. METHODS: Patients with GC who received preoperative chemotherapy or chemoimmunotherapy and had records of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0-1 and 2-3 are considered as corresponding to complete response (CR)/partial response (PR) and stable disease (SD)/progress disease (PD) in RECIST 1.1, respectively. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Survival analysis was performed using the Kaplan Meier method. RESULT: One hundred fifty seven GC patients were enrolled, including 125 with preoperative chemotherapy and 32 with chemoimmunotherapy. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results between RECIST 1.1 and TRG. TRG was correlated with both OS and DFS (P = 0.02 and 0.03, respectively) while response according to RECIST1.1 was not (P = 0.86 and 0.23, respectively). The median DFS had not reached in the TRG 0-1 group and was 16.13 months in TRG 2-3 group. TRG 2-3 was associated with young age and peritoneal or liver metastasis. Besides, preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone (34.4% vs 8.0%, P < 0.001). CONCLUSION: TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received preoperative therapy.

An overview of sucrose transporter (SUT) genes family in rice.

INTRODUCTION: Photosynthesis provides the energy basis for the life activities of plants by producing organic compounds, mainly sugar. As the main energy form of photosynthesis, sugar affects the growth and development of plants. During long-distance transportation, sucrose is the main form of transportation. The rate of sugar transport and the allocation of carbohydrates affect the biomass of crops and are closely related to the reproductive growth of crops. MAIN TEXT: The transportation of sugar is divided into active transportation and passive transportation. So how does the sucrose transporters (SUT) genes, which are the main carriers of sucrose in active transportation, affect the performance of rice agronomic traits is still to be explored. In this article, we describe the structure of inflorescence and review the transport forms and metabolic processes of sucrose in rice, such as how CO2 is fixed, carbohydrate assimilation, and transport of organic matter. Sucrose transporters exhibited remarkable effects on the development of reproductive organs in rice. CONCLUSIONS: Here, the effects of different factors, such as the effects of anthers morphology on starch enrichment of pollen, effects of biotic and abiotic factors on sucrose transporters, effects of changes in trace elements on sucrose transporters, were discussed. Moreover, the regulation of transcription or translation level provides ideas for future research on sucrose transporters.

Efficacy and safety of PD-1 inhibitors combined with chemotherapy as first-line therapy for advanced esophageal cancer: A systematic review and network meta-analysis.

BACKGROUND: Different clinical trials for advanced esophageal cancer have investigated diverse immuno-oncology combinational treatment in first-line setting, but the optimal choice has not been identified. METHODS: We used PubMed, Embase, and Cochrane Library databases for systematic retrieval. The primary endpoint was overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (AEs) between immune checkpoint inhibitors combined with chemotherapy and chemotherapy. RESULTS: A total of five phase-III randomized controlled trials involving 3,163 patients met the inclusion criteria. Significantly improved OS (HR: 0.69, 95% CI: 0.62-0.76, P＜0.001), PFS (HR: 0.62, 95% CI: 0.55-0.70, P < 0.001) and ORR (RR: 1.41, 95% CI: 1.23-1.62, P＜0.001) were observed when programmed death 1 (PD-1) inhibitor was added to chemotherapy. Toripalimab plus chemotherapy achieved the best OS benefit than any other treatment examined (HR: 0.58, 95% CI: 0.43-0.78). The longest PFS was founded in both sintilimab-chemotherapy and camrelizumab-chemotherapy combination (HR: 0.56, 95% CI: 0.46-0.68). Patients treated with nivolumab-chemotherapy got the best ORR improvement as compared to other combinations (RR: 1.73, 95% CI:1.40-2.14). Camrelizumab-chemotherapy and pembrolizumab-chemotherapy caused a relatively lower incidence of grade ≥ 3 AEs than other immunotherapy combination regimens. Subgroup analyses suggested significant OS advantage in programmed death-ligand 1(PD-L1) tumor-positive score (TPS) ≥ 10% groups and obviously longer PFS in PD-L1 combined positive score (CPS) ≥ 10 groups. CONCLUSIONS: In advanced esophageal cancer, PD-1 inhibitors combined with chemotherapy as first-line therapy have better survival outcomes than chemotherapy with greater but manageable toxicity. Toripalimab-chemotherapy showed the best OS benefit over chemotherapy, while sintilimab-chemotherapy and camrelizumab-chemotherapy generated the best PFS. The highest ORR improvement was founded in patients receiving nivolumab plus chemotherapy.

