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Background All commercial Hepatitis C virus antibody (anti-HCV) assays use a combination of recombinant antigens to detect antibody response. Antibody responses to individual antigenic regions (core, NS3/4 and NS5) used in assays have not been investigated. Methods In this study, we quantified HCV viral load, tested anti-HCV with four commercial assays (Ortho-ELISA, Murex-ELISA, Architect-CMIA and Elecsys-ECLIA) in 682 plasma specimens. In antigenic region ELISA platform, microwells were coated with three antigens: core (c22-3), NS3/4 (c200) and NS5 individually. The signal-to-cutoff (S/Co) values of different assays, and antibody responses to individual antigens were compared. The specimens were divided into HCV RNA positive group, anti-HCV consistent group, and anti-HCV discrepant group. Results Anti-core and anti-NS3/4 were simultaneously detected in 99.2% of HCV RNA positive specimens and showed great consistency with total anti-HCV signals. Responses to the core region were more robust than those to the NS3/4 region in anti-HCV consistent group (p Conclusion Antibody responses to the core and NS3/4 antigens were stronger, whereas responses to the NS5 antigen were the weakest, indicating that individual antigenic regions played different roles in total anti-HCV signals. This study provides an impetus for optimizing commercial anti-HCV assays.

Background Although programmed cell death‐ligand 1 (PD‐L1) plays a well‐known function in immune checkpoint response by interacting with programmed cell death‐1 (PD‐1), the cell‐intrinsic role of PD‐L1 in tumors is still unclear. Here, we explored the molecular regulatory mechanism of PD‐L1 in the progression and metastasis of ovarian cancer. Methods Immunohistochemistry of benign tissues and ovarian cancer samples was performed, followed by migration, invasion, and angiogenesis assays in PD‐L1‐knockdown ovarian cancer cells. Immunoprecipitation, mass spectrometry, and chromatin immunoprecipitation were conducted along with zebrafish and mouse experiments to explore the specific functions and mechanisms of PD‐L1 in ovarian cancer. Results Our results showed that PD‐L1 induced angiogenesis, which further promoted cell migration and invasion in vitro and in vivo of ovarian cancer. Mechanistically, PD‐L1 was identified to directly interact with vascular endothelial growth factor receptor‐2 (VEGFR2) and then activated the FAK/AKT pathway, which further induced angiogenesis and tumor progression, leading to poor prognosis of ovarian cancer patients. Meanwhile, PD‐L1 was found to be regulated by the oncogenic transcription factor c‐JUN at the transcriptional level, which enhanced the expression of PD‐L1 in ovarian cancer. Furthermore, we demonstrated that PD‐L1 inhibitor durvalumab, combined with the antiangiogenic drug, apatinib, could enhance the effect of anti‐angiogenesis and the inhibition of cell migration and invasion. Conclusion Our results demonstrated that PD‐L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c‐JUN/VEGFR2 signaling axis, suggesting that the combination of PD‐L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients., This manuscript demonstrated that PD‐L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c‐JUN/VEGFR2 signaling axis, and suggested that the combination of PD‐L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients.

Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.

Background: Due to its high ability of metastasis, ovarian cancer remains the most lethal gynecological malignancy, yet its underlying mechanism remains unconfirmed. Objectives: The main purpose is to probe into the role and regulation mechanism of octamer-binding transcription factor 4 (OCT4) in angiogenesis and metastasis in ovarian cancer.Methods: Immunohistochemistry (IHC) and immunofluorescence in epithelial ovarian cancer specimens and benign ovarian tumor samples were performed, followed by RNA-sequencing and examination of angiogenesis, cell migration and invasion in OCT4 knockdown cell lines and the controls. Co-Immunoprecipitation (Co-IP), mass spectrometry, immunoblotting, immunofluorescence and chromatin immunoprecipitation (ChIP) analyses were conducted along with models of zebrafishes and nude mice of transplanted tumors to gain insights into the specific functions and mechanisms of action of OCT4 in ovarian cancer.Results: Firstly, we discovered that OCT4 expression was enhanced in ovarian cancer tissues significantly, especially in the metastatic lesions, indicating that OCT4 might be a key for the metastasis of ovarian cancer. Furtherly, we observed and verified that OCT4 promoted cell migration and invasion, and induced angiogenesis in vitro and in vivo. Mechanistically, OCT4 modulated the transcription of leucine‑rich PPR motif‑containing protein (LRPPRC)，and furtherly interacted with vascular endothelial growth factor receptor 2 (VEGFR2)/LRPPRC complex and ultimately triggered the downstream FAK/AKT signaling pathway . Conclusions: Together, through models of ovarian cancer cells, zebrafishes and tumor-transplanted mice, this study highlighted the importance of OCT4/LRPPRC/VEGFR2 signaling axis in metastasis of ovarian cancer and angiogenesis. Thus, our finding supplied a potential novel molecular-targeted approach for the treatment of ovarian cancer.

Ovarian cancer (OC) is one of the most common malignant tumors in women. OC is associated with the activation of oncogenes, the inactivation of tumor suppressor genes, and the activation of abnormal cell signaling pathways. Moreover, epigenetic processes have been found to play an important role in OC tumorigenesis. Epigenetic processes do not change DNA sequences but regulate gene expression through DNA methylation, histone modification, and non-coding RNA. This review comprehensively considers the importance of epigenetics in OC, with a focus on microRNA and long non-coding RNA. These types of RNA are promising molecular markers and therapeutic targets that may support precision medicine in OC. DNA methylation inhibitors and histone deacetylase inhibitors may be useful for such targeting, with a possible novel approach combining these two therapies. Currently, the clinical application of such epigenetic approaches is limited by multiple obstacles, including the heterogeneity of OC, insufficient sample sizes in reported studies, and non-optimized methods for detecting potential tumor markers. Nonetheless, the application of epigenetic approaches to OC patient diagnosis, treatment, and prognosis is a promising area for future clinical investigation.

Background Ovarian cancer is highly lethal and has a poor prognosis due to metastasis. Long non-coding RNAs (lncRNAs) are key regulators of tumor development, but their role in ovarian cancer metastasis remains unclear. Methods The expression of lnc-CTSLP8 in ovarian cancer was analyzed in public databases (TCGA and GEO) and validated via qRT-PCR. Lnc-CTSLP8 overexpression and knockout cell lines were constructed using a lentiviral vector and the CRISP/Cas9 system. Cell proliferation, colony formation, migration, and invasion were analyzed. An ovarian orthotopic tumor mouse model was used for the in vivo study. Changes in autophagosomes, autolysosomes, and mitochondria in ovarian cancer cells were observed via transmission electron microscopy. EMT markers were detected by immunoblotting and immunofluorescence assays. RNA immunoprecipitation, RNA pull-down, and dual luciferase reporter assays were performed to confirm the interaction between lnc-CTSLP8 and miR-199a-5p. Results A novel pseudogene, lnc-CTSLP8, was identified in ovarian cancer, with significantly elevated expression in metastatic tumor tissues compared to primary ovarian tumors. When overexpressed, lnc-CTSLP8 promoted ovarian cancer in vitro and in vivo by acting as a sponge for miR-199a-5p. Autophagy and EMT in ovarian cancer were also enhanced by lnc-CTSLP8. Mechanistically, lnc-CTSLP8 upregulated CTSL1 as a competitive endogenous RNA and exhibited oncogenic effects. Moreover, CTSL1 inhibitor treatment and miR-199a-5p overexpression abrogated the effects of lnc-CTSLP8 overexpression. Conclusions lnc-CTSLP8 acts as a ceRNA in ovarian cancer and represents a potential therapeutic target for metastatic ovarian cancer.

Background So far, the prevalence of human T-lymphotropic virus (HTLV) type 1 and 2 in some highly populated countries such as China is still unknown. In this study, a multi-center nationwide serological survey was designed and performed, to reveal the seroprevalence of HTLV infection among Chinese blood donors. Results Among 8,411,469 blood donors from 155 blood establishments, 435 were finally confirmed as HTLV carriers. The prevalence of HTLV infection in China varied in different provinces: Fujian had the highest prevalence of 36.240/100,000 (95% CI 31.990–41.050) and eleven provinces did not find HTLV-seropositive donors in the three years. no HTLV-2 infection was found. The overall prevalence of HTLV-1 in China decreased from 2016 to 2018. Female was identified as an independent risk factor of HTLV infection in China. Besides, seroconversion was observed in two of seven seroindeterminate donors 85 and 250 days after their last donation, respectively. Conclusions The seroprevalence of HTLV infection in most areas of China among blood donors is quite low, but it varies significantly in different geographic areas. Screening anti-HTLV-1/2 antibody and follow-up of serointederminate donors are essential to ensure blood safety especially in areas where we have found HTLV infected donors.