Atomically-resolved interlayer charge ordering and its interplay with superconductivity in YBa2Cu3O6.81.

High-temperature superconductive (SC) cuprates exhibit not only a SC phase, but also competing orders, suppressing superconductivity. Charge order (CO) has been recognized as an important competing order, but its microscopic spatial interplay with SC phase as well as the interlayer coupling in CO and SC phases remain elusive, despite being essential for understanding the physical mechanisms of competing orders and hence superconductivity. Here we report the achievement of direct real-space imaging with atomic-scale resolution of cryogenically cleaved YBa2Cu3O6.81 using cross-sectional scanning tunneling microscopy/spectroscopy. CO nanodomains are found embedded in the SC phase with a proximity-like boundary region characterized by mutual suppression of CO and superconductivity. Furthermore, SC coherence as well as CO occur on both CuO chain and plane layers, revealing carrier transport and density of states mixing between layers. The CO antiphase correlation along the c direction suggests a dominance of Coulomb repulsion over Josephson tunneling between adjacent layers.

Cronkhite-Canada syndrome with steroid dependency: A case report.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare nonhereditary disease characterized by chronic diarrhoea, diffuse gastrointestinal polyposis and ectodermal manifestations. The lethality of CCS can be up to 50% if it is untreated or if treatment is delayed or inadequate. More than 35% of the patients do not achieve long-term clinical remission after corticosteroid administration, with relapse occurring during or after the cessation of glucocorticoid use. The optimal strategy of maintenance therapy of this disease is controversial. CASE SUMMARY: A 47-year-old man presented to the hospital with a 3-mo history of frequent watery diarrhoea, accompanied by macular skin pigmentation that included the palms and soles, and onychodystrophy of the fingernails and toenails. Gastroscopy and colonoscopy revealed numerous polyps in the stomach and colon. After other possibilities were ruled out by a series of examinations, CCS was diagnosed and treated with prednisone. The patient took prednisone for more than 1 year before achieving complete resolution of his symptoms and endoscopic findings. The patient was then given prednisone 5 mg/d for 6 mo of maintenance therapy. With clinical improvement and polyp regression, prednisone was discontinued. Eight mo after the discontinuation of prednisone, the diarrhoea and gastrointestinal polyps relapsed. Therefore, the patient was given the same dose of prednisone, and complete remission was achieved again. CONCLUSION: It is necessary to extend the duration of prednisone maintenance therapy for CCS. Prednisone is still effective when readministered after relapse. Surveillance endoscopy at intervals of 1 year or less is recommended to assess mucosal disease activity.

NIK­ and IKKß­binding protein contributes to gastric cancer chemoresistance by promoting epithelial­mesenchymal transition through the NF­κB signaling pathway.

Systematic chemotherapy is indispensable for gastric cancer patients with advanced stage disease, but the occurrence of chemoresistance drastically limits treatment effectiveness. There is a tremendous need for identifying the underlying mechanism of chemoresistance. NIK­ and IKKß­binding protein (NIBP) (also known as TRAPPC9, trafficking protein particle complex 9) is a regulator of the cytokine­induced NF­κB signaling pathway which has been proven to play pivotal roles in the progression of various malignancies. Nevertheless, it is still ambiguous whether NIBP is involved in the chemoresistance of gastric cancer. The aim of the present study was to investigate the effect of NIBP on chemotherapy resistance of gastric cancer (GC) and to research the mechanisms of Ginkgo biloba extract 761 (EGb 761®) on reversing chemoresistence which has been confirmed in our previous study. In the present study, the results of immumohistochemisty revealed that the positive staining rates of NIBP, NF­κB p65 and NF­κB p­p65 in gastric cancer tissues were obviously higher than those in normal tissues. Furthermore, a close correlation was found to exist between the expression of NIBP and NF­κB p65 (p­p65) in gastric cancer tissues. Moreover, the overexpression of NIBP was closely related to tumor differentiation, depth of invasion, clinical stage and lymphatic metastasis in gastric cancer. Western blot analysis, real­time PCR, MTT assay and flow cytometric analysis were performed and the results demonstrated that compared with the gastric cancer SGC­7901 cells, the expression of NIBP, NF­κB p65, NF­κB p­p65 and mesenchymal marker vimentin were significantly increased in gastric cancer multidrug­resistant SGC­7901/CDDP cells, and the epithelial cell marker ZO­1 was significantly decreased. Meanwhile, it was found that SGC­7901/CDDP cells were accompanied by spindle­like mesenchymal appearance and upregulation of stem cell marker CD133 which has been verified to be an upstream regulatory gene of epithelial­mesenchymal transition (EMT). Further research confirmed that downregulation of NIBP by Ginkgo biloba extract (EGb) 761 EGb 761 suppressed the cis­diamminedichloroplatinum(II) (CDDP)­induced NF­κB signaling pathway, EMT and the expression of CD133 in SGC­7901 and SGC­7901/CDDP cells. Altogether, these data indicate that the NIBP­regulated NF­κB signaling pathway plays a pivotal role in the chemoresistance of gastric cancer by promoting CD133­induced EMT.