Serological tests have been widely used for detecting human T-cell lymphotropic virus type 1/2 (HTLV-1/2) antibodies in the endemic areas, but their performance in low-risk populations is rarely reported. The aim of this study was to evaluate the performance of four HTLV-1/2 screening assays and to discuss a strategy for diagnosis of HTLV-1/2 infection in a non-endemic area. At the present study, 1546 specimens repeatedly reactive (RR) by one screening ELISA were collected from blood centers/banks from January 2016 to April 2019. Avioq-ELISA, Murex-ELISA, Roche-ECLIA and Fujirebio-CLIA were independently performed on each plasma sample and compared to WB and LIA confirmatory tests. Positive or indeterminate specimens with blood available were quantified by qPCR. The results showed that 48 samples were finally confirmed as HTLV-1 positive, 13 were HTLV positive, 151 were indeterminate, and 387 were negative. All the WB-positive samples were also LIA-positive. Roche-ECLIA showed the highest sensitivity that was able to detect 91.8% positives and combined with the Murex-ELISA would significantly increase the positive detection rate (98.4%). In addition, LIA yield more indeterminate and HTLV-untyped results than WB (152 vs. 27), but was able to resolve infection status of some individuals with an indeterminate WB. Besides, 3 WB indeterminate and 1 LIA-untyped samples were confirmed as HTLV-1 positive by qPCR. Based on these findings, we put forward a proper test strategy for HTLV-1/2 diagnosis in low-prevalence areas. If possible, the Roche-ECLIA with the highest sensitivity is suggested as a second screening assay in primary labs. If not, all RR specimens are recommended to be firstly retested by Roche-ECLIA and Murex-ELISA in the reference lab. Secondly, samples reactive to any one of the two tests were quantified by qPCR, and then the NAT-negatives were furtherly submitted to LIA for confirmation. Thereby, the cost can be reduced and the diagnostic accuracy would be improved.

Quantitative PCR (qPCR) assay using TaqMan™ probe was widely used in the detection of different nucleic acids. However, this technology has several drawbacks, including false negative results caused by primer-dimer (PD) and false positive issues due to primer-probe aggregations. Here, we designed a modified TaqMan™-Molecular Beacon probe by adding an antisense base and a new type of primer pair named central-homo primer pairs bearing 5-10 bases homologous sequence on the 3' end. Using the HBV qPCR assay as a proof of concept, the new design significantly improved the accuracy of the TaqMan™ qPCR assay for HBV detection. Application of the central-homo primer pair led to significantly delayed Ct values by 5-10 cycles compared with conventional primer design. The modified probe containing an antisense base did not produce any detectable signal in repeating primer-probe aggregation experiments. Furthermore, the use of the central-homo primer pair and the non-competitive internal control could solve the false negative problem caused by PD formation. We validated this customized duplex qPCR system using 208 clinical samples collected from patients in clinic showing accuracy was higher than that of the conventional qPCR method.

Neurensin-2 (NRSN2) is a 24KD protein, which is reported located in the membrane, while its biological functions remain unknown, not to mention in the field of tumor biology. In current study, we aimed to analyze the functions of NRSN2 in ovarian cancer. We screened TCGA database and surprisingly found that its copy number and mRNA level are gained and heightened respectively in parts of serous ovarian cancer patients. In current study, both loss- and gain- function assays found that NRSN2 is associated with the malignant phenotype in ovarian cancer cells, because NRSN2 plays a remarkable role in anchorage-independent colony formation, subcutaneous tumor formation, cell invasion, and chemoresistance. Furthermore, we found that the level of NRSN2 was positively correlated with the expression of stem cell marker CD133. In addition, Wnt canonical signaling and Twist/Akt/Erk axis were also regulated by NRSN2. In conclusion, we found that a poorly studied protein, NRSN2, which is associated with the malignant phenotype of serous ovarian cancer and as a membrane protein; it could be a target for serous ovarian cancer treatment.

Background: Smoking is a risk factor for many human diseases. DNA methylation has been related to smoking, but genome-wide methylation data for smoking in Chinese populations is limited. Objectives: We aimed to investigate epigenome-wide methylation in relation to smoking in a Chinese population. Methods: We measured the methylation levels at > 485,000 CpG sites (CpGs) in DNA from leukocytes using a methylation array and conducted a genome-wide meta-analysis of DNA methylation and smoking in a total of 596 Chinese participants. We further evaluated the associations of smoking-related CpGs with internal polycyclic aromatic hydrocarbon (PAH) biomarkers and their correlations with the expression of corresponding genes. Results: We identified 318 CpGs whose methylation levels were associated with smoking at a genome-wide significance level (false discovery rate < 0.05), among which 161 CpGs annotated to 123 genes were not associated with smoking in recent studies of Europeans and African Americans. Of these smoking-related CpGs, methylation levels at 80 CpGs showed significant correlations with the expression of corresponding genes (including RUNX3, IL6R, PTAFR, ANKRD11, CEP135 and CDH23), and methylation at 15 CpGs was significantly associated with urinary 2-hydroxynaphthalene, the most representative internal monohydroxy-PAH biomarker for smoking. Conclusion: We identified DNA methylation markers associated with smoking in a Chinese population, including some markers that were also correlated with gene expression. Exposure to naphthalene, a byproduct of tobacco smoke, may contribute to smoking-related methylation. Citation: Zhu X, Li J, Deng S, Yu K, Liu X, Deng Q, Sun H, Zhang X, He M, Guo H, Chen W, Yuan J, Zhang B, Kuang D, He X, Bai Y, Han X, Liu B, Li X, Yang L, Jiang H, Zhang Y, Hu J, Cheng L, Luo X, Mei W, Zhou Z, Sun S, Zhang L, Liu C, Guo Y, Zhang Z, Hu FB, Liang L, Wu T. 2016. Genome-wide analysis of DNA methylation and cigarette smoking in Chinese. Environ Health Perspect 124:966–973; http://dx.doi.org/10.1289/ehp.1509834

Background The high prevalence of hepatitis C virus (HCV) infection and the resulting burden of the disease are significant issues to public health worldwide. Although direct-acting antiviral drugs (DAAs) with good tolerance and bioavailability are available, resistance-associated substitutions (RASs) often jeopardize the successful sustainment of virological responses in HCV treatment. High-frequency baseline RASs in treatment-naive patients can lead to failures in DAA treatment. Clinical data on HCV RASs in patients from China are limited and require investigations. Methods 262 HCV RNA positive plasma from Chinese blood donors were genotyped and amplified with subtype-specific primers for NS3 and NS5A regions. RASs were analyzed using Geno2pheno. The codon usage of each resistance-associated substitution was calculated for genetic barrier analysis. Results The two main subtypes in mainland China were 1b and 2a, followed by subtype 6a, 3b, 3a, and 1a. In NS3 region of 1b subtype, substitutions (T54S, V55A, Y56F, Q80 K/L, S122 G/T, R117 H/C, V170I and S174A) were present in 89.7% (96/107) of the samples. Other RASs (M28L, R30Q, P58 L/S and Y93H) were observed in 22.1% (25/113) of the samples in NS5A region. A crucial RAS, Q80K, and two other mutations (S122G + V170I) was identified in the same sequence, which reduced its susceptibility to protease inhibitor ASV and resulted in resistance to SMV. In NS5A, Y93H was detected in 9.7% (11/113) of the 1b samples, leading to medium-to-high level resistance to all six commercialized NS5A inhibitors. S122G-NS3 and Y93H-NS5A occurred simultaneously in 38.1% (7/22) of the samples with mutations in both two regions. Moreover, codon usage of S122G-NS3 and Y93H-NS5A revealed that both variants had the lowest genetic barrier and required only one transition to confer resistance. Conclusions Low genetic barriers facilitated the generation of resistance mutants and threated the efficacy of DAA regimens. The baseline RASs posed a great challenge to real-world DAA application.