Quantification of biomolecules responsible for biomarkers in the surface-enhanced Raman spectra of bacteria using liquid chromatography-mass spectrometry.

Recently, specific biomarkers in the surface-enhanced Raman scattering (SERS) spectra of bacteria have been successfully exploited for rapid bacterial antibiotic susceptibility testing (AST) - dubbed SERS-AST. The biomolecules responsible for these bacterial SERS biomarkers have been identified as several purine derivative metabolites involved in bacterial purine salvage pathways (W. R. Premasiri, J. C. Lee, A. Sauer-Budge, R. Theberge, C. E. Costello and L. D. Ziegler, Anal. Bioanal. Chem., 2016, 408, 4631). Here we quantified these metabolites in the SERS spectra of Staphylococcus aureus and Escherichia coli using ultra-performance liquid chromatography/electrospray ionization-mass spectrometry (UPLC/ESI-MS). The time dependences of the concentrations of these molecules were measured using 13C- or 12C-purine derivatives as internal and external standards respectively in UPLC/ESI-MS measurements. Surprisingly, a single S. aureus and an E. coli cell were found to release millions of adenine and hypoxanthine into a water environment in an hour respectively. Furthermore, simulated SERS spectra of bacterial supernatants based on the mixtures of purine derivatives with measured concentrations also show great similarity with those of the corresponding bacterial samples. Our results not only provide a quantitative foundation for the emerging SERS-AST method but also suggest the potential of exploiting SERS for in situ monitoring the changes in bacterial purine salvage processes in response to different physical and chemical challenges.

Single and combined use of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and carcinoembryonic antigen in diagnosing gastric cancer.

To investigate the value of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and carcinoembryonic antigen (CEA), alone or in combination, in diagnosing gastric cancer (GC), we retrospectively analyzed a cohort of 201 patients with GC, 161 patients with benign gastric lesions, and 157 healthy subjects. We obtained routine blood indices and CEA levels to evaluate the diagnostic value of NLR, PLR and CEA for GC, based on receiver operating characteristic (ROC) curves. We found that serum NLR, PLR and CEA in the GC group were significantly higher than those in the benign lesion group (PNLR < 0.001,PPLR < 0.001,PCEA = 0.034) or the healthy control group (PNLR < 0.001,PPLR < 0.001,PCEA = 0.028). Moreover, there were significant differences in NLR and PLR among different serosa invasion, lymph node metastasis, tumor size and stage. CEA showed a difference in distant metastasis and tumor size. Combining PLR with CEA produced a larger AUC (AUC: 0.780, 95% CI: 0.734-0.822) than using PLR (P = 0.011) or CEA (P < 0.001) alone. Similarly, NLR + CEA produced a larger AUC (AUC: 0.756, 95% CI:0.709-0.800) than using NLR (P = 0.004) or CEA (P = 0.001) alone. Whereas NLR, PLR and CEA are known to help distinguish GC from benign gastric lesions, combining CEA with PLR or NLR offers better diagnostic value for GC than any of them used alone.

[Down-regulation of sphingosine kinase 1 (SphK1) enhances the chemosensitivity to cisplatin in human colon cancer RKO cells].

Objective To investigate the effect of sphingosine kinase 1 (SphK1) gene silence on the sensitivity to cisplatin (DDP) in RKO colon cancer cell line and the potential mechanism. Methods Targeted SphK1 gene lentivirus virus was constructed to infect RKO cells. The relative mRNA expression of SphK1 was detected by quantitative real-time PCR (qRT-PCR) and the protein level of SphK1 was determined by Western blotting. Then RKO cells were divided into three groups: down-regulated SphK1 group (shSphK1 group), negative control group (shControl group) and blank control group (control group). Cells of these groups were incubated for 0, 24, 48 and 72 hours with 0, 2, 4, 8, 16, 32 µg/mL DDP. After treatment, cell viability was evaluated by MTT assay. Cell apoptosis index was determined by TUNEL. The expressions of ki67, Bcl-2, caspase-9 and caspase-3 were tested by Western blotting. Results Down-regulation of SphK1 inhibited cell proliferation and enhanced apoptosis of RKO cells, expecially after exposed to DDP. Silence of SphK1 sensitized RKO cells to DDP in a concentration- and time-dependent manner. Cell proliferation of shSphK1 group was obviously reduced compared with control group or shControl group, and cell apoptosis rate of shSphK1 group significantly increased compared with control group or shControl group. Moreover, with the down-regulation of SphK1, the expressions of ki67 and Bcl-2 were depressed; the expressions of caspase-9 and caspase-3 were raised, especially after treated with DDP. Conclusion Down-regulation of SphK1 may decrease the expression of Bcl-2, increase the expressions of caspase-9 and caspase-3, inhibit cell proliferation, and promote cell apoptosis, thus improving chemosensitivity of colon cancer RKO cells to DDP.

SphK1 modulates cell migration and EMT-related marker expression by regulating the expression of p-FAK in colorectal cancer cells.

Sphingosine kinase 1 (SphK1) plays an important role in colorectal carcinoma metastasis. However, whether SphK1 modulates epithelial-mesenchymal transition (EMT)-related marker expression and the underlying mechanisms remain unclear. In this study, in order to clarify this issue, we used various colorectal cancer (CRC) cell lines, Caco2, HT29, RKO and HCT116. Each of the cell lines was divided into 3 groups as follows: the control group, SKI-Ⅱ (SphK1 inhibitor) group and PF-562271 [focal adhesion kinase (FAK) inhibitor] group. The migratory ability of the cells was examined by Transwell chamber assay. The mRNA and protein expression levels of SphK1, FAK (p-FAK), Slug, vimentin, N-cadherin and E-cadherin were detected by PCR and western blot analysis, respectively. The results revealed that the suppression of SphK1 reduced the cell migratory ability, and decreased the expression of Slug, vimentin and N-cadherin; however, the expression of E-cadherin was increased. Moreover, the inhibition of SphK1 reduced the expression of p-FAK. The inhibition of FAK (p-FAK) also decreased the cell migratory ability, and decreased the expression of Slug, vimentin and N-cadherin, whereas the expression of E-cadherin was increased. Thus, our data suggest that SphK1 modulates the expression of EMT-related markers and cell migration by regulating the expression of p-FAK in CRC cells. Thus, SphK1 may play a functional role in mediating the EMT process in CRC.

Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells.