Background: Aging is related to an increased risk of morbidity and mortality and is affected by environmental factors. Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health outcomes; but the association of such exposure with DNA methylation aging, a novel aging marker, is unclear. Objectives: Our aim was to investigate the association of PAH exposure with methylation aging. Methods: We trained and validated a methylation age predictor suitable for Chinese populations using whole blood methylation data in 989 Chinese and 160 Caucasians. We defined two aging indicators: Δage, as methylation age minus chronological age; and aging rate, the ratio of methylation to chronological age. The association of PAH exposure with aging indicators was evaluated using linear regressions in three panels of healthy Chinese participants (N=539, among the aforementioned 989 Chinese participants) whose exposure levels were assessed by 10 urinary monohydroxy-PAH metabolites. Results: We developed a methylation age predictor providing accurate predictions in both Chinese individuals and Caucasian persons (R=0.94–0.96, RMSE=3.8–4.3). Among the 10 urinary metabolites that we measured, 1-hydroxypyrene and 9-hydroxyphenanthrene were associated with methylation aging independently of other OH-PAHs and risk factors; 1-unit increase in 1-hydroxypyrene was associated with a 0.53-y increase in Δage [95% confidence interval (CI): 0.18, 0.88; false discovery rate (FDR) FDR=0.004] and 1.17% increase in aging rate (95% CI: 0.36, 1.98; FDR=0.02), whereas for 9-hydroxyphenanthrene, the increase was 0.54-y for Δage (95% CI: 0.17, 0.91; FDR=0.004), and 1.15% for aging rate (95% CI: 0.31, 1.99; FDR=0.02). The association direction was consistent across the three Chinese panels with the association magnitude correlating with the panels’ exposure levels; the association was validated by methylation data of purified leukocytes. Several cytosine-phosphoguanines, including those located on FHL2 and ELOVL2, were found associated with both aging indicators and monohydroxy-PAH levels. Conclusions: We developed a methylation age predictor specific for Chinese populations but also accurate for Caucasian populations. Our findings suggest that exposure to PAHs may be associated with an adverse impact on human aging and epigenetic alterations in Chinese populations. https://doi.org/10.1289/EHP2773

High expression of Aurora kinase A (Aurora-A) has been found to confer cancer cell radio- and chemoresistance, however, the underlying mechanism is unclear. In this study, by using Aurora-A cDNA/shRNA or the specific inhibitor VX680, we show that Aurora-A upregulates cell proliferation, cell cycle progression, and anchorage-independent growth to enhance cell resistance to cisplatin and X-ray irradiation through dysregulation of DNA damage repair networks. Mechanistic studies showed that Aurora-A promoted the expression of ATM/Chk2, but suppressed the expression of BRCA1/2, ATR/Chk1, p53, pp53 (Ser15), H2AX, γH2AX (Ser319), and RAD51. Aurora-A inhibited the focus formation of γH2AX in response to ionizing irradiation. Treatment of cells overexpressing Aurora-A and ATM/Chk2 with the ATM specific inhibitor KU-55933 increased the cell sensitivity to cisplatin and irradiation through increasing the phosphorylation of p53 at Ser15 and inhibiting the expression of Chk2, γH2AX (Ser319), and RAD51. Further study revealed that BRCA1/2 counteracted the function of Aurora-A to suppress the expression of ATM/Chk2, but to activate the expression of ATR/Chk1, pp53, γH2AX, and RAD51, leading to the enhanced cell sensitivity to irradiation and cisplatin, which was also supported by the results from animal assays. Thus, our data provide strong evidences that Aurora-A and BRCA1/2 inversely control the sensitivity of cancer cells to radio- and chemotherapy through the ATM/Chk2-mediated DNA repair networks, indicating that the DNA repair molecules including ATM/Chk2 may be considered for the targeted therapy against cancers with overexpression of Aurora-A.

Rationale: Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated. Objective: We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS. Methods and Results: We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine-phosphoguanine sites (discovery: false discovery rate P + T cells, CD4 + T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including IL6R , FASLG , and CCL18 ; P −4 ), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell–mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine-phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol ( P enrichment ≤1×10 −5 ). Conclusions: Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.