Kinase suppressor of Ras 1 (KSR1) is a scaffold protein that modulates the activation of the oncogenic mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. Ginkgo biloba extract (EGb) 761 has been demonstrated to possess antitumor activity that may be related to the KSR1-mediated ERK signaling pathway. However, the roles and its underlying mechanism in gastric cancer are unclear. In the present study, 62 gastric cancer and matched normal tissues were exploited for immunohistochemistry and real-time fluorescent quantitative PCR detection. Results of the immunohistochemistry showed that the expression of ERK1/2 and p-ERK1/2 was correlated to the expression of KSR1 and p-KSR1 in the gastric cancer tissues, and the overexpression of KSR1, p-KSR1, ERK1/2 and p-ERK1/2 was significantly associated with histological grade, TNM stage, lymph node and distant metastasis. Compared with the normal tissues, the relative mRNA copy values of KSR1, ERK1 and ERK2 in the cancer tissues were 2.43 ± 0.49, 2.10 ± 0.44 and 3.65 ± 0.94. In addition, the expression of KSR1, p-KSR1, ERK1/2 and p-ERK1/2 in human gastric cancer multidrug resistant SGC-7901/CDDP cells was higher than that in the SGC-7901 cells as detected by the methods of immunocytochemistry and western blot analysis. EGb 761 not only suppressed expression of these proteins induced by cisplatin (CDDP) and etoposide in SGC-7901 cells, but also inhibited expression of these proteins in the SGC-7901/CDDP cells. Meanwhile, the proliferation-suppressing and apoptosis-inducing capacities of CDDP and etoposide were enhanced following combined treatment with EGb 761. Moreover, EGb 761 reduced the malondialdehyde (MDA) content and elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the tumor cells. These results confirmed that activation of the KSR1-mediated ERK1/2 signaling pathway may contribute to tumorigenesis, metastasis and chemoresistance of human gastric cancer. EGb 761 enhanced the chemotherapy sensitivity and reversed the chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells, and the underlying mechanism may be related to its antioxidative activity.

Mechanisms of GOLPH3 associated with the progression of gastric cancer: a preliminary study.

STUDY DESIGN: To investigate the specific mechanisms by which Golgi phosphoprotein 3 (GOLPH3) affects the progression of gastric cancer and to explore its clinical significance. METHODS: Immunohistochemical analysis was used to evaluate the correlations between GOLPH3, phosphorylated mTOR (p-mTOR), phosphorylated Akt (p-Akt), phosphorylated p70S6 (p-p70S6), phosphorylated 4E-BP1 (p-4E-BP1) and the clinicopathological features of gastric cancer. The mRNA expression levels of GOLPH3, mTOR, Akt, p70S6 and 4E-BP1 in gastric cancer, carcinoma-adjacent and paired normal tissue were analyzed using RT-PCR. Western blotting was used to determine the protein expression of GOLPH3, p-mTOR, p-Akt, p-p70S6 and p-4E-BP1 in tissues. RESULTS: High expression protein levels of GOLPH3, p-AKT, p-mTOR, p70S6, p-4E-BP1 were positively associated with histological grade (p<0.05), depth of invasion (p<0.05), distant metastasis (p<0.05) and lymph node involvement (p<0.05). Compared with carcinoma-adjacent and paired normal tissues, the mRNA expression levels of GOLPH3, AKT, mTOR, p70S6 and 4EBP1 in gastric cancer tissues were significantly higher. The protein expression levels of GOLPH3, p-AKT, p-mTOR, p-p70S6 and p-4E-BP1 in gastric cancer tissues were also significantly higher than in carcinoma-adjacent and paired normal tissues. A strong positive correlation was observed between GOLPH3, p-mTOR, p-p70S6 and p-4EBP1 expression (r = 0.410, 0.303 and 0.276, respectively, p<0.05), but no significant correlation between the expression of GOLPH3 and p-Akt was observed. CONCLUSIONS: The GOPLH3 expression level is highly correlated with Akt/mTOR signaling in human gastric cancer samples. GOLPH3 combined with Akt/mTOR signaling activation may play an important role in the development, differentiation, invasion and metastasis of gastric cancer.

Custom-designed arrays of anodic alumina nanochannels with individually tunable pore sizes.

We demonstrate a process to selectively tune the pore size of an individual nanochannel in an array of high-aspect-ratio anodic aluminum oxide (AAO) nanochannels in which the pore sizes were originally uniform. This novel process enables us to fabricate arrays of AAO nanochannels of variable sizes arranged in any custom-designed geometry. The process is based on our ability to selectively close an individual nanochannel in an array by using focused ion beam (FIB) sputtering, which leads to redeposition of the sputtered material and closure of the nanochannel with a capping layer of a thickness depending on the energy of the FIB. When such a partially capped array is etched in acid, the capping layers are dissolved after different time delays due to their different thicknesses, which results in differences in the time required for the following pore-widening etching processes and therefore creates an array of nanochannels with variable pore sizes. The ability to fabricate such AAO templates with high-aspect-ratio nanochannels of tunable sizes arranged in a custom-designed geometry paves the way for the creation of nanophotonic and nanoelectronic devices.