The thermal dissipation technique is widely used to estimate transpiration of individual trees and forest stands, but there are conflicting reports regarding its accuracy. We compared the rate of water uptake by stems of six tree species in potometers with sap flow (F S) estimates derived from thermal dissipation sensors to evaluate the accuracy of the technique. To include the full range of xylem anatomies (i.e., diffuse-porous, ring-porous, and tracheid), we used saplings of sweetgum (Liquidambar styraciflua), eastern cottonwood (Populus deltoides), white oak (Quercus alba), American elm (Ulmus americana), shortleaf pine (Pinus echinata), and loblolly pine (Pinus taeda). In almost all instances, estimated F S deviated substantially from actual F S, with the discrepancy in cumulative F S ranging from 9 to 55%. The thermal dissipation technique generally underestimated F S. There were a number of potential causes of these errors, including species characteristics and probe construction and installation. Species with the same xylem anatomy generally did not show similar relationships between estimated and actual F S, and the largest errors were in species with diffuse-porous (Populus deltoides, 34%) and tracheid (Pinus taeda, 55%) xylem anatomies, rather than ring-porous species Quercus alba (9%) and Ulmus americana (15%) as we had predicted. New species-specific α and β parameter values only modestly improved the accuracy of F S estimates. However, the relationship between the estimated and actual F S was linear in all cases and a simple calibration based on the slope of this relationship reduced the error to 1–4% in five of the species, and to 8% in Liquidambar styraciflua. Our calibration approach compensated simultaneously for variation in species characteristics and sensor construction and use. We conclude that species-specific calibrations can substantially increase the accuracy of the thermal dissipation technique.

Background: This study was to explore the expression profile of endometrial carcinoma (EC) and identify the potential molecular mechanism and therapeutic targets. Methods: Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified in EC using mRNA and miRNA sequencing data released by the Cancer Genome Atlas database; then, gene function and pathway of DEGs were analyzed based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases; finally, the transcription factors (TFs) latently regulating the DEGs and DEMs were predicted and a TF-miRNA-Gene network was then established to summarize the regulatory links between TFs, DEMs and DEGs. Results: One thousand five hundred and forty two upregulated and 1,885 downregulated DEGs, 34 upregulated and 12 downregulated DEMs were identified. The principal DEGs-enriched functions were cell differentiation, cell migration, and cell surface receptor signaling pathway. The DEGs-enriched cell signaling pathways including the MAPK, Wnt signaling pathway, and the p53 signaling pathway. As shown in the TF-miRNA-Gene network, TFs such as CPBP and GKLF, miRNAs such as miR-141-3p and miR-130b-3p, regulated most of DEGs and DEMs. Conclusion: These results may contribute to the study of the molecular mechanism and therapeutic targets in EC, and facilitate the discovery of new biomarkers for screening, diagnosis and monitoring.

It is well-known that overexpression of Aurora-A promotes tumorigenesis, but the role of Aurora-A in the development of cancer has not been fully investigated. Recent studies indicate that Aurora-A may confer cancer cell chemo- and radioresistance through dysregulation of cell cycle progression and DNA damage response. Direct evidences from literatures suggest that Aurora-A inhibits pRb, p53, p21(waf1/cip1), and p27(cip/kip) but enhances Plk1, CDC25, CDK1, and cyclin B1 to repeal cell cycle checkpoints and to promote cell cycle progression. Other studies indicate that Aurora-A suppresses BRCA1, BRCA2, RAD51, poly(ADP ribose) polymerase (PARP), and gamma-H2AX to dysregulate DNA damage response. Aurora-A may also interact with RAS and Myc to control DNA repair indirectly. In this review, we summarized the potential role of Aurora-A in DNA repair from the current literatures and concluded that Aurora-A may function as a DNA repair modulator to control cancer cell radio- and chemosensitivity, and that Aurora-A-associated DNA repair molecules may be considered for targeted cancer therapy.

Small ribosomal protein subunit S7 (RPS7) has been reported to be associated with various malignancies, but the role of RPS7 in ovarian cancer remains unclear. In this study, we found that silencing of RPS7 by a specific shRNA promoted ovarian cancer cell proliferation, accelerated cell cycle progression, and slightly reduced cell apoptosis and response to cisplatin treatment. Knockdown of RPS7 resulted in increased expression of P85α, P110α, and AKT2. Although the basal levels of ERK1/2, MEK1/2, and P38 were inconsistently altered in ovarian cancer cells, the phosphorylated forms of MEK1/2 (Ser217/221), ERK1/2 (Thr202/Tyr204), JNK1/2 (Thr183/Tyr185), and P38 (Thr180/Tyr182) were consistently reduced after RPS7 was silenced. Both the in vitro anchorage-independent colony formation and in vivo animal tumor formation capability of cells were enhanced after RPS7 was depleted. We also showed that silencing of RPS7 enhanced ovarian cancer cell migration and invasion. In sum, our results suggest that RPS7 suppresses ovarian tumorigenesis and metastasis through PI3K/AKT and MAPK signal pathways. Thus, RPS7 may be used as a potential marker for diagnosis and treatment of ovarian cancer.

Abstract Background and Purpose-Ovarian cancer is the most lethal gynecological malignancy in women, but the essential mechanism remains unclear. Studies have shown that many ribosomal proteins are dysfunctional in various tumors. The small ribosomal protein subunit S7 (RPS7) has been reported to interact with MDM2 and may function as a tumor suppressor, but its role in cancer development is largely unknown. Here, we examined the molecular function of RPS7 in human ovarian cancer. Experimental Design-Retrovirus-mediated small hairpin RNA (shRNA) was used to silence the expression of RPS7 in ovarian cancer cell lines SKOV3 and OVCA433, named SKOV3-RPS7i, OVCA433-RPS7i plus their GFP shRNA (GFPi) controls. Cell proliferation, cell cycle, apoptosis, cell migration and invasion, and tumor growth were tested to determine the function of RPS7 in ovarian cancer. Results-Immunostaining of RPS7 showed that RPS7 was higher in ovarian cancer tissues than in nomal tissues. Silencing of RPS7 in SKOV3 and OVCA433 cells promoted cell growth and markedly enhanced anchorage-independent colony formation. Depletion of RPS7 accelerated cell cycle progression through G1-S transition, which was evidenced by alterations of cell cycle regulatory proteins including p21waf1/cip1, CDK2/4, Cyclin B1, and Cyclin D1. Knockdown of RPS7 weakened cell apoptosis by increasing the expression of anti-apoptotic proteins including BCL2 and BCL-XL, and decreasing the expression of apoptotic molecules including p27cip/kip, BAK, and BAD. However, knockdown of RPS7 reduced cell migration and invasion. Further analysis showed that the expression of β-catenin, MMP2, and MMP13 was decreased, but E-cadherin was increased in RPS7-silenced cells compared with in controls, indicating that RPS7 is associated with metastasis. Moreover, P85α, P110α and AKT1/2 were decreased in SKOV3-RPS7i and OVCA433-RPS7i, suggesting that RPS7 functions through PI3K/AKT signal pathway. Although the basal levels of ERK 1/2, MEK1/2, and p38 were inconsistently altered, but the phosphorylation of MEK1/2 (Ser217/221), ERK1/2 (Thr202/Tyr204), and p38 (Thr180/Tyr182) was reduced in SKOV3-RPS7i and OVCA433-RPS7i cells, compared with in controls. Thus, our results suggested that RPS7 appears to regulate cell proliferation, apoptosis, and tumorigenesis through PI3K/AKT and MAPK signal pathways. Conclusion-RPS7 may function as an anti-tumor factor in ovarian tumorigenesis through PI3K/AKT and MAPK signal pathways. Citation Format: Ziliang Wang, Lili Lu, Jianmin Sun, Jiao Meng, Wen Gao, Yan Wang, Huizhen Sun, Jin Hou, Hongyu Gu, Zhen Wang, Yuhu Xin, Gong Yang. The Small Ribosomal Protein Subunit S7 Functions as a Tumor Suppressor to regulate ovarian tumorigenesis through PI3K/AKT and MAPK pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4303. doi:10.1158/1538-7445.AM2013-4